CADTH Reimbursement Review

Lutetium (¹⁷⁷Lu) oxodotreotide (Lutathera)

Sponsor: Advanced Accelerator Applications

Therapeutic area: Gastroenteropancreatic neuroendocrine tumours

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Submitted for Review

GEP = gastroenteropancreatic; NET = neuroendocrine tumour; NOC = Notice of Compliance; SSA = somatostatin analogue; SSR = somatostatin receptor.

Introduction

Neuroendocrine tumours (NETs) are a heterogenous group of cancers that arise from the secretory cells of the diffuse neuroendocrine system.¹ Pancreatic neuroendocrine tumours (pNETs) are a subset of gastroenteropancreatic (GEP) NETs (GEPNETs). Somatostatin receptors (SSRs) are expressed in the majority (> 80%) of well-differentiated NETs.² GEPNETs are the second most prevalent type of digestive cancer.¹ The annual incidence of pNETs is less than 1 per 100,000 persons.³ Compared to other types of NETs, pNETs have a worse prognosis, typically resulting in less than 5 years’ survival.³ Due to the heterogenous nature of pNETs, patients may not follow the same disease trajectory. Diagnosis of pNETs is typically through biopsy. Staging of disease is typically conducted using imaging — usually CT or MRI scans, although gallium PET scans are becoming a more standard form of imaging for this group of patients.

For localized solid tumours, surgery is typically the initial treatment option. For patients with metastatic disease, systemic drug therapies are used, although surgery can play a role as well. Somatostatin analogues (SSAs) are the usual first-line therapy for patients with unresectable metastatic disease or with hormonal overproduction syndromes. SSAs that patients may receive include octreotide and lanreotide. For patients who have progressed while receiving SSAs, treatment options include everolimus, sunitinib, and capecitabine plus temozolomide. The clinical experts consulted by CADTH for this review stated that currently available treatment options for patients with pNETs are palliative in nature. They may increase the length and the quality of life; however, patients are expected to eventually progress on these therapies. The clinical experts also identified surgery, radiofrequency ablation, and liver embolization therapy for patients with liver-dominant metastatic pNETs. Radiolabelled SSAs have also been developed for SSR-positive well-differentiated NETs that have progressed after first-line therapy with SSAs; this type of therapy is part of a group of treatments called peptide receptor radionuclide therapy (PRRT).² The clinical experts consulted by CADTH for this review stated that the choice between PRRT and other therapies is not necessarily difficult, although it is not guided by strong evidence. PRRT is better tolerated than currently available options. In addition, the dosing schedule of PRRT is preferred by patients because it involves only 4 sessions, compared to higher numbers of sessions for other options; sessions result in fatigue and loss of appetite. While PRRT is not funded for patients with pNETs in most of Canada, it is funded in Quebec, which introduces issues of inequity among patients in Canada with pNETs.

Lutetium-177 (¹⁷⁷Lu) oxodotreotide is a radiolabelled SSA that binds to SSRs. ¹⁷⁷Lu oxodotreotide is administered intravenously at a recommended dose of 7.4 GBq (200 mCi) over 30 minutes every 8 weeks, for a total of 4 doses. ¹⁷⁷Lu oxodotreotide is administered alongside octreotide long-acting release (LAR), which continues monthly for up to 18 months. ¹⁷⁷Lu oxodotreotide received a Notice of Compliance from Health Canada on January 9, 2019. The indication approved by Health Canada is for the treatment of unresectable or metastatic, well-differentiated, SSR-positive GEPNETs in adults with progressive disease. CADTH reviewed this Health Canada–approved indication in 2019 and the CADTH pan-Canadian Oncology Drug Review Expert Review Committee (pERC) provided a positive recommendation for patients with SSR-positive midgut NETs whose disease had progressed on an SSA and was unresectable; however, the recommendation did not support treatment for patients with SSR-positive foregut and hindgut NETs whose disease had progressed and was unresectable. The previous CADTH review for ¹⁷⁷Lu oxodotreotide did not support use among patients with pNETs, as these patients were excluded from the pivotal NETTER-1 trial. The sponsor’s reimbursement request for this current CADTH reassessment is for adult patients with unresectable or metastatic, well-differentiated, SSR-positive pNET tumours whose disease has progressed after treatment with an SSA, unless there is a contraindication or intolerance.

The objective of this review is to perform a systematic review of the beneficial and harmful effects of ¹⁷⁷Lu oxodotreotide at 7.4 GBq (200 mCi) as an IV infusion over 30 minutes every 8 weeks, for a total of 4 doses, for the treatment of unresectable or metastatic, well-differentiated, SSR-positive pNETs in adults whose disease has progressed after treatment with an SSA, unless there is a contraindication or intolerance.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups that responded to CADTH’s call for patient input and from clinical expert(s) consulted by CADTH for the purpose of this review.

Patient Input

CADTH received 1 submission from the Canadian Neuroendocrine Tumour Society (CNETS) for the review of ¹⁷⁷Lu oxodotreotide for patients with GEPNETs. The information used to inform the submission was based on an online questionnaire that was promoted on the CNETS website and across its social media platforms from February 25 to March 25, 2022, to patients with neuroendocrine cancer. A total of 57 patients responded to the survey, including 21 (37%) patients with pNETs and 36 (63%) patients with gastrointestinal (GI)-NETs; 33 (58%) patients reported having experience with ¹⁷⁷Lu oxodotreotide.

Survey respondents reported that their NET cancer negatively affected their quality of life. Symptoms of fatigue, weakness, and diarrhea had an extremely high impact on quality of life. The most commonly used therapies for the management of NET cancer reported by respondents were SSA therapies, surgery, and PRRT. Respondents indicated that benefits of currently available treatments included temporarily slowing the progression of the disease and achieving symptom control, while the challenges were long recovery times, debilitating side effects, and complications. None of the respondents reported that current treatments had cured or stopped the progression of their NET cancer. Respondents described current treatments as effective for control of symptoms (e.g., bloating, diarrhea, constipation, and energy levels), and as slightly effective or ineffective for stopping disease progression, shrinking or stopping tumour growth, or preventing metastasis. According to respondents, common barriers to access included lack of private-payer coverage, personal financial difficulties, inaccessibility through their physician, or lack of funding for their specific type of NET cancer.

All 33 respondents with experience with ¹⁷⁷Lu oxodotreotide agreed that its side effects were tolerable or manageable and the treatment experience was easier than the lengthy recovery from surgery or the debilitating side effects from chemotherapy. The most commonly reported benefits of ¹⁷⁷Lu oxodotreotide included reduced progression of disease (69%), tumour shrinkage (59%), and decrease in disease symptoms (45%), while the most commonly reported side effects were increased fatigue (58%), and nausea and vomiting (27%).

The majority (98%) of respondents indicated that disease progression is the most important outcome of NET cancer to control, followed by fatigue (36%), diarrhea (35%), and flushing (29%). Overall, patients reported a need for equitable access to ¹⁷⁷Lu oxodotreotide for NET cancer to overcome challenges, including the lack of funding for their type of NETs and the need to travel long distances to access treatment.

Clinician Input

Input from Clinical Experts Consulted by CADTH

CADTH gathered input from 2 clinical specialists with expertise in the diagnosis and management of pNETs. The clinical experts highlighted an unmet need for treatments that extend patient’s lives and improve their quality of life. As patients eventually become refractory to all currently available treatment options, the clinical experts stated that sequencing of ¹⁷⁷Lu oxodotreotide would be individualized to each patient’s circumstance. In most instances, patients should have progressed on SSAs before receiving ¹⁷⁷Lu oxodotreotide. The clinical experts stated that identifying patients eligible for ¹⁷⁷Lu oxodotreotide will require gallium PET scans. They specified that eligibility should not be based on strict criteria for Ki-67 index, as there is too much variability in Ki-67 among different specimens from the same patient. In addition, there is subjectivity in interpreting the specimens, which can result in variability in determining eligibility based on Ki-67. The patient’s response to therapy can be assessed through clinical assessment, radiographic information, and analysis of biomarkers (i.e., 5-hydroxyindoleacetic acid). They advised that clinical assessments be conducted every few months initially and before every cycle of PRRT, and that radiographic assessments be conducted every 3 to 6 months initially, depending on the clinical needs of the patient. Discontinuation of therapy is based on serious toxicities, including permanent renal toxicities and bone marrow toxicity (e.g., myelodysplastic syndrome [MDS]), and disease progression. Administration of ¹⁷⁷Lu oxodotreotide requires referral to a tertiary centre with dedicated nuclear medicine and/or radiation oncology.

Clinician Group Input

Seven clinician groups provided input to CADTH for the review of ¹⁷⁷Lu oxodotreotide. These included:

• 2 clinicians from the Ontario Health Cancer Care Ontario (OH-CCO) Gastrointestinal Cancer Drug Advisory Committee

• 1 clinician from the Canadian Association of Nuclear Medicine (CANM)

• 9 clinicians from the CNETS Scientific and Medical Advisory Board (SMAB)

• 1 clinician from the Centre hospitalier universitaire (CHU) de Québec, Université Laval Research Centre — Oncology Axis; the Hôtel-Dieu de Québec — Nuclear Medicine Department; the Fondation du CHU de Québec — Research Chair in Theranostics; and the Association des médecins spécialistes en médecine nucléaire du Québec (AMSMNQ).

The clinician groups identified the following unmet needs in patients with NETs, including pNETs: currently available treatments are not effective for all patients, are not well tolerated, and can lead to the development of resistance; also, disease can become refractory to current treatments. Further, the clinician groups expressed the need for treatments to slow the progression of the disease, control hormonal symptoms, and improve progression-free survival (PFS).

Clinicians from CANM; CNETS SMAB; CHU de Québec, Université Laval Research Centre — Oncology Axis; the Hôtel-Dieu de Québec — Nuclear Medicine Department; the Fondation du CHU de Québec — Research Chair in Theranostics; and AMSMNQ indicated that Lutathera should be second-line treatment for patients with NETs, including pNETs, who have progressed on a somatostatin analogue. In contrast, OH-CCO indicated Lutathera should be a fourth-line treatment option following SSAs, everolimus, and sunitinib.

Drug Program Input

The drug programs identified the following jurisdictional implementation issues: relevant comparators, considerations for initiation of therapy, considerations for discontinuation of therapy, considerations for prescribing of therapy, funding algorithm, care provision issues, and system and economic issues. The clinical experts consulted by CADTH weighed evidence from the key study submitted by the sponsor and clinical expertise to provide responses to the drug program implementation questions (Table 4).

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

The NETTER-R study was a non-interventional, non-comparative, post-authorization retrospective registry study to assess long-term efficacy and safety of treatment with ¹⁷⁷Lu oxodotreotide in patients with SSR-positive pNETs who had unresectable or metastatic, progressive disease based on radiological, biochemical, or clinical assessment. The approximate number of patients to be enrolled was based on the number of potentially eligible patients included in the compassionate use program (CUP) and those identified by investigators who were receiving commercial ¹⁷⁷Lu oxodotreotide at the selected study sites. To be included in the study, patients must have been treated with ¹⁷⁷Lu oxodotreotide either through the Advanced Accelerator Applications (AAA) Lutathera CUP, which was approved in 10 European countries since 2011 to 2012, or with a commercial drug. The study included 110 patients from Spain, France, and the UK who met the pre-specified criteria for inclusion. Most of the patients with pNETs who received treatment in this study were part of the CUP in 1 of the European Neuroendocrine Tumor Society Centers participating in this program. The retrospective data collection from medical records began on October 31, 2018, at the first study site. Data were tentatively collected at follow-up visits every 3 months, depending on the standard care in local practice and source document availability at the sites. The primary objective of the NETTER-R study was to determine the efficacy of ¹⁷⁷Lu oxodotreotide in patients with pNET according to a set of pre-specified eligibility criteria. The secondary objective of the study was to determine the safety and tolerability of ¹⁷⁷Lu oxodotreotide.⁴ All inclusion criteria and none of the exclusion criteria had to be met in order for patients to be eligible for the NETTER-R study. Eligibility criteria included patients with SSR-positive, unresectable or metastatic, well-differentiated pNETs with progressive disease who had been treated with ¹⁷⁷Lu oxodotreotide. Patients were not eligible if they were diagnosed with NETs of other origins.⁵

Patients in the NETTER-R study had a mean age of 58 years (||||||||; range, 28.0 to 89.0 years). Relatively equal proportions of male (53%) and female (47%) patients were enrolled. |||| of patients were white (||||). The primary sites of metastases before patients started treatment with ¹⁷⁷Lu oxodotreotide were the liver (96%), lymph nodes (43%), bone (29%), and lungs (4%). The liver tumour burden was 10% to 25% in 29% of patients, and more than 25% or more than 2 metastatic organs in 36% of patients. More than half of patients had nonfunctional tumours (57%), 30% of patients had functional tumour status, and the remainder lacked an assessment of tumour functionality (11%). Most patients had a Ki-67 index of 3% to 20% (66%), while 24% had a Ki-67 index of 2% or less. Most patients had a histopathological intermediate (grade 2; 65%) or low (grade 1; 27%) grade of disease.⁶ Many patients received an octreotide scan (||||) or a gallium-68 (⁶⁸Ga) PET scan (||||). Of patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) assessed, most patients had an ECOG PS of 0 (||||) or 1 (||||).⁵ Most patients had received prior anticancer treatments (92%) and had received a mean 4.7 prior or concomitant therapies. Of patients, 91% had received prior anticancer therapy for NET disease; patients mostly received chemotherapy (||||), radiotherapy (||||), or other therapies (91%).⁵ Seventy percent had received prior somatostatins and analogues, mainly lanreotide or octreotide (||| ||||). Thirty-eight percent had received prior tyrosine kinase inhibitors (TKIs), mainly everolimus (33%) or sunitinib (20%). Just more than |||| of patients (||||) had received prior surgical and medical procedures; patients most commonly underwent pancreatic operation (||||), followed by liver operation (||||) and radiotherapy (||||).

Efficacy Results

Overall Survival

A median follow-up time of 24.5 months was reported. There were 55 patients (50%) who experienced an overall survival (OS) event (i.e., death due to any cause) in the NETTER-R study. The median OS was 41.4 months (95% confidence interval [CI], 28.6 to 50.2). Half of all patients were censored for the analysis of OS.

Progression-Free Survival

Results for the primary end point of PFS were based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In the primary analysis of PFS, there were 41 PFS events (66%), of which most were progression (||||), and |||| were deaths (||||). The median PFS was 24.8 months (95% CI, 17.5 to 34.5). PFS was also assessed using the RECIST version 1.1 criteria, based on investigator’s opinion as a secondary end point. PFS based on investigator’s opinion 1 was based on tumour assessments and other radiological assessments. PFS based on investigator’s opinion 2 was based on other radiological, clinical, biomarker, and metabolic assessments. The additional analyses of PFS were consistent with the primary analysis of PFS.

Objective Response Rate

Objective response rate (ORR), based on the primary analysis, was assessed in 62 patients. The ORR was 40.3% (95% CI, 28.1 to 53.6). None of the patients had a complete response, according to RECIST version 1.1 criteria. Partial response was reported in 40.3% of patients. Stable disease and progressive disease were reported for 35.5% and 21.0% of patients, respectively. Results for ORR based on investigators’ opinion 1 and 2 were consistent with the primary analysis of ORR, although the response was slightly better for ORR assessed by investigator’s opinion 2.

Duration of Response

The median duration of response (DOR) was 60.7 months (95% CI, 13.1 to 62.1). At the time of the analysis, there were 8 PFS events observed. The DOR based on investigator’s opinion 1 and 2 were both shorter than the primary analysis of DOR. The median DOR based on investigator’s opinion 1 was 31.1 months (95% CI, 16.8 to 62.1) with |||| PFS events, while the DOR based on investigator’s opinion 2 was 28.3 months (95% CI, 16.8 to 60.7) with |||| PFS events.

Time to Tumour Progression

There was a total of |||| (||||) time to tumour progression (TTP) events, with a median TTP of 29.5 months (95% CI, 21.4 to 67.6; Figure 9). As with PFS, TTP was assessed based on investigator’s opinion 1 and 2, the results of which were both consistent with the primary analysis of TTP.

Health-Related Quality of Life

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Harms Results

Adverse Events

Adverse events (AEs) were reported in 79 patients (72%). The most common AEs included nausea (28%), fatigue (23%), abdominal pain (16%), vomiting (||||), upper abdominal pain (||||), anemia (||||), diarrhea, lymphopenia, and thrombocytopenia (||| ||||). Grade 3 or 4 AEs were reported in 30 patients (27%). The incidence of grade 3 or 4 AEs was generally infrequent, with each event occurring in less than 5% of patients. The most common grade 3 or 4 AEs were lymphopenia (||||), abdominal pain, ascites, hypercalcemia, and liver abscess (|| ||||).

Serious Adverse Events

Serious adverse events (SAEs) were reported in 29 patients (26%). SAEs were infrequently reported, occurring in less than 3% of patients. The most common SAEs were liver abscess, ascites, and hypercalcemia (|||| ||||).

Withdrawals Due to Adverse Events and Dose Modifications

There were no treatment-emergent AEs (TEAEs) that resulted in treatment discontinuation. TEAEs leading to dose modification were infrequent, occurring in 10 patients (9%). The most common TEAEs that led to dose modifications were lymphopenia and nausea (|| ||||).

Mortality

There was a total of ||||| deaths (|||) due to AEs in the NETTER-R study. The causes of death were reported to be abdominal abscess, hepatorenal syndrome and metabolic encephalopathy, hepatic encephalopathy, ascites, and lower respiratory tract infection and pulmonary embolism.

Notable Harms

Notable harms were detailed in the CADTH systematic review protocol and included myelotoxicity, renal toxicity, transformation to leukemia or MDS, nausea and/or vomiting, and fatigue.

Hematological toxicities were reported among || patients (|||). Hematological toxicities were mostly grade 1 or 2 (||||), with 5 patients with grade 3 events. Nausea and fatigue were the 2 most commonly reported AEs in the NETTER-R study, occurring in 31 patients (28%) and 25 patients (23%), respectively. Renal toxicity was infrequently reported among 6 patients (6%); of these, 3 patients had grade 1 or 2 events and 3 patients had grade 3 events. There were no reports of secondary hematological malignancies (acute leukemia or MDS) in any patient.

Table 2: Summary of Key Results From Pivotal and Protocol-Selected Studies

AE = adverse event; CI = confidence interval; DOR = duration of response; FAS = full analysis set; MDS = myelodysplastic syndrome; PD = progressive disease; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event.

^aEstimated by the Kaplan-Meier method.

Source: NETTER-R Clinical Study Report.⁵

Critical Appraisal

NETTER-R was a retrospective, non-comparative, registry-based, observational study. Without a comparison group, the safety and effectiveness of ¹⁷⁷Lu oxodotreotide relative to currently available therapies is unknown. Moreover, due to lack of an adequate control group, the estimate of long-term efficacy was compromised. In particular, no causal inference could be made as to whether the treatment effect (e.g., changes on PFS or OS) could be completely attributable to ¹⁷⁷Lu oxodotreotide or could be due to temporality changes in other factors, including concomitant therapies or natural course of disease. In a retrospective observational cohort study of drug effectiveness based on existing medical records, lack of a sound study design to make an adjustment or control of potential bias has been recognized as fatal limitation by various real-world evidence study guidance documents.

The CADTH team considered that the retrospective design of the NETTER-R study could have allowed for a matched comparator group of patients who had received relevant comparator therapies, such as everolimus or sunitinib. The clinical experts consulted by CADTH for this review agreed that a retrospective study with a matched analysis incorporating a comparator group would have improved the strength of evidence for this funding request for ¹⁷⁷Lu oxodotreotide for treatment of pNETs. It was also acknowledged that a matched analysis would depend on whether such data were available.

There was a large amount of censoring for all efficacy analyses. For example, in the estimate of PFS, about 1-third of patients were censored at the date of their last evaluable tumour assessment if they had not experienced disease progression or if they had not died at the time of data collection, in the context of time-to-event analyses. Similarly, in the assessment of OS, half of the patients were censored on their last date of contact if they were still alive or if their status was unknown. The large amount of censoring (e.g., non-informative) for most efficacy outcomes (i.e., OS, PFS, DOR, TTP) would have resulted in biased estimates of the absolute changes over time, as illustrated by the Kaplan-Meier curves, on those efficacy outcomes and would have further introduced uncertainty concerning the true effect of ¹⁷⁷Lu oxodotreotide on OS and progression of patients with pNETs.

The median follow-up time of the NETTER-R study was 24.5 months. The clinical experts consulted by CADTH for this review commented that, while no control group was part of the study, efficacy results for PFS and OS showed benefit to patients treated with ¹⁷⁷Lu oxodotreotide. However, longer-term data may have benefited the study by providing evidence of the impact of treatment with ¹⁷⁷Lu oxodotreotide over a longer period.

The NETTER-R study was conducted in Europe, with patients enrolled from the UK, France, and Spain. Consultation with clinical experts engaged by CADTH for this review suggested that eligibility criteria and baseline characteristics were generally representative of patients in Canada who might be treated in clinical practice, although centres in European countries may have more experience administering PRRT than those in Canada. The clinical experts commented that 1 patient in the NETTER-R study received dactolisib as a prior therapy, which is not approved by Health Canada and not used among patients in Canada. The impact of this is expected to be low. It was also noted that eligibility criteria of the NETTER-R study specified inclusion of patients with unresectable or metastatic pNETs. The clinical experts confirmed that inclusion of these patients would be unlikely to affect study outcomes. pNETs are a heterogeneous group of tumours that result in aggressive disease, and results of treatment with ¹⁷⁷Lu oxodotreotide based on the NETTER-R study will likely apply to these patients as well.

Regarding prior therapies received by patients, 70% of patients received prior treatment with SSAs and 30% did not. The funding request by the sponsor specifies that a patient’s disease must have progressed after prior treatment with an SSA unless an SSA was contraindicated or the patient was intolerant to SSAs. Further, the NETTER-R study did not specify that patients must have had prior treatment with SSAs. While this is not in exact alignment with the funding request, CADTH’s consultation with clinical experts for this review confirmed that results of the NETTER-R study would still be generalizable to most patients in Canadian clinical practice.

The NETTER-R study did not include a comparator group. Consultation with clinical experts for this review suggested that a randomized trial may not have been possible, as it would have been unlikely for patients to have accepted assignment to a treatment group that did not include ¹⁷⁷Lu oxodotreotide. In addition, treatment with PRRT has been accepted in Europe and in the US, based on data from the NETTER-1 study that was extrapolated to patients with pNETs.

Indirect Comparisons

Description of Studies

Sponsor’s Indirect Treatment Comparison

The aim of the sponsor’s indirect treatment comparison (ITC) was to compare ¹⁷⁷Lu oxodotreotide to relevant comparators. Due to the lack of published clinical trial data, the sponsor conducted matching-adjusted indirect comparisons (MAICs) comparing ¹⁷⁷Lu oxodotreotide to everolimus and sunitinib. The RADIANT-3 trial, comparing everolimus to placebo, and NCT00428597, comparing sunitinib to placebo, were compared with the NETTER-R study though MAICs. Comparison of key eligibility across the trials suggested that characteristics were comparable across the trials. The median age was similar across all studies (between 56 and 58 years of age), with similar proportions of male and female participants. The majority of patients across all trials had an ECOG PS of 1 or 2, although the proportion of patients with an ECOG PS of 1 was greater in the RADIANT-3 and NCT00428597 studies (> 60%) than in the NETTER-R study (33%). Similar proportions of patients in the NETTER-R and NCT00428597 studies had a time from disease progression to randomization or receipt of study treatment of 3 to 12 months (26% versus 28%, respectively). There were some differences noted across the populations of the included studies. Specifically, there were differences in the proportions of patients with organ involvement, time from disease progression to randomization of receipt of study treatment, and prior therapies. Classification of tumour functionality was not reported consistently across the trials.

Khan et al. (2021)

The aim of the ITC by Khan et al. (2021)⁷ was to use MAICs to indirectly compare PFS in patients with GI-NETs or pNETs, and OS in patients with pNETs, after treatment with ¹⁷⁷Lu oxodotreotide, everolimus, sunitinib, or best supportive care across different studies. Khan et al. (2021) compared ¹⁷⁷Lu oxodotreotide to everolimus and sunitinib using data from the ERASMUS, RADIANT-3, and NCT00428597 studies. The authors concluded that there were no differences in key covariates among the ERASMUS, RADIANT-3, and NCT00428597 studies. Age, ECOG PS, previous chemotherapy, and previous radiotherapy were reported to be statistically significantly associated with PFS and OS in the ERASMUS study at the 20% level and were adjusted for in the MAICs.

Efficacy Results

Sponsor’s Indirect Treatment Comparison

Progression-Free Survival: The median PFS of ¹⁷⁷Lu oxodotreotide before adjustment was |||| |||||| |||| ||| |||| || |||||. After adjustment, the median PFS of ¹⁷⁷Lu oxodotreotide was |||| |||||| |||| ||| |||| || |||||, which was longer than the median PFS of everolimus at |||| |||||| |||| ||| |||| || |||||. The hazard ratio (HR) for PFS between ¹⁷⁷Lu oxodotreotide and everolimus favoured treatment with ¹⁷⁷Lu oxodotreotide (|||||||| ||| ||| |||| || ||||).

The median PFS of ¹⁷⁷Lu oxodotreotide before adjustment was |||| |||||| |||| ||| ||||| || |||||. After adjustment, the median PFS of ¹⁷⁷Lu oxodotreotide remained the same, at |||| |||||| |||| ||| ||||| || |||||, which was longer than the median PFS of sunitinib at |||| |||||| |||| ||| |||| || |||. The HR for PFS also favoured ¹⁷⁷Lu oxodotreotide over sunitinib (|||||||| ||| ||| |||| || ||||).

Overall Survival: The median OS of ¹⁷⁷Lu oxodotreotide before adjustment was |||| |||||| |||| ||| |||| || |||||. After adjustment, the median PFS of ¹⁷⁷Lu oxodotreotide was |||| |||||| |||| ||| |||| || |||. The median OS of everolimus was ||| ||||||||| |||| ||| |||| || |||. The 95% CI of HR for OS between ¹⁷⁷Lu oxodotreotide and everolimus ||||||| ||| |||| |||||, although the point estimate was in favour of ¹⁷⁷Lu oxodotreotide over everolimus (|||||||| ||| ||| |||| || ||||).

The median OS of ¹⁷⁷Lu oxodotreotide before adjustment was |||| |||||| |||| ||| |||| || |||||. After adjustment, the median OS of ¹⁷⁷Lu oxodotreotide remained the same, at |||| |||||| |||| ||| |||| || |||, which was longer than the median OS of sunitinib at |||| |||||| |||| ||| |||| || |||||. The HR for OS failed to show a statistically significant difference in favour of ¹⁷⁷Lu oxodotreotide over sunitinib (|||||||| ||| ||| |||| || ||||).

Khan et al. (2021)

Progression-Free Survival: The MAIC suggested that PFS improved more in patients treated with ¹⁷⁷Lu oxodotreotide than in those treated with sunitinib (HR = 0.36; 95% CI, 0.18 to 0.70) and everolimus (HR = 0.46; 95% CI, 0.30 to 0.71). Results of the sensitivity analyses also supported improvement with ¹⁷⁷Lu oxodotreotide over sunitinib and everolimus.

Overall Survival: The MAIC suggested that OS was improved more in patients treated with ¹⁷⁷Lu oxodotreotide compared with sunitinib (HR = 0.42; 95% CI, 0.25 to 0.72) and everolimus (HR = 0.53; 95% CI, 0.33 to 0.87). Results of the sensitivity analyses also supported improvement with ¹⁷⁷Lu oxodotreotide over sunitinib and everolimus.

Harms Results

No analyses for harms were conducted in either ITC.

Critical Appraisal

Sponsor’s Indirect Treatment Comparison

Patient demographic and disease characteristics across the 3 studies were mostly similar. However, there were some differences regarding organ involvement, time from initial diagnosis, time between disease progression and randomization, tumour functionality, and prior treatments. There may be residual confounding bias because the matching adjustment was limited to a number of pre-identified covariates. As mentioned, the MAICs chosen for comparisons between ¹⁷⁷Lu oxodotreotide and everolimus or sunitinib were designed based on the combination of covariates that resulted in the highest effective sample size (ESS). The ESS for the MAICs between ¹⁷⁷Lu oxodotreotide versus everolimus and ¹⁷⁷Lu oxodotreotide versus sunitinib were ||| and |||, respectively. The reductions in ESS for these MAICs may indicate that there was little overlap between the individual patient-level data of the NETTER-R study and the RADIANT-3 and NCT00428597 studies, with less overlap between the NETTER-R and RADIANT-3 studies than between the NETTER-R and NCT00428597 studies. The lack of high overlap between patients across the studies may indicate heterogeneity across patient characteristics, which may, in turn, suggest additional unknown prognostic and predictive factors and introduce bias in the comparisons of efficacy between ¹⁷⁷Lu oxodotreotide and everolimus or sunitinib.

The results of the MAICs suggested that ¹⁷⁷Lu oxodotreotide was favoured over everolimus and sunitinib for PFS but not for OS. The median OS was not reached in either the RADIANT-3 and NCT00428597 studies. Therefore, the interpretability of the efficacy analyses of the sponsor’s MAICs, in particular for OS, is limited.

In general, the MAICs rely on statistical assumptions and a limited list of known predictive and prognostic covariates, which are difficult to confirm. The MAICs reduced the sample size significantly by excluding more than half of the patients in the NETTER-R study, which compromised the generalizability and reliability of the results.

Khan et al. (2021)

Some differences in baseline characteristics were observed across the included studies. There were some differences noted in patient’s sex, tumour functionality, and previous treatments. These characteristics were not included in the matching between the ERASMUS and the NCT00428597 and RADIANT-3 studies. After matching, these characteristics were not well-balanced. The differences in patient characteristics may affect the validity of the comparisons between ¹⁷⁷Lu oxodotreotide and everolimus and sunitinib.

The authors conducted matching with key covariates between the ERASMUS study and the comparator studies (NCT00428597 and RADIANT-3). The ESS after matching with the sunitinib comparator group in the NCT00428597 study was 77% of the initial sample. However, the ESS was much lower (35%) after matching with the everolimus group in the RADIANT-3 study. The characteristics of patients that were unadjusted for were not well-balanced, as illustrated by the differences in the patients’ sex, previous surgery, and tumour functionality. Therefore, any unknown covariates are likely not balanced across studies. There is likely little patient overlap between the ERASMUS and comparator studies, although this is more the case with the RADIANT-3 study.

As mentioned previously, OS was not reached in either the RADIANT-3 and NCT00428597 studies. Therefore, the efficacy analyses for OS based on immature data may suffer from high uncertainty.

Other Relevant Evidence

Three separate non-comparative observational studies by Fröss-Baron et al. (2021),⁸ Marinova et al. (2018),⁹ and Zandee et al. (2019)¹⁰ are briefly summarized here to provide additional efficacy and safety data on ¹⁷⁷Lu oxodotreotide in patients with pNETs.

Description of Studies

Fröss-Baron et al. (2021)⁸ Study

Fröss-Baron et al. (2021)⁸ conducted a retrospective study to determine the efficacy (PFS and OS) and safety of ¹⁷⁷Lu oxodotreotide in 102 adult patients with metastatic and/or locally advanced pNETs who have been previously treated with chemotherapy. Patients in Sweden treated with ¹⁷⁷Lu oxodotreotide between 2005 and 2014 were identified using hospital records, and medical and radiological reports were retrospectively examined. Patients received 7.4 GBq ¹⁷⁷Lu oxodotreotide per cycle with an intended 6- to 8-week interval between each cycle.

Marinova et al. (2018)⁹ Study

Marinova et al. (2018)⁹ conducted a retrospective study to determine the change in health-related quality of life (HRQoL) and symptom burden in 68 adult patients with pNETs following treatment with ¹⁷⁷Lu oxodotreotide. Patients treated with ¹⁷⁷Lu oxodotreotide between 2007 and 2015 at a hospital in Germany were identified, and data were retrospectively analyzed. Briefly, inclusion criteria for the study were that unresectable metastatic pNETs were confirmed with histopathology, the patient had an ECOG PS of 0 to 2, the intended number of cycles were administered, follow-up was completed at 3 months after the last cycle, and the European Organisation for Research and Treatment of Cancer – Quality of Life of Cancer Patients questionnaire, Version 3.0 (EORTC QLQ-C30) was completed before the first cycle and at least once after the last cycle. Patients received a mean activity of 7.6 GBq (standard deviation [SD] = not reported) ¹⁷⁷Lu oxodotreotide per cycle. Change in HRQoL and symptom status were evaluated according to the EORTC QLQ-C30. Higher scores on the Global Health Status and functional scales indicate better function, and higher scores on the symptom scales and single items indicate significant symptoms. Patients completed the EORTC QLQ-C30 at baseline and every 3 months following each treatment cycle for up to 12 months.

Zandee et al. (2019)¹⁰ Study

Zandee et al. (2019)¹⁰ conducted a retrospective study to determine the efficacy and safety of ¹⁷⁷Lu oxodotreotide in 34 adult patients with functional pNETs — 14 patients with insulinoma, 8 with glucagonoma, 7 with gastrinoma, and 5 with VIPoma. Patients treated with ¹⁷⁷Lu oxodotreotide between 2000 and 2017 at a centre in the Netherlands were identified. Patients received up to 4 cycles of 7.4 GBq ¹⁷⁷Lu oxodotreotide per cycle, with an intended interval of 6 to 10 weeks and an intended cumulative activity of 27.8 to 29.6 GBq. Patients were admitted for clinical observation or treatment of hormonal syndrome, per protocol. The study aimed to evaluate symptomatic, biochemical, and radiological response, as well as toxicity. Hematology, kidney, and liver function tests were completed following each cycle and at follow-up visits (6 weeks, 3 months, and 6 months following the last cycle, and every 6 months thereafter). CT or MRI imaging was completed within 3 months of the first cycle and at each follow-up visit. Patients completed the EORTC QLQ-C30 at all visits.

Efficacy Results

Fröss-Baron et al. (2021)⁸ Study

The median follow-up period was 34 months (range, 4 to 160), and survival data for patients (46.1%) were based on the Swedish National Health Registry up to 2018. PFS was calculated using the Kaplan-Meier method and was based on the first date of treatment to the date of radiologically confirmed progression, per RECIST version 1.1, or death from any cause. OS was calculated using the Kaplan-Meier method and was based on the first day of treatment with ¹⁷⁷Lu oxodotreotide to the day of death or the last day of follow-up. The median PFS was 24 months (95% CI, 17 to 28), and the median OS was 42 months (95% CI, 29 to 61). During follow-up, 63 (61.8%) patients died; tumour progression was reported as the cause of death in 60 patients. Tumour response was assessed with RECIST version 1.1 criteria in 100 patients. Complete response was reported in 4 (4.0%) patients, partial response in 45 (45.0%) patients, stable disease in 44 (44.0%) patients, and progressive disease in 7 (7.0%) patients. Forty-nine percent of patients reached objective response, which was defined as patients with complete or partial response. The median time to best response was 14.8 months (range, 3 to 108). Disease control, which was defined as complete response, partial response, or stable disease, was reported in 91.0% of 92 patients with progressive disease at baseline.

Marinova et al. (2018)⁹ Study

The primary analysis using the EORTC QLQ-C30 was according to data collected at baseline and 3 months following the last cycle (follow-up). The mixed longitudinal (panel) model was used to evaluate the data, and a non-parametric Skilling-Mack test was used to verify the unbalanced panel data; a value of less than 0.05 was considered statistically significant. An increase in the mean Global Health Status score was reported (P = 0.008); the mean score was 58.2 (95% CI, 53.1 to 63.2) at baseline and 69.3 (95% CI, 61.4 to 77.2) at follow-up. An increase in the mean social functioning score was reported (P = 0.049); the mean score was 63.9 (95% CI, 56.7 to 71.2) at baseline and 70.9 (95% CI, 61.1 to 80.7) at follow-up. A decrease in the mean fatigue symptom score was reported (P = 0.029); the mean score was 42.4 (95% CI, 36.3 to 48.4) at baseline and 32.0 (95% CI, 22.2 to 41.7) at follow-up. A decrease in the mean appetite loss symptom score was reported (P = 0.015); the mean score was 25.7 (95% CI, 19.5 to 31.9) at baseline and 11.6 (95% CI, 0.7 to 22.5) at follow-up. The differences in change from baseline in the mean scores on the remaining functional and symptom scales were not considered statistically significant. Further, the investigators reported a significantly greater improvement (magnitude of benefit was not reported) on the diarrhea and dyspnea symptom scale scores in patients with functional versus nonfunctional pNETs. The subanalysis of EORTC QLQ-C30 was based on data collected at baseline and at 3 months following the first, second, and third cycle. Changes from baseline in the EORTC QLQ-C30 in the subanalysis were generally consistent with those observed in the primary analysis.

Zandee et al. (2019)¹⁰ Study

The median follow-up period was 39.3 months (range, NR). PFS was calculated using the Kaplan-Meier method and was based on the time from the first cycle of ¹⁷⁷Lu oxodotreotide to objective progression, change to a new line of therapy, or death from any cause. The median PFS was 18.1 months (interquartile range, 3.3 to 35.7). A primary event was reported in 31 patients, of whom 24 had progressive disease, 5 changed to a new line of therapy, and 2 died. Tumour response was evaluated with RECIST version 1.1 criteria in 34 patients. Complete response was reported in 1 (2.9%) patient, partial response in 19 (55.9%) patients, stable disease in 8 (23.6%) patients, and progressive disease in 6 (17.6%) patients. Disease control, which was defined as patients with complete response, partial response, or stable disease, was reported in 18 of the 23 patients with progressive disease at baseline.

HRQoL was assessed in 22 patients using the EORTC QLQ-C30 by comparing the scores 3 months after the last cycle (follow-up) to those at baseline. A paired t-test and the Wilcoxon signed-rank test were used for normally distributed and non-normally distributed variables in the comparison of continuous variables, respectively. An increase in the mean Global Health Score/Quality of Life was reported (P = 0.002); the mean score was 61.7 (95% CI, NR) at baseline and 79.5 (95% CI, NR) at follow-up. An increase in the mean physical functioning score was reported (P = 0.008); the mean score was 79.7 (95% CI, NR) at baseline and 90.0 (95% CI, NR) at follow-up. An increase in the mean role functioning score was reported (P = 0.006); the mean score was 62.7 (95% CI, NR) at baseline and 90.3 (95% CI, NR) at follow-up. An increase in the mean emotional functioning score was reported (P = 0.002); the mean score was 74.1 (95% CI, NR) at baseline and 84.5 (95% CI, NR) at follow-up. An increase in the mean social functioning score was reported (P = 0.047); the mean score was 77.3 (95% CI, NR) at baseline and 85.6 (95% CI, NR) at follow-up. A decrease in the mean fatigue symptom score was reported (P = 0.02); the mean score was 27.3 (95% CI, NR) at baseline and 17.2 (95% CI, NR) at follow-up. The difference in change from baseline in the mean scores on the remaining functional and symptom scales were not considered statistically significant.

Harms Results

Fröss-Baron et al. (2021)⁸ Study

Bone marrow, liver, and kidney toxicity were defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3 or 4 bone marrow toxicity was reported in 11 (10.8%) patients. Grade 3 toxicity of white blood cells and/or granulocytes was reported in 5 (4.9%) patients, grade 3 or 4 toxicity of platelets was reported in 5 (4.9%) patients, and grade 3 toxicity of hemoglobin was reported in 2 (1.9%) patients. Grade 4 (lethal) thrombocytopenia and acute myeloid leukemia were reported in 1 (1.0%) patient each. Fatal liver toxicity was reported in 1 (1.0%) patient; the cause of death was also considered related to tumour progression. Grade 3 or 4 nephrotoxicity was not observed. Treatment discontinuations were due to the following: termination according to the dosimetry-guided protocol was applied to 51 (50.0%) patients, disease progression in 17 (16.7%) patients, bone marrow toxicity in 11 (10.8%) patients, the standard 4-cycle protocol was applied to 9 (8.8%) patients, reduced tumour load in 3 (2.9%) patients, deterioration in 2 (1.9%) patients, death in 2 (1.9%) patients, and a combination of factors not specified in 7 (6.8%) patients.

Marinova et al. (2018)⁹ Study

No analyses for harms were conducted.

Zandee et al. (2019)¹⁰ Study

Nausea, vomiting, and pain were reported in 22 (17.6%), 6 (4.8%), and 10 (8.0%) of the 125 cycles administered in total, respectively. Toxicity was defined according to the CTCAE 4.03 criteria. Grade 3 anemia and grade 3 thrombocytopenia were reported in 1 (2.9%) patient each, and grade 3 leukopenia was reported in 3 (8.8%) patients. Hormonal crisis, which was defined as an acute complication of hormonal secretion following treatment with ¹⁷⁷Lu oxodotreotide and requiring medical care, was reported in 3 (8.8%) patients, and late toxicity with myelodysplastic syndrome was reported in 1 (2.9%) patient. There were several reasons that patients did not receive the intended cumulative activity of 29.6 GBq ¹⁷⁷Lu oxodotreotide. A reduced cumulative activity of 18.5 to 25.9 GBq ¹⁷⁷Lu oxodotreotide was administered in 5 (14.7%) patients due to hepatotoxicity. Only 1 cycle was administered in 3 (8.8%) patients each due to noncompliance, unexplained progressive cognitive decline, and patient withdrawal. Only 3 cycles were provided to 1 (2.9%) patient due to clinical progression, and the last patient case was not reported.

Critical Appraisal

In the absence of an active comparator or placebo group, the interpretation of the efficacy and safety results from the 3 non-comparative observational studies^8-10 is limited. The interpretation of treatment benefit is further limited by the retrospective nonrandomized study design and a relatively small sample size. This is compounded by the relatively large number of patients who were excluded from the analysis due to their incomplete questionnaires, as indicated in the study conducted by Marinova et al. (2018).⁹ However, the clinical experts consulted by CADTH indicated that patients with NETs in general were rare, and Zandee et al. (2019)¹⁰ also indicated that pNETs were rare. Although treatment with ¹⁷⁷Lu oxodotreotide can be ascertained by the use of hospital records, data were sourced from 1 hospital in either Sweden,⁸ Germany,⁹ or Netherlands¹⁰ and retrospectively analyzed. The use of a single source for the recruitment of patients may introduce the risk of selection bias, because patients under the care of 1 team may share common characteristics, including treatment history, disease severity, and level of supportive care, which can bias the estimation of treatment effect and limit the external validity of the results. Notably, the place of ¹⁷⁷Lu oxodotreotide in the treatment sequence varied within the cohort and was preceded by various therapies, which the clinical experts suggested can bias the median OS. Marinova et al. (2018)⁹ indicated that they used the validated German version of EORTC QLQ-C30 but did not identify a clinically meaningful difference; Zandee et al. (2019)¹⁰ also did not identify a clinically meaningful difference. Although patients did not undergo further therapies after treatment with ¹⁷⁷Lu oxodotreotide and follow-up,⁹ it was unclear whether patients received any concomitant therapy that could bias the reporting on the HRQoL questionnaire.

A number of baseline characteristics of the cohorts in the studies, specifically the mean age,^8-10 proportion of patients with liver metastases,^8,10 and the proportion of patients with an ECOG status of 0,^8,9 were similar to those of the NETTER-R⁵ study, which the clinical experts consulted by CADTH suggested were representative of patients seen in clinical practice in Canada. (A detailed description of the patient population in NETTER-R is presented in the Systematic Review section.) The retrospective studies included patients with experience with various treatments; therefore, ¹⁷⁷Lu oxodotreotide was in various lines in the treatment sequence, preceded by different therapies. Only 56.9%, 36.8%, and 64.7% of patients received an SSA before treatment with ¹⁷⁷Lu oxodotreotide in the studies by Fröss-Baron et al. (2021),⁸ Marinova et al. (2018),⁹ and Zandee et al. (2019),¹⁰ respectively, and thus match the reimbursement request for this review. Further, the number of cycles administered and the intervals between the cycles, such as the application of the dosimetry-guided protocol⁸ and the use of 3-month intervals,⁹ varied among studies. Last, Zandee et al. (2019)¹⁰ included patients with functional pNETs, specifically patients with insulinoma, glucagonoma, gastrinoma, and VIPoma, but did not include patients with nonfunctional pNETs.

Conclusions

The NETTER-R study was provided in this reassessment of ¹⁷⁷Lu oxodotreotide for treatment of patients with pNETs. The previous recommendation for ¹⁷⁷Lu oxodotreotide did not support use for patients with pNETs because they were excluded from the pivotal NETTER-1 study. Due to the small sample size, lack of comparator group, retrospective design, and missing data, the results of the NETTER-R study are difficult to interpret and cannot be used to draw firm conclusions about the relative benefits of ¹⁷⁷Lu oxodotreotide in the treatment of pNETs. Evidence from other observational studies by Fröss-Baron et al. (2021),⁸ Marinova et al. (2018),⁹ and Zandee et al. (2019)¹⁰ were largely consistent with NETTER-R but were associated with the same level of uncertainty. Indirect evidence available from the sponsor and the literature provided comparative results between ¹⁷⁷Lu oxodotreotide with everolimus and sunitinib and suggested improved efficacy with ¹⁷⁷Lu oxodotreotide over everolimus and sunitinib. The indirect evidence had methodological limitations, which introduced uncertainty in the interpretation of the comparative data. Based on the totality of the evidence and their experience treating patients with pNETs, clinical experts agreed that ¹⁷⁷Lu oxodotreotide would be a safe and effective regimen, preferred over everolimus or sunitinib. Direct comparative evidence may help reduce uncertainty and inform whether ¹⁷⁷Lu oxodotreotide would be beneficial for patients with pNETs.

Introduction

Disease Background

NETs are a heterogenous group of cancers that arise from the secretory cells of the diffuse neuroendocrine system.¹ Almost half of NETs are in the bowels and pancreas. These NETs often present with distant metastases.¹¹ pNETs are a subset of GEPNETs. pNETs share some common features with GI-NETs, such as an overexpression of SSRs, expression of certain neuroendocrine markers (i.e., chromogranin A), and localization methods used for treatment of both GI-NETs and pNETs.¹² GEPNETs can present as hormonally functional or nonfunctional tumours, which indicates whether the NETs are hormone-producing or non–hormone-producing, respectively. Depending on the functionality, the tumours may present with distinct clinical features based on their site of origin. pNETs typically present as silent hormonally, but can produce many peptide hormones, including insulin, gastrin, and glucagon, which cause insulinoma syndrome, gastrinoma syndrome, and glucagonoma syndromes, respectively.¹ SSRs are expressed in the majority (> 80%) of well-differentiated NETs.²

GEPNETs are the second most prevalent type of digestive cancer.¹ The annual incidence of pNETs is less than 1 per 100,000 persons.³ The median OS for patients with NETs, irrespective of the type of NET and grade of disease, is estimated to be approximately 9 years.¹¹ Compared to other types of NETs, advanced pNETs have a worse prognosis, typically resulting in less than 5 years’ survival.³

According to clinical experts consulted by CADTH for this review, diagnosis of pNETs is typically through biopsy. Staging of disease is typically conducted using imaging — usually CT or MRI scans, although ⁶⁸Ga-PET scans are becoming a more standard form of imaging for this group of patients. The clinical experts highlighted the importance of tissue diagnosis and reliance on tertiary care centres for the diagnosis and management of pNETs.

Standards of Therapy

Management of NET is often influenced by the disease grade, stage of disease, and underlying pathobiology of the neuroendocrine cell type or its direction of differentiation.¹¹ Input from the clinical experts consulted by CADTH for this review highlighted that management of NETs requires a multidisciplinary team and that some care may involve tertiary care centres. Due to the heterogenous nature of pNETs, patients may not follow the same disease trajectory. For localized solid tumours, surgery is typically the initial treatment option. For patients with metastatic disease, systemic drug therapies are used, although surgery can play a role as well. SSAs are the usual first-choice therapy for patients with unresectable metastatic disease or with hormonal overproduction syndromes. SSAs may include octreotide or lanreotide. For patients who have progressed on SSAs, treatment options may include everolimus, sunitinib, and capecitabine plus temozolomide. The clinical experts consulted by CADTH for this review stated that currently available treatment options for patients with pNETs are palliative in nature. They may increase the length and the quality of life. However, patients are expected to eventually progress on these therapies. The clinical experts also identified surgery, radiofrequency ablation, and liver embolization therapy for patients with liver-dominant metastatic pNETs.

Radiolabelled SSAs have also been developed for SSR-positive well-differentiated NETs that have progressed after first-line therapy with SSAs; this type of therapy is part of a group of treatments called PRRT.² PRRT consists of a radioisotope linked to another molecule that targets peptide receptors on cancer cells, allowing targeted delivery of radiation. ¹⁷⁷Lu oxodotreotide is considered PRRT and has been studied since the 1990s.² The clinical experts consulted by CADTH for this review stated that the decision between PRRT and other therapies can be challenging. In addition, the administration schedule of PRRT is more convenient for patients because it is limited to 4 sessions, compared to other, lengthier treatment options that result in toxicity issues, such as fatigue and loss of appetite. While PRRT is not funded for patients with pNETs in most of Canada, it is funded in Quebec, which introduces issues of inequity among patients in Canada with pNETs, according to the clinical experts.

Drug

¹⁷⁷Lu oxodotreotide is a radiolabelled SSA that binds to SSRs. ¹⁷⁷Lu oxodotreotide has the highest affinity for subtype 2 SSRs (SSRT2). Binding of ¹⁷⁷Lu oxodotreotide to cells that express SSRs, which include malignant tumours expressing SSRs, results in cellular damage in SSR-positive cells as well as in neighbouring cells.^{13 177}Lu oxodotreotide is administered IV at a recommended dose of 7.4 GBq (200 mCi) over 30 minutes every 8 weeks, for a total of 4 doses. ¹⁷⁷Lu oxodotreotide is administered alongside octreotide LAR, which continues monthly.

¹⁷⁷Lu oxodotreotide received a Notice of Compliance from Health Canada on January 9, 2019. The indication approved by Health Canada is for the treatment of unresectable or metastatic, well-differentiated, SSR-positive GEPNETs in adults with progressive disease. CADTH reviewed this Health Canada–approved indication in 2019 and pERC provided a positive recommendation for patients with SSR-positive midgut NETs whose disease had progressed on an SSA and was unresectable; however, the recommendation did not support treatment for patients with SSR-positive foregut and hindgut NETs whose disease had progressed and was unresectable. The previous CADTH review for ¹⁷⁷Lu oxodotreotide did not support use among patients with pNETs, as these patients were excluded from the pivotal NETTER-1 trial. The sponsor’s reimbursement request for this current CADTH reassessment is for adult patients with unresectable or metastatic, well-differentiated, SSR-positive pNET tumours whose disease has progressed after treatment with an SSA, unless there is a contraindication or intolerance.

Table 3: Key Characteristics of ¹⁷⁷Lu Oxodotreotide, Everolimus, and Sunitinib

¹⁷⁷Lu = ¹⁷⁷lutetium; ECOG = Eastern Cooperative Oncology Group; GEPNET = gastroenteropancreatic neuroendocrine tumour; HRQoL = health-related quality of life; LVEF = left ventricular ejection fraction; MDS = myelodysplastic syndrome; NA = not applicable; OS = overall survival; PFS = progression-free survival; pNET = pancreatic neuroendocrine tumour.

^aHealth Canada–approved indication.

Source: Lutathera product monograph,¹³ Afinitor Disperz product monograph,¹⁴ Sutent product monograph,¹⁵ Temodal product monograph,¹⁶ and Xeloda product monograph.¹⁷

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

About the Patient Group and Information Gathered

One patient group, CNETS, provided input on ¹⁷⁷Lu oxodotreotide for the treatment of GEPNETs. CNETS is an organization that helps to improve the quality of life and survival for patients with NETs by raising awareness of the condition and the latest available diagnostics and treatments. In addition, CNETS helps to ensure that patients, caregivers, health care professionals, and others have the information they need regarding medical and scientific research, treatment, and support. CNETS helps patients navigate the health care system to obtain the best care options. CNETS helps to provide support and education about NETs and advocates on behalf of individual patients and for policies to support NET patients.

CNETS obtained information from NET patients using an online questionnaire that was promoted on the CNETS website and social media (i.e., Facebook). The survey was conducted from February 25, 2022, to March 25, 2022, and contained quantitative and qualitative questions, including open-ended questions for patients to provide their own experiences. A total of 57 respondents with NETs completed the online survey, including 21 (37%) patients with pNETs and 36 (63%) patients with GI-NETs; 19 (33%) respondents were male and 38 (67%) were female. Most respondents were between 50 and 79 years of age (n = 50; range, 29 to 80). Respondents included individuals residing across Canada, with most being from Ontario (47%), as well as 3 respondents from outside of Canada.

Disease Experience

Respondents reported that their condition had a generally negative impact on their quality of life. When asked to rate how symptoms of NETs affected day-to-day life, respondents indicated that fatigue, weakness, and diarrhea had the most negative impact on their quality of life. Further, the impact on respondent’s energy levels and emotions, as well as the requirements for travel, were reported as having an extremely high negative impact on their quality of life. Other important considerations included effects on their social life, their ability to work, and their ability to participate in leisure activities. Comments from respondents also highlighted the negative impact of fatigue and pain due to NETs, as well as the impacts of surgery.

CNETS also reported experiences of 1,928 NET patients from a global survey conducted by the International Neuroendocrine Cancer Alliance and Novartis Pharmaceuticals Corporation; of the patients included, 22% were reported to have pNETs. The global survey indicated that decreased energy levels and emotional issues were common concerns among patients. Most respondents to the global survey (80%) reported being unable to work due to NETs. Other issues reported by respondents included impacts on their diet and physical activity, and greater time and money spent on appointments.

Experience with Treatment

The most common treatments respondents reported were SSAs (i.e., octreotide, lanreotide; 80%), surgery (64%), and PRRT (60%). Other treatments included liver-directed therapies (e.g., embolization; 29%), ablative techniques (i.e., radiofrequency ablation, cryotherapy; 22%), chemotherapy (22%), radiation therapy (15%), biologically targeted therapies (i.e., everolimus, sunitinib; 13%), immunotherapies (4%), and others (9%). According to CNETS, respondents reported that treatments temporarily slowed disease progression and controlled symptoms. However, treatments were also associated with long recovery times, debilitating side effects, and complications. No therapies were reported to stop progression of their NET cancer. Patients described treatments for control of symptoms such as bloating, diarrhea, constipation, and energy levels as effective. Treatments for the condition (i.e., surgery, embolization, radiation, chemotherapy, and biologic drugs) were reported to be slightly effective or not effective at stopping disease progression and preventing spread to other organs. Some patients also reported difficulties in accessing and receiving treatments due to lack of private insurance, financial difficulties, inability to access their therapy through their physician, lack of funding for a specific treatment for their type of NET cancer, and inability to travel to where the drug is administered. In fact, respondents provided many comments on needing to travel long distances to receive treatment.

A total of 33 respondents (60%) reported having been treated, or current treatment, with ¹⁷⁷Lu oxodotreotide. Respondents reported accessing ¹⁷⁷Lu oxodotreotide through various clinical trials across the country, provincial reimbursement, compassionate access, and private insurance. According to CNETS, respondents reported that they could tolerate or manage side effects of treatment with ¹⁷⁷Lu oxodotreotide. Compared to other treatment options, such surgery, respondents indicated that treatment with ¹⁷⁷Lu oxodotreotide involved a quicker recovery and had less debilitating side effects. Respondents reported that benefits from treatment with ¹⁷⁷Lu oxodotreotide included slower progression of their disease (69%), tumour shrinkage (59%), decrease in disease symptoms (45%), and overall improved well-being (41%). Side effects associated with treatment with ¹⁷⁷Lu oxodotreotide included increased fatigue (58%), nausea and vomiting (27%), increased diarrhea (8%), and increased pain (4%). Many respondents (38%) also reported “other” side effects; respondents’ comments highlighted side effects related to fatigue and neurocognitive issues. Respondents’ comments were generally positive toward ¹⁷⁷Lu oxodotreotide, with patients highlighting the effectiveness of this treatment in controlling their NET cancer.

Improved Outcomes

When asked what aspects of NET cancer are most important to control, almost all (98%) respondents reported a need to control disease progression. Other answers included a need to control fatigue, diarrhea, flushing, and wheezing. Respondents also commented on other aspects of disease that they would like greater management of, including energy levels, shortness of breath, high blood pressure, and cardiac symptoms.

CNETS also highlighted the ⁶⁸Ga-dotatate PET scan companion diagnostic test to ¹⁷⁷Lu oxodotreotide. CNETS stated that the ⁶⁸Ga-PET scan has advantages over the octreotide scan because it has higher-resolution images, detects smaller lesions, provides better guidance to treatment and dosage, exposes patients to less radiation, has greater efficiency and cost-effectiveness, is easier to access, and is more convenient for patients.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of pNETs.

Unmet Needs

The clinical experts highlighted an unmet need for treatments that extent patients’ lives and improve their quality of life. Because patients eventually become refractory to all currently available treatment options, the clinical experts indicated that ¹⁷⁷Lu oxodotreotide is another treatment option that is also highly tolerated.

Place in Therapy

The clinical experts stated that sequencing of ¹⁷⁷Lu oxodotreotide is individualized to each patient’s circumstance. In most instances, patients should have progressed on SSAs before receiving ¹⁷⁷Lu oxodotreotide. However, the clinical experts stated that recommending use of other treatments before ¹⁷⁷Lu oxodotreotide would not be appropriate, given that each patient’s treatment options may be individualized to their needs. In some cases of locally advanced pNETs, ¹⁷⁷Lu oxodotreotide may be used as an induction (preoperative) strategy.

Patient Population

The clinical experts stated that identifying patients eligible for ¹⁷⁷Lu oxodotreotide requires gallium PET scans. They specified that eligibility should not be based on strict criteria for Ki-67 index, as there is too much variability in Ki-67 among different specimens from the same patient. In addition, there is subjectivity in interpreting the specimens, which can result in variability in determining eligibility based on Ki-67. The clinical experts indicated fluorodeoxyglycose PET scans are not widely available but could be used.

Assessing Response to Treatment

Patients’ response to therapy is assessed through clinical assessment, radiographic information, and analysis of biomarkers (i.e., 5-hydroxyindoleacetic acid), according to the clinical experts. Clinical assessments were advised every few months initially and before every cycle of PRRT. Radiographic assessments were advised every 3 to 6 months initially, depending on the clinical needs of the patients.

Discontinuing Treatment

The clinical experts stated discontinuation of therapy is based on serious toxicities, including permanent renal toxicities and bone marrow toxicity (e.g., MDS), and disease progression.

Prescribing Conditions

The clinical experts stated that administration of ¹⁷⁷Lu oxodotreotide requires referral to a tertiary referral centre with dedicated nuclear medicine and/or radiation oncology. |

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups.

Four groups provided clinician input on the review of ¹⁷⁷Lu oxodotreotide for the treatment of pNETs:

• OH-CCO’s Gastrointestinal Cancer Drug Advisory Committee (prepared by 2 clinicians)

• CANM (prepared by 1 clinician)

• the CNETS SMAB and other neuroendocrine cancer treating clinicians (prepared by 9 clinicians)

• a collaboration between the CHU de Québec, Université Laval Research Centre — Oncology Axis; Hôtel-Dieu de Québec, Nuclear Medicine Department; Fondation du CHU de Québec — Research Chair in Theranostics; and AMSMNQ (prepared by 1 clinician).

The OH-CCO Gastrointestinal Cancer Drug Advisory Committee provides timely evidence-based clinical and health system guidance on drug-related issues in support of CCO’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. CANM aims to achieve excellence in the practice of diagnostic and therapeutic nuclear medicine by promoting the continued professional competence of nuclear medicine specialists, establishing guidelines of clinical practice, and encouraging biomedical research. The CHU de Québec, Université Laval Research Centre — Oncology Axis is composed of researchers and students who aim to bring clarity and resolution to complex problems related to cancer for the benefit of patients and society. The Hôtel-Dieu de Québec, Nuclear Medicine Department is composed of world-renowned research groups in theranostics in patients with NETs, using PRRT. It includes the highest concentration of physicians with the most post-graduate and post-residency training in nuclear oncology and theranostics in Canada. The Fondation du CHU de Québec — Research Chair in Theranostics was launched on June 8, 2021, at the CHU de Québec to further advancements in clinical research based on research projects and experience with ¹⁷⁷Lu octreotate and PRRT. The Quebec association of nuclear medicine specialists (AMSMNQ) is a non-profit organization representing all 116 board-certified nuclear medicine specialists in the province of Quebec, advocating for better and equal access to nuclear medicine for patients, and the development of clinical guidelines for the appropriate use of technology in nuclear medicine in Quebec. CNETS includes a SMAB, composed of leading Canadian neuroendocrine cancer multidisciplinary clinicians and scientists who provide expert scientific, clinical, and strategic advice to the CNETS board of directors. The SMAB works alongside the patient group to support best practices across the spectrum of research pillars, partnerships, advocacy, and scientific and medical matters relevant to the organization’s mission. As part of its mandate, CNETS is committed to raising awareness about the disease and the latest evidence concerning diagnosis and treatment, and ensuring that patients, caregivers, and health care professionals have the information they need in the areas of medical and scientific research, treatment, and support.

Unmet Needs

All clinician groups highlighted a need for treatments that improve OS, slow the progression of disease, and control hormonal symptoms. The clinician groups stated that most NETs eventually progress, with metastases to multiple organ systems, eventually causing death. CANM stated that PFS is a key metric in assessing NET therapies. Over time, nearly all patients will develop resistance to treatments. They highlighted that there are limited effective treatment options after standard first-line treatment with SSAs. AMSMNQ stated that, once the disease is considered metastatic and/or unresectable, all further treatments are considered palliative. The goals of treatment become to reduce symptoms, prevent complications, and prolong patient survival, by delaying disease progression and death. However, currently available treatments, such as everolimus and sunitinib, have many significant side effects and complications and are poorly tolerated

Also, many pNETs produce excess hormones, including insulin and gastrin, which can have devastating clinical implications, such as dangerous bouts of marked hypoglycemia (insulinomas) and severe gastritis (gastrinomas). Therefore, CANM highlighted the importance of maintaining or improving quality of life for these patients. CANM also highlighted that patients with metastatic NETs of pancreatic origin that progress on SSAs have a high unmet need for treatment.

Place in Therapy

In general, there was disagreement among the clinician groups regarding the optimal place in therapy for ¹⁷⁷Lu oxodotreotide.

The OH-CCO Gastrointestinal Cancer Drug Advisory Committee stated that there are 4 established lines of therapy for patients with pNETs. Treatments available to patients include SSAs, capecitabine plus temozolomide, everolimus, and sunitinib. The OH-CCO Gastrointestinal Cancer Drug Advisory Committee acknowledged that, while the patient population of pNETs in the Ontario is small (representing between 10% to 20% of NET cases), there is high demand for therapies from both clinicians and patients. The OH-CCO Gastrointestinal Cancer Drug Advisory Committee suggested that ¹⁷⁷Lu oxodotreotide would fit as a fourth-line therapy.

CANM described first-line therapy for metastatic pNETs as non-radiolabelled SSAs, such as octreotide or lanreotide. It was acknowledged that most patients would eventually progress and require other therapies to control symptoms and slow the progression of their disease. Other treatment options include targeted therapies, such as everolimus or sunitinib. CANM stated that everolimus and sunitinib were effective and have a worse side effect profile than ¹⁷⁷Lu oxodotreotide. Targeted therapies were also stated to be more expensive, especially with longer use, than ¹⁷⁷Lu oxodotreotide, which is delivered to patients 4 times under the current therapeutic regimen.

CANM stated that chemotherapy is ineffective for treatment of most NETs, which are low-grade, although a small proportion of high-grade NETs may be treated with chemotherapy regimens (e.g., capecitabine plus temozolomide). High-grade NETs do not express SSRs, making treatment with SSAs, such as ¹⁷⁷Lu oxodotreotide, ineffective. CANM, CNETS SMAB, and AMSMNQ agreed that ¹⁷⁷Lu oxodotreotide would be an optimal second-line treatment for patients with NETs who had progressed on SSAs. The impact of ¹⁷⁷Lu oxodotreotide on treatment sequencing is minimal, according to these 3 clinician groups, as ¹⁷⁷Lu oxodotreotide is the preferred second-line treatment for patients who have progressed on SSAs.

Patient Population

All clinician groups agreed that patients with advanced, unresectable or metastatic pNETs who had progressed after first-line treatment with SSAs and who had demonstrated SSR positivity via imaging with a ⁶⁸Ga-dotatate PET scan or indium-111 (¹¹¹In)-octreotide scan would be best suited for ¹⁷⁷Lu oxodotreotide. Imaging includes a combination of anatomic imaging (CT or MRI) as well as functional imaging (i.e., ⁶⁸Ga-dotatate PET scan). CANM also stated that, depending on the level of local expertise assessment of potential therapy for NETs, multidisciplinary tumour boards can be helpful in deciding when ¹⁷⁷Lu oxodotreotide is best used for patients’ treatment.

According to CANM, patients least suitable for treatment include those who do not express SSRs. CANM stated that NETs often demonstrate significant variability among metastases, even within the same patient. Therefore, ⁶⁸Ga-dotatate PET scans are important for identifying patients most likely to exhibit a response to treatment, according to these experts. If ⁶⁸Ga-PET scans are not available, indium-111 (¹¹¹In)-octreotide scanning was acknowledged to be a suitable surrogate test, and it is more widely available.

Assessing Response to Treatment

The clinician groups agreed that patients’ response to treatment is assessed based on symptoms, quality of life, and the size of measurable lesions. Progression could be identified based on a combination of clinical symptoms, biochemical monitoring of hormonal levels, imaging monitoring of disease bulk, or involvement of important organs or structures. A clinically meaningful response to treatment considers improvement or stability of symptoms and/or disease bulk.

According to CANM, there is no consensus among clinicians about the optimum follow-up for patients. CANM stated that, when ¹⁷⁷Lu oxodotreotide treatment has been administered to patients with midgut NETs, both functional and anatomic imaging is generally conducted every 4 to 6 months following the completion of the 4 treatments of ¹⁷⁷Lu oxodotreotide. For monitoring thereafter, anatomic imaging was suggested every 4 to 6 months, with functional imaging as indicated on an individual basis.

Discontinuing Treatment

All clinician groups stated that treatment should be discontinued when patients experience disease progression or unacceptable toxicity (e.g., myelosuppression and renal dysfunction). Treatment may also be discontinued based on patient preference.

Prescribing Conditions

CANM highlighted that ¹⁷⁷Lu oxodotreotide is a radioactive therapy that can be administered only in select centres with appropriate training and with certification by the Canadian Nuclear Safety Commission. Appropriate training in handling radioisotopes and therapy administration, including all relevant radiation precautions and medical concerns for this specific treatment, are required for all personnel involved in the treatment (i.e., physicians, nurses, and nuclear medicine technologists). There was general agreement among all clinician groups that administration of ¹⁷⁷Lu oxodotreotide would require a multidisciplinary team to optimize benefits and risks of the intervention. Therefore, it is expected that ¹⁷⁷Lu oxodotreotide will be administered at limited sites. The clinician groups also stated that ¹⁷⁷Lu oxodotreotide therapy can be administered on an outpatient basis in the majority of patients.

Additional Considerations

CNETS SMAB and AMSMNQ noted that there is currently inequity in treatment options for patients across Canada and internationally. ¹⁷⁷Lu oxodotreotide is available for patients with pNETs in Europe, the UK, and Australia, as well as in Quebec. AMSMNQ also acknowledged that approximately 30% of patients receiving treatment with ¹⁷⁷Lu oxodotreotide at their centre are Canadians from outside of the province of Quebec.

Many clinician groups also pointed out the favourable toxicity profile of ¹⁷⁷Lu oxodotreotide and the improved effect of treatment on PFS compared to other treatments for pNETs. AMSMNQ also stated that it had conducted a phase II trial at the CHU de Québec, which assessed the safety and efficacy of personalized dosimetry for PRRT.¹⁸ There were 52 patients who had completed 4 cycles, of which 13 were patients with pNETs; of these patients with pNETs, 11 (85%) had a partial or minor response.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

¹⁷⁷Lu = lutetium-177; ⁶⁸Ga = gallium-68; FDG = fluorodeoxyglucose; IM = intramuscularly; LAR = long-acting release; PAG = Provincial Advisory Group; pERC = pCODR Expert Review Committee; pNET = pancreatic neuroendocrine tumour; PRRT = peptide receptor radionuclide therapy; SPECT = single-photon emission CT; SSA = somatostatin analogue; SSR = somatostatin receptor.

Clinical Evidence

The clinical evidence included in the review of ¹⁷⁷Lu oxodotreotide is presented in 3 sections. The first section, the Systematic Review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of¹⁷⁷Lu oxodotreotide at 7.4 GBq (200 mCi) as an IV infusion over 30 minutes every 8 weeks for a total of 4 doses. ¹⁷⁷Lu oxodotreotide is being reviewed for the treatment of unresectable or metastatic, well-differentiated, SSR-positive pNETs in adults whose disease has progressed after treatment with an SSA, unless there is a contraindication or intolerance.

Methods

Studies selected for inclusion in the systematic review include pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 5: Inclusion Criteria for the Systematic Review

¹⁷⁷Lu = ¹⁷⁷lutetium; AE = adverse event; DOR = duration of response; HRQoL = health-related quality of life; MDS = myelodysplastic syndrome; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; RCT = randomized controlled trial; SAE = serious adverse event; TTP = time to tumour progression; WDAE = withdrawal due to adverse event.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.¹⁹

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were lutetium Lu 177 oxodotreotide and pancreatic neuroendocrine tumours. Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on April 21, 2022. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee (pERC) on August 10, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist.²⁰ Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

Findings From the Literature

A total of 1 study was identified from the literature for inclusion in the systematic review (Figure 1). The included study is summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of Included Studies

¹¹¹In = indium-111; ¹⁷⁷Lu = ¹⁷⁷lutetium; ⁶⁸Ga = gallium-68; DOR = duration of response; HRQoL = health-related quality of life; NA = not applicable; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; pNET = pancreatic neuroendocrine tumour; SSR = somatostatin receptor; TTP = time to tumour progression.

Source: NETTER-R Clinical Study Report.⁵

Description of Studies

In a previous CADTH review for ¹⁷⁷Lu oxodotreotide, the recommendation did not support use of ¹⁷⁷Lu oxodotreotide among patients with pNETs, since these patients were excluded from the pivotal study (NETTER-1 trial). The NETTER-R post-marketing study was provided for this reassessment for ¹⁷⁷Lu oxodotreotide for patients with pNETs. The NETTER-R study was a non-interventional, non-comparative, post-authorization retrospective registry study to assess long-term efficacy and safety of treatment with ¹⁷⁷Lu oxodotreotide in patients with SSR-positive pNETs who had unresectable or metastatic, progressive disease. Progressive disease was assessed both radiologically and clinically, through investigator opinion. Approximately 120 patients across 3 countries were planned to be enrolled for data collection; specifically, 85 patients from 3 sites in the UK, 25 patients from 4 sites in France, and 15 patients from 4 sites in Spain. In fact, the study included 110 patients who met the pre-specified criteria for inclusion (Table 6). The approximate number of patients planned to be enrolled was based on the number of potentially eligible patients included in the CUP and those identified by investigators who were receiving commercial ¹⁷⁷Lu oxodotreotide at the selected study. To be included in the study, patients must have been treated with ¹⁷⁷Lu oxodotreotide either through the AAA Lutathera CUP, which was approved in 10 European countries since 2011 to 2012, or with a commercial drug. Patients’ paper-based and electronic medical records were collected in 3 of the countries where the CUP was in place, including the UK, France, and Spain. Most of the patients with pNETs who received treatment in this study were part of the CUP in 1 of the European Neuroendocrine Tumor Society Centers participating in this program. The retrospective data collection from medical records began on October 31, 2018, at the first study site. Data were tentatively collected at follow-up visits every 3 months, depending on the standard care in local practice and source document availability at the sites.

The primary objective of the NETTER-R study was to determine the efficacy of ¹⁷⁷Lu oxodotreotide, in patients with pNET according to a set of pre-specified eligibility criteria. The secondary objective of the study was to determine the safety and tolerability of ¹⁷⁷Lu oxodotreotide.⁴

Populations

Inclusion and Exclusion Criteria

A complete list of eligibility criteria is reported in Table 6; to be eligible for the NETTER-R study, patients had to meet all eligibility criteria and none of the exclusion criteria. Eligibility criteria included patients with SSR-positive, unresectable or metastatic, well-differentiated pNETs with progressive disease who had been treated with ¹⁷⁷Lu oxodotreotide. Patients were not eligible if they were diagnosed with NETs of other origins.⁵

Baseline Characteristics

A summary of baseline characteristics of patients in the NETTER-R study are reported in Table 7. A total of 110 patients were enrolled, with a mean age of 58 years (||||||||; range, 28.0 to 89.0 years). Relatively equal proportions of males (53%) and females (47%) were enrolled. |||| of patients were white (|||), although for many patients, race was not reported (43%). The primary sites of metastases before patients started treatment with ¹⁷⁷Lu oxodotreotide were the liver (96%), lymph nodes (43%), bone (29%), and lungs (4%). The liver tumour burden was from 10% to 25% in 29% of patients and more than 25% or more than 2 metastatic organs in 36% of patients. More than half of patients had nonfunctional tumours (57%), 30% of patients had functional tumour status, and the remainder lacked an assessment of tumour functionality (11%). Most patients had a Ki-67 index of 3% to 20% (66%) and 24% had a Ki-67 index of 2% or less. Most had a histopathological intermediate (grade 2; 65%) or low (grade 1; 27%) grade of disease. The majority of patients (74.5%) had an inoperable tumour, leaving approximately 1-quarter of patients (25.5%) who did not have an inoperable tumour; based on the eligibility criteria, patients with operable tumours should not have been included in the NETTER-R study. The sponsor clarified that patients with advanced pNETs with uncontrolled symptoms are considered for debulking surgery; patients who underwent debulking surgery were not excluded from the trial and were aligned with the indication for ¹⁷⁷Lu oxodotreotide approved in Europe.⁶ Many patients received an Octreoscan (|||) or a ⁶⁸Ga-PET scan (|||). Of patients with ECOG PS assessed, most patients had an ECOG PS of 0 (|||) or 1 (|||).⁵

Most patients had received prior anticancer treatments (92%), with a mean 4.7 prior or concomitant therapies. Prior anticancer therapy specifically for pNET disease was received by 91% of patients; these patients received mainly chemotherapy (|||), radiotherapy (|||), or other therapies (91%).⁵ Seventy percent of patients had received prior somatostatins and analogues, mainly lanreotide or octreotide (||| ||||). Prior TKIs were received by 38% of patients, mainly everolimus (33%) or sunitinib (20%). Slightly more than |||| of patients (|||) had received prior surgical and medical procedures. Patients most commonly underwent a pancreatic operation (|||), with others having a liver operation (|||), or radiotherapy (|||).

Table 7: Summary of Patient Characteristics (Full Analysis Set)

¹⁷⁷Lu = ¹⁷⁷lutetium; ⁶⁸Ga = gallium-68; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; GEPNET = gastroenteropancreatic neuroendocrine tumour; PS = performance status; SD = standard deviation.

^aIncludes celiac, ileal mass, mesenteric, pancreas, pelvis, pleura and spleen (n = 1 for each).

^bTumour uptake other than ⁶⁸Ga-PET and octreotide scan.

^cPercentages are based on the population who have performed the ECOG test.

^dPercentages are based on the population who have performed the ECG test.

Source: NETTER-R Clinical Study Report.⁵

Table 8: Prior Therapies (Full Analysis Set)

Source: NETTER-R Clinical Study Report.⁵

Treatments

¹⁷⁷Lu oxodotreotide was administered in 4 infusions of 7,400 MBq each. The study included patients with pNETs who received any dosage of ¹⁷⁷Lu oxodotreotide (regardless of the duration and number of doses administered) and discontinued the treatment for any reason. Patients could withdraw from the protocol at any time without giving a reason for doing so. Information on concomitant therapies and surgeries was also captured.

Outcomes

The efficacy end points identified in the CADTH review protocol that were assessed in the included study are provided in Table 9. These end points are further summarized in this section. Tumour response was based on local investigator assessment. Attempts were made to retrospectively collect radiological response according to RECIST version 1.1 and according to other local assessments, if available, including biochemical, clinical, and/or metabolic assessments (based on somatostatin receptor imaging; e.g., octreotide scan, Tektrotyd, ⁶⁸Ga-PET). For efficacy assessments based on tumour assessments (i.e., PFS, ORR, DOR, TTP), 2 versions of the end points were derived: 1 version included only RECIST version 1.1 tumour assessments, while the other version included all assessments available (i.e., including biochemical, metabolic, clinical, and radiological assessments, if different from RECIST 1.1) and was labelled as investigator opinion.

Table 9: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; DOR = duration of response; NCI = National Cancer Institute; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; TTP = time to tumour progression.

Source: NETTER-R Clinical Study Report.⁵

Statistical Analysis

Descriptive statistic and graphical presentations of data were the primary focus of the statistical analysis. Continuous variables were presented as the number of non-missing values, mean, SD, median, range, and quartiles. Descriptive statistics for categorical variables included counts and percentages per category, and 95% CIs were computed where appropriate. Exploratory analyses were performed to explore the impact on the outcomes of population characteristics that were thought to bias any comparisons of results from the NETTER-R study with those of other studies.

Outcomes analyzed in the NETTER-R study, along with their definitions, are summarized in Table 9.

Progression-Free Survival

A summary of the number of patients with PFS events was reported, along with summary statistics obtained from the Kaplan-Meier estimates, including median PFS with 95% CIs and 25th and 75th percentiles, and PFS probabilities at key time points after their first dose, if relevant, along with 95% CIs. A Kaplan-Meier plot was produced. Patients were censored at the date of their last evaluable tumour assessment if they had not experienced disease progression or died by the time of data collection, in the context of time-to-event analyses. Patients were also censored at their treatment start date if they did not have any post-baseline assessments. Two sensitivity analyses were performed: 1 that censored PFS for cases if 2 adjacent tumour assessments were more than 9 months apart, and another that censored patients on the date of their last available assessment before new anticancer therapy (if they received a new anticancer therapy before disease progression).⁴

Objective Response Rate

The data cut-off date was the last data point collected, provided that enough efficacy data were available. ORRs and 95% CIs were presented descriptively.⁴

Base response rates were presented descriptively using frequencies and percentages. A summary of the number of unconfirmed responses who will fall under the stable disease category was also provided. The best overall response (BOR) was derived following these 2 steps:

1. All available post-baseline tumour assessments that were on or before the minimum on non-missing dates were kept among first radiological progressive disease, start date of new anticancer therapy, and cut-off date. When all 3 dates were missing, all available post-baseline tumour assessments were included. If patients had at least 1 post-baseline tumour assessment with an overall response of complete response, then the BOR equated to complete response; further, if a patient had at least 1 post-baseline tumour assessment an overall response of partial response, then BOR equated to partial response; and if a patient had at least 1 post-baseline tumour assessment with an overall response of stable disease, the BOR equated to stable disease.

2. If BOR could not be obtained based on the previous step, the following step was conducted to capture BOR:

   1. If a patient had at least 1 radiological progressive disease, BOR equated to progressive disease; otherwise, if a patient had at least 1 available post-baseline target or non-target lesion, then BOR equated to not evaluable or to “No post-baseline scan.”

Duration of Response

The Kaplan-Meier method was used to assess median DOR and its associated 95% CI. A Kaplan-Meier plot was also produced. Patients were censored on the date of their last adequate radiological assessment if they never had documented progression.

Time to Tumour Progression

TTP was analyzed in the same manner as PFS, except that patients who died without measured progression were not considered a progression event; instead, these patients were censored at their date of last tumour assessment. The median TTP, 95% CI, 25th and 75th percentile, and TTP probabilities at key time points after patient’s first dose, if relevant, with 95% CIs, were provided using the Kaplan-Meier method. A Kaplan-Meier plot was produced.

Overall Survival

The analysis of OS consisted of summary statistics, along with data obtained from Kaplan-Meier estimates, including the median OS with associated 95% CIs, 25th and 75th percentiles, and survival probabilities at key time points. A Kaplan-Meier plot was produced. Patients were censored on their last date of contact if they were still alive or if their status was unknown.

Safety

AEs were coded using the available version of MedDRA (version 20.1 or later). Frequencies and proportions were reported for AEs.

Missing Data

No imputation was performed for missing data.⁴

Analysis Populations

A summary of analysis sets used in the NETTER-R study is reported in Table 10. The full analysis set (FAS) was used for efficacy analyses, while the safety analysis set (SAS) was used for safety analyses.⁴ An addendum was made to the statistical analysis plan of the NETTER-R study, which included a post hoc analysis using the modified FAS (mFAS) for efficacy end points. Patients who would were excluded from the FAS due to a lack of adequate post-baseline imaging were included in the mFAS. However, both the FAS and mFAS were considered interchangeable, as all 110 patients were included in both. PFS, ORR, and TTP were analyzed using the mFAS.

Table 10: Analysis Sets in the NETTER-R Study

Source: NETTER-R Protocol.⁴

Results

Patient Disposition

A summary of the patient disposition of the NETTER-R study is provided in Table 11. A total of 110 patients were enrolled, including 66 patients from the UK, 21 from France, and 23 from Spain. Of these, 76% completed the treatment with ¹⁷⁷Lu oxodotreotide. The primary reasons for stopping treatment were disease progression (10%), death (6%), the patient’s best interest in the opinion of the investigator (|||), other (|||), and AEs (1%).

Table 11: Patient Disposition

AE = adverse event; DOR = duration of response; FAS = full analysis set; mFAS = modified full analysis set; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors; TTP = time to tumour progression.

^aFor Patient A-LUT-ES02 to 0097 to 0003, the reason for end of treatment phase was not consistent with the action taken field for AEs in the case report form. Therefore, this patient is not counted for the analysis of TEAEs leading to discontinuation.

Source: NETTER-R Clinical Study Report.⁵

Protocol Deviations

| ||||| || |||| |||||||| |||||| ||| | ||||| |||||||| |||||||||. These protocol deviations were due to not meeting inclusion or exclusion criteria, mainly having no progressive disease at baseline visit (in 4 patients), baseline tumour SSR uptake equal to grade 1 (in 3 patients), and having a tumour that was not well-differentiated (in 2 patients). According to the sponsor, the major protocol deviations did not lead to exclusion of patients from the FAS or the SAS.⁵

||||| |||||||| |||||||||| |||| |||||||| || || ||||||| ||||||||. The most common reasons for minor protocol deviations involved baseline diagnoses; specifically, 21 patients (19.1%) had missing baseline tumour uptake, 6 patients (5.5%) did not have information on well-differentiated tumour, and 5 patients (4.5%) had unknown tumour uptake. Other minor protocol deviations, such as deviations due to visit dates out of the scheduled time window or lab parameters not evaluated, were also reported in a limited number of patients (n < 3).⁵

Exposure to Study Treatments

A summary of study treatment exposure is provided in Table 12. All 110 patients (100.0%) patients received ¹⁷⁷Lu oxodotreotide under the AAA CUP in Europe. Most patients received 4 doses of ¹⁷⁷Lu oxodotreotide (70%), with some patients (11% and 12%) receiving 3 or 2 doses, respectively. The cumulative dose of ¹⁷⁷Lu oxodotreotide received was high, with most patients receiving from 720 to 880 mCi (66%), and a third of patients receiving less than 720 mCi. The average dose per administration of ¹⁷⁷Lu oxodotreotide was 199.8 mCi (SD = 15.80), which is in line with the standard dose of ¹⁷⁷Lu oxodotreotide of 200 mCi ± 10%. The mean total duration of first to last dose of ¹⁷⁷Lu oxodotreotide was 8.8 months (SD = 4.15), which is also in line with a standard course of 4 administrations of ¹⁷⁷Lu oxodotreotide within 12 months. In general, dose intensity results for ¹⁷⁷Lu oxodotreotide in the NETTER-R study suggests that a full dose of ¹⁷⁷Lu oxodotreotide is tolerable.⁵

After the initial treatment period, there were 12 patients who received additional doses of ¹⁷⁷Lu oxodotreotide; 3 patients had received 1 additional dose, 7 patients received 2 additional doses, and additional 3 and 4 doses were given to 1 patient each. The average dose per administration was 187 mCi among these patients, with a mean duration from first to last administration of 6.4 months (SD = 5.11).

Table 12: Exposure to Study Drug (Safety Analysis Set)

SD = standard deviation.

Source: NETTER-R Clinical Study Report.⁵

Concomitant Medications

A summary of concomitant medications taken by patients in the NETTER-R study is provided in Table 13. Concomitant therapies were received by ||| of patients. The most common type of concomitant therapy was other (|||) and chemotherapy (|||), with few patients (||||) receiving radiotherapy. Patients receiving other therapies mostly received somatostatin and analogues (|||).⁵

Dose Modifications

Dose modifications are provided in Table 14. |||||||| ||||| |||| ||| |||| |||||||||||||| |||| ||||||||||||| |||| |||||||| || || |||||||| |||||| |||| |||||||| |||||||| ||| || |||||||| ||||| ||||| |||| |||||||| |||||||| ||| ||| |||||||| ||||.

Table 13: Concomitant Therapies (Safety Analysis Set)

NET = neuroendocrine tumour.

Source: NETTER-R Clinical Study Report.⁵

Table 14: Dose Modifications (Safety Analysis Set)

| |||| |||||||||||| |||||||| |||| |||||||| ||| |||| ||||||||| || |||| ||||| || |||| ||||||||||||| | ||||||| || ||||||| |||| ||||||| |||| |||||||| || ||||||| || |||| |||| ||| |||||||||||| ||||| | ||| ||||| ||| |||| |||| |||||||| || ||||||| || |||| |||| ||| |||||||||||| ||||| ||| |||| ||| ||||||||| |||| |||| ||| |||||||| |||| |||| ||| |||| |||||||| ||||| ||||||||| |||| |||| ||| |||||||| ||||| || || |||| |||| ||||| ||| |||| ||||||||

Source: NETTER-R Clinical Study Report.⁵

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported in this section. All analyses are considered descriptive. Refer to Appendix 3 for detailed efficacy data.

Overall Survival

Detailed outcome data for OS are provided in Table 15. A median follow-up time of 24.5 months was reported. There were 55 patients (50%) who experienced an OS event in the NETTER-R study. The median OS was 41.4 months (95% CI, 28.6 to 50.2; Figure 2). Half of patients were censored for the analysis of OS.

Table 15: Overall Survival (Full Analysis Set)

CI = confidence interval.

^aEstimated by the Kaplan-Meier method.

Notes: OS is defined as the time from the date of treatment start to the date of death due to any cause.

Data cut-off date: October 27, 2020.

Source: NETTER-R Clinical Study Report.⁵

Figure 2: Kaplan-Meier Plot of Overall Survival (Full Analysis Set)

LU = ¹⁷⁷Lu oxodotreotide.

Notes: Overall survival is defined as the time from treatment start to the date of death due to any cause, unless censored.

Data cut-off date: October 27, 2020.

Source: NETTER-R Clinical Study Report.⁵

Progression-Free Survival

Results for the primary end point of PFS were based on RECIST version 1.1 in the mFAS (Table 16). Results using the FAS were nearly identical. In the primary analysis of PFS, there were 41 PFS events (66%), of which most were progression (|||), and |||| were deaths (|||). The median PFS was 24.8 months (95% CI, 17.5 to 34.5). PFS was also assessed using the RECIST version 1.1 criteria based on investigator’s opinion as a secondary end point (Figure 3). PFS based in investigator’s opinion 1 was based on tumour assessments and other radiological assessments. PFS based on investigator’s opinion 2 was based on other radiological, clinical, biomarker, and metabolic assessments. The additional analyses of PFS were consistent with the primary analysis of PFS (Figure 4; Figure 5).

Sensitivity analyses are not reported here but were consistent with the primary analyses of PFS.

Table 16: Progression-Free Survival — RECIST Version 1.1 (Patients With Post-Baseline Scan per RECIST 1.1 in Modified FAS)

CI = confidence interval.

^aEstimated by the Kaplan-Meier method.

Note: Long-time elapsed missing assessments are defined as more than 9 months after the last radiological assessment (i.e., 270 days following the previous visit).

Source: NETTER-R Clinical Study Report.⁵

Figure 3: Kaplan-Meier Plot of PFS — RECIST 1.1 (Patients With Post-Baseline Scan per RECIST 1.1 in Modified FAS)

LU = ¹⁷⁷Lu oxodotreotide.

Notes: Progression-free survival is defined as the time from treatment start to documented assessed disease progression, per RECIST version 1.1, or death due to any cause, unless censored.

Data cut-off date: October 27, 2020.

Source: NETTER-R Clinical Study Report.⁵

Figure 4: Kaplan-Meier Plot of PFS — Based on RECIST 1.1 or Radiological Assessments (Investigator Opinion 1) (Patients With Post-Baseline Scan Per Investigator Opinion 1 in Modified FAS) — Redacted

Figure contained confidential information and was removed at the request of the sponsor.

Source: NETTER-R Clinical Study Report.⁵

Figure 5: Kaplan-Meier Plot of PFS — Based on RECIST 1.1, or Radiological, Clinical, Metabolic, or Biomarker Assessments (Investigator Opinion 2) (Patients With Post-Baseline Tumour Assessment per Investigator Opinion 2 in Modified FAS) — Redacted

Figure contained confidential information and was removed at the request of the sponsor.

Source: NETTER-R Clinical Study Report.⁵

Objective Response Rate

ORR based on the primary analysis was assessed in 62 patients. The ORR was 40.3% (95% CI, 28.1 to 53.6). None of the patients had a complete response, according to RECIST version 1.1 criteria. Partial response was reported in 40.3% of patients. Stable disease and progressive disease were reported for 35.5% and 21.0% of patients, respectively. As with PFS, ORR was also assessed using the RECIST version 1.1 criteria based on investigator’s opinion as a secondary end point. Results for ORR, based on investigators’ opinions 1 and 2, were consistent with the primary analysis of ORR, although the response was slightly better for ORR assessed by investigator’s opinion 2 (Table 17).

Table 17: Overall Tumour Response or Objective Response — RECIST 1.1 (Patients With Post-Baseline Scan per RECIST 1.1 in Modified FAS)

Source: NETTER-R Clinical Study Report.⁵

Duration of Response

The median DOR was 60.7 months (95% CI, 13.1 to 62.1; Figure 6). At the time of the analysis, there were 8 PFS events observed. As with PFS, DOR was assessed via investigators’ opinions 1 and 2. The DOR based on investigators’ opinions 1 and 2 was shorter than the primary analysis of DOR. The median DOR based on investigator’s opinion 1 was 31.1 months (95% CI, 16.8 to 62.1; Figure 7), with ||| PFS events, while the DOR based on investigator’s opinion 2 was 28.3 months (95% CI, 16.8 to 60.7; Figure 8), with ||| PFS events.

Figure 6: Kaplan-Meier Plot of Duration of Response — RECIST 1.1 Patients With Post-Baseline Scan per RECIST 1.1 in Modified FAS — Redacted

Figure contained confidential information and was removed at the request of the sponsor.

Source: NETTER-R Clinical Study Report.⁵

Figure 7: Kaplan-Meier Plot of Duration of Response Based on RECIST Version 1.1, or Radiological Assessments (Investigator’s Opinion 1) Patients With Post-Baseline Scan per Investigator’s Opinion 1 in Modified FAS — Redacted

Figure contained confidential information and was removed at the request of the sponsor.

Source: NETTER-R Clinical Study Report.⁵

Figure 8: Kaplan-Meier Plot of Duration of Response Based on RECIST Version 1.1, or Radiological, Clinical, Metabolic, or Biomarker Assessments (Investigator’s Opinion 2) Patients With Post-Baseline Tumour Assessment Per Investigator’s Opinion 2 in Modified FAS — Redacted

Figure contained confidential information and was removed at the request of the sponsor.

Source: NETTER-R Clinical Study Report.⁵

Time to Tumour Progression

Results for TTP are reported in Table 18. There was a total of ||| (|||) TTP events, with a median TTP of 29.5 months (95% CI, 21.4 to 67.6; Figure 9). As with PFS, TTP was assessed via investigators’ opinions 1 (Figure 10) and 2 (Figure 11), the results of which were both consistent with the primary analysis of TTP.

Table 18: Time to Tumour Progression — RECIST Version 1.1

FAS = full analysis set; PD = progressive disease; TTP = time to tumour progression.

Source: NETTER-R Clinical Study Report.⁵

Figure 9: Kaplan-Meier Plot of Time to Tumour Progression RECIST 1.1 (Patients With Post-Baseline Scan per RECIST 1.1 in Modified FAS) — Redacted

Figure contained confidential information and was removed at the request of the sponsor.

Source: NETTER-R Clinical Study Report.⁵

Figure 10: Kaplan-Meier Plot of Time to Tumour Progression RECIST 1.1, or Radiological Assessments (Investigator’s Opinion 1) (Patients With Post-Baseline Scan per Investigator’s Opinion 1 in Modified FAS) — Redacted

Figure contained confidential information and was removed at the request of the sponsor.

Source: NETTER-R Clinical Study Report.⁵

Figure 11: Kaplan-Meier Plot of Time to Tumour Progression RECIST 1.1, or Radiological, Clinical, Metabolic, or Biomarker Assessments (Investigator’s Opinion 2) RECIST 1.1, or Radiological, Clinical, Metabolic, or Biomarker Assessments (Investigator’s Opinion 2) — Redacted

Figure contained confidential information and was removed at the request of the sponsor.

Source: NETTER-R Clinical Study Report.⁵

Health-Related Quality of Life

|||||| ||| |||||| ||||||||||||| ||||||||||||| || ||||| || || |||||||| ||||||||| ||| ||||||| ||||||||| ||||||||||||| |||| || |||||||||||| ||||||||| ||||||||| ||||||||| || ||||| ||||||||| ||| |||||| ||| ||||| |||||| || |||||||| || |||||||||| ||| ||| |||| ||||||| || ||| |||| || ||||| |||| ||| |||| || ||||||| |||| |||| ||||||||| |||||| |||||||| ||||| |||||||| || |||||| |||||||||||||| |||| ||||| || |||||||| |||| ||||| || ||| ||||| |||||||||| ||| ||||||| ||||||| || ||| |||||||| |||| |||||||||| |||| ||||| |||| ||||||| |||| || ||||||||| | ||||| || || |||||||| ||||||| |||||||| |||||| |||||||| ||||||||| |||| || |||||| ||| ||||| ||||||||| ||||||||| |||||||| || ||||||||||5 ||||||| ||| |||||||| ||||| ||||||||||||| |||||||| ||| ||| |||||| ||| |||||||| ||| ||||||||||||| ||||| ||| || ||||||||||| || |||| |||| ||| ||||||||| |||| ||| |||| |||||||| || ||||||||| ||||| |||| ||||||| | ||| | |||||||| ||| |||||||| |||| ||| |||| ||||||||||||||5

Harms

Only those harms identified in the review protocol are reported in this section. Refer to Table 19 for detailed harms data.

Adverse Events

AEs were reported in 79 patients (72%). The most common AEs included nausea (28%), fatigue (23%), abdominal pain (16%), vomiting (|||), upper abdominal pain (|||), anemia (|||), diarrhea, lymphopenia, and thrombocytopenia (||| ||||). Grade 3 or 4 AEs were reported in 30 patients (27%). The incidence of grade 3 or 4 AEs was generally infrequent, with each event occurring in less than 5% of patients. The most common grade 3 or 4 AEs were lymphopenia (||||), abdominal pain, ascites, hypercalcemia, and liver abscess (|| ||||).

Serious Adverse Events

SAEs were reported in 29 patients (26%). SAEs were infrequently reported; no SAE occurred in more than 3% of patients. The most common SAEs were liver abscess, ascites, and hypercalcemia (|||| ||||).

Withdrawals Due to Adverse Events and Dose Modifications

No TEAEs resulted in treatment discontinuation. TEAEs leading to dose modification were infrequent, occurring in 10 patients (9%). The most common TEAEs that led to dose modifications were lymphopenia and nausea (|| ||||).

Mortality

There was a total of |||| deaths (||||) due to AEs in the NETTER-R study. The causes of death were reported to be abdominal abscess, hepatorenal syndrome and metabolic encephalopathy, hepatic encephalopathy, ascites, and lower respiratory tract infection and pulmonary embolism.

Notable Harms

Notable harms were detailed in the CADTH systematic review protocol and included myelotoxicity, renal toxicity, transformation to leukemia or MDS, nausea and/or vomiting, and fatigue.

Hematological toxicities were reported among ||| patients (||||). Hematological toxicities were mostly grade 1 or 2 (||||), with 5 patients experiencing grade 3 events. Nausea and fatigue were the 2 most commonly reported AEs in the NETTER-R study, occurring in 31 patients (28%) and 25 patients (23%), respectively. Renal toxicity was reported among 6 patients (6%); of these, 3 patients had grade 1 or 2 events and 3 patients had grade 3 events. There were no reports of secondary hematological malignancies (acute leukemia or MDS) in any patient.

Table 19: Summary of Harms (Safety Analysis Set)

AE = adverse event; MDS = myelodysplastic syndrome; SAE = serious adverse event.

^aFrequency > 4%.

^bFrequency > 2%.

^cAt each level of summarization, a subject is counted only once.

Source: NETTER-R Clinical Study Report.⁵

Critical Appraisal

Internal Validity

The NETTER-R study was a retrospective, non-comparative, registry-based, observational study. Without a comparison group, the safety and effectiveness of ¹⁷⁷Lu oxodotreotide relative to currently available therapies is unknown. Moreover, due to lack of an adequate control group, the estimate of long-term efficacy was compromised. In particular, no causal inference could be made concerning whether the treatment effect (e.g., changes on PFS or OS) could be completely attributable to ¹⁷⁷Lu oxodotreotide or to temporality changes in other factors, including concomitant therapies, subsequent therapies, or natural course of disease. In a retrospective, observational cohort study of drug effectiveness based on existing medical records, lack of a sound study design to make an adjustment or control of potential bias has been recognized as fatal limitation by various real-world evidence study guidance documents.

The CADTH team considered that the retrospective design of the NETTER-R study could have allowed for a matched comparator group of patients who had received relevant comparator therapies, such as everolimus or sunitinib. The clinical experts consulted by CADTH for this review agreed that a retrospective study with a matched analysis incorporating a comparator group would have improved the strength of evidence for this funding request for pNETs. It was also acknowledged that a matched analysis would depend on whether such data were available.

There was a large amount of censoring for all efficacy analyses. For example, in the estimate of PFS, about 1-third of patients were censored at the date of their last evaluable tumour assessment if they had not experienced disease progression or if they had not died at the time of data collection, in the context of time-to-event analyses. Similarly, in the assessment of OS, half of the patients were censored on their last date of contact if they were still alive or if their status was unknown. The large amount of censoring (e.g., non-informative) for most efficacy outcomes (i.e., OS, PFS, DOR, TTP) would have resulted in biased estimates of the absolute changes over time, as illustrated by the Kaplan-Meier curves, in those efficacy outcomes and would have further introduced uncertainty concerning the true effect of ¹⁷⁷Lu oxodotreotide on OS and progression of patients with pNETs.

The median follow-up time of the NETTER-R study was 24.5 months. The clinical experts consulted by CADTH for this review commented that, while no control group was part of the study, efficacy results for PFS and OS showed benefit to patients treated with ¹⁷⁷Lu oxodotreotide. However, longer-term data may have benefited the study by providing evidence of the impact of treatment with ¹⁷⁷Lu oxodotreotide over a longer period.

||||| |||| | ||||| || |||| |||||||| |||||| ||| ||| | ||||| |||||||| ||||||||| || ||| |||||||| |||||. The major protocol deviations were due to patients not meeting eligibility criteria specified for the study. The sponsor reported that the major protocol deviations did not result in exclusion of these patients from the efficacy and safety analyses sets. As the NETTER-R study was retrospective in nature, the inclusion of patients who did not meet study eligibility criteria could have been avoided. However, since there were few patients with major protocol deviations, the impact is expected to be low.

External Validity

The NETTER-R study was conducted in Europe, with patients enrolled from the UK, France, and Spain. Consultation with clinical experts engaged by CADTH for this review suggested that eligibility criteria and baseline characteristics were generally representative of patients in Canada who might be treated in clinical practice, although European countries may have more experience administering PRRT than Canada. The clinical experts commented that, while 1 patient received dactolisib as a prior therapy in the NETTER-R study, this treatment is not approved by Health Canada and not used among patients in Canada; the impact of this is expected to be low, since only 1 patient received this treatment. Eligibility criteria of the NETTER-R study specified that patients with unresectable or metastatic pNETs be included in the study. The clinical experts confirmed that inclusion of these patients would be unlikely to affect study outcomes; pNETs are a heterogenous group of tumours that result in aggressive disease, and results of treatment with ¹⁷⁷Lu oxodotreotide based on the NETTER-R study will likely apply to these patients as well.

Regarding prior therapies received by patients, 70% of patients received prior treatment with SSAs, leaving 30% of patients who had not received prior treatment with SSAs. The funding request by the sponsor specifies that patient’s disease must have progressed after prior treatment with an SSA unless there was a contraindication or intolerance. Further, the NETTER-R study did not specify that patients must have had prior treatment with SSAs. While this is not in exact alignment with the funding request, consultation by CADTH with clinical experts for this review confirmed that results of the NETTER-R study would still be generalizable to most patients in Canadian clinical practice.

The NETTER-R study did not include a comparator group. Consultation with clinical experts for this review suggested that a randomized trial may not have been possible, because patients would have been unlikely to have accepted assignment to a treatment group that did not include ¹⁷⁷Lu oxodotreotide. In addition, treatment with PRRT has been accepted in Europe and in the US, based on data from the NETTER-1 study, which was extrapolated to patients with pNETs.

Information regarding subsequent therapies was not reported for the NETTER-R study. Due to lack of information, it is impossible to know whether the choices of subsequent therapies reflect Canadian treatment practices for patients with pNETs and how subsequent therapies may have affected patients’ OS.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

The objective of this section is to summarize and critically appraise available indirect evidence comparing ¹⁷⁷Lu oxodotreotide to other relevant treatments (identified in the CADTH protocol) for patients with pNETs.

A focused literature search for network meta-analyses dealing with GEPNETS was run in MEDLINE All (1946–) on April 20, 2022. No limits were applied to the search. Of 183 records identified by the CADTH literature search, 1 published ITC by Khan et al. (2021)⁷ was included.

Description of Indirect Comparisons

Selection criteria for studies to be included in the sponsor’s ITC and published ITC are described in Table 20.

Table 20: Study Selection Criteria and Methods for ITCs

AE = adverse event; GEPNET = gastroenteropancreatic neuroendocrine tumour;; GI-NET = gastrointestinal neuroendocrine tumour; HRQoL = health-related quality of life; ICTRP = International Clinical Trials Registry Platform; ITC = indirect treatment comparison; NET = neuroendocrine tumour; NICE = UK National Institute for Health and Care Excellence; NIH = US National Institutes of Health; OS = overall survival; PFS = progression-free survival; pNET = pancreatic neuroendocrine tumour; SSA = somatostatin analogue; WHO = WHO.

^aPatients can only receive Lutathera (¹⁷⁷Lu oxodotreotide) if they are SSR-positive; however, this is not a requirement patients have to fulfill to receive alternative therapies, and therefore it has not been included in the description of the patient population for this systematic review.

^bTreatments can be used individually or in combination with SSAs.

Source: Sponsor’s ITC,^6,22 Khan et al. (2021).⁷

Methods of the Sponsor’s ITC

Objectives

The aim of the sponsor’s ITC was to compare ¹⁷⁷Lu oxodotreotide to relevant comparators. Specifically, the sponsor conducted MAICs comparing ¹⁷⁷Lu oxodotreotide to everolimus and sunitinib.

Study Selection Methods

To identify relevant studies for the sponsor’s ITC, a literature search was conducted based on eligibility criteria reported in Table 20. Databases used for identification of relevant studies were searched using the Ovid platform. In addition, studies were also identified through clinical trial registries. The reference lists of studies were hand-searched to identify any additional published or unpublished material. Full-text review for potentially relevant studies was conducted by 2 independent researchers. Data were extracted for included studies based on predefined forms.²² The literature search was initially conducted in 2017 and then updated twice, in 2020 and 2021.⁶ Only 2 studies included outcomes data for patients with pNET, including the RADIANT-3 and NCT00428597 studies. These 2 studies were compared with the NETTER-R study.²²

ITC Analysis Methods

Due to a lack of available networks of relevant studies (randomized controlled trials), a network meta-analysis was not feasible. Therefore, the sponsor conducted MAICs by matching and adjusting for patient demographic and disease characteristics between the study populations.²² Patient-level data from the NETTER-R study were used along with Kaplan-Meier data from the RADIANT-3 (everolimus) and NCT00428597 (sunitinib) studies for the MAICs of OS and PFS comparing ¹⁷⁷Lu oxodotreotide with everolimus and sunitinib. The Kaplan-Meier data from the RADIANT-3 and NCT00428597 studies were digitized, and the Guyot method was used to reconstruct individual event times and censoring times.²² Hazard ratios were estimated through weighted Cox proportional hazards models.²²

The method for estimation of model parameters was based on a method of moments approach outlined in Signorovitch et al. (2010).²³ Weights were applied for baseline characteristics, based on guidelines developed by the Decision Support Unit commission by the UK National Institute for Health and Care Excellence. The weighting scheme was based on regression models. The effect of weights was assessed through analysis of distribution of patient characteristics. The ESS was assessed as a measure of the extent of the population matching.²² All analyses were conducted in R version 4.0.5 or above by 1 statistician and checked by another statistician.

Identification of Covariates

The sponsor removed from the analyses of OS and PFS patients in the NETTER-R study who would not have been included in the comparator studies because they would not have met eligibility criteria related to the key covariates identified by the sponsor. These included bone metastasis, prior radiotherapy, ECOG PS, lung metastasis, number of disease sites as 1 and 2, surgery, lymph metastasis, time from initial diagnosis ≤ 24 months, median age of 58 years, sex, liver metastasis, and radiofrequency ablation. The list of key covariates was confirmed by the sponsor through consultation with clinical experts who identified covariates of prognostic importance in the treatment of pNETs. A detailed description of eligibility and baseline characteristics across studies is reported in this section.²²

The key covariates for inclusion into the ITC were determined by ranking P values from univariate analysis for OS and PFS for baseline characteristics. Cox proportional hazards models were used for continuous variables, and log-rank tests were used for categorical variables. Covariates were considered for inclusion in the models if they were statistically significant at the 20% level; covariates with an ESS of less than 75% of the initial population size were excluded if they were not statistically significant at the 10% level (starting from the covariates with the largest P values). Kaplan-Meier plots and log-cumulative hazard plots were used to visualize the results. Scenario analyses were also conducted to determine which combination of covariates resulted in the highest ESS value.²²

For the MAIC between ¹⁷⁷Lu oxodotreotide and everolimus, the following covariates were included: ECOG PS, prior radiotherapy, bone metastasis, and liver metastasis. The sponsor noted that the P value for liver metastasis was low but included liver metastasis in the MAIC, since the proportion of patients with liver metastasis was almost the same before matching when the 2 trials (NETTER-R and RADIANT-3) were compared. The ESS for this MAIC was 51 patients, accounting for 46% of the total number of available patients for analysis (N = 110).²²

For the MAIC between ¹⁷⁷Lu oxodotreotide and sunitinib, the following covariates were included: ECOG PS, prior radiotherapy, median time from initial diagnosis of 2.4 years, and prior radiofrequency ablation. The ESS for this MAIC was 74 patients, accounting for 67% of the total number of available patients for this analysis (N = 110).²²

Results of the Sponsor’s ITC

Summary of Included Studies

A total of 2 studies were retrieved from the sponsor’s systematic literature review for inclusion in the ITC: the RADIANT-3 trial, comparing everolimus to placebo, and NCT00428597 comparing sunitinib to placebo. These 2 studies were compared with the NETTER-R study though the MAIC.

The sponsor compared eligibility criteria across the 3 studies included in their MAIC. A list of key eligibility criteria from the 3 studies is reported in Table 21. The studies had somewhat varied inclusion and exclusion criteria. However, in general, the studies recruited patients with measurable pancreatic disease and excluded patients with uncontrolled comorbid conditions. The sponsor concluded that the eligibility criteria of the RADIANT-3 and NCT00428597 studies were fairly similar to those of the NETTER-R study. Consultation by CADTH with clinical experts for this review confirmed that characteristics were comparable across the trials.

Table 21: Eligibility Criteria Across Studies Included in the Sponsor's ITC

¹⁷⁷Lu = lutetium-177; ITC = indirect treatment comparison; NET = neuroendocrine tumour; pNET = pancreatic neuroendocrine tumour; PS = performance score; SSA = somatostatin analogue; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor; WHO = WHO.

Source: Sponsor’s ITC.²²

The end points of interest across these 3 studies were OS and PFS. The definition of PFS was assumed to be the same across the trials. PFS was assessed using RECIST version 1.0 criteria in the RADIANT-3 trial, while the version of RECIST was not specified in the NCT00248597 trial. The NETTER-R used RECIST version 1.1 for assessment of PFS.

Baseline Characteristics

A summary of baseline characteristic across the intervention groups of the trials is reported in Table 22. The median age was similar across all studies (between 56 and 58 years of age), with similar proportions of males and females. The majority of patients across all trials had an ECOG PS of 1 or 2, although the proportion of patients with an ECOG PS of 1 was greater in the RADIANT-3 and NCT00428597 (> 60%) than the NETTER-R study (|||).

While patients in the NCT00428597 study did not report whether patients with organ involvement were enrolled, patients in the NETTER-R and RADIANT-3 had high proportions of liver (> 90%) and lymph node (33% to 43%) involvement. Patients in the RADIANT-3 also had higher proportions of pancreas (44%) and lung (14%) involvement, while patients in the NETTER-R study had greater proportions of bone involvement (29.1%). The time from initial diagnosis was similar for both the RADIANT-3 and NETTER-R studies; similar information was not reported for the NCT00428597 study, although the median time from initial diagnosis was 2.4 months (range, 0.1 to 25.6). Similar proportions of patients in the NETTER-R and NCT00428597 study had a time from disease progression to randomization or receipt of study treatment of 3 to 12 months (26% versus 28%, respectively). However, more patients in the RADIANT-3 trial had a time from disease progression to randomization of less than 3 months, while more patients in the NETTER-R study had a time from disease progression to randomization or receipt of study treatment of greater than 12 months. Classification of tumour functionality was not reported consistently across the trials.

There were differences in the types of previous treatments received by patients across the trials. There were few patients who had prior radiotherapy, chemoembolization, and radiofrequency ablation. However, more patients in the NCT00428597 study had prior surgery (88%) than in the NETTER-R study (30%), and more patients in the NETTER-R study (62%) had prior chemotherapy than in the NCT00428597 study (n = 0). Prior SSA was reported in 70% of patients in the NETTER-R study, 25% of patients in the NCT00428597 study, and 49% of patients in the RADIANT-3 study.

The baseline characteristics pre- and post-matching for the MAICs with everolimus and sunitinib are provided in Table 23 and Table 24. The matching was considered successful.

Table 22: Baseline Characteristics Across Studies Included in the Sponsor's ITC

ECOG PS = Eastern Cooperative Oncology Group Performance Status; ITC = indirect treatment comparison; NA = not available; NR = not reported; SSA = somatostatin analogue.

Source: Sponsor’s ITC.²²

Table 23: Comparison of Baseline Characteristics for NETTER-R (Pre- and Post-MAIC) With Radiant-3 Trial

|||| | ||||||| ||||||||||| |||||||| |||||| || | ||||||||||| |||||||

Source: Sponsor’s ITC.²²

Table 24: Comparison of Baseline Characteristics for NETTER-R (Pre- and Post-MAIC) With NCT00428597 (Sunitinib) Trial

||| | ||||||||| |||| | ||||||| ||||||||||| |||||||| |||||| || | ||||||||||| |||||||

Source: Sponsor’s ITC.²²

Risk of Bias

The sponsor did not report the results of their risk-of-bias assessment, conducted for their ITC.

Results

The results of the survival analysis, based on the NETTER-R patient-level data and reconstructed data for the comparators, as well as the median PFS and OS based on reconstructed Kaplan-Meier data, are reported in Table 25.

Progression-Free Survival

The Kaplan-Meier curves for the MAIC for PFS between ¹⁷⁷Lu oxodotreotide and everolimus and ¹⁷⁷Lu oxodotreotide and sunitinib are depicted in Figure 12 and Figure 13.

The median PFS of ¹⁷⁷Lu oxodotreotide before adjustment was |||| |||||| |||| ||| |||| || |||||. After adjustment, the median PFS of ¹⁷⁷Lu oxodotreotide was |||| |||||| |||| ||| |||| || |||||, which was longer than the median PFS of everolimus at |||| |||||| |||| ||| |||| || |||||. The HR for PFS between ¹⁷⁷Lu oxodotreotide and everolimus favoured treatment with ¹⁷⁷Lu oxodotreotide (|||||||| ||| ||| |||| || ||||).

The median PFS of ¹⁷⁷Lu oxodotreotide before adjustment was |||| |||||| |||| ||| ||||| || |||||. After adjustment, the median PFS of ¹⁷⁷Lu oxodotreotide remained the same at |||| |||||| |||| ||| ||||| || |||||, which was longer than the median PFS of sunitinib at |||| |||||| |||| ||| |||| || |||. The HR for PFS also favoured ¹⁷⁷Lu oxodotreotide over sunitinib ||||||||| ||| ||| |||| || |||||.

Figure 12: Progression-Free Survival for Everolimus Versus ¹⁷⁷Lu Oxodotreotide Pre- and Post-MAIC — Redacted

Figure contained confidential information and was removed at the request of the sponsor.

Source: Sponsor’s ITC.²²

Figure 13: Progression-Free Survival for Sunitinib Versus ¹⁷⁷Lu Oxodotreotide Pre- and Post-MAIC — Redacted

Figure contained confidential information and was removed at the request of the sponsor.

Source: Sponsor’s ITC.²²

Overall Survival

The Kaplan-Meier curves for the MAIC for OS between ¹⁷⁷Lu oxodotreotide and everolimus and ¹⁷⁷Lu oxodotreotide and sunitinib are depicted in Figure 14 and Figure 15.

The median OS of ¹⁷⁷Lu oxodotreotide before adjustment was |||| |||||| |||| ||| |||| || |||||. After adjustment, the median PFS of ¹⁷⁷Lu oxodotreotide was |||| |||||| |||| ||| |||| || |||. The median OS of everolimus was ||| ||||||||| |||| ||| |||| || |||. The 95% CI of HR for OS between ¹⁷⁷Lu oxodotreotide and everolimus ||||||| ||| |||| |||||, although the point estimate was in favour of ¹⁷⁷Lu oxodotreotide over everolimus ||||||||| ||| ||| |||| || |||||.

The median OS of ¹⁷⁷Lu oxodotreotide before adjustment was |||| |||||| |||| ||| |||| || |||||. After adjustment, the median OS of ¹⁷⁷Lu oxodotreotide remained the same at |||| |||||| |||| ||| |||| || |||, which was longer than the median OS of sunitinib at |||| |||||| |||| ||| |||| || |||||. The HR for OS failed to show a statistically significant difference in favour of ¹⁷⁷Lu oxodotreotide over sunitinib ||||||||| ||| ||| |||| || |||||.

Figure 14: Overall Survival for Everolimus Versus ¹⁷⁷Lu Oxodotreotide Pre- and Post-MAIC — Redacted

Figure contained confidential information and was removed at the request of the sponsor.

Source: Sponsor’s ITC.²²

Figure 15: Overall Survival for Sunitinib and ¹⁷⁷Lu Oxodotreotide Pre- and Post-MAIC — Redacted

Figure contained confidential information and was removed at the request of the sponsor.

Source: Sponsor’s ITC.²²

Critical Appraisal of the Sponsor’s ITC

The sponsor reported that it had conducted a quality assessment of studies included in its ITC. However, the results of the quality assessment were not reported, although it is likely that the quality level of evidence was not consistent among the 3 studies used in the MAICs. This is likely due to the fact that the NETTER-R study was a retrospective, single-group study, whereas the RADIANT-3 and NCT00428597 studies were phase III randomized trials.

Patient demographic and disease characteristics across the 3 studies were mostly similar. However, there were some differences regarding organ involvement, time from initial diagnosis, time between disease progression and randomization, tumour functionality, and prior treatments. Residual confounding bias may exist, as the matching adjustment was limited to a number of pre-identified covariates. As mentioned, the MAICs chosen for comparisons between ¹⁷⁷Lu oxodotreotide and everolimus or sunitinib were designed based on the combination of covariates that resulted in the highest ESS. The ESS for the MAICs between ¹⁷⁷Lu oxodotreotide versus everolimus and ¹⁷⁷Lu oxodotreotide versus sunitinib were ||| and |||, respectively. The reductions in ESS for these MAICs may indicate that there was little overlap between the individual patient-level data of the NETTER-R study and the RADIANT-3 and NCT00428597 studies, with less overlap between the NETTER-R and RADIANT-3 studies than between NETTER-R and NCT00428597 studies. The lack of high overlap between patients across the studies may serve as an indicator of heterogeneity across patient characteristics, which may suggest additional unknown prognostic and predictive factors and introduce bias into the comparisons of efficacy between ¹⁷⁷Lu oxodotreotide and everolimus or sunitinib.

The results of the MAICs suggested that ¹⁷⁷Lu oxodotreotide was favoured over everolimus and sunitinib for PFS but not for OS. It should be noted that the median OS was not reached in either the RADIANT-3 and NCT00428597 studies. Therefore, the efficacy analyses of the sponsor’s MAICs, in particular for OS, is of limited interpretability.

In general, the MAICs rely on statistical assumptions and a limited list of known predictive and prognostic covariates, which are difficult to confirm. The MAIC has resulted in a significant reduction of sample size by excluding more than half of NETTER-R patients, which would have compromised the generalizability and reliability of the results.

Methods of Khan et al. (2021)⁷

Objectives

The aim of the ITC by Khan et al. (2021) was to use MAICs to indirectly compare PFS in patients with GI-NETs or pNETs, and OS in patients with pNETs, after treatment with ¹⁷⁷Lu oxodotreotide, everolimus, sunitinib, or best supportive care across different studies.

Study Selection Methods

Some details of the literature searched conducted by Khan et al. (2021) are reported in Table 20. The literature search was performed in 2015 and then updated in 2018. A total of 3 studies were considered relevant for inclusion in the MAICs conducted by Khan et al. (2021) (ERASMUS, RADIANT-3, and NCT00428597).

ITC Analysis Methods

Data for OS and PFS for patients with pNETs were obtained from the RADIANT-3 and NCT00428597 studies. The authors reported that the definitions of OS and PFS were the same in all studies.

As the RADIANT-3 and NCT00428597 studies had published Kaplan-Meier data, the data were digitized, and the Guyot method was used to reconstruct individual even times and censoring times. Individual patient-level data were available from the ERASMUS study. To identify the covariates for inclusion in the MAICs, covariates that were reported in the ERASMUS study and at least 1 of the RADIANT-3 and NCT00428597 studies were compiled in a list. An investigation was made into the relationship of each covariate with OS and PFS for subgroups of patients with both pNETs and GI-NETs in the ERASMUS study; a log-rank test was used for categorical variables and a Cox proportional hazards model was used for continuous variables. Results were visualized using Kaplan-Meier plots and log-cumulative hazard plots. Covariates found to be statistically significant at the 20% level with OS or PFS were included in the MAICs if they were reported for the comparator study.

Logistic regression analysis was used to estimate the weight for each patient in the ERASMUS study, describing the propensity to enrol in the ERASMUS study versus the relevant comparator in the comparator trial. The balancing of the covariates was checked to ensure that the weighting procedure was conducted correctly; the distribution of weights was summarized using medians, ranges, and histograms. The ESS was also calculated; models with large reductions in ESS were not reported.

The median time-to-event and Kaplan-Meier curves were used to describe OS and PFS in the original ERASMUS population and the reweighted population. Data from the reweighted ERASMUS population and from each comparator treatment group were combined in Cox proportional hazards regression models to estimate hazard ratios.

Sensitivity analyses were conducted to assess the sensitivity of the results to a number of key assumptions underlying the MAICs.

All analyses were conducted using T version 3.3.2 and were in accordance with the UK National Institute for Health and Care Excellence Decision Support Unit guidelines.

Results of ITC by Khan et al. (2021)

Summary of Included Studies

The authors conducted MAICs for patients with GI-NETs and pNETs. Only the results pertaining to patients with pNETs are reported here.

The authors concluded that there were no differences in key covariates among the ERASMUS, RADIANT-3, and NCT00428597 studies. Age, ECOG PS, previous chemotherapy, and previous radiotherapy were reported to be statistically significantly associated with PFS and OS in the ERASMUS study at the 20% level and were adjusted for in the MAICs. A summary of baseline characteristics pre- and post-matching with the NCT00428597 and RADIANT-3 studies are reported in Figure 16 and Figure 17. Matching was considered successful; however, the ESS was greatly reduced for the ERASMUS study. Covariates that were not adjusted for were not well-balanced. There were more male patients in the ERASMUS study than in the NCT00428597 study. Fewer patients in the ERASMUS study had received prior surgery compared to the NCT00428597 study, and fewer patients in the ERASMUS study had nonfunctional tumours compared to the NCT00428597 study. The results pre- and post-matching with the RADIANT-3 study were similar. The ESS after matching with the RADIANT-3 study was much lower than with the NCT00428597 study, which may suggest low population overlap. The covariates that were not adjusted were also not well-balanced.

Figure 16: Patient Characteristics in the ERASMUS Study Before and After Matching to the NCT00428597 Study

Source: Khan et al. (2021).⁷ Copyright 2021 Elsevier Ltd. Reprinted in accordance with CC BY-NC-ND.

Figure 17: Patient Characteristics in the ERASMUS Study Before and After Matching to RADIANT-3

BSC = best supportive care; ECOG = Eastern Cooperative Oncology Group; NA = not available.

Source: Khan et al. (2021).⁷ Copyright 2021 Elsevier Ltd. Reprinted in accordance with CC BY-NC-ND.

Results

Progression-Free Survival

Results for analyses of PFS are reported in Figure 18. The MAIC suggested that PFS improved more in patients treated with ¹⁷⁷Lu oxodotreotide than in those treated with sunitinib (HR = 0.36; 95% CI, 0.18 to 0.70) and everolimus (HR = 0.46; 95% CI, 0.30 to 0.71). Results of the sensitivity analyses also supported improvement with ¹⁷⁷Lu oxodotreotide over sunitinib and everolimus.

Figure 18: Hazard Ratios Estimated From Matching-Adjusted Indirect Comparisons for PFS in pNETs

BSC = best supportive care; CI = confidence interval; PFS = progression-free survival; pNET = pancreatic neuroendocrine tumour; NR = not reported.

Source: Khan et al. (2021).⁷ Copyright 2021 Elsevier Ltd. Reprinted in accordance with CC BY-NC-ND.

Overall Survival

Results for analyses of OS are reported in Figure 19. The MAIC suggested that OS improved more in patients treated with ¹⁷⁷Lu oxodotreotide than in those treated with sunitinib (HR = 0.42; 95% CI, 0.25 to 0.72) and everolimus (HR = 0.53; 95% CI, 0.33 to 0.87). Results of the sensitivity analyses also supported improvement with ¹⁷⁷Lu oxodotreotide over sunitinib and everolimus.

Figure 19: Hazard Ratios Estimated From Matching-Adjusted Indirect Comparisons for OS in pNETs

BSC = best supportive care; CI = confidence interval; OS = overall survival; pNET = pancreatic neuroendocrine tumour; NR = not reported.

Source: Khan et al. (2021).⁷ Copyright 2021 Elsevier Ltd. Reprinted in accordance with CC BY-NC-ND.

Critical Appraisal of ITC by Khan et al. (2021)

Some differences in baseline characteristics were observed across the included studies. There were some differences noted in patient’s sex, tumour functionality, and previous treatments. These characteristics were not included in the matching between the ERASMUS study and the NCT00428597 and RADIANT-3 studies. After matching, these characteristics were not well-balanced. These differences in patient characteristics may affect the validity of the comparisons between ¹⁷⁷Lu oxodotreotide and everolimus and sunitinib.

The authors conducted matching with key covariates between the ERASMUS study and the comparator studies (NCT00428597 and RADIANT-3). The ESS after matching with the sunitinib comparator group in the NCT00428597 study was 77% of the initial sample. However, the ESS was much lower (35%) after matching with the everolimus group in the RADIANT-3 study. Characteristics of patients that were unadjusted for were not well-balanced, as illustrated by the differences in patient’s sex, previous surgery, and tumour functionality. Therefore, any unknown covariates are likely not balanced across studies. There is likely little patient overlap between the ERASMUS and comparator studies, although this is more the case with the RADIANT-3 study.

As mentioned previously, OS was not reached in either the RADIANT-3 and NCT00428597 studies. Therefore, the efficacy analyses for OS based on immature data may suffer from high uncertainty.

Details regarding the risk-of-bias assessment were not reported. Therefore, the quality of the studies included is not known; the risk of bias in each study is important for consideration, as the quality of the study may reveal important insights regarding study methodology and impact of these biases on the ITC study outcomes.

Other Relevant Evidence

This section includes submitted long-term extension studies and additional relevant studies included in the sponsor’s submission to CADTH that were considered to address important gaps in the evidence included in the systematic review.

Three separate non-comparative observational studies by Fröss-Baron et al. (2021),⁸ Marinova et al. (2018),⁹ and Zandee et al. (2019)¹⁰ are briefly summarized here to provide additional efficacy and safety data on ¹⁷⁷Lu oxodotreotide in patients with pNETs. Only those efficacy outcomes identified in the review protocol are reported here.

Description of Studies

Fröss-Baron et al. (2021)⁸ Study

Fröss-Baron et al. (2021)⁸ conducted a retrospective study to determine the efficacy and safety of ¹⁷⁷Lu oxodotreotide in 102 adult patients with metastatic and/or locally advanced pNETs who had been previously treated with chemotherapy. Patients in Sweden treated with ¹⁷⁷Lu oxodotreotide between 2005 and 2014 were identified using hospital records, and medical and radiological reports were retrospectively examined. Patients received 7.4 GBq ¹⁷⁷Lu oxodotreotide per cycle, with an intended 6- to 8- week interval between each cycle. The standard 4-cycle protocol was applied to the first 12 patients, and the dosimetry-guided protocol (greater than 4 cycles) was applied to the following 90 patients. Notably, patients with functional pNETs continued to receive therapy with an SSA during treatment with ¹⁷⁷Lu oxodotreotide. The study aimed to analyze PFS, OS, toxicity, and their determinants. CT or MRI imaging was completed at baseline, before every second cycle, 3 months after the last cycle, and every 6 months thereafter, until disease progression was documented, per RECIST version 1.1. Apart from patients with early progression or death, all patients had at least 12 months of follow-up.

The majority of patients (64 [62.7%]) were male, and the mean age was 57.1 years (SD = not reported; range, 29 to 79). A total of 72 patients (70.6%) had a nonfunctional tumour, and 97 patients (95.1%) had liver metastases. Most patients (76 [74.5%]) had a Ki-67 index of 3% to 20%, and most patients (56 [54.9%]) had an ECOG PS of 0. All patients received 1 to 3 lines of chemotherapy, and 58 patients (56.9%) received an SSA before ¹⁷⁷Lu oxodotreotide. For most patients (92 [90.2%]), treatment with ¹⁷⁷Lu oxodotreotide was indicated due to tumour progression. A mean activity of 32 GBq (SD = 10.9; range, 7.4 to 74) was administered in a median of 4 cycles (range, 1 to 10), with 44 patients (43.1%) having received more than 4 cycles.

Marinova et al. (2018)⁹ Study

Marinova et al. (2018)⁹ conducted a retrospective study to determine the change in HRQoL and symptom burden in 68 adult patients with pNETs following treatment with ¹⁷⁷Lu oxodotreotide. Patients treated with ¹⁷⁷Lu oxodotreotide between 2007 and 2015 at a hospital in Germany were identified, and data were retrospectively analyzed. Briefly, inclusion criteria for the study were that unresectable metastatic pNETs were confirmed with histopathology, the patient had an ECOG PS of 0 to 2, the intended number of cycles were administered, follow-up was completed at 3 months after the last cycle, and the EORTC QLQ-C30 was completed before the first cycle and at least once after the last cycle. Patients received a mean activity of 7.6 GBq (SD = NR) ¹⁷⁷Lu oxodotreotide per cycle. Change in HRQoL and symptom status were evaluated according to the EORTC QLQ-C30. EORTC QLQ-C30 is a 30-item, self-reported questionnaire used to assess HRQoL in patients with cancer. It consists of single- and multi-item measures, and scores can range from 0 to 100. Higher scores on the Global Health Status and functional scales indicate better function, and higher scores on the symptom scales and single items indicate significant symptoms. Patients completed the EORTC QLQ-C30 at baseline and every 3 months following each treatment cycle for up to 12 months.

Most (37 [54.4%]) patients were male, and the mean age was 61.4 years (SD = NR; range, 14 to 85). The majority (46 [67.6%]) of patients had a nonfunctional tumour. Most (40 [58.8%]) patients had a Ki-67 index of 3% to 20%, and most (39 [57.4%]) patients had an ECOG PS of 0. A total of 26 (38.2%) and 25 (36.8%) patients received chemotherapy and SSAs as therapies before ¹⁷⁷Lu oxodotreotide, respectively. Most (49 [72.1%]) patients had a documented morphological or clinical progression before the first treatment cycle. A total of 53 (77.9%) patients received all 4 cycles; with the exception of 2 reported deaths, treatment discontinuation was decided by an interdisciplinary tumour board. A median cumulative activity of 28.2 GBq (range, NR) was administered in intervals of 3 months and up to 4 cycles. Notably, patients did not receive further therapies during treatment with ¹⁷⁷Lu oxodotreotide and follow-up.

Zandee et al. (2019)¹⁰ Study

Zandee et al. (2019)¹⁰ conducted a retrospective study to determine the efficacy and safety of ¹⁷⁷Lu oxodotreotide in 34 adult patients with functional pNETs — 14 patients with insulinoma, 8 with glucagonoma, 7 with gastrinoma, and 5 with VIPoma. Patients treated with ¹⁷⁷Lu oxodotreotide between 2000 and 2017 at a centre in the Netherlands were identified. Patients received up to 4 cycles of 7.4 GBq ¹⁷⁷Lu oxodotreotide per cycle, with an intended interval of 6 to 10 weeks and an intended cumulative activity of 27.8 to 29.6 GBq. Patients were admitted for clinical observation or treatment of hormonal syndrome, per protocol. The study aimed to evaluate symptomatic, biochemical, and radiological response, as well as toxicity. Hematology, kidney, and liver function tests were completed following each cycle and at follow-up visits (6 weeks, 3 months, and 6 months following the last cycle, and every 6 months thereafter). CT or MRI imaging was completed within 3 months of the first cycle and at each follow-up visit. Patients completed the EORTC QLQ-C30 at all visits.

The mean age was 59.0 years (SD = 11.3), and 17 (50%) patients were male. All patients had metastatic pNETs, and 33 patients (97.1%) had liver metastases. Most patients (18 [52.9%]) had a grade 2 tumour, according to the European Neuroendocrine Tumor Society criteria. The majority of patients (22 [64.7%]) had received an SSA as previous treatment. Most patients (14 [41.2%]) received ¹⁷⁷Lu oxodotreotide due to tumour progression only. Notably, 2 patients were receiving concomitant treatment with capecitabine in a clinical trial. The majority of patients (24 [70.6%]) received the intended cumulative activity of 29.6 GBq ¹⁷⁷Lu oxodotreotide.

Summary of Findings

Fröss-Baron et al. (2021)⁸ Study

The median follow-up period was 34 months (range, 4 to 160), and survival data for patients (46.1%) were based on the Swedish National Health Registry up to 2018. PFS was calculated using the Kaplan-Meier method and was based on the first date of treatment to the date of radiologically confirmed progression, per RECIST version 1.1, or death from any cause. OS was calculated using the Kaplan-Meier method and was based on the first day of treatment with ¹⁷⁷Lu oxodotreotide to the day of death or the last day of follow-up. The median PFS was 24 months (95% CI, 17 to 28), and the median OS was 42 months (95% CI, 29 to 61). During follow-up, 63 (61.8%) patients died; tumour progression was reported as the cause of death in 60 patients.

Tumour response was assessed with RECIST version 1.1 criteria in 100 patients. Complete response was reported in 4 (4.0%) patients, partial response in 45 (45.0%) patients, stable disease in 44 (44.0%) patients, and progressive disease in 7 (7.0%) patients. Forty-nine percent of patients reached objective response, which was defined as patients with complete or partial response. The median time to best response was 14.8 months (range, 3 to 108). Disease control, which was defined as complete response, partial response, or stable disease, was reported in 91.0% of 92 patients with progressive disease at baseline.

Bone marrow, liver, and kidney toxicity were defined by the CTCAE version 3.0. Grade 3 or 4 bone marrow toxicity was reported in 11 (10.8%) patients. Grade 3 toxicity of white blood cells and/or granulocytes was reported in 5 (4.9%) patients, grade 3 or 4 toxicity of platelets was reported in 5 (4.9%) patients, and grade 3 toxicity of hemoglobin was reported in 2 (1.9%) patients. Grade 4 (lethal) thrombocytopenia and acute myeloid leukemia were reported in 1 (1.0%) patient each. Fatal liver toxicity was reported in 1 (1.0%) patient; the cause of death was also considered related to tumour progression. Grade 3 or 4 nephrotoxicity was not observed.

Treatment discontinuations were due to the following: termination according to the dosimetry-guided protocol was applied to 51 (50.0%) patients, disease progression in 17 (16.7%) patients, bone marrow toxicity in 11 (10.8%) patients, the standard 4-cycle protocol was applied to 9 (8.8%) patients, reduced tumour load in 3 (2.9%) patients, deterioration in 2 (1.9%) patients, death in 2 (1.9%) patients, and a combination of factors not specified in 7 (6.8%) patients.

Marinova et al. (2018)⁹ Study

The primary analysis using the EORTC QLQ-C30 was according to data collected at baseline and 3 months following the last cycle (follow-up). The mixed longitudinal (panel) model was used to evaluate the data, and a non-parametric Skilling-Mack test was used to verify the unbalanced panel data; a value of less than 0.05 was considered statistically significant. An increase in the mean Global Health Status score was reported (P = 0.008); the mean score was 58.2 (95% CI, 53.1 to 63.2) at baseline and 69.3 (95% CI, 61.4 to 77.2) at follow-up. An increase in the mean social functioning score was reported (P = 0.049); the mean score was 63.9 (95% CI, 56.7 to 71.2) at baseline and 70.9 (95% CI, 61.1 to 80.7) at follow-up. A decrease in the mean fatigue symptom score was reported (P = 0.029); the mean score was 42.4 (95% CI, 36.3 to 48.4) at baseline and 32.0 (95% CI, 22.2 to 41.7) at follow-up. A decrease in the mean appetite loss symptom score was reported (P = 0.015); the mean score was 25.7 (95% CI, 19.5 to 31.9) at baseline and 11.6 (95% CI, 0.7 to 22.5) at follow-up. The differences in change from baseline in the mean scores on the remaining functional and symptom scales were not considered statistically significant. Further, the investigators reported a significantly greater improvement (magnitude of benefit was not reported) on the diarrhea and dyspnea symptom scale scores in patients with functional versus nonfunctional pNETs. The subanalysis of EORTC QLQ-C30 was based on data collected at baseline and at 3 months following the first, second, and third cycle. Changes from baseline in the EORTC QLQ-C30 in the subanalysis were generally consistent with those observed in the primary analysis.

Zandee et al. (2019)¹⁰ Study

The median follow-up period was 39.3 months (range, NR). PFS was calculated using the Kaplan-Meier method and was based on the time from the first cycle of ¹⁷⁷Lu oxodotreotide to objective progression, change to a new line of therapy, or death from any cause. The median PFS was 18.1 months (interquartile range, 3.3 to 35.7). A primary event was reported in 31 patients, of whom 24 had progressive disease, 5 changed to a new line of therapy, and 2 died.

Tumour response was evaluated with RECIST version 1.1 criteria in 34 patients. Complete response was reported in 1 (2.9%) patient, partial response in 19 (55.9%) patients, stable disease in 8 (23.6%) patients, and progressive disease in 6 (17.6%) patients. Disease control, which was defined as patients with complete response, partial response, or stable disease, was reported in 18 of the 23 patients with progressive disease at baseline.

Symptomatic response was reported in 17 of the 23 patients with uncontrolled symptoms at baseline, of whom 6 experienced a reduction in hypoglycemic events, 4 experienced a reduction in diarrhea, 5 experienced a reduction in skin lesions or weight increase, and 2 experienced a reduction in pyrosis or diarrhea.

HRQoL was assessed in 22 patients using the EORTC QLQ-C30 by comparing the scores 3 months after the last cycle (follow-up) to those at baseline. A paired t-test and the Wilcoxon signed-rank test were used for normally distributed and non-normally distributed variables in the comparison of continuous variables, respectively. An increase in the mean Global Health Score/Quality of Life was reported (P = 0.002); the mean score was 61.7 (95% CI, NR) at baseline and 79.5 (95% CI, NR) at follow-up. An increase in the mean physical functioning score was reported (P = 0.008); the mean score was 79.7 (95% CI, NR) at baseline and 90.0 (95% CI, NR) at follow-up. An increase in the mean role functioning score was reported (P = 0.006); the mean score was 62.7 (95% CI, NR) at baseline and 90.3 (95% CI, NR) at follow-up. An increase in the mean emotional functioning score was reported (P = 0.002); the mean score was 74.1 (95% CI, NR) at baseline and 84.5 (95% CI, NR) at follow-up. An increase in the mean social functioning score was reported (P = 0.047); the mean score was 77.3 (95% CI, NR) at baseline and 85.6 (95% CI, NR) at follow-up. A decrease in the mean fatigue symptom score was reported (P = 0.02); the mean score was 27.3 (95% CI, NR) at baseline and 17.2 (95% CI, NR) at follow-up. The difference in change from baseline in the mean scores on the remaining functional and symptom scales were not considered statistically significant.

Nausea, vomiting, and pain were reported in 22 (17.6%), 6 (4.8%), and 10 (8.0%) of the 125 cycles administered in total, respectively. Toxicity was defined according to the CTCAE 4.03 criteria. Grade 3 anemia and grade 3 thrombocytopenia were reported in 1 (2.9%) patient each, and grade 3 leukopenia was reported in 3 (8.8%) patients. Hormonal crisis, which was defined as an acute complication of hormonal secretion following treatment with ¹⁷⁷Lu oxodotreotide and requiring medical care, was reported in 3 (8.8%) patients and late toxicity with myelodysplastic syndrome was reported in 1 (2.9%) patient.

There were several reasons that patients did not receive the intended cumulative activity of 29.6 GBq ¹⁷⁷Lu oxodotreotide. A reduced cumulative activity of 18.5 to 25.9 GBq ¹⁷⁷Lu oxodotreotide was administered in 5 (14.7%) patients due to hepatotoxicity. Only 1 cycle was administered in 3 (8.8%) patients each due to noncompliance, unexplained progressive cognitive decline, and patient withdrawal. Only 3 cycles were provided to 1 (2.9%) patient due to clinical progression, and the last patient case was not reported.

Critical Appraisal

In the absence of an active comparator or placebo group, the interpretation of the efficacy and safety results from the 3 non-comparative observational studies^8-10 is limited. The interpretation of treatment benefit is further limited by the retrospective nonrandomized study design and a relatively small sample size. This is compounded by the relatively large number of patients who were excluded from the analysis due to their incomplete questionnaires as indicated in the study conducted by Marinova et al. (2018).⁹ However, the clinical experts consulted by CADTH indicated that patients with NETs in general were rare, and Zandee et al. (2019)¹⁰ also indicated that pNETs were rare. Although treatment with ¹⁷⁷Lu oxodotreotide can be ascertained by the use of hospital records, data were sourced from 1 hospital in either Sweden,⁸ Germany,⁹ or Netherlands¹⁰ and retrospectively analyzed. The use of a single source for the recruitment of patients may introduce the risk of selection bias, because patients under the care of 1 team may share common characteristics, including treatment history, disease severity, and level of supportive care, which can bias the estimation of treatment effect and limit the external validity of the results. Notably, the place of ¹⁷⁷Lu oxodotreotide in the treatment sequence varied within the cohort and was preceded by various therapies, which the clinical experts suggested can bias the median OS. Marinova et al. (2018)⁹ indicated that they used the validated German version of EORTC QLQ-C30 but did not identify a clinically meaningful difference; Zandee et al. (2019)¹⁰ also did not identify a clinically meaningful difference. Although patients did not undergo further therapies after treatment with ¹⁷⁷Lu oxodotreotide and follow-up,⁹ it was unclear whether patients received any concomitant therapy that could bias the reporting on the HRQoL questionnaire.

A number of baseline characteristics of the cohorts in the studies, specifically the mean age,^8-10 proportion of patients with liver metastases,^8,10 and the proportion of patients with an ECOG status of 0,^8,9 were similar to those of the NETTER-R⁵ study, which the clinical experts consulted by CADTH suggested were representative of patients seen in clinical practice in Canada. (A detailed description of the patient population in NETTER-R is presented in the Systematic Review section.) The retrospective studies included patients with experience with various treatments; therefore, ¹⁷⁷Lu oxodotreotide was in various lines in the treatment sequence, preceded by different therapies. Only 56.9%, 36.8%, and 64.7% of patients received an SSA before treatment with ¹⁷⁷Lu oxodotreotide in the study conducted by Fröss-Baron et al. (2021),⁸ Marinova et al. (2018),⁹ and Zandee et al. (2019),¹⁰ respectively, and thus match the reimbursement request for this review. Further, the number of cycles administered and the intervals between the cycles, such as the application of the dosimetry-guided protocol⁸ and the use of 3-month intervals,⁹ varied among studies. Last, Zandee et al. (2019)¹⁰ included patients with functional pNETs, specifically patients with insulinoma, glucagonoma, gastrinoma, and VIPoma, but did not include patients with nonfunctional pNETs.

Discussion

Summary of Available Evidence

One non-interventional, non-comparative, post-authorization retrospective registry study (N = 110) (NETTER-R),⁵ 1 sponsor-provided ITC,²² 1 published ITC,⁷ and 3 studies providing supplemental information (Fröss-Baron et al. (2021)⁸ [N = 102], Marinova et al. (2018)⁹ [N = 68], and Zandee et al. (2019)¹⁰ [N = 34]) contributed evidence to this report. Patients assessed in the NETTER-R study included those with SSR-positive, unresectable or metastatic, well-differentiated pNETs who had progressive disease and were treated with ¹⁷⁷Lu oxodotreotide. Patients were not eligible if they were diagnosed with NETs of other origins. The primary end point was PFS. The study by Fröss-Baron et al. (2021)⁸ was a retrospective study that assessed the efficacy and safety of ¹⁷⁷Lu oxodotreotide in patients in Sweden with metastatic and/or locally advanced pNETs, who had been previously treated with chemotherapy. The study by Marinova et al. (2018)⁹ was a retrospective analysis assessing the change in HRQoL and symptom burden in German patients with pNETs who had been treated with ¹⁷⁷Lu oxodotreotide. The study by Zandee et al. (2019)¹⁰ was a retrospective analysis of efficacy and safety of patients in the Netherlands with pNETs treated with ¹⁷⁷Lu oxodotreotide.

Patients included in the NETTER-R study had a mean age of 58 years (||||||||; range, 28.0 to 89.0 years), with relatively equal proportions of males (53%) and females (47%). |||| of patients were white (|||). The primary sites of metastases before the patients started treatment with ¹⁷⁷Lu oxodotreotide were the liver (96%), lymph nodes (43%), bone (29%), and lungs (4%). The liver tumour burden was from 10% to 25% in 29% of patients and more than 25% or more than 2 metastatic organs in 36%. More than half of patients had nonfunctional tumours (57%), 30% of patients had functional tumour status, and the remainder lacked assessment of tumour functionality (11%). Most patients had inoperable tumours (75%). Most patients had a Ki-67 index of 3% to 20% (66%), and 24% had a Ki-67 index of 2% or less. Most had a histopathological intermediate (grade 2; 65%) or low (grade 1; 27%) grade of disease. The. Of patients with ECOG PS assessed, most had an ECOG PS of 0 (|||) or 1 (|||).⁵ Most patients completed a standard regimen of ¹⁷⁷Lu oxodotreotide.

Interpretation of Results

Efficacy

The NETTER-R study demonstrated a median OS of 41.4 months (95% CI, 28.6 to 50.2), and a median PFS of 24.8 months (95% CI, 17.5 to 34.5). Due to the nature of the study, all statistical analyses of the NETTER-R study were considered descriptive. In addition, the NETTER-R study lacked a comparative group. The lack of formal statistical analyses and a comparator group introduces difficulty in interpreting the efficacy of ¹⁷⁷Lu oxodotreotide and ascribing the latter as the causal factor for the observed outcomes. The clinical experts consulted by CADTH for this review confirmed that the PFS and OS observed in the NETTER-R study were clinically meaningful. While the interpretability of results of the NETTER-R is limited, the clinical experts commented that the observed PFS and OS were impressive and longer than those expected for patients with pNETs not treated with ¹⁷⁷Lu oxodotreotide. While there is no comparator group, the clinical experts commented that OS and PFS of patients in Canada treated with regimens currently available in clinical practice are not as long as what is suggested with treatment with ¹⁷⁷Lu oxodotreotide, based on results of the NETTER-R study. The clinical experts also commented that other secondary end points of the NETTER-R study, including ORR, DOR, and TTP, were also clinically meaningful.

The NETTER-1 study was considered the pivotal trial in the previous CADTH review of ¹⁷⁷Lu oxodotreotide; NETTER-1 compared ¹⁷⁷Lu oxodotreotide to high-dose long-acting octreotide. As patients with pNETs were not included in the NETTER-1 study, they were excluded from the reimbursement recommendation issued by CADTH. To address this gap, the sponsor submitted evidence based on the NETTER-R post-marketing study. Only patients with GI-NETs, specifically of the midgut, were included in the NETTER-1 trial. The primary end point of the NETTER-1 trial was PFS, and a secondary end point was OS. At the time of the initial CADTH review, the median PFS and OS were not reached in patients who received ¹⁷⁷Lu oxodotreotide in the NETTER-1 trial. Results of the final analysis of the NETTER-1 trial were based on a median follow-up of more than 76 months. The median OS was 48.0 months (95% CI, 37.4 to 55.2) in the ¹⁷⁷Lu oxodotreotide group compared to 36.3 months (95% CI, 25.9 to 51.7) in the control group (HR = 0.84; 95% CI, 0.60 to 1.17; unstratified 2-sided log-rank P value = 0.30).^24,25 OS results can be considered numerically similar in NETTER-1 and NETTER-R studies, although it is impossible to directly compare these populations and studies, and results are associated with serious imprecision, as demonstrated by the wide 95% CI. Both studies have limitations, such as subsequent treatments affecting analysis of OS, that introduce complexities when interpreting efficacy data, in particular for patients with pNETs in the NETTER-R study.

Everolimus and sunitinib were identified as relevant comparators for patients in Canada with pNETs. However, as mentioned, the NETTER-R study was a single-group study. The sponsor-provided indirect comparative evidence through MAICs that compared ¹⁷⁷Lu oxodotreotide to everolimus and sunitinib for PFS and OS. Additional published indirect evidence was also found in the literature. Khan et al. (2021)⁷ conducted similar analyses using MAICs to compare ¹⁷⁷Lu oxodotreotide to everolimus and sunitinib for PFS and OS. Both sets of MAICs favoured treatment with ¹⁷⁷Lu oxodotreotide over sunitinib and everolimus in terms of PFS. The sponsor’s MAIC in terms of OS did not achieve statistical significant differences between ¹⁷⁷Lu oxodotreotide and everolimus or sunitinib, while MAICs published by Khan et al. (2021)⁷ did suggest greater improvement with ¹⁷⁷Lu oxodotreotide over both everolimus and sunitinib. This may be explained by the use of different studies for the ¹⁷⁷Lu oxodotreotide arms of the MAICs (the NETTER-R study for the sponsor’s ITC, and the ERASMUS study for the published ITC). Nevertheless, both the sponsor-provided and published MAICs faced similar limitations, which may have affected the validity of the results, including potential residual confounding and reduced sample sizes from matching. In particular for OS, the sponsor-provided MAICs and the published MAICs included the RADIANT-3 and NCT00428597 studies, which reported immature OS data. Therefore, all sets of indirect comparisons were faced with limitations, which introduce considerable uncertainty in the evidence comparing ¹⁷⁷Lu oxodotreotide to everolimus and sunitinib.

Capecitabine plus temozolomide was also considered a relevant comparator, according to the clinical experts consulted by CADTH, but was not included in an ITC. Therefore, the relative efficacy and safety of ¹⁷⁷Lu oxodotreotide versus this drug combination is unknown.

HRQoL was considered an important outcome for patients by clinician and patient groups who provided input, as well as clinicians consulted by CADTH for this review. HRQoL results were not available for the NETTER-R study. Based on the analysis conducted by Marinova et al. (2018),⁹ there was improvement in HRQoL from baseline to 3 months’ follow-up after the last cycle of treatment with ¹⁷⁷Lu oxodotreotide. There was a statistically significant increase in the Global Health Status and the mean social functioning score. However, there was a statistically significant decrease in the mean fatigue symptom score and mean appetite loss symptom score. The authors also reported significant improvement in diarrhea and dyspnea symptoms in patients with functional pNETs versus patients with nonfunctional pNETs.⁹ In the study by Zandee et al. (2019)¹⁰ in 22 patients, HRQoL was also assessed using the EORTC QLQ-C30. The authors reported an increase in the mean Global Health Score (P = 0.002), which is in line with results from the study by Marinova et al. (2018).⁹ The patient group (CNETS) highlighted diarrhea and fatigue as important symptoms to control, because they have a negative impact on patients’ quality of life. These symptoms were also included as notable harms in the CADTH systematic literature review protocol. There are limitations to these studies, including a retrospective design with analyses that are likely underpowered and descriptive. The HRQoL results of the studies by Marinova et al. (2018)⁹ and Zandee et al. (2019)¹⁰ align with the efficacy analyses of the NETTER-R study, which demonstrate longer PFS and OS for patients with pNETs than might be expected with other treatments, according to clinical experts consulted by CADTH for this review.

As mentioned in the Critical Appraisal section for the NETTER-R study, it is unlikely that the sponsor could have conducted a randomized study in patients with pNETs who had received prior therapy, because patients may be hesitant to agree to receive an alternative therapy to PRRT. In addition, ¹⁷⁷Lu oxodotreotide is used in Europe, Australia, and the US on the basis of results from the NETTER-1 study that were extrapolated to patients with pNETs. The NETTER-1 study did not enrol patients with pNETs but enrolled patients with other types of GEPNETs. The clinical experts consulted by CADTH for this review suggested that the division between pNETs and non-pNETs may not be an important consideration. While pNETs tend to be more aggressive and have a poorer survival outlook compared to other NETs, the clinical experts suggested that there is little basis for treatment with ¹⁷⁷Lu oxodotreotide in patients with pNETs to differ from treatment for patients with other NETs. Overall, the clinical experts endorsed that ¹⁷⁷Lu oxodotreotide would be efficacious in patients with pNETs.

Harms

The dose intensity of ¹⁷⁷Lu oxodotreotide in the NETTER-R study suggested that most patients received all 4 doses (70%) of ¹⁷⁷Lu oxodotreotide and that most patients could tolerate near the full dose of ¹⁷⁷Lu oxodotreotide. The average dose per administration of ¹⁷⁷Lu oxodotreotide was 199.8 mCi (SD = 15.80), which is in line with a standard dose of ¹⁷⁷Lu oxodotreotide, at 200 mCi ± 10%. The clinical experts consulted by CADTH, as well as the clinician groups providing input for this review, reported that clinicians and patients generally agree that the toxicity of ¹⁷⁷Lu oxodotreotide is tolerable. As most patients in the NETTER-R study could receive most doses of ¹⁷⁷Lu oxodotreotide, and few discontinued due to AEs, there is evidence that the tolerability of ¹⁷⁷Lu oxodotreotide is high. Input from the patient group also reported that, among 33 patients who had received ¹⁷⁷Lu oxodotreotide, they found that side effects of treatment were manageable and less debilitating, with a quicker recovery time, than standard therapies for pNETs.

Notable harms included in the CADTH systematic review protocol, in consultation with clinical experts, included myelotoxicity, renal toxicity, transformation to leukemia, nausea and/or vomiting, and fatigue. Input from the patient group reported that side effects from ¹⁷⁷Lu oxodotreotide included fatigue, nausea and vomiting, diarrhea, and pain. While there is no comparator group in the NETTER-R study to provide a relative toxicity profile, the NETTER-R study did report nausea (28%), fatigue (23%), abdominal pain (16%), vomiting (|||), upper abdominal pain (|||), and anemia (|||) as the most commonly reported AEs, supporting input provided by the patient group. Hematological toxicities were also reported in 26% of patients. Renal toxicities were highlighted as being of concern for patients with pNETs, although the NETTER-R study reported few patients with renal toxicities (6%). No patients had a secondary transformation to leukemia or MDS. The clinical experts consulted by CADTH for this review stated that the lack of secondary hematological malignancies was unexpected, as this is a harm typically noted among this patient population, but the outcome is possible and may further indicate the favourable toxicity profile of ¹⁷⁷Lu oxodotreotide.

Neither ITCs reviewed in this report conducted analyses for safety. Therefore, the toxicity profile of ¹⁷⁷Lu oxodotreotide relative to everolimus and sunitinib is not known.

Conclusions

The NETTER-R study was provided in this reassessment of ¹⁷⁷Lu oxodotreotide for treatment of patients with pNETs. The previous recommendation for ¹⁷⁷Lu oxodotreotide did not support use for patients with pNETs because they were excluded from the pivotal NETTER-1 study. Due to the small sample size, lack of comparator group, retrospective design, and missing data, the results of the NETTER-R study are difficult to interpret and cannot be used to draw firm conclusions about the relative benefits of ¹⁷⁷Lu oxodotreotide in the treatment of pNETs. Evidence from other observational studies by Fröss-Baron et al. (2021),⁸ Marinova et al. (2018),⁹ and Zandee et al. (2019)¹⁰ were largely consistent with NETTER-R but were associated with the same level of uncertainty. Indirect evidence available from the sponsor and the literature provided comparative results between ¹⁷⁷Lu oxodotreotide with everolimus and sunitinib and suggested improved efficacy of ¹⁷⁷Lu oxodotreotide over everolimus and sunitinib. The indirect evidence had methodological limitations that introduced uncertainty in the interpretation of the comparative data. Based on the totality of the evidence and their experience treating patients with pNETs, clinical experts agreed that ¹⁷⁷Lu oxodotreotide would be a safe and effective regimen, preferred over everolimus or sunitinib. Direct comparative evidence may help reduce uncertainty and inform whether ¹⁷⁷Lu oxodotreotide would be beneficial for patients with pNETs.

References

1.Cives M, Strosberg JR. Gastroenteropancreatic Neuroendocrine Tumors. CA Cancer J Clin. 2018;68(6):471-487. PubMed

2.Das S, Al-Toubah T, El-Haddad G, Strosberg J. (177)Lu-DOTATATE for the treatment of gastroenteropancreatic neuroendocrine tumors. Expert Rev Gastroenterol Hepatol. 2019;13(11):1023-1031. PubMed

3.Dasari A, Shen C, Halperin D, et al. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With Neuroendocrine Tumors in the United States. JAMA Oncol. 2017;3(10):1335-1342. PubMed

4.Drug Reimbursement Review sponsor submission: Lutathera (lutetium (177Lu) oxodotreotide), 370 mMBq/mL at calibration [internal sponsor's package]. Mississauga (ON): Advanced Accelerator Applications Canada Inc.; 2022 Apr 1.

5.Clinical Study Report: A-LUT-T-E01-401/CAAA601A12401. An international, non-interventional, post-authorization retrospective registry of subjects treated with Lutathera (lutetium (177Lu) oxodotreotide), to assess the efficacy and safety of Lutathera for the treatment of pancreatic neuroendocrine tumors (pNETS) - NETTER-R [internal sponsor's report]. Basel (CH): Advanced Accelerator Applications; 2020 Jun 1.

6.Advanced Accelerator Applications response to May 25, 2022 DRR request for additional information regarding Lutathera DRR review [internal additional sponsor's information]. Toronto (ON): Advanced Accelerator Applications; 2022.

7.Khan MS, Stamp E, Sammon C, Brabander T, de Herder WW, Pavel ME. Matching-adjusted indirect treatment comparison of [(177)Lu]Lu-DOTA-TATE, everolimus and sunitinib in advanced, unresectable gastroenteropancreatic neuroendocrine tumours: Relative effectiveness of [(177)Lu]Lu-DOTA-TATE in gastroenteropancreatic neuroendocrine tumours. EJC Suppl. 2021;16:5-13. PubMed

8.Fross-Baron K, Garske-Roman U, Welin S, et al. 177Lu-DOTATATE Therapy of Advanced Pancreatic Neuroendocrine Tumors Heavily Pretreated with Chemotherapy: Analysis of Outcome, Safety, and Their Determinants. Neuroendocrinology. 2021;111(4):330-343. PubMed

9.Marinova M, Mucke M, Mahlberg L, et al. Improving quality of life in patients with pancreatic neuroendocrine tumor following peptide receptor radionuclide therapy assessed by EORTC QLQ-C30. Eur J Nucl Med Mol Imaging. 2018;45(1):38-46. PubMed

10.Zandee WT, Brabander T, Blazevic A, et al. Symptomatic and Radiological Response to 177Lu-DOTATATE for the Treatment of Functioning Pancreatic Neuroendocrine Tumors. J Clin Endocrinol Metab. 2019;104(4):1336-1344. PubMed

11.Clift AK, Kidd M, Bodei L, et al. Neuroendocrine Neoplasms of the Small Bowel and Pancreas. Neuroendocrinology. 2020;110(6):444-476. PubMed

12.Ito T, Igarashi H, Jensen RT. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res Clin Gastroenterol. 2012;26(6):737-753. PubMed

13.Lutathera® (lutetium [177Lu] oxodotreotide): Sterile Solution for Intravenous Infusion 370 MBq/mL at calibration [product monograph]. Milburn (NJ): Advanced Accelerator Applications USA, Inc.; 2021 May 13.

14.Afinitor Disperz (everolimus): tablets for oral suspension, 2 mg, 3 mg and 5 mg, oral [product monograph]. Dorval (QC): Novartis Pharmaceuticals Canada Inc.; 2021 Nov 30: https://www.ask.novartispharma.ca/download.htm?res=afinitor_scrip_e.pdf&resTitleId=705#:~:text=AFINITOR%C2%AE%20(everolimus)%20is%20indicated%20for%3A&text=the%20treatment%20of%20postmenopausal%20women,treatment%20with%20letrozole%20or%20anastrozole. Accessed 2022 Apr 22.

15.Sutent (sunitinib capsules): 12.5 mg, 25 mg, 37.5§ mg, 50 mg sunitinib per capsule (as sunitinib malate) [product monograph]. Kirkland (QC): Pfizer Canada ULC; 2019 Jul 11: https://www.pfizer.ca/sites/default/files/201908/SUTENT_PM_DC_E_226908_11July2019.pdf. Accessed 2022 Apr 22.

16.Temodal (temozolomide): 5 mg, 20 mg, 100 mg, 140 mg and 250 mg capsules [product monograph]. Kirkland (QC): Merck Canada Inc.; 2017 Jun 23: https://pdf.hres.ca/dpd_pm/00039947.PDF Accessed 2022 Apr 21.

17.Xeloda (capecitabine tablets): tablets 150 mg and 500 mg [product monograph]. Mississauga (ON): Hoffmann-La Roche Limited; 2022 Apr 4: https://www.rochecanada.com/PMs/Xeloda/Xeloda_PM_E.pdf. Accessed 2022 Apr 21.

18.Del Prete M, Buteau FA, Arsenault F, et al. Personalized (177)Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: initial results from the P-PRRT trial. Eur J Nucl Med Mol Imaging. 2019;46(3):728-742. PubMed

19.McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V, Lefebvre C. PRESS Peer Review of Electronic Search Strategies: 2015 guideline statement. J Clin Epidemiol. 2016;75:40-46. PubMed

20.Grey matters: a practical tool for searching health-related grey literature. Ottawa (ON): CADTH; 2019: https://www.cadth.ca/grey-matters. Accessed 2022 Apr 21.

21.Clement D, Navalkissoor S, Srirajaskanthan R, et al. Efficacy and safety of (177)LuDOTATATE in patients with advanced pancreatic neuroendocrine tumours: data from the NETTER-R international, retrospective study. Eur J Nucl Med Mol Imaging. 2022;07:07.

22.A matching adjusted indirect comparison of Lutathera, everolimus and sunitinib in conjunction with the treatment of pancreatic neuroendocrine tumours (P-NETs) [internal sponsor's report]. In: Drug Reimbursement Review sponsor submission: Lutathera, 370 MBq/mL, IV. Toronto (Ontario): Advanced Accelerator Applications; 2022 January 24.

23.Signorovitch JE, Wu EQ, Yu AP, et al. Comparative effectiveness without head-to-head trials: a method for matching-adjusted indirect comparisons applied to psoriasis treatment with adalimumab or etanercept. Pharmacoeconomics. 2010;28(10):935-945. PubMed

24.Strosberg JR, Caplin ME, Kunz PL, et al. Final overall survival in the phase 3 NETTER-1 study of lutetium-177-DOTATATE in patients with midgut neuroendocrine tumors. J Clin Oncol. 2021;39(15_suppl):4112-4112.

25.Strosberg JR, Caplin ME, Kunz PL, et al. 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22(12):1752-1763. PubMed

Appendix 1: Literature Search Strategy

Note that this appendix has not been copy-edited.

Clinical Literature Search

Overview

Interface: Ovid

Databases:

• MEDLINE All (1946-present)

• Embase (1974-present)

Note: Subject headings and search fields have been customized for each database. Duplicates between databases were removed in Ovid.

Date of search: April 21, 2022

Alerts: Bi-weekly search updates until project completion

Search filters applied: No filters were applied to limit the retrieval by study type.

Limits:

• Humans

• Conference abstracts: excluded

Table 26: Syntax Guide

Multi-Database Strategy

1. (Lutathera* or lutate or AE221IM3BB or 177Lu-dota* or 177Ludota* or 177Lutetium).ti,ab,kf,ot,hw,nm,rn.

2. ((177* or 177-Lu* or 177Lu* or Lu-177* or Lu177* or 177lutetium* or 177-lutetium* or Lu) adj5 (octreotate or dota-tate or dotatate or ludotatate or oxodotreotide)).ti,ab,kf,ot,hw,nm,rn.

3. ((177* or 177-Lu* or 177Lu* or Lu-177* or Lu177*) adj5 lutetium*).ti,ab,kf,ot,hw,nm,rn.

4. or/1-3

5. (exp Neuroendocrine tumors/ and ((pancreat* or pancreas* or GEP-NET? or GEPNET? or P-NET? or PNET? or gastroenteropancreatic* or islet or foregut or fore-gut or midgut or mid-gut or hindgut or hind-gut).ti,ab,kf. or exp pancreas/)) or exp Pancreatic Neoplasms/

6. ((alpha cell or beta cell or diarrheogenic or foregut or fore-gut or midgut or mid-gut or hindgut or hind-gut or gastroenteropancreatic* or pancreat* or pancreas* or islet) adj3 (adenoma? or argentaffinoma* or cancer* or carcinoid* or carcinoma? or gastrinoma? or malignanc* or neoplas* or neoplasm* or NET or NETs or paraganglioma* or polypeptidoma or sarcoma* or tumor* or tumour*)).ti,ab,kf.

7. ((endocrine adj2 neoplasia*) or glucagonoma? or insulinoma* or MEN1 or P-NET? or PNET? or GEP-NET? or GEPNET? or somatostatinoma* or Verner-Morrison or VIPoma* or (Wermer adj2 Syndrome) or Zolinger-Ellison).ti,ab,kf.

8. or/5-7

9. 4 and 8

10. 9 use medall

11. *oxodotreotide lutetium lu 177/

12. (Lutathera* or lutate or AE221IM3BB or 177Lu-dota* or 177Ludota* or 177Lutetium).ti,ab,kf,dq.

13. ((177* or 177-Lu* or 177Lu* or Lu-177* or Lu177* or 177lutetium* or 177-lutetium* or Lu) adj5 (octreotate or dota-tate or dotatate or ludotatate or oxodotreotide)).ti,ab,kf,dq.

14. ((177* or 177-Lu* or 177Lu* or Lu-177* or Lu177*) adj5 lutetium*).ti,ab,kf,dq.

15. or/11-14

16. exp gastroenteropancreatic neuroendocrine tumor/ or exp pancreas cancer/ or exp pancreas disease/

17. ((alpha cell or beta cell or diarrheogenic or foregut or fore-gut or midgut or mid-gut or hindgut or hind-gut or gastroenteropancreatic* or pancreat* or pancreas* or islet) adj3 (adenoma? or argentaffinoma* or cancer* or carcinoid* or carcinoma? or gastrinoma? or malignanc* or neoplas* or neoplasm* or NET or NETs or paraganglioma* or polypeptidoma or sarcoma* or tumor* or tumour*)).ti,ab,kf,dq.

18. ((endocrine adj2 neoplasia*) or glucagonoma? or insulinoma* or MEN1 or P-NET? or PNET? or GEP-NET? or GEPNET? or somatostatinoma* or Verner-Morrison or VIPoma* or (Wermer adj2 Syndrome) or Zolinger-Ellison).ti,ab,kf,dq.

19. or/16-18

20. 15 and 19

21. 20 use oemezd

22. (conference review or conference abstract).pt.

23. 21 not 22

24. 10 or 23

25. exp animals/

26. exp animal experimentation/ or exp animal experiment/

27. exp models animal/

28. nonhuman/

29. exp vertebrate/ or exp vertebrates/

30. or/25-29

31. exp humans/

32. exp human experimentation/ or exp human experiment/

33. or/31-32

34. 30 not 33

35. 24 not 34

36. remove duplicates from 35

Clinical Trials Registries

ClinicalTrials.gov

Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.

• [Search -- Studies with results | lutathera, lutetium, 177 Lu]

WHO ICTRP

International Clinical Trials Registry Platform, produced by the WHO. Targeted search used to capture registered clinical trials.

• [Search terms -- lutathera, lutetium, 177 Lu]

Health Canada’s Clinical Trials Database

Produced by Health Canada. Targeted search used to capture registered clinical trials.

• [Search terms -- lutathera, lutetium, 177 Lu]

EU Clinical Trials Register

European Union Clinical Trials Register, produced by the European Union. Targeted search used to capture registered clinical trials.

• [Search terms -- lutathera, lutetium, 177 Lu]

Grey Literature

Search dates: April 8, 2022, to April 14, 2022

Keywords: lutathera, lutetium, 177 Lu, P-NETs, pancreatic neuroendocrine tumour*

Limits: none

Updated: Search updated before the meeting of CADTH pan-Canadian Oncology Drug Review Expert Committee (pERC).

Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool for Searching Health-Related Grey Literature were searched:

• Health Technology Assessment Agencies

• Health Economics

• Clinical Practice Guidelines

• Drug and Device Regulatory Approvals

• Advisories and Warnings

• Drug Class Reviews

• Clinical Trials Registries

• Databases (free)

• Health Statistics

• Internet Search

• Open Access Journals

Appendix 2: Excluded Studies

Note that this appendix has not been copy-edited.

Table 27: Excluded Studies

Appendix 3: Detailed Outcome Data

Note that this appendix has not been copy-edited.

Figure 20: Kaplan-Meier Plot of Progression-Free Survival — RECIST 1.1 — Sensitivity Analysis Patients With Post-Baseline Scan per RECIST 1.1 in Modified FAS — Redacted

Figure contained confidential information and was removed at the request of the sponsor.

Source: NETTER-R Clinical Study Report.⁵

Table 28: PFS — RECIST 1.1 (Sensitivity Analysis) (Patients With Post-Baseline Scan per RECIST 1.1 in Modified FAS)

^aEstimated by the Kaplan-Meier method.

Note: Long-time elapsed missing assessments is defined as more than 9 months after the last radiological assessment (i.e., 270 days following the previous visit).

Subgroup Analysis for OS

Risk factors for PRRT were also assessed, but were inconsistently reported for some patients. The sponsor reported that the drug category was at times incorrectly understood including SSAs or protein kinase inhibitor (PKI) treatments as “chemotherapy.” Therefore, results for subgroup analyses related to risk factors for PRRT are not reported in this CADTH report.

Table 29: Subgroup Analyses for OS (FAS)

NE = not estimable; OS = overall survival.

Source: NETTER-R Clinical Study Report.⁵

Subgroup Analysis for PFS

Risk factors for PRRT were also assessed, but were inconsistently reported for some patients. The sponsor reported that the drug category was at times incorrectly understood including SSAs or PKI treatments as “chemotherapy.” Therefore, results for subgroup analyses related to risk factors for PRRT are not reported in this CADTH report.

Table 30: Subgroup Analyses for PFS

FAS = full analysis set; NE = not estimable; PFS = progression-free survival.

Source: NETTER-R Clinical Study Report.⁵

Subgroup Analysis for ORR

Risk factors for PRRT were also assessed, but were inconsistently reported for some patients. The sponsor reported that the drug category was at times incorrectly understood including SSAs or PKI treatments as “chemotherapy.” Therefore, results for subgroup analyses related to risk factors for PRRT are not reported in this CADTH report.

Table 31: Subgroup Analyses for ORR

FAS = full analysis set; NE = not estimable; ORR = objective response rate.

Source: NETTER-R Clinical Study Report.⁵

Pharmacoeconomic Review

Executive Summary

The executive summary comprises 2 tables (Table 1 and Table 2) and a conclusion.

Table 1: Submitted for Review

NOC = Notice of Compliance.

Table 2: Summary of Economic Evaluation

¹⁷⁷Lu = lutetium-177; AE = adverse event; ICER = incremental cost-effectiveness ratio; ITC = indirect treatment comparison; LY = life-year; PFS = progression-free survival; MAIC = matching-adjusted indirect comparison; OS = overall survival; QALY = quality-adjusted life-year; RDI = relative dose intensity; WTP = willingness to pay.

Conclusions

There has been no head-to-head evidence comparing lutetium-177 (¹⁷⁷Lu) oxodotreotide to everolimus or sunitinib. Therefore, the sponsor used unanchored matching-adjusted indirect comparisons (MAICs) alongside the NETTER-R study, which was a retrospective single-group study. The clinical report found that the NETTER-R study, due to various limitations and missing data, had results that were difficult to interpret and that cannot be used to draw firm conclusions about the relative benefits of ¹⁷⁷Lu in the treatment of pancreatic neuroendocrine tumours (pNETs). The sponsor’s MAICs suggested that ¹⁷⁷Lu oxodotreotide was associated with improved progression-free survival (PFS) but comparable overall survival (OS) compared to everolimus or sunitinib. However, the sponsor-submitted indirect treatment comparisons (ITCs) had limitations that may affect the validity and increase the uncertainty of the study results.

CADTH identified several key limitations of the sponsor’s economic analyses, in particular, the lack of robust evidence on the comparative clinical efficacy of ¹⁷⁷Lu oxodotreotide, the uncertainty associated with long-term benefits of ¹⁷⁷Lu oxodotreotide, and the incorrect estimation of ¹⁷⁷Lu oxodotreotide and comparator costs and quality-adjusted life-years (QALYs). Due to the methodological concerns about the NETTER-R study and the submitted ITCs, the comparative clinical effects of ¹⁷⁷Lu oxodotreotide are highly uncertain. As a result, CADTH was unable to conduct a base case and instead carried out exploratory reanalyses.

In CADTH’s reanalyses, the acquisition and administration costs of octreotide long-acting release 30 mg were corrected to reflect the ¹⁷⁷Lu oxodotreotide product monograph. For the comparison with sunitinib, CADTH also replaced the unit cost of sunitinib with the publicly available drug price. For both reanalyses, CADTH assumed the same proportion of patients requiring octreotide long-acting release and a single set of health utility values across comparators; CADTH applied health utility decrements due to adverse events (AEs) during treatment duration; CADTH used the median treatment duration to calculate drug acquisition and AE costs of comparators; and CADTH used alternative parametric survival models to predict OS curves.

In CADTH’s reanalyses, the incremental cost-effectiveness ratio (ICER) for ¹⁷⁷Lu oxodotreotide compared with everolimus was $120,931 per QALY. A price reduction of at least 41% was required to make ¹⁷⁷Lu oxodotreotide cost-effective at a willingness to pay (WTP) of $50,000 per QALY. Compared with sunitinib, the ICER for ¹⁷⁷Lu oxodotreotide was $466,632 per QALY, and a price reduction of at least 63% was required for ¹⁷⁷Lu oxodotreotide to be a cost-effective option.

Scenario analyses highlighted that assumptions on costing, treatment waning, and health utility values were key drivers of CADTH’s reanalyses for both comparators. CADTH was unable to address the uncertainty regarding the comparative clinical efficacy of ¹⁷⁷Lu oxodotreotide or the potential survival bias because of the sponsor’s model structure. In the absence of comparative clinical information, sequential analysis could not be conducted to determine the most cost-effective treatment option for the modelled population. As a result, greater price reductions may be required to ensure the cost-effectiveness of ¹⁷⁷Lu oxodotreotide.

Stakeholder Input Relevant to the Economic Review

This section is a summary of the feedback received from the patient groups, registered clinicians, and drug plans that participated in the CADTH review process—specifically, information that pertains to the economic submission.

Patient input, received from the Canadian Neuroendocrine Tumour Society, was collected through a survey of patients with neuroendocrine cancer (N = 57) in and outside of Canada from February 25, 2022, to March 25, 2022. The respondents included 21 patients with pNETs and 36 patients with gastrointestinal NETs. Patients reported symptoms that affected quality of life, including fatigue and weakness, diarrhea, side effects of surgery with ablation, pain, impaired cognitive ability, appetite changes, back pain, isolation, lack of energy, and inability to travel. Patients noted that NET negatively affects their quality of life and ability to work. Current treatments included somatostatin analogue (SSA) therapies (octreotide, lanreotide), surgery, peptide receptor radionuclide therapy (PRRT), liver-directed therapies (embolization), ablative techniques (radiofrequency ablation, cryotherapy), chemotherapy, radiation therapies, biologically targeted therapies (everolimus, sunitinib), and immunotherapies. These treatments have helped temporarily slow disease progression and control symptoms but have long recovery times, debilitating side effects, and complications. There is a need for therapies that cure disease or halt progression. Patients who had experience with the drug under review reported slower disease progression and tumour shrinkage. Almost half of these patients reported side effects such as increased fatigue, nausea and/or vomiting, diarrhea, and pain, which were generally considered tolerable.

Clinician input was received from a group comprised of researchers, specialists, and clinicians treating neuroendocrine cancer, collected via interviews with national and international clinicians, Drug Advisory Committee meetings, literature reviews of available evidence, and attendance at conferences. The input noted that current treatments available in Canada for patients with metastatic or unresectable disease include biologic therapy (SSAs such as octreotide, octreotide long-acting release, and lanreotide), targeted agents (everolimus and sunitinib), combination chemotherapy (capecitabine plus temozolomide regimen and platinum-based chemotherapy), and PRRT with ¹⁷⁷Lu oxodotreotide. Clinicians noted that the goal of treatment is to slow disease progression, prolong PFS, minimize treatment toxicities, reduce societal burden of disease, and control hormonal symptoms caused by insulinomas and severe gastritis. Clinicians noted ¹⁷⁷Lu oxodotreotide will be used to treat patients with unresectable or metastatic, well-differentiated, somatostatin receptor-positive gastroenteropancreatic NETs, including pNETs, who experience disease progression on currently available first-line therapies. ¹⁷⁷Lu oxodotreotide is not suitable for patients with octreotide non-avid disease, high-grade or poorly differentiated tumours, significant renal impairment or bone marrow dysfunction, or those who have previously received PRRT with no clinical benefit.

Drug plan input received for this review noted that relevant comparators may include sunitinib, everolimus, or combination temozolomide plus capecitabine. The plans indicated issues with therapy access and care provision, noting that administration of ¹⁷⁷Lu oxodotreotide is restricted to specialized centres that have the infrastructure to handle, prepare, administer, and dispose of lutetium safely. This may require patients to travel long distances to access treatment. The plans also noted that drug wastage is a concern, because ¹⁷⁷Lu oxodotreotide has a shelf life of 72 hours. Further, ¹⁷⁷Lu oxodotreotide may be used earlier in the treatment paradigm, and chosen over an SSA, if it is better tolerated.

Several of these concerns were addressed in the sponsor’s model:

• The sponsor included everolimus and sunitinib as comparators in the submitted economic evaluations. The comparative treatment efficacy for ¹⁷⁷Lu oxodotreotide and each comparator was derived using MAICs.

• The sponsor’s model considered the impact of ¹⁷⁷Lu oxodotreotide and comparators on progression, survival, and quality of life.

• The sponsor considered health care utilization and associated costs used to monitor pNETs. Costs and health utility decrements due to AEs were also accounted for in the sponsor’s model.

In addition, CADTH addressed some of these concerns:

• Drug wastage was considered by assuming a relative dose intensity (RDI) of 100% in a scenario analysis.

CADTH was unable to address the following concerns raised from stakeholder input:

• Cost-effectiveness of ¹⁷⁷Lu oxodotreotide compared to a combination of capecitabine plus temozolomide was unknown due to the lack of comparative efficacy data.

Economic Review

The current review is a reassessment for ¹⁷⁷Lu oxodotreotide (Lutathera), solely in the reimbursement request population, for the treatment of unresectable or metastatic, well-differentiated, somatostatin receptor-positive pNETs in adults whose disease has progressed after treatment with an SSA. The previous recommendation for ¹⁷⁷Lu did not support use for patients with pNETs, as they were excluded from the pivotal NETTER-1 study.

Economic Evaluation

Summary of Sponsor’s Economic Evaluation

Overview

The sponsor submitted 2 cost-utility analyses of ¹⁷⁷Lu oxodotreotide. In 1 analysis, the sponsor compared ¹⁷⁷Lu oxodotreotide with everolimus, and, in another analysis, the sponsor compared ¹⁷⁷Lu oxodotreotide with sunitinib. The modelled population was adult patients with unresectable or metastatic, well-differentiated, somatostatin receptor-positive pNETs whose disease has progressed after treatment with an SSA. The population was in line with the reimbursement request and representative of a subset of the Health Canada–approved indication.

¹⁷⁷Lu oxodotreotide is available as 370 MBq/mL in a single-dose vial (10 mCi/mL). According to the product monograph, the recommended dosage is 7.4 GBq (200 mCi) as an IV infusion over 30 minutes every 8 weeks for a total of 4 doses, administered on weeks 0, 8, 16, and 24. The cost of ¹⁷⁷Lu oxodotreotide is $35,000 per vial, equating to an average monthly cost of $23,333. The sponsor assumed a ||||| RDI in its drug cost calculation. The sponsor’s analysis also assumed a monthly cost of $4,823 for everolimus (91.3% RDI) and $5,470 for sunitinib (86% RDI).

The clinical outcomes were QALYs and life-years. The economic analysis was undertaken over a time horizon of 20 years from the perspective of a Canadian publicly funded health care system. Costs and QALYs were discounted at a rate of 1.5% per annum.

Model Structure

The sponsor used a partitioned survival model (PSM) with 3 health states: PFS, post-progression survival, and death (Appendix 3; Figure 1). The proportion of patients who were progression-free, who experienced post-progression, or who were dead at any time over the model horizon was derived from non-mutually exclusive survival curves. All patients entered in the PFS state and were assumed to receive treatments (¹⁷⁷Lu oxodotreotide, everolimus, or sunitinib). Patients could discontinue treatment but remain in the PFS health state until disease progression. At the end of each monthly cycle, the proportion of patients with post-progression survival or death was derived based on the area under the survival curves. Specifically, OS was partitioned to estimate the proportion of patients in the death state, while the PFS was used to estimate the proportion of patients in the PFS health state. The difference between the OS curve and PFS curve was partitioned at each time point to estimate the proportion of patients in the post-progression survival health state. Disease progression was determined by investigator assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criterion.^1,2

Model Inputs

The modelled population reflected the baseline patient characteristics of the enrolled population in the NETTER-R study, an international, retrospective, single-arm study of patients treated with ¹⁷⁷Lu oxodotreotide as per the European label in the UK, France, and Spain.^1,2 The sponsor’s model assumed a median age of 58 years and a median weight of 68.9 kg.

Transitions from the pre-progression health state to post-progression survival health state was informed by PFS curves obtained from the NETTER-R study. At baseline, 96.4% of patients had progressive disease. The median follow-up after the first cycle of ¹⁷⁷Lu oxodotreotide was 24.5 months (range = 2.0 to 123.4 months). The sponsor derived the relative treatment benefits of ¹⁷⁷Lu oxodotreotide versus each comparator from an unanchored MAIC, which used patient-level data obtained from the NETTER- R study and aggregated data from published relevant trials (RADIANT-3 study for everolimus and NCT00428597 for sunitinib).^3,4 Weighted Cox proportional hazards models were fitted to estimate hazard ratios (HRs), which were applied to PFS and OS of ¹⁷⁷Lu oxodotreotide predicted from the NETTER-R study. The joint parametric survival models were used to represent the relative PFS and OS benefits of ¹⁷⁷Lu oxodotreotide and each comparator.⁴ The gamma and exponential models were used to predict long-term PFS of ¹⁷⁷Lu oxodotreotide for the comparison with everolimus and sunitinib, respectively. A log-logistic model was used to predict OS of ¹⁷⁷Lu oxodotreotide for both everolimus and sunitinib comparisons.

The model accounted for AEs of grade 3 or higher. Health-state–specific utility values were assumed to be independent of treatments; however, the sponsor used different values and data sources for each analysis. For everolimus, the sponsor mapped European Organisation for Research and Treatment of Cancer – Quality of Life questionnaire (EORTC QLQ-C30) scores reported in the ERASMUS study to EQ-5D values; the utility values for pre-progression and post-progression health states were 0.800 (standard error [SE] = 0.081) and 0.790 (SE = 0.079), respectively.⁵ The ERASMUS study was a randomized controlled trial comparing the efficacy and safety of ¹⁷⁷Lu oxodotreotide in 1,214 progressed patients with gastroenteropancreatic NETs and bronchial NETs in the Netherlands.⁶ For sunitinib, the sponsor obtained utility values from a UK study that reviewed published literature and conducted in-depth interviews with patients and clinical experts to elicit utility values using a time trade-off (TTO) method for patients with NETs.⁷ According to this UK study, the utility values for pre-progression and post-progression health states were 0.768 (SE = 0.077) and 0.613 (SE = 0.061). The sponsor’s analyses adjusted utility decrements due to grade 3 or 4 AEs, which were obtained from the published literature.

Costs included drugs (acquisition and administration), monitoring, AEs, and palliative care. Drug acquisition costs for each treatment were sourced from the Ontario Drug Benefit formulary and published Canadian literature. Drug costs for ¹⁷⁷Lu oxodotreotide included the drug ingredient and supportive medications, which consisted of octreotide long-acting release 30 mg for up to a maximum of 24 months during pre-progression. The sponsor assumed that 10% of patients without and with disease progression may receive octreotide 30 mg subcutaneously for symptom management. This dosing regimen was validated by Canadian expert clinicians. Drug administration costs included costs of pharmacist preparation, chair time, hourly wages of pharmacist and nurse, and overhead facility costs. The sponsor further assumed that 5% of patients receiving ¹⁷⁷Lu oxodotreotide were admitted to a hospital. Resource utilization to monitor pNETs in the model was informed by the NETTER-1 trial and input from Canadian clinicians. The sponsor’s model assumed that all patients would receive octreotide 30 mg after disease progression. A palliative care cost was applied to patients who died. The cost estimate was obtained from a published cost-effectiveness of everolimus for the treatment of advanced NETs of gastrointestinal or lung origin in Canada, but this cost-effectiveness study did not provide a source for the palliative care cost.⁸

Summary of Sponsor’s Economic Evaluation Results

All analyses were run probabilistically with 2,000 iterations. Deterministic and probabilistic results were consistent for a comparison of ¹⁷⁷Lu oxodotreotide with everolimus but not for a comparison with sunitinib. CADTH noted that the probabilistic ICER of ¹⁷⁷Lu oxodotreotide compared to sunitinib was 22% lower than the deterministic ICER ($27,006 versus $34,791 per QALY). The probabilistic findings are presented in this section.

Base-Case Results

In the sponsor’s base-case analysis over a 20-year time horizon, ¹⁷⁷Lu oxodotreotide was associated with an ICER of $45,077 and $27,006 per QALY compared to everolimus and sunitinib, respectively (Table 3). At a WTP of $50,000 per QALY, the probability of ¹⁷⁷Lu oxodotreotide being cost-effective was 69.7% compared to everolimus and 73.9% compared to sunitinib.

The main cost drivers were parametric survival models for PFS and OS data prediction, followed by assumptions concerning the duration of therapy and the use of short- and long-acting octreotide. At the end of the model time horizon (i.e., 20 years), 8.4% of patients in the comparison of ¹⁷⁷Lu oxodotreotide and everolimus and 7.5% of patients in the comparison of ¹⁷⁷Lu oxodotreotide and sunitinib were still alive. A breakdown of the sponsor-submitted results for the base-case population by trial duration (i.e., 7 years) and extrapolated period shows that 42.4% of the expected QALY gains of ¹⁷⁷Lu oxodotreotide versus everolimus and 44.5% of the expected QALY gains of ¹⁷⁷Lu oxodotreotide versus sunitinib come from the time beyond the NETTER-R’s retrospective registry study period (i.e., 13 years).