CADTH Reimbursement Review

Selpercatinib (Retevmo)

Sponsor: Eli Lilly Canada Inc.

Therapeutic area: Thyroid cancer

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.

Introduction

Thyroid cancer is 1 of the most commonly diagnosed cancers in Canada and the world. It is considered the most common endocrine malignancy and the fifth most common cancer in women.^1,2 In 2020, the incidence of thyroid cancer in Canada was estimated to be 23 per 100,000 or about 8,600 new cases.³ Women are 3 times more at risk of having thyroid cancer than men.

Medullary thyroid cancer (MTC) is a less common type (1% to 2%) of thyroid cancer that originates from the parafollicular neuroendocrine cells of the thyroid (c cells) and is usually detected as a solitary thyroid nodule in patients in the fourth or sixth decade of life. Metastases to cervical lymph nodes is a common initial presentation; distant metastases can also occur. A common initial presentation is diarrhea, redness of the trunk and face skin (flushing), and an accompanying thyroid nodule. Of all MTC cases, approximately 75% are sporadic and 25% are hereditary. Of the sporadic cases, 50% will present somatic mutations in the rearranged during transfection (RET) proto-oncogene.⁴ Of the hereditary cases, almost all (98%) will present a germline RET mutation (inherited as autosomal dominant).⁵ Hereditary cases occur mostly in patients who have an inherited multiple endocrine neoplasia syndrome.^5,6 RET genetic analysis is recommended when the diagnosis of MTC has been established because it allows defining the sporadic or hereditary nature of MTC and thus can guide future diagnostic and therapeutic options and strategies. The prognosis of MTC is unfavourable, with a 10-year survival rate of approximately 50%⁴ and a 5-year survival rate varying from 62% to 87%, according to different epidemiological studies series.^7-10

Early diagnosis and total thyroidectomy with resection of local and regional metastases is the basis for initial treatment, plus subsequent hormone replacement with L-thyroxine.^4,6 The treatment goals in patients with MTC are aimed at improving survival, delaying disease progression, and improving health-related quality of life (HRQoL).¹¹ For patients with unresectable advanced or metastatic RET-mutant MTC — a condition with a very low cure rate — several targeted therapies have been used as first-line treatments,^4,11,12 such as cabozantinib¹³ and vandetanib,¹⁴ which have both shown improvement in progression-free survival (PFS).^13,14 Only vandetanib is approved and funded in Canada. After first-line treatments, patients can only continue using best supportive care (BSC) and, optionally, enter clinical trials.¹¹

Selpercatinib (Retevmo or LOXO-292), 40 mg and 80 mg oral, is a new, highly selective inhibitor of the RET receptor that is indicated as monotherapy for the treatment of RET-mutant MTC in adult and pediatric patients 12 years of age and older with unresectable advanced or metastatic disease. Other indications include RET fusion–positive differentiated thyroid cancer (DTC) in adult patients with advanced or metastatic disease (not amenable to surgery or radioactive iodine therapy) following prior treatment with sorafenib and/or lenvatinib, and metastatic RET fusion–positive non–small cell lung cancer (NSCLC).¹⁵ The product monograph recommends confirming the presence of a RET gene mutation before starting treatment. The recommended dosage of selpercatinib is based on body weight as (< 50 kg) 120 mg twice daily or (≥ 50 kg) 160 mg twice daily. Selpercatinib received a Notice of Compliance with Conditions on June 15, 2021. It is the first Health Canada–approved therapy for patients with advanced RET-driven lung and thyroid cancers and it has not been previously reviewed by CADTH for MTC. Warnings in the product monograph include corrected QT (QTc) interval prolongation on electrocardiogram (ECG), hypertension, hypersensitivity, hepatotoxicity, hemorrhage, and embryo-fetal toxicity. These situations warrant caution and it is recommended that dosages be adjusted for these adverse events (AEs).¹⁵

The objective of this report is to perform a systematic review of the beneficial and harmful effects of selpercatinib (Retevmo) 40 mg and 80 mg capsules for the treatment of RET-mutant MTC in adult and pediatric patients 12 years of age and older with unresectable advanced or metastatic disease.

Stakeholder Perspectives

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

Patient Input

Input was obtained from 2 patient groups: the CanCertainty Coalition and Canadian Cancer Society (CCS) together with Thyroid Cancer Canada. Raw patient input is presented in Appendix 1.

The CanCertainty Coalition, which is composed of more than 30 Canadian patient groups, caregiver organizations, and charities as well as oncologists and cancer care professionals, strives to improve the accessibility of cancer treatment. The group used the thyroid cancer incidence from Statistics Canada to estimate the number of RET-mutated thyroid cancer cases (both medullary and papillary) each year by age and province (i.e., the estimated number of Canadian residents who will become eligible for selpercatinib each year) and provided input on estimates of financial hardships for cancer patients from their database of surveys of 1,600 Nova Scotians. The group states that a cancer diagnosis could lead to financial hardships, especially when patients do not have private health insurance. Even though multiple programs support individuals who have high drug costs, there are administrative barriers in many provinces and territories. Patients often face weeks of delay in starting cancer treatments.

The CCS does research and provides advocacy and support to patients living with cancer. CCS’s patient panels and networks provided survey results from patients with thyroid cancer. In addition, Thyroid Cancer Canada’s patient networks submitted survey results and 2 testimonials from staff or board members who have had thyroid cancer. A total of 17 survey responses were collected across Canada between October 22 and November 10, 2021. None of the respondents had any direct or indirect experience with selpercatinib. Patients living with MTC referred to issues that impacted daily work and life, such as fatigue; brain fog; issues with mental health, body image, and cognitive ability; concerns about cancer returning; and concerns about the regulation of thyroid medications. Overall, 71% reported a financial barrier related to treatments, especially loss of income due to absence from work, parking costs, drug costs, and blood tests. Patients responded that they would like to see new treatments with improvements regarding cost, access, and support to improve their quality of life.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

The clinical experts consulted by CADTH agreed there is an unmet need for drugs that are better tolerated and with better safety profiles that can be used in patients with RET-mutant, advanced or metastatic MTC who, after surgery, have very few options. Treatment goals are improving overall survival (OS), PFS, and HRQoL by controlling symptoms such as diarrhea, flushing, minimizing adverse effects of treatments, and increasing work–life productivity. The experts indicated that selpercatinib would be an appropriate therapy for RET-driven thyroid malignancies, including using it as first-line therapy. At this stage, there is only 1 approved and/or funded therapy (vandetanib) in Canada, and the experts expect that selpercatinib will cause a shift in the current treatment paradigm.

The clinical experts consider that patients with RET-driven MTC whose disease cannot be managed or cured by locoregional (surgical) interventions and who are experiencing or are expected to experience symptomatic disease progression within the near future are the most likely to benefit from the use of selpercatinib. The experts did not find specific baseline characteristics or variables of prognostic value and indicated that patients’ responses will not differ based on any disease characteristics (e.g., presence or absence of certain symptoms, stage of disease). They suggested that patients with progressive metastatic MTC need to be screened for RET mutations and rearrangements using locally available comprehensive molecular tests, which should be available in institutions treating patients with progressive metastatic MTC.

Patients should be assessed to measure evidence of response or stabilization of the disease, based on clinical grounds and radiological examination such as Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) criteria, number and severity of symptoms, PFS, serum calcitonin, and carcinoembryonic antigen (CEA). All of these measurements are mostly aligned with clinical trial end points. Improvement in survival, PFS, and reduction in frequency and severity of symptoms (e.g., diarrhea) will be used to measure an adequate response, approximately every 3 to 6 months. Deterioration of symptoms, functional status, radiological evidence of disease progression (together with other clinical criteria), and unacceptable toxicity from treatment are among the issues that could be used to decide on a case-by-case basis whether to discontinue treatment.

Targeted therapies can have significant toxicity and related harms; the experts concluded that patients should only receive selpercatinib in a specialty outpatient clinic setting from clinicians with experience in the treatment of thyroid cancer.

Clinician Group Input

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

Two clinician group summaries were received: 1 from the Pediatric Oncology Group of Ontario (POGO) and the other from the Ontario Health (Cancer Care Ontario) (OH-CCO) Head and Neck and Thyroid Cancer Drug Advisory Committee (DAC), gathering input from a total of 5 clinicians.

Overall, the clinician groups agreed with the input provided by the clinical experts consulted by CADTH.

These groups explained that for RET-mutant MTC, the only currently approved and funded option is vandetanib, which requires special training and monitoring (e.g., for QTc prolongation). Hence, an important goal of an ideal treatment would be reducing treatment-related toxicities. Once patients have progressed on currently available therapies, there is no other option.

In the treatment-naive adult setting, OH-CCO noted that some clinicians may want to use selpercatinib in the first-line setting. Although selpercatinib appears more active and less toxic, a phase III trial (LIBRETTO-531 comparing selpercatinib with a physician’s choice of cabozantinib or vandetanib) in the first-line setting is still ongoing.¹⁶ Given the broader receptor profile of vandetanib, OH-CCO also expressed that clinicians would also like to be able to use vandetanib in patients progressing on (or intolerant of) selpercatinib. OH-CCO highlighted that some clinicians may reserve selpercatinib for patients with RET-mutant MTC who are intolerant or unsuitable for vandetanib. In the previously treated population, OH-CCO expressed that selpercatinib offers a treatment option to those who have exhausted currently available treatments

In the pediatric setting, POGO highlighted that for children with MTC, the best chance of cure is comprehensive initial surgery, and that POGO continues to advocate comprehensive initial surgery as first-line therapy. For the rare child with residual disease, however, existing therapies (cabozantinib and vandetanib) are associated with inferior response rates and higher toxicities; thus, POGO would recommend selpercatinib as the initial second-line therapy. POGO also highlighted that a rare subset of pediatric patients with unresectable tumours may be considered for first-line therapy with selpercatinib in a neoadjuvant context to facilitate eventual surgical control.

The groups state that to identify eligible patients, RET testing is available in Ontario as part of reflex testing on all metastatic thyroid cancer. Patients whose disease does not have a RET mutation or those with a performance status that would not allow selpercatinib treatment would be the least suitable population.

Response to selpercatinib would be measured primarily by response rates while addressing other key outcomes such as PFS and toxicity. Clinically meaningful response to treatment can be determined by a reduction in tumour burden based on clinical assessment and/or imaging, cancer-related symptoms, and tumour marker levels. Treatment with selpercatinib should be reassessed every 8 to 12 weeks for the first 6 months to 1 year, then every 12 to 16 weeks thereafter, especially in patients who had initial responses, feel well, and have reduced CEA and/or calcitonin levels. However, specific intervals should not be mandated. In cases of a lack of response and/or the emergence of treatment-related toxicities, selpercatinib should be discontinued. As an oral, take-home cancer drug, selpercatinib is suitable for the community setting.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

One clinical study, LIBRETTO-001, is included in this report. This is an ongoing, multi-centre, open-label, phase I and II, single-arm study of oral selpercatinib (LOXO-292) in patients with advanced solid tumours, including RET fusion–positive solid tumours, MTC, and other tumours with RET activation. This CADTH report focuses on the population with MTC. The sponsor used different cut-off dates: first, a June 17, 2019 cut-off date was used for the initial submissions to the FDA and European Medicines Agency. Then, a December 16, 2019 data cut-off served as the basis of the summary of clinical efficacy in LIBRETTO-001, which was used in the submissions to the FDA, Health Canada, and the European Medicines Agency. The pre-planned analysis at the December 16, 2019 data cut-off was conducted to support the submission of the day 60 efficacy and safety update for the FDA, which provided at least 6 months of follow-up information for all patients enrolled as of the initial data cut-off of June 17, 2019. Furthermore, data for a cut-off of March 30, 2020, submitted by the sponsor, is described in this report. The main analyses of efficacy are presented in this report, with a data December 16, 2019 cut-off date, where the pre-planned primary analysis set (PAS) is described

There are 2 main phases in the LIBRETTO-001 study. The dose-escalation phase (phase I) and the dose-expansion phase (phase II). For both phases, patients were to be enrolled into 1 of 5 phase II cohorts to characterize the safety and efficacy of selpercatinib in specific RET abnormalities. Cohort 1 includes patients with a RET fusion–positive solid tumour who have progressed on or were intolerant to 1 or more prior standard first-line therapies. Cohort 2 includes patients with a RET fusion–positive solid tumour who have not had any prior standard first-line therapy. Cohort 3 includes patients with RET-mutant MTC who progressed on or were intolerant to 1 prior standard first-line therapy (cabozantinib and/or vandetanib). Cohort 4 includes patients with RET-mutant MTC who have not received a prior standard first-line therapy (cabozantinib or vandetanib or another kinase inhibitors) with anti-RET activity, and cohort 5 includes patients from cohorts 1 through 4:

• without measurable disease

• with MTC not meeting the requirements for cohorts 3 or 4

• with MTC syndrome-spectrum cancers (e.g., MTC, pheochromocytoma)

• with DTCs that are poorly differentiated and have other RET alterations or activations

• with circulating cell-free DNA that is positive for a RET gene alteration not known to be present in a tumour sample.

This CADTH review focuses on the MTC population that was included in cohorts 3 and 4.

For phase I, the primary objective of the study was to determine the maximum tolerated dose (MTD) (recommended phase II dose [RP2D]) of selpercatinib. The secondary objectives for phase I included determining the safety and tolerability of selpercatinib, characterization of the pharmacokinetic (PK) properties, and assessment of the antitumour activity of selpercatinib. For phase II, the primary objective was to assess, for each expansion cohort, the antitumour activity of selpercatinib by determining the objective response rate (ORR) using RECIST 1.1 or Response Assessment in Neuro-Oncology (RANO), as appropriate to tumour type. Secondary objectives for phase II included other efficacy parameters including best change in tumour size from baseline, duration of response (DOR), central nervous system (CNS) ORR, CNS DOR, time to any and best response, clinical benefit rate, PFS, OS, and determination of the safety and tolerability of selpercatinib, and characterization of the PK properties. The exploratory objectives were PK and the collection of patient-reported outcomes data to explore disease-related symptoms and HRQoL. After MTD was defined, a dose-expansion assessment was conducted to obtain the recommended RP2D of 160 mg twice a day, selected by the safety review committee (SRC).

ORR was calculated based on the maximum likelihood estimator (i.e., crude proportion of patients with a best overall response of complete response [CR] or partial response [PR]) with 95% confidence intervals (CIs). DOR was defined, using Kaplan-Meier estimates for the median, as the number of months from the start date of the CR or PR for: right-censored patients with subsequent anti-cancer therapy or cancer-related surgery in the absence of documented disease progression, patients who died or experienced documented disease progression after missing 2 or more consecutively scheduled disease assessment visits, and patients alive and without documented disease progression on or before the data cut-off date. OS and PFS were assessed with methods similar to those used for DOR. All efficacy results presented were evaluated by an independent review committee (IRC).

For the December 16, 2019 data cut-off (n = 226), the mean age of patients with RET-mutant MTC was | | ||||| |||| |||| | |||||||| ||||| |||| |||| || ||||| || |||| ||| ||| |||||| ||||||| || ||| || ||||| || |||| || ||||| || ||||| || |||||||||||| || |||| ||||| |||| || ||| |||| ||| |||||| |||| |||||||| |||| |||| || |||||| || | || || |||| |||| || |||||| |||||||||| || |||| || || |||| || ||||||| || || |||||| ||||| |||||||||| ||| ||| ||| |||||||| ||| ||||||| || |||||||||| |||||||| |||| |||||||| ||||||||| |||||||| || |||||||| |||||||.

Efficacy Results

In the population of patients from LIBRETTO-001 with RET-mutant MTC (cut-off date December 16, 2019), for OS, with | |||||| |||||||| || |||||| || || |||| |||||| |||||||||||||| ||||| ||||| |||| || ||||| ||| |||||| ||| |||||||| ||| ||| ||||||| |||||||| ||| |||| | ||||| || |||||||| |||||||||| ||||||| |||| |||||||||||| || ||||||||||| |||||||||| ||| ||| ||||||| |||||| |||||| ||| |||||| || ||||| |||| |||| ||| || ||| |||||||||| ||| ||||| |||||||||| || |||||||| ||| ||| ||||| |||| |||| ||| || |||| |||||||. The rate of survival at 12 months or more was ||||| || ||| |||||||||| |||| || |||| || |||||. For the March 30, 2020 cut-off date, the group of patients in the PAS (n = 55) reached a median OS of 33.2 months (range 1.1+ to 33.3+) (+ indicates censored observation); values were similar in the integrated analysis set (IAS) group. The supplemental analysis set (SAS) did not reach the median of survival (Table 2).

For PFS (cut-off date December 16, 2019) with a median duration of follow-up of 16.7 months (||| |||| || ||||), the median for PFS for the PAS population was not reached and the range went from | || |||| ||||||. The rate of PFS at 12 months or more was ||||| of the population. For the March 30, 2020 cut-off date, no patients among the groups evaluated (PAS, IAS, SAS) reached a median for PFS (range 0.0+ to 32.2+).

The percentage of patients reaching an ORR (December 16, 2019 cut-off date) was 69.1% (95% CI, 55.2 to 80.9); overall, it was similar across the different sets. For the March 30, 2020, cut-off date, the results for the ORR were similar (69.1% for the PAS and similar across other sets).

With a median follow-up of 14.06 months ( | | | | | ||), the median DOR (December 16, 2019 cut-off date) was not reached in any analysis set except for SAS 1 (DOR of 21.9 months, ||||| ||| || ||). For the March 30, 2020 cut-off date, the results were similar, except for SAS 1, where the DOR reached a median of 21.9 months (range, 1.5 to 24.1), but with a median follow-up of 9.2 months. The percentage of patients who reached a DOR (December 16, 2019 cut-off date) of more than 12 months was 55.2% in the PAS. For the March 30, 2020 cut-off date, the percentage of patients reaching a DOR of more than 12 months was 68.4% in the PAS.

Published HRQoL data that included patients from the December 16, 2019 cut-off date was obtained from 1 sponsor publication.¹⁷ Of the 226 patients included, 88 (41.5%) were treatment-naive and 124 (58.5%) had previously received multikinase inhibitors (MKIs) at study entry. Of all patients evaluated, 18.7% (36 out of 193) met the criteria for a definite improvement and 13.0% (25 out of 193) met the criteria for a definite worsening in physical function in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Among the patients in the treatment-naive and previously treated subgroups, respectively, 10.5% and 22.5% met the criteria for definite improvement and 14.5% and 11.3% met the criteria for a definite worsening in physical function in the EORTC QLQ-C30. Most patients improved or remained stable on the global health status/QoL (quality of life) subscale at each cycle (cycles of 28 days) during study treatment with selpercatinib. Of all patients, 29.0% (56 out of 193) met the criteria for a definite improvement in global health status and 13.0% (25 out of 193) met the criteria for a definite worsening in global health status. Among the treatment-naive and previous treatment subgroups, respectively, 26.3% and 31.3% met the criteria for definite improvement and 17.1% and 12.5% met the criteria for a definite worsening in the global health status/QoL subscale. Most patients’ diarrhea improved or remained stable at each cycle during study treatment with selpercatinib. Of all patients, 43.5% (84 out of 193) met the criteria for definite improvement in diarrhea and 9.8% (19 out of 193) met the criteria for a definite worsening in diarrhea.

Harms Results

AEs were reported in all but 2 patients taking selpercatinib. Among the 299 patients with RET-mutant MTC included in the safety population, ||| ||||||| ||||||||| || ||||| ||| ||| |||| ||||| ||| || |||| ||||| ||| ||| | ||| ||||||||||||| | ||||| || || |||||||| |||||| ||| ||| ||| |||||||||||| ||| ||||. The most commonly reported AEs (> 20% of patients with at least 1 of these) included hypertension, diarrhea, constipation, fatigue, headache, peripheral edema, nausea, and abdominal pain.

Serious AEs occurred in || ||||||| || ||| ||| |||||||| || ||| |||||| ||||||||||| |||| || |||||| ||||||||||| || ||||| ||||||| || |||||||||||||| ||||| |||||| | |||| |||||||| ||| | ||||| ||. The most common serious adverse events (SAEs) were |||||||||| ||||||||||||| ||| ||||||||||||| ||||| |||| ||||||| || ||||| ||||| ||| || || |||||||| ||||||||||||.

Among the 299 patients in the safety population with RET-mutant MTC, | |||||| |||||| |||||||| |||||| || |||| || |||| |||| || ||||||||||||| || ||| || ||||||| |||||||||||| | ||| || ||||||| |||||||| ||| || |||||| |||||||| |||| |||| || |||| ||||| ||| |||| ||||| || ||||| || |||||| ||| || ||||||| |||||||||||| | ||| || ||||||| ||||||| | ||| || ||||| |||||| |||||||||.

For harms of special interest, elevations of liver enzymes occurred frequently, with || ||||||| ||| || ||||||| |||||||| alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations, respectively, although most were of low grade (Table 13). Hypertension was reported (reported as an AE by preferred term) in ||| ||||||| of patients. Diarrhea was present in || ||||||| of patients at any point, and hypersensitivity was rare (3 patients). A common concern among clinicians was QTc prolongation, which was reported in ||| ||||||| of patients with values that had increased by more than 30 msec from baseline, and || |||||||| ||||||| with values that had increased more than 60 msec.

For the March 30, 2020 cut-off date, the harm events were similar to the ones presented in the cut-off of December 16, 2019 with a total of 313 patients (99.4%) experiencing AEs and 97 patients (30.8%) experiencing at least 1 SAE. At this cut-off, 28 out of 315 deaths (8.9%) occurred within 28 days of the last dose of selpercatinib (18 due to disease progression, 8 due to AEs, and 2 due to other), and no death occurred more than 28 days after the last dose. The most common AEs (> 5%) included dry mouth ||||||, diarrhea ||||||, hypertension (|||), fatigue (|||), constipation (|||), increased AST (|||), increased ALT (|||), peripheral edema (|||), nausea (|||), increased blood creatinine level (|||), abdominal pain (|||), QT interval prolonged on ECG ( | |), arthralgia ( | |), cough ( | |), and rash ( | ||||). The safety data were analyzed by grade and SAEs.

Critical Appraisal

The LIBRETTO-001 study is a single-arm, open-label, phase I and phase II study. As such, the study is descriptive in nature, as it does not formally evaluate the primary or secondary end points (e.g., ORR, DOR, OS, or PFS) with adjustment for multiple comparisons. These limitations stem from its single-arm design and lack of comparator groups and constrain the estimation of the relative effects of treatment with selpercatinib. The open-label design may also increase uncertainty in patient-reported outcomes (HRQoL), introducing bias due to the inherent subjectivity of the outcome in an unblinded assessor. This bias would be less likely in more objective outcomes such as ORR, OS, and PFS if evaluated against a properly a priori set hypothesis. Furthermore, HRQoL outcomes were evaluated as exploratory end points with no adjustments for multiplicity.

As of the December 16, 2019 cut-off date, ||||| of patients discontinued the study drug and ||||| discontinued from the study within the efficacy population, mostly due to disease progression and death, respectively. At the March 30, 2020 cut-off date, the discontinuation rates remained consistent (17.1% of patients discontinued treatment and 12.7% discontinued from the study, with 7.9% and 4.4% of patients discontinuing treatment due to progressive disease [PD] and AEs, respectively). The sponsor evaluates all 226 patients in the efficacy population and 299 patients in the safety population for primary and secondary end points.

There were fewer concerns about the generalizability of the population included and about the effects on survival and response. According to the clinical experts consulted by CADTH, except for the proportion of females, the baseline characteristics of the population included in the LIBRETTO-001 study were, overall, representative of the population of patients with RET-mutant MTC that is seen in Canadian clinical practice. The inverse ratio of female to male patients being lower than expected was noted by the clinical experts, although they did not consider it to be a concern for applicability. Most patients had good baseline performance status (i.e., low number of patients with an ECOG PS of 2 or higher), suggesting that the included population might be healthier when compared with Canadian clinical practice; however, the clinical experts did not consider it highly different from what would be expected. All outcomes measured in the LIBRETTO-001 study are of clinical relevance and, according to the clinical experts, important for patients and well known and used by clinicians in Canada. A main concern was the limitation of the follow-up, i.e., that it might be considered too short for assessing longer periods of observations for those patients continuing the study and for assessing OS.

Indirect Comparisons

Description of Studies

The sponsor submitted an indirect treatment comparison (ITC) that involved a systematic review and used an unanchored matching-adjusted indirect comparison (MAIC) to evaluate the relative clinical efficacy of selpercatinib versus cabozantinib, vandetanib, lenvatinib, sorafenib, and placebo for the treatment of advanced RET mutation–positive MTC. Of these comparators, cabozantinib, vandetanib, and placebo are considered relevant for this review. Three outcomes were analyzed: OS, PFS, and ORR. As part of the MAIC that compares selpercatinib and cabozantinib, weights were generated using propensity score matching with logistic regression. The same weights were reused for the comparison of selpercatinib with placebo.

Efficacy Results

The sponsor-submitted ITC reported that, after weighting, there was a statistically significant improvement in PFS for selpercatinib versus placebo ||| ||||| ||| ||| ||||| ||||| ||||||||, and a statistically significant improvement in OS for selpercatinib versus placebo ||| ||||| ||| ||| ||||| ||||| |||||||||. Sources of heterogeneity between the studies include differences in patient characteristics such as age, ECOG PS, RET M918T mutation status, and difference in trial design (single- versus multi-arm trials). The variables included in the weighting model were |||| ||||||| |||| ||||||||||| ||||||| |||| ||||||| ||||||| ||| ||| ||||| |||||||| ||||||. The effective sample size after matching was |||||.

Critical Appraisal

The sponsor-submitted ITC had several limitations, including the lack of inclusion of all prognostic factors and effect modifiers in the MAIC weighting process, which leads to a high risk of residual confounding; use of MAIC weights calculated for 1 comparison that involves a different patient population than another comparison; heterogeneity between the patient populations used in different components of the ITC; and lack of consideration and inclusion of outcomes from the CADTH systematic review protocol, including DOR, HRQoL, and safety outcomes. Given these limitations, there is uncertainty around the relative treatment effects estimated by the MAIC, which undermines the internal and external validity of the ITC.

Other Relevant Evidence

CADTH identified 3 ongoing studies relevant to this submission. LIBRETTO-531 (phase III randomized controlled trial of selpercatinib versus cabozantinib or vandetanib), LIBRETTO-321 (phase II conducted in China), and LIBRETTO-121 (phase I and II study in a pediatric population), none of which have peer-reviewed published data available at this time (except for LIBRETTO-121, the results for which are presented from a conference abstract); the studies are expected to be completed by 2026, 2025, and 2024, respectively.

New Data for Request for Reconsideration

New data as of a June 15, 2021 cut-off date, were submitted by the sponsor as part of a request to CADTH for reconsideration, requesting to include only adults (18 years of age and older) with unresectable advanced or metastatic RET-mutant MTC in the first-line setting. This represents an extension of the follow-up (now with a median of 26.3 months for OS and 24.5 months for PFS), supplementing the immature data observed in the analyses of the data from the initial cut-off dates, with agreement between the reported results from the base case and the later cut-off analyses. In this update, of 142 patients in SAS 1, 115 (81%) were treatment-naive and 27 (19%) had been treated with a prior systemic therapy other than cabozantinib and vandetanib. At the time of data cut-off, the ORR by IRC assessment in SAS 1 was 81.0% (95% CI; 73.6 to 87.1), which is similar to but numerically higher than the ORR observed at the previous data cut-off. With a median follow-up of 20.3 months, the median DOR by IRC assessment was not evaluable (|||||| ||||| ||||| ||||||). However, 81.7% of responders were still on treatment with no documented disease progression by IRC assessment at the time of data cut-off. For OS, the median by IRC assessment was not reached, with a median duration of follow-up of 26.3 months (||||||||||||| ||||| ||||| |||| || ||||) (Table 12). ||| ||||||| ||||| ||| || ||| |||| |||||| ||| ||||||||||. The rates of survival at 12 months or more and 24 months or more were 99.3% and 95.0%, respectively. Within the total MTC safety analysis set (N = 319), harm events at the June 15, 2021 data cut-off were similar to the ones presented from the March 30, 2020, data cut-off.

Conclusions

The evidence from a single-arm, open-label, unblinded study (LIBRETTO-001) suggests that treatment with selpercatinib is associated with survival and response end points that were considered relevant to both patients and clinicians (OS, PFS, ORR, DOR, HRQoL) when compared with the typical effects and clinical evolution observed by clinical experts among patients with RET-mutant, advanced and/or metastatic MTC after surgery.

Overall, the clinical experts deemed the harms and safety profile of selpercatinib better than the undesirable effects usually seen in clinical practice with vandetanib or cabozantinib. However, major limitations generate uncertainty around any effect estimates due to immature data, lack of comparative evidence, a high risk of bias (no blinding, attrition), no adjustment for multiple comparisons, and imprecision in time-to-event outcomes.

Evidence from a sponsor-submitted ITC is also associated with major limitations for the comparison between selpercatinib and BSC due to residual confounding (i.e., incomplete inclusion of prognostic factors and effect modifiers), surrogate use of weights for comparisons, and heterogeneity among included populations.

Overall, there is uncertain evidence that suggests that selpercatinib provides clinical benefits with similar or lower risks of harms (i.e., toxicity) when compared with what is expected with relevant comparators.

Introduction

Disease Background

Thyroid cancer is 1 of the most commonly diagnosed cancers in Canada and the world. Although it embodies less than 1% of all tumours, it is considered the most common endocrine malignancy and the fifth most common cancer in women.^1,2 It is estimated that 8,200 new cases of thyroid cancer will be diagnosed in people living in Canada in 2019 and about 230 will die from it.¹⁹ For 2020, the incidence of thyroid cancer in Canada was estimated to be 23 per 100,000 patients or about 8,600 new cases.³

Thyroid cancer can originate from either thyroid follicular cells or parafollicular cells (c cells). Thyroid cancers arising from follicular cells include DTC, which groups papillary thyroid cancer (PTC), follicular thyroid cancer, Hurthle cell cancer. Among all types of thyroid cancer, DTC is the most common, accounting for more than 95% of cases.^5,6

MTC originates from the parafollicular neuroendocrine cells of the thyroid (c cells). It is a less common condition, accounting for 1% to 2% of all thyroid cancers, and it is usually detected as a solitary thyroid nodule in patients in the fourth or sixth decade of life. Lymphadenopathy is also a common initial presentation due to frequent metastases to cervical lymph nodes, with up to 15% of sporadic cases presenting distant metastases in the mediastinum, liver, lungs, and bones. A common initial presentation is the presence of diarrhea with an accompanying thyroid nodule.

Of all MTC cases, approximately 75% are sporadic and 25% are hereditary. Of the sporadic cases, 50% will present somatic mutations in the RET proto-oncogene (of which the most common is the M918T), a small proportion (about 20% to 25%) will present a rat sarcoma (RAS) mutation, and about 20% to 25% will be defined as orphan mutations (yet to be identified).⁴ Of the hereditary cases, almost all (98%) will present a germline RET mutation (inherited as autosomal dominant).⁵ Hereditary cases occur mostly in patients who have an inherited multiple endocrine neoplasia syndrome.^5,6

Diagnosis is based on physical examination, neck ultrasound, and ultrasound-guided fine-needle aspiration cytology. Levels of calcitonin are helpful, as they are usually diagnostic of MTC, especially with levels above 100 pg/mL.⁴ Other biomarkers can also be helpful, such as the serum CEA, which is usually elevated in advanced cases when distant metastases are present. RET germline mutation analysis is recommended when the diagnosis of MTC has been established because it allows defining the sporadic or hereditary nature of MTC, which can guide future diagnostic and therapeutic options and strategies.

The prognosis of MTC not cured by surgery is unfavourable, with a 10-year survival rate of approximately 50%,⁴ and a 5-year survival rate varying from 62% to 87%, according to different series.^7-10 Early diagnosis and early appropriate surgical treatment are considered to positively affect the prognosis of these patients.

Standards of Therapy

In patients with both sporadic and hereditary MTC, early diagnosis and surgical therapy with total thyroidectomy and resection of local and regional metastases is the basis for initial treatment and the possibility of cure.⁶ Hereditary cases must also be investigated for the presence of pheochromocytoma and/or hyperparathyroidism, regardless of age and presenting symptoms; hence, serum calcitonin and CEA are part of the initial biochemical testing.⁴ After surgery, hormone replacement therapy with L-thyroxine (LT4) should be started to keep thyrotropin values within the normal range.

The treatment goals in patients with MTC are aimed at cure, improving survival, delaying disease progression, and improving HRQoL by controlling symptoms such as diarrhea, minimizing adverse effects of treatments, and increasing work–life productivity.¹¹

For patients who have unresectable advanced or metastatic RET-mutant MTC — a condition with a very low cure rate — several targeted therapies have been used as first-line treatments.^4,11,12 These include several multi-targeted tyrosine kinase inhibitors (TKIs), cabozantinib¹³ and vandetanib¹⁴ among them and which have both shown improvement in PFS in phase III randomized controlled trials.^13,14 However, among these, only vandetanib has been approved and funded in Canada and can be prescribed regardless of RET mutational status. Cabozantinib is approved in Canada only for the treatment of renal and hepatocellular carcinoma; it is neither funded nor approved for use in patients with MTC.

Once patients progress on currently available therapies, or if vandetanib has to be discontinued due to side effects, there are no further best options. Presently, after first-line treatment, patients with RET-mutant advanced or metastatic MTC can only continue using BSC and, optionally, enter clinical trials.¹¹

Vandetanib is prone to frequent AEs (as are other TKIs), and its administration requires special training and monitoring (for example, for QTc prolongation). An ideal treatment for patients with MTC should reduce treatment-related toxicities while increasing survival and improving HRQoL.

Drug

Selpercatinib (Retevmo or LOXO-292) as 40 mg and 80 mg capsules (oral), is a new chemical entity: a highly selective, adenosine triphosphate–competitive small-molecule inhibitor of the RET receptor. Selpercatinib is indicated as monotherapy for the treatment of RET-mutant MTC in adult and pediatric patients 12 years of age and older with unresectable advanced or metastatic disease. Other indications include RET fusion–positive DTC in adult patients with advanced or metastatic disease (not amenable to surgery or radioactive iodine therapy) following prior treatment with sorafenib and/or lenvatinib, and metastatic RET fusion–positive NSCLC.¹⁵

To start treatment with selpercatinib, the product monograph recommends that physicians confirm the presence of a RET gene fusion (for patients with NSCLC or thyroid cancer) or a RET gene mutation (for patients with MTC) using a validated test before starting treatment. The recommended dosage of selpercatinib is based on body weight:

• less than 50 kg: 120 mg twice daily

• 50 kg or greater: 160 mg twice daily

It should be administered approximately every 12 hours until disease progression or unacceptable toxicity. Health Canada has not authorized its use in children younger than 12 years of age. The product monograph also recommends dose modifications for QT interval prolongation, increased AST or ALT, hypersensitivity, hypertension, hemorrhagic events, and other grade 3 or 4 adverse reactions.

Selpercatinib (Retevmo) received a Notice of Compliance with Conditions on June 15, 2021, pending the submission of new data from phase II and III studies (LIBRETTO-001 and LIBRETTO-531). It is the first Health Canada–approved therapy for patients with advanced RET-driven lung and thyroid cancers.

Several warnings and precautions are stated in the product monograph, such as QTc interval prolongation on ECG, hypertension, hypersensitivity, hepatotoxicity, hemorrhage, and embryo-fetal toxicity. These situations warrant caution and it is recommended that doses be adjusted for these AEs.¹⁵

Selpercatinib has not been previously reviewed by CADTH. However, at the time of this submission, 1 CADTH review for the treatment of RET fusion–positive DTC in adult patients with advanced or metastatic disease (not amenable to surgery or radioactive iodine therapy) following prior treatment with sorafenib and/or lenvatinib, and 1 for metastatic RET fusion–positive NSCLC were under way.

The characteristics of selpercatinib and vandetanib are presented in Table 4.

Table 4: Key Characteristics of Selpercatinib and Vandetanib

ALT = alanine aminotransferase; AST = aspartate aminotransferase; DTC = differentiated thyroid carcinoma; KDR = kinase insert domain receptor; MTC = medullary thyroid cancer; NSCLC = non–small cell lung cancer; QTc = corrected QT interval; RET = rearranged during transfection.

^aHealth Canada–approved indication.

Source: Selpercatinib (Retevmo)¹⁵ and vandetanib (Caprelsa)²⁰ product monographs.

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. Input was obtained from 2 patient groups and is summarized subsequently. At the time of the open call to patient groups, input for both MTC and DTC was obtained; therefore, the input from the patient groups for these 2 conditions has been combined for this report.

CanCertainty Coalition

The CanCertainty Coalition, which is composed of more than 30 Canadian patient groups, caregiver organizations, and charities as well as oncologists and cancer care professionals, strives to improve the accessibility of cancer treatment. CanCertainty’s submission focused on financial burdens and safety issues associated with oral cancer medication.

For patients with cancer under the age of 65 living in British Columbia, Alberta, Saskatchewan, Manitoba, Quebec, Northwest Territories, Yukon, and Nunavut, oral oncology medication is covered. In Ontario and the Atlantic provinces, only medications for people over the age of 65 are covered. For the small number of patients under the age of 65 with RET-mutant MTC living in these provinces, a cancer diagnosis could lead to financial hardship, especially when they do not have private health insurance. Even though multiple programs support individuals who have high drug costs, there are administrative barriers. To qualify for assistance programs, patients and their families must submit a significant amount of personal and financial information. Therefore, the patients often face weeks of delay in starting cancer treatments until the issues with paperwork and approvals are resolved. Alternatively, they often pay out of pocket for the first few weeks of treatment, which may not be reimbursed. The access to cancer treatments is difficult in many hospitals and cancer centres across Canada. As a result, in Ontario, a new type of social worker known as a drug access navigator and an organization that supports these navigators, the Oncology Drug Access Navigators of Ontario, were established. Even for patients with private insurance, many face significant co-pays, deductibles, or annual or lifetime caps. For example, some private insurance plans have a cap of $2,000 per year for prescription drugs, even though many take-home cancer drugs cost more than $20,000 per year. A survey of more than 1,600 Nova Scotians commissioned by the CanCertainty Coalition, demonstrated that 3 out 5 people (60%) in Nova Scotia would consider leaving the province if faced with cancer therapy costs. Only 7% could afford monthly drug costs of more than $200. Patients deal with their financial burden by delaying or foregoing care. They may take less medication than prescribed, use over-the-counter drugs in place of prescribed medications, decline procedures, and skip appointments to reduce costs. Patients who are younger, uninsured, and earning a lower income appear to be at greater risk of medication nonadherence. Moreover, the evidence suggests that those with a shorter time since diagnosis, more severe cancers, and unemployed, have higher rates of financial burden.

There is also a safety issue with take-home cancer drugs. Some patients receive their medication from hospital pharmacies, specialty pharmacies, and community pharmacies that lack specialization and training to handle cancer medications. Safety and quality deficits have been reported related to the current method of dispensing take-home cancer drugs in the community, including incorrect handling and dosing, limited monitoring, nonadherence (leading to under- or over-dosing), SAEs, morbidity, and mortality. Thus, take-home cancer drugs require processes similar to those that have been developed for IV cancer drugs, where delivery is comprehensive, organized, safe, and patient-centred.

Canadian Cancer Society and Thyroid Cancer Canada

The CCS aims to improve the lives of all those affected by cancers through research, advocacy, and support, with the purpose of taking control of cancer. The CCS’s patient panels and networks provided survey results from patients with thyroid cancer. In addition, Thyroid Cancer Canada’s patient networks submitted survey results and 2 testimonials from staff or board members who have had thyroid cancer. A total of 17 survey responses were collected across Canada between October 22 and November 10, 2021. None of the respondents had any direct or indirect experience with selpercatinib.

The ability to concentrate (65%), exercise (59%), and work (41%) were the top 3 day-to-day activities that respondents said have been impacted in moderate or significant degrees by thyroid cancer. Seven respondents added that fatigue; brain fog; issues related to mental health, body image, and cognitive ability; concerns about their cancer returning, and concerns about the regulation of thyroid medications were the areas that have been affected by thyroid cancer. Overall, 71% reported a financial barrier related to treatments. The most significant financial barriers were loss of income due to absence from work (24%), parking costs (23%), and drug costs (12%). There was 1 patient (6%) who responded that blood test monitoring (thyroid-stimulating hormone, T3, T4) was the greatest financial barrier. Seven patients (29%) were being treated with surgery, 6 patients (25%) were not actively treated, and 4 patients (17%) were on hormone therapy. Of note, 9 out of 17 patients were on thyroid hormone replacement or suppression therapy, e.g., levothyroxine (Synthroid, Eltroxin). The treatment-related side effects that had a moderate or significant impact on patients were fatigue (71%), concentration and focus (64%), and weight changes (58.5%). Three respondents indicated that mental health issues (mood swings, suicidal thoughts, and feelings of loneliness and fear) were of concern. One patient said, “Synthroid is very difficult to adjust and regulate which leads to emotional ups and downs. I’ve been suicidal through this due to being over medicated and an emotional mess when under medicated.” For patients with experience with radioactive iodine or radiation therapy, there were additional concerns, such as the impact on salivary glands (dry mouth and increased risk of dental problems), long-term impacts of treatment, and isolation associated with radiation. One patient said, “Isolation of radiation, no one tells you how long to stay away from pets. How lonely it is because no support groups or info given on how to live afterwards with the fear of relapse or clear stages of the cancer.” From the submitted testimonials, fertility issues were raised as another significant concern along with difficulties with body temperature, weight, mood, energy, and regulating heart rate. Seven patients responded that they would like a new treatment with improvements regarding the cost of drugs, difficulty regulating drugs, low levels of access to information, long treatment wait times, and the lower level of support that thyroid cancer gets compared with other types of cancer, as thyroid cancer is treated outside of cancer clinics. One patient said, “I would like to be seen in a cancer clinic rather than be followed outside of the clinic. There is not enough support for thyroid cancer patients.”

Clinician Input

Input From the Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding 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 thyroid cancer.

Unmet Needs

Treatment goals are improving OS, PFS, and HRQoL by controlling symptoms such as diarrhea, flushing, minimizing the adverse effects of treatments, and increasing work–life productivity. Both clinical experts agree there is an unmet need for better treatments that are available for patients who do not respond to or progress after first-line therapy, or for whom treatment with vandetanib or cabozantinib has to be discontinued or the dose reduced due to side effects; also, ideally, these treatments should have fewer harms.

Place in Therapy

According to the clinical experts consulted by CADTH, selpercatinib would be an appropriate therapy for RET-driven thyroid malignancies, including as first-line therapy rarely used in combination with local treatments. The mechanism of action would not lend itself to combination therapy with the other active drugs available at this time.

Since there is only 1 approved and funded systemic therapy option (vandetanib) in Canada, and patients usually do not have further options after first-line therapies, there is a place in therapy for selpercatinib, which is expected to cause a shift in the current treatment paradigm. Both clinical experts agree it would be more appropriate if selpercatinib were used as first-line therapy due to reports of better efficacy and tolerance compared with other options.

Patient Population

The clinical experts consider that patients with RET-driven MTC whose disease cannot be managed or cured by locoregional (surgical) interventions and who are experiencing or expected to experience symptomatic disease progression in the near future are the most likely to benefit from the use of selpercatinib, and it should be offered in every case. The experts did not find specific baseline characteristics or variables of prognostic value and consider that patients’ responses will not differ based on any disease characteristics (e.g., presence or absence of certain symptoms, stage of disease).

Patients with progressive metastatic MTC need to be screened for RET mutations and rearrangements using locally available comprehensive molecular tests, which should be available in institutions treating patients with progressive metastatic MTC.

Assessing Response to Treatment

Patients are assessed with clinical examinations and evaluations of symptoms to measure evidence of response or stabilization of the disease, based on clinical grounds and radiological examination, such as RECIST criteria, number and/or severity of symptoms, PFS, serum calcitonin, and CEA. All of these measurements are mostly aligned with the clinical trial end points.

Improvement in survival, PFS, and a reduction in the frequency and severity of symptoms (e.g., diarrhea) will be used to measure an adequate response approximately every 3 to 6 months.

Discontinuing Treatment

Deterioration of symptoms, functional status, radiological evidence of disease progression (together with other clinical criteria), and unacceptable toxicity from treatment are among the issues commonly used in clinical practice to decide on a case-by-case basis whether to discontinue treatment.

Prescribing Conditions

Targeted therapies can have significant toxicity and related harms; patients should only receive selpercatinib from clinicians with experience in the treatment of thyroid cancer in a specialty outpatient clinic setting. A specialized team should be available to provide care in diagnosis, treatment, monitoring, and palliative care. The physicians involved will mostly be medical or surgical oncologists and endocrinologists.

According to the clinical experts, with the availability of selpercatinib, it must become standard practice to test patients with MTC for somatic RET fusions or mutations. Institutions treating patients with MTC must have a stepwise molecular testing strategy in place.

Clinician Group Input

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

Two clinician group summaries were received: 1 from the POGO and the other from the OH-CCO Head and Neck and Thyroid Cancer DAC, gathering input from a total of 5 clinicians.

POGO

This group represents 5 pediatric cancer centres and advises the Ministry of Health and Long-Term Care on pediatric cancer care. POGO’s Therapeutic and Technology Advisory Committee members with clinical experience and insight into the use of selpercatinib contributed to the survey.

Pediatric MTC is a rare disease with approximately 75% of children carrying germline RET mutations and the majority of the remaining 25% carrying somatic RET mutations. Children with a family history get prophylactic thyroidectomy to avoid malignant transformation. Those without a family history often present with advanced diseases not amenable to complete resection.

Treatment options for metastatic disease, which has a very low cure rate, include multi-targeted TKIs, such as cabozantinib and vandetanib. Since these multi-targeted TKIs have limited impact on PFS and substantial DLTs, improved PFS and minimized off-target effects are desirable goals for the treatment of metastatic MTC. As the first-line treatment for the best chance of cure, children with MTC should undergo comprehensive initial surgery. For a rare population with residual disease, selpercatinib should be used as the preferred second-line therapy over existing therapies (i.e., cabozantinib or vandetanib), due to reduced toxicities and more favourable response rates to RET-driven MTC. For another rare population with unresectable tumours, selpercatinib may be considered as the first-line therapy in a neoadjuvant setting to facilitate eventual surgical control.

For children with progressive, metastatic MTC requiring systemic therapy, selpercatinib would replace existing MKIs as first-line treatment. Children with high-volume residual disease following surgery, residual disease threatening vital structures, PD (either structural or biochemical) that is not surgically resectable, or those with a post-operative serum calcitonin level greater than 150 pg/mL are best suited for selpercatinib if their disease is driven by a RET mutation. These children can be identified at a specialized tertiary centre and reviewed at tumour boards. Patients without structurally persistent disease, i.e., negative imaging following initial surgery, should not be considered for selpercatinib. Those with MTC with a germline or somatic RET mutation confirmed by tumour analysis are most likely to respond to selpercatinib. Responses to treatment can be assessed radiologically and biochemically in the known residual disease sites.

Clinically meaningful responses would be a reduction and/or resolution of known residual disease based on cross-sectional imaging and tumour markers, i.e., calcitonin and CEA. Those with miliary lung disease can be monitored for an objective improvement of respiratory status. Treatment response should be assessed every 3 to 6 months. In case of disease progression despite properly dosed and administered therapy or significant hypersensitivity not responsive to steroids and/or dose reduction, selpercatinib should be discontinued. Selpercatinib can be administered in an outpatient setting with a multidisciplinary team experienced in the care of pediatric MTC; however, diagnosis and monitoring should involve pediatric endocrinologists and head and neck pediatric surgeons.

OH-CCO Head and Neck and Thyroid Cancer DAC

The OH-CCO Head and Neck and Thyroid Cancer DAC, which provides evidence-based clinical and health system guidance, submitted input collected via email and teleconferences.

This group explained that for adult RET-mutant MTC, the only currently approved and funded option is vandetanib, which is prescribed regardless of RET mutational status. Cabozantinib is neither funded nor approved for MTC in Canada. Administering vandetanib requires special training and monitoring, e.g., blood tests and ECGs, since it has a black box warning for QTc prolongation that can lead to arrhythmia, which is caused by combined epidermal growth factor receptor, vascular endothelial growth factor, and RET TKI activities. Hence, an important goal of an ideal treatment would be reducing treatment-related toxicities. Once disease has progressed on currently available therapies, there is no other option; therefore, adult patients with metastatic, unresectable RET-mutant MTC would be the population with the greatest unmet need for selpercatinib.

If patients have been previously treated, selpercatinib would be the next line of therapy. In treatment-naive patients, selpercatinib would be an alternate treatment option based on its favourable toxicity profile. Some clinicians may want to use selpercatinib in the first-line setting due to its multiple advantages over existing therapies. Given the broader effect of vandetanib on other receptors, vandetanib would be used if patients progressed on or are intolerant to selpercatinib. Even though selpercatinib appears to be more active and less toxic, phase III trial data in the first-line setting are still ongoing. Thus, some clinicians may reserve selpercatinib for patients with RET-mutant MTC who are intolerant to or unsuitable for vandetanib.

To identify eligible patients, RET testing is available in Ontario as part of reflex testing on all metastatic thyroid cancer. Patients without a RET mutation or those with a performance status that would not allow selpercatinib treatment would be the least suitable population.

Response to selpercatinib would be measured primarily by response rate, and secondary outcomes of interest would be PFS and toxicity. A clinically meaningful response to treatment can be determined by a reduction in tumour burden based on clinical assessment and/or imaging, cancer-related symptoms, and tumour marker levels. Treatment with selpercatinib should be reassessed every 8 to 12 weeks for the first 6 months to 1 year then every 12 to 16 weeks thereafter, especially in patients who had initial responses, feel well, and have reduced CEA and/or calcitonin levels. However, specific intervals should not be mandated. In case of a lack of response and/or if treatment-related toxicities emerge, selpercatinib should be discontinued. As an oral take-home cancer drug, selpercatinib is suitable for the community setting.

Drug Program Input

Drug Program Input

The drug programs identified relevant implementation issues to be addressed through the CADTH’s reimbursement review process. Refer to Table 5 for more details.

In terms of considerations for the initiation of therapy, there were 2 main concerns. First, the uncertainty of selpercatinib use in the pediatric population since, in the LIBRETTO-001 trial, only 3 adolescent patients with MTC are included. The clinical experts acknowledged the scarcity of evidence, although they did not expect significant variations in outcomes for pediatric patients.

Regarding concerns about the discontinuation of therapy, the experts expressed that it would be difficult to state specific criteria, since different metastatic locations could respond differently in the same patient but, overall, they considered that patients with no signs of toxicity with selpercatinib would be able to continue treatment.

In terms of considerations for generalizability, there were issues with the low number of pediatric patients, very few of whom had an ECOG PS above 2. Experts considered that patients with an ECOG PS of 2 or greater should be judged to be able to receive treatment with selpercatinib on a case-by-case basis. The same applies for pediatric cases, as indicated earlier.

In general, the experts considered that selpercatinib will have a major impact on the current treatment paradigm in Canada.

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

CEA = carcinoembryonic antigen; ECOG PS = Eastern Cooperative Oncology Group Performance Status; HRQoL = health-related quality of life; MTC = medullary thyroid cancer; OS = overall survival; pERC = CADTH pan-Canadian Oncology Drug Review Expert Review Committee; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors; RET = rearranged during transfection.

Clinical Evidence

The clinical evidence included in the review of selpercatinib (Retevmo) 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 studies selected according to an a priori protocol. The second section covers indirect evidence from the sponsor and indirect evidence selected from the literature that meet the selection criteria specified in the review. The third section includes sponsor-submitted, long-term extension studies and additional relevant studies that are 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 of selpercatinib (Retevmo) 40 mg and 80 mg capsules for the treatment of RET-mutant MTC in adult and pediatric patients 12 years of age and older with unresectable advanced or metastatic disease.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 6. The outcomes included in the CADTH review protocol reflect the outcomes considered important to patients, clinicians, and drug plans.

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.²¹

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) through Ovid and Embase (1974–) through 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 concept was selpercatinib. Clinical trial registries were searched: the US National Institutes of Health’s clinicaltrials.gov, the WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit retrieval by study type. 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 November 24, 2021. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee (pERC) on April 13, 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.²² Included in this search were the websites of regulatory agencies (the FDA and European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented by reviewing the bibliographies of key papers and through contacts with appropriate experts. In addition, the sponsor of the drug was contacted for information regarding unpublished studies.

A focused literature search for network meta-analyses dealing with thyroid cancer was run in MEDLINE All (1946–) on November 24, 2021. No limits were applied to the search.

Findings From the Literature

One study was identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 7. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

The LIBRETTO-001 study is a multi-centre, open-label, phase I and II, single-arm study of oral selpercatinib (LOXO-292) in patients with advanced solid tumours, including RET fusion–positive solid tumours, MTC, and other tumours with RET activation. The main focus for this CADTH review is the population of patients with RET-mutant MTC.

This study is still ongoing and is being conducted in 84 investigational sites among several countries and regions, including Canada, the US, Australia, Japan, Hong Kong, Taiwan, Israel, Singapore, and Europe.

Description of the phases and Cohorts of the LIBRETTO-001 Study

The study consisted of 2 main phases, the dose-escalation phase (phase I), and the dose-expansion phase (phase II), depicted in Figure 2. In these 2 phases, the sponsor generated 5 cohorts with the intention of better characterizing the safety and efficacy of the study drug in patients with specific anomalies in the RET gene. Cohort 1 included patients with a RET fusion–positive solid tumour who progressed on or were intolerant to 1 or more standard first-line therapies, while cohort 2 included patients with a RET fusion–positive solid tumour not previously treated with a standard first-line therapy. The population of interest for this CADTH report is cohort 3, which comprises patients with mutant RET MTC who progressed on or were intolerant to standard first-line treatments; however, cohort 4, comprising patients whose disease was not treated with standard first-line treatment (cabozantinib or vandetanib or other kinase inhibitors with anti-RET activity), will be described.

Cohort 5 includes patients from cohorts 1 to 4 without measurable disease, with MTC not meeting the requirements for cohorts 3 or 4, with other RET-altered solid tumours or other RET alterations or activations, or with circulating cell-free DNA that is positive for a RET gene alteration not known to be present in a tumour sample.

For phase I, the primary objective of the study was to determine the MTD (RP2D) for selpercatinib. Secondary objectives for phase I included the determination of the safety and tolerability of selpercatinib, characterization of the PK properties, and assessment of the antitumour activity of selpercatinib.

For phase II, the primary objective was to assess, for each expansion cohort, the antitumour activity of selpercatinib by determining the ORR using RECIST 1.1 or RANO criteria, as appropriate to tumour type. Secondary objectives for phase II included other efficacy parameters, including best change in tumour size from baseline, DOR, CNS ORR, CNS DOR, time to any and best response, clinical benefit rate, PFS, OS, determination of the safety and tolerability of selpercatinib, and the characterization of the PK properties.

Figure 2: Phase I and II of the LIBRETTO-001 Study

cfDNA = circulating cell-free DNA; MTC = medullary thyroid cancer; MTD = maximum tolerated dose; RET = rearranged during transfection.

Source: LIBRETTO-001 Clinical Study Report.¹⁸

The exploratory objectives of phase I and II included determination of the relationship between PK and drug effects, evaluation of serum tumour markers, CEA and calcitonin, and adrenocorticotropic hormone or cortisol (for patients with Cushing disease related to their cancer). Additional exploratory objectives include characterization of RET gene fusions and mutations and concurrently activated oncogenic pathways by molecular assays, and collection of patient-reported outcome data to explore disease-related symptoms and HRQoL.

During phase I, a dose-escalation strategy was conducted, starting the dose of selpercatinib at 20 mg/day and then proceeding through all dose levels or until the SRC and sponsor determined that a suitable dose was achieved based on available data (safety, PK exposure, clinical activity) using a modified Fibonacci dose escalation.²⁷ The SRC evaluated whether the cohort at the prior dose level was considered to be receiving the MTD. Dose escalation was to proceed through the planned dose-escalation cohort levels or until the MTD was reached.

During phase II, a dose expansion was evaluated to obtain the RP2D of selpercatinib. An RP2D of 160 mg twice a day was selected by the SRC during phase I of the study. The LIBRETTO-001 study is currently ongoing and continuing to enrol up to approximately 750 patients with advanced solid tumours with evidence of a RET gene alteration in a tumour and/or blood.

Amendments to the Protocol of the Study

A detailed description of the major changes made to the protocol of the LIBRETTO-001 study is presented in Appendix 5. Of note was amendment 5.0 (May 2018) which updated the trial design from a 2-part phase I (dose escalation and dose expansion) study to a phase I and II study due to “promising early evidence” of durable antitumour activity in patients with RET-altered cancers (e.g., RET fusion–positive cancers and RET-mutant MTC), including those with resistance to prior MKIs and those with brain metastases.

Cut-Off Dates

The sponsor used different cut-off dates data based on regulatory submissions, which also had an effect on how the population sets were created and reported through interactions with regulators. An overview is presented in Figure 3.

Figure 3: Cut-Off Dates and Accrual of Patients With RET-Mutant MTC Included in the LIBRETTO-001 Study

MTC = medullary thyroid cancer; RET = rearranged during transfection.

^a Defined as those with at least 1 dose of selpercatinib and 6 months of follow-up.

Source: LIBRETTO-001 Clinical Study Report.¹⁸

The first planned cut-off date was on June 17, 2019 for FDA and European Medicines Agency submissions. This date was chosen so that the MTC efficacy-evaluable patients for ORR assessment had an opportunity to be followed for at least 6 months. At this cut-off date, the number of patients available for the safety analysis (i.e., those who had received at least 1 dose of selpercatinib) was 226, with 132 of these patients (58%) eligible for the efficacy analysis (those who received at least 1 dose of selpercatinib and were followed-up for at least 6 months).

An analysis using the December 16, 2019 cut-off date was conducted to support the FDA submission request to assess at least the day 60 efficacy and safety of selpercatinib for all patients initially enrolled (i.e., 6 months after the initial data cut-off of June 17, 2019). This pre-planned analysis at this cut-off point evaluated 299 patients for safety and 226 of these for efficacy using different analysis sets described in the next section. This cut-off date was also used for the submission to Health Canada and the pre-planned analysis and includes the 55 patients with MTC in the PAS for the primary end points assessed (defined subsequently).

Sponsor-submitted data for the March 30, 2020 cut-off date were also included and assessed by CADTH and are described in the tables addressing efficacy and harms in this report.

Derivation of New Analysis Sets Supporting Regulation Applications

Interactions with the FDA prompted the sponsor to create a different set of efficacy and safety analysis sets designed to support the indications sought. These agreed-upon analysis sets were not the same as those specified in the study protocol and are distinct from those described in the full Clinical Study Report. First, the efficacy datasets were categorized into broad groupings of patients with RET fusion–positive NSCLC, RET-mutant MTC, and RET fusion–positive thyroid cancer — of which MTC is the main focus for this CADTH review.

These grouping formed the basis for defining the PAS in patients with RET-mutant MTC who received prior cabozantinib or vandetanib, as shown in Figure 4. The MTC PAS was defined as the first 55 patients with RET-mutant MTC enrolled in LIBRETTO-001 who had been previously treated with cabozantinib or vandetanib. The PAS is a subset of the IAS, which includes all patients with RET-mutant MTC enrolled in LIBRETTO-001 who met the same eligibility criteria as the PAS by the June 17, 2019 data cut-off for the initial US submission (N = 124). SASs include SAS 1, comprising treatment-naive patients (n = 88), and SAS 2 (n = 14), comprising the patients in cohort 5 (defined earlier).

Figure 4: Overview of the LIBRETTO-001 Study Design and Populations Included

Cabo = cabozantinib; chemo = chemotherapy; IAS = integrated analysis set; MTC = medullary thyroid cancer; NSCLC = non–small cell lung cancer; PAS = primary analysis set; RET = rearranged during transfection; SAS = supplemental analysis set; Vande = vandetanib.

¹Other tumours that do not fit the other disease cohorts.

Source: LIBRETTO-001 Clinical Study Report.¹⁸

Populations

Inclusion and Exclusion Criteria

As described in Table 7, patient inclusion criteria included those with a locally advanced or metastatic solid tumour whose disease has progressed on or who are intolerant to standard therapy, or no standard therapy exists or, in the opinion of the investigator, are not candidates for or would be unlikely to tolerate or derive significant clinical benefit from standard therapy, or who decline standard therapy.

Patients should have been at least 18 years of age. However, for countries and sites where approved, patients as young as 12 years of age could be enrolled. An ECOG PS score of 0, 1, or 2 (age ≥ 16 years) or a Lansky Performance Score of 40% or greater (age < 16 years) with no sudden deterioration 2 weeks before the first dose of the study treatment was used for inclusion. For patients being enrolled into a specific phase II dose expansion, evidence of a RET gene alteration in a tumour (i.e., not just blood), was required (a positive germline test for a RET mutation was acceptable for patients with MTC). Adequate hematologic, renal, and hepatic status was necessary to enter the study.

When considering previous treatment failure with standard of care, cabozantinib and vandetanib were both considered standard-of-care therapies for patients with RET-mutant MTC (cohort 3 of the entire LIBRETTO-001 study).

Patients were excluded if they had a specific oncogenic driver that could cause resistance to selpercatinib treatment. Also, they could be excluded if they had received prior treatment with RET inhibitors, an investigational drug, or an anti-cancer therapy within 5 half-lives or 2 weeks (whichever is shorter) before the planned start of selpercatinib. In addition, no concurrent investigational anti-cancer therapy was permitted. Major surgery, radiotherapy, unresolved toxicities from prior therapies, and symptomatic CNS tumour and metastases were considered exclusion criteria.

Baseline Characteristics

Baseline demographic information, disease characteristics, and prior medications are described in Table 8. This table reports on the subpopulation with RET-mutant MTC for the 3 cut-off dates.

The median age of the group was |||| ||||| |||| |||| | |||||||| ||||| |||| |||| || ||||| || |||| ||| |||||| ||||||| || ||| || ||||| || |||| || ||||| || ||||| || |||||||||||| || |||| ||||| |||| || ||| |||| ||| |||||. Most patients had an ECOG PS status of 0 or 1, with only || |||||| presenting with an ECOG PS of 2, and the majority were stage IV or above at diagnosis, |||| || ||||||| || || |||||| ||||| |||||||||. All but ||| patients had a history of metastatic disease. The majority of patients ( | |) had the M918T RET mutation type. |||| |||||||| ||||||||| |||||||| || |||||||| ||||||||.

In terms of previous therapies, the majority ||||||| had received prior systemic therapies at baseline, mostly consisting of vandetanib ||||||| and cabozantinib ||||||||. Only ||||| had not received any prior systemic regimen. Prior cancer-related therapy was reported in ||||| of patients.

Interventions

Selpercatinib was to be administered as either oral capsule or suspension, once or twice daily, depending on cohort assignment. Dosing followed a fixed milligram format (as opposed to being based on weight or on body surface area).

In the dose-escalation phase (phase I) of the study, patients were to be assigned in a sequential (non-randomized) fashion to the planned dose levels. The starting dose of selpercatinib used was 20 mg, given once daily. Selpercatinib was provided in various forms for oral dosing as capsules (powder) containing 20 mg of the drug. These were provided to the sites in bottles of 25 capsules. Selpercatinib was also provided in a simple blend with excipients in a capsule in dose strengths of 10 mg, 20 mg, and 80 mg. A third option was the use of liquid suspension (from protocol version 5.0). Dose escalation continued to 240 mg twice a day.

The RP2D of selpercatinib was set at 160 mg twice a day; this dose was selected by the sponsor in conjunction with the SRC for the LIBRETTO-001 study. The RP2D is used in the phase II portion of the study, in which all patients began dosing at the recommended dose that was determined to be safe in the escalation portion.

Distribution of all patients from the LIBRETTO-001 study to the cohorts established (Figure 2) was made by the sites according to tumour type and was reviewed by the sponsor during screening. Patients in all cohorts received the same study drug in a non-randomized, non-blinded fashion.

Allowed concomitant medications included standard supportive medications used in accordance with institutional guidelines and investigator discretion. Examples include hematopoietic growth factors to treat neutropenia, anemia, or thrombocytopenia; anti-emetic, analgesics, and antidiarrheal medications; glucocorticoids, including short courses to treat asthma, chronic obstructive pulmonary disease, and so forth; thyroid replacement therapy for hypothyroidism, bisphosphonates, denosumab, and other medications for the treatment of osteoporosis and the prevention of skeletal-related events from bone metastases; and/or hypoparathyroidism. Local treatment while receiving selpercatinib (e.g., palliative radiation therapy or surgery for bone metastases) was permitted with sponsor approval.

Concomitant systemic anti-cancer drugs, hematopoietic growth factors for prophylaxis in cycle 1, therapeutic monoclonal antibodies, drugs with immunosuppressant properties, or medications known to be strong inhibitors or inducers of CYP3A4 were not allowed during the study, nor were other investigational drugs and proton pump inhibitors.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 9. These end points are further summarized subsequently. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

OS was derived for each patient as the number of months from the date of the first dose of the study drug to the date of death, irrespective of cause. Patients who were alive or lost to follow-up as of a data analysis cut-off date were right-censored. The censoring date was determined from the last date the patient was known to be alive or the data analysis cut-off date, whichever occurred first.

PFS was derived for each patient as the number of months from the date of the first dose of the study drug to the earlier of documented PD or death due to any cause. Patients who were alive and without documented PD as of a data analysis cut-off date were right-censored according to the censoring methods of the OS and DOR. PFS was right-censored for patients who met 1 or more of the following conditions:

• no post-baseline disease assessments unless death occurred before the first planned assessment (in which case death will be considered a PFS event)

• subsequent anti-cancer therapy or cancer-related surgery in the absence of documented disease progression

• died or documented disease progression after missing 2 or more consecutively scheduled disease assessment visits

• alive and without documented disease progression on or before the data cut-off date.

If a patient met more than 1 of these conditions, then the scenario that occurs first was used for analysis.

ORR was assessed in the LIBRETTO-001 study using RECIST 1.1 or RANO criteria as appropriate to tumour type. The analysis of ORR was conducted both by the responses determined by each investigator and responses as determined by IRC.

DOR was calculated for patients who achieved a CR or PR. For such patients, DOR was defined as the number of months from the start date of CR or PR (whichever response status is observed first) and subsequently confirmed, to the first date that PD was objectively documented. If a patient died, irrespective of cause, without documentation of PD beforehand, then the patient’s date of death was used to denote the response end date. DOR will be right-censored for patients who meet 1 or more of the following conditions:

• subsequent anti-cancer therapy or cancer-related surgery in the absence of documented disease progression

• died or experienced documented disease progression after missing 2 or more consecutively scheduled disease assessment visits

• alive and without documented disease progression on or before the data cut-off date.

HRQoL end points were measured with the EORTC QLQ-C30, a commonly used patient-reported outcome measure in oncology clinical trials²⁸ that consists of 30 questions. The questions are scored to create 5 multi-item functional scales, 3 multi-item symptom scales, 6 single-item symptom scales, and a 2-item QoL scale. The tool uses a 1-week recall period for assessing function and symptoms. Most questions have 4 response options (not at all, a little, quite a bit, very much), with scores on these items ranging from 1 to 4.29. For the 2 items that form the global QoL scale, however, the response format is a 7-point Likert-type scale, with anchors between 1 (very poor) and 7 (excellent). Each raw scale score is converted to a standardized score that ranges from 0 to 100 using a linear transformation, with a higher score reflecting better function on the function scales, higher symptoms on the symptom scales, and better QoL (i.e., higher scores simply reflect higher levels of response on that scale). Thus, a decline in score on the symptom scale would reflect an improvement, whereas an increase in score on the function and QoL scales would reflect an improvement. Although this scale has been validated in different settings and clinical entities, no studies have assessed the validity and reliability in patients with RET-mutant MTC or other thyroid cancers. A clinically meaningful difference was defined by the sponsor as a 10-point difference (of the standardized 0 to 100 overall scale) from baseline for each patient based on a single study.²⁹

Another HRQoL instrument used in the LIBRETTO-001 trial was the use of diarrhea or bowel diaries. The bowel diary used was a questionnaire-modified version of the Systemic Therapy Induced Diarrhea Assessment Tool (STIDAT), a standardized patient-reported questionnaire used to assess diarrhea in patients with cancer actively treated with chemotherapy or systemic therapies (with or without radiation) that are considered to have a high risk of causing diarrhea. The modified STIDAT (mSTIDAT) contains 11 questions and assesses all the dimensions in the original STIDAT except for use of antidiarrheal medication, which can reduce bowel movement frequency. In the mSTIDAT, the QoL subscale asks patients to rank the impact of bowel habits (questions 7 to 9) and diarrhea (questions 10 to 11) on their daily living from 0 (no impact) to 10 (extreme impact). The psychometric properties of STIDAT have not been validated in patients with thyroid cancer and/or those on targeted therapy. Also, no minimally important difference (MID) has been estimated for the STIDAT in either a general population or patients with thyroid cancer. Based on the ranges of scores for each severity, clinicians may categorize scores from 0 to 1.1 as no diarrhea, greater than 1.1 to 2 as mild diarrhea, greater than 2 to 3 as moderate diarrhea, and greater than 3 as severe diarrhea.

Statistical Analysis

Phase I of the study was aimed at evaluating the MTD and the RP2D (optimal dose) based on the dose-escalation process previously described. The primary end point of phase II of the LIBRETTO-001 study was to determine the antitumour activity of selpercatinib by determining the ORR using RECIST 1.1 with DOR, OS, and PFS stated as secondary end points. The frequency, severity, and relatedness of treatment-emergent adverse events (TEAEs) and SAEs, changes in hematology and blood chemistry values, assessments of physical examinations, vital signs, and ECGs were considered in both phases.

The primary analysis for the interim analysis of this study was based on data available at a cut-off of June 17, 2019. Additional 6-month follow-up data were assessed based on a December 16, 2019 cut-off date and used by the sponsor at the request of Health Canada. For the primary analysis, the PAS is presented in both cut-off dates; hence, the results from the December 16, 2019 cut-off point is the focus of this CADTH review.

Power and Sample Size

A total of approximately 120 patients was estimated to be enrolled in phase I.

For phase II of the study, in cohort 3 (patients with RET-mutant MTC who progressed on or were intolerant to vandetanib and/or cabozantinib), a true ORR of 35% or greater was hypothesized when selpercatinib was administered to such patients. A sample size of 83 patients was estimated to provide 85% power to achieve a lower boundary of a 2-sided 95% exact binomial CI for the estimated ORR that exceeds 20%. Ruling out a lower limit of 20% was considered clinically meaningful in patients who have failed prior MKI therapy (e.g., cabozantinib) and currently have limited treatment options for their advancing disease.

For cohort 4 (patients with RET-mutant MTC who are MKI-naive), a true ORR of ≥ 50% was hypothesized when selpercatinib was administered to such patients. A sample size of 55 patients was estimated to provide 85% power to achieve a lower boundary of a 2-sided 95% exact binomial CI for the estimated ORR that exceeds 30%.

Statistical Tests and Models for Efficacy End Points

The previously described safety analysis set was used for studying the primary end points of antitumour activity of selpercatinib. The sponsor presents efficacy analyses by each phase II cohort of the LIBRETTO-001 study. Patients treated during the phase I portion of the study who met the phase II eligibility criteria for 1 of the phase II cohorts were included as part of the evaluable patients for that cohort for the efficacy analyses. The analysis of response for the interim Clinical Study Report (June 6, 2019) was based on the responses determined by the investigator.

The estimate of ORR was calculated based on the maximum likelihood estimator (i.e., crude proportion of patients with a best overall response of CR or PR). The estimate of the ORR was accompanied by a 2-sided 95% exact binomial CI. Best overall response for each patient (CR, PR, stable disease, PD, or non-evaluable) occurring between the first dose of selpercatinib and the date of documented disease progression or the date of subsequent anti-cancer therapy or cancer-related surgery was determined based on the RECIST 1.1 criteria for primary solid tumours.

OS, PFS, and DOR were summarized descriptively using the Kaplan-Meier method. The Kaplan-Meier estimate with 95% CI calculated using the Brookmeyer and Crowley method was provided for the median. The event-free rate with the 95% CI calculated using the Greenwood formula was provided for selected time points. The median follow-up for each of these end points was estimated according to the Kaplan-Meier estimate of potential follow-up.³⁰

EORTC QLQ-C30 (version 3.0) was assessed using descriptive analyses reporting the median or quartile, mean (SD), and mean change (standard deviation [SD]) from baseline for each subscale at each study visit for the study cohort. The sponsor reported the number and percentage of patients whose conditions were improving, stable, or worsening at each visit time point for all patients, and the number and proportion of patients experiencing definite improvement and time to definite improvement (defined as an improvement from baseline by 10 or more points without any further deterioration in score by 10 or more points). Similarly, the number and proportion of patients experiencing definite worsening and time to definite worsening (defined as time until the first worsening from baseline, i.e., a decrease of 10 or more points without any further improvement of 10 or more points) were also reported.

The results of the Pediatric Quality of Life Inventory 4.0 core module were also reported descriptively to report HRQoL in patients aged 13 to 17 years (using the teen version) and in patients aged 12 years (using the version for children).

The bowel diary questionnaire was used with a modified version of the STIDAT, a standardized patient-reported questionnaire used to assess systemic therapy–induced diarrhea in oncology patients. For this end point, the Kaplan-Meier method was used to evaluate time to first improvement (among those with diarrhea at baseline) and time to first worsening (for the entire MTC cohort), respectively, for which worsening is defined as any stepwise categorical decline in the diarrhea item 1 (e.g., no diarrhea to mild, moderate, or severe; mild to moderate or severe; moderate to severe), and improvement is defined as any stepwise improvement (e.g., mild to no diarrhea; moderate to mild or no diarrhea; severe to moderate, mild, or no diarrhea). For patients with improvement, the duration of improvement (defined as the time from the first improvement until any stepwise categorical decline) was reported as median with 95% CI, mean (SD) days.

Subgroup analyses were not determined a priori in the protocol stage or the main interim analysis (June 17, 2019); however, subgroups are presented in a latter cut-off date report (December 16, 2019) for ORR based on age at enrolment, sex, race, ECOG PS, RET mutation type, metastatic disease, and prior systemic therapies.

For these end points and analyses, an approach accounting for multiple testing was not described.

Sensitivity and Subgroup Analyses

Sensitivity analyses were described for an interim analysis as using report data based on IRC or based on investigator assessments. No specific sensitivity analyses are described in the protocol.

Similarly, subgroups were not defined in the protocol. However, a section of efficacy outcomes is presented descriptively without subgroup effects analyses for the December 16, 2019 cut-off date, based on age, sex, race, ECOG PS, RET mutation type, metastatic disease, prior systemic therapies, and RET molecular assay; all of these were described only for the outcome of ORR.

Analysis Populations

Analysis sets in all the LIBRETTO-001 populations are described in the Description of Studies and Populations sections of this report. The analysis sets created for the main analysis were the following:

• Safety analysis set. The safety analysis set included all enrolled patients who received 1 or more doses of selpercatinib. The safety analysis was conducted on the SAS. A baseline measurement of at least 1 laboratory or other safety-related measurement obtained after treatment with the study drug may have been required for a specific safety parameter to be included in the analysis.

• Dose-limiting toxicity (DLT) analysis set. The DLT analysis set included all patients enrolled in the phase I dose-escalation phase who had a DLT within the first 28 days on study, or those without a DLT but who completed safety assessments through the first 28 days of treatment in cycle 1 and received at least 75% of the planned total dose during cycle 1. Patients who were replaced for the determination of MTD were not included in this analysis set. Each patient who received less than 75% of planned doses during cycle 1 was reviewed by the SRC. If the SRC determined that the reason or reasons for treatment discontinuation were not related to the patient’s underlying disease, other medical condition, or concomitant medications, the treatment discontinuation was considered a DLT. The DLT summary was conducted on the DLT analysis set for the phase I dose escalation for each dose level.

• Patient-reported outcome analysis set. These analysis sets were defined separately for each patient-reported outcome instrument and included all treated patients who had a baseline and at least 1 post-baseline patient-reported outcome assessment.

• Efficacy analysis set. For the interim Clinical Study Report (cut-off date June 17, 2019), the efficacy analysis was conducted on the SAS by phase II cohort, unless otherwise specified. Patients enrolled during dose escalation and dose expansion (phase I) were to be included in the appropriate phase II cohort dataset if they met the enrolment criteria for that cohort.

For the population including patients with RET-mutant MTC, the analysis sets included the following:

• PAS. This includes the first 55 patients with RET-mutant MTC enrolled in the phase I and phase II portions of LIBRETTO-001 as of June 17, 2019, who had been previously treated with cabozantinib or vandetanib.

• IAS. This includes all patients with RET-mutant MTC enrolled in LIBRETTO-001 who met the same eligibility criteria as the PAS by the June 17, 2019 data cut-off for the initial US submission (N = 124). The PAS is a subset of patients in the IAS who had been previously treated with cabozantinib or vandetanib. This IAS provides further information on the efficacy of selpercatinib in a larger number of patients, providing increased information in the PAS results. The efficacy data presented in the Canadian submission is based on a December 16, 2019 cut-off date.

• SAS 1. This includes all cabozantinib or vandetanib treatment-naive patients with RET-mutant MTC.

• SAS 2. This includes patients without measurable disease by RECIST 1.1.

Results

Patient Disposition

The LIBRETTO-001 study screened a total of ||| patients of all populations for the initial inclusion criteria, of which || ||||||| did not meet the eligibility criteria, as shown in Table 10. The study included 531 patients in the efficacy population (i.e., those who received ≥ 1 dose of selpercatinib as of the June 17, 2019 and December 16, 2019 cut-off dates).

The study focus for this review is the population with RET-mutant MTC, which consisted of 226 patients in the efficacy population and 299 in the safety population. Of the patients in the efficacy population, ||||| |||||||||||| ||| ||||| ||||| |||||| ||| || ||||||| ||||||||||| || ||||||| |||||| ||| | |||||||| |||||||||||| ||||| |||| ||| || |||||.

As shown in Figure 3 and Figure 4, of the 226 patients within the MTC efficacy population, 88 were included in the treatment-naive (not treated with cabozantinib or vandetanib) patient group (SAS 1), 124 were among those previously treated with cabozantinib or vandetanib (IAS), and 14 were in cohort 5 with non-measurable disease (SAS 2). The first 55 patients previously treated with cabozantinib or vandetanib were included in the PAS, which is a subset of the IAS.

Exposure to Study Treatments

At the time of the December 16, 2019 interim analysis, of the 531 patients (all populations from the LIBRETTO-001 study) who received selpercatinib, the majority || | |||| were started at a phase II dose of 160 mg twice daily. Of the 439 patients who started at the phase II dose of 160 mg twice daily, ||| ||||||| patients were continuing treatment. The median actual dose intensity (milligrams of selpercatinib per day) was influenced by the fact that the patients underwent intra-patient dose escalation and, therefore, although actual dose intensity increased with increasing doses, many patients ultimately received higher doses than their starting dose, most often 160 mg twice a day. The median relative dose intensity (actual dose intensity divided by the planned dose intensity) ranged from |||||| || |||||| for all dose levels.

The 226 patients with RET-mutant MTC had a mean || |||| ||||||||| ||||||||| |||| || || |||||| || ||||||||| ||| | |||||| || |||| |||||| |||||||| |||| ||| || |||| |||||||.

Among the 299 patients in the safety analysis set, the most common concomitant medications used (in more than 20% of patients) included thyroid hormones in | | | |||||| | |||| | ||| | ||||||| | |||| | |||||||| | | | | |||||| | ||||||||| | | | |||||| | ||||||||| | ||||||||| | |||| | ||||||||| | | | |||||| | ||||||||||||| | | | |||||| | ||||||||||| | ||||||||||||||| | |||| | ||||| | | | |||||| | | | ||||||||||||| | | ||||||||.

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported subsequently, and the primary analysis is focused on the PAS for the December 16, 2019 cut-off date. When available, the results of the previous data cut-offs of June 17, 2019 and March 30, 2020 are also presented. All of the efficacy results presented were evaluated by IRC.

Survival

Overall Survival

OS in the efficacy population with MTC (December 16, 2019 data cut-off date) had a median duration of follow-up of |||| |||||| |||||||||||||| ||||| ||||| |||| || ||||| ||| ||| |||||| ||| |||||||| ||| ||| ||| |||||||||| ||| ||| ||||||| |||||| |||||| ||| |||||| || ||||| |||| |||| ||| || ||| |||||||||| ||| ||||| |||||||||| || |||||||| ||| ||| ||||| |||| |||| ||| || |||| |||||| (Table 11 and Figure 5). The rate of survival at 12 months or more was ||||| || ||| |||||||||| |||| || |||| || ||||||.

For the March 30, 2020 cut-off date, the group of patients in the PAS (n = 55) reached a median OS of 33.2 months (range, 1.1+ to 33.3+) with similar values in the treatment-naive IAS group. The SAS group did not reach the median of survival (Table 11).

Table 11: Efficacy Outcomes of Survival — LIBRETTO-001 December 16, 2019 and March 30, 2020 Cut-Off Dates

CI = confidence interval; FAS = full analysis set; IAS = integrated analysis set; IQR = interquartile range; IRC = independent review committee; ITT = intention to treat; LS = least squares; NE = not estimable; NR = not reported; PAS = primary analysis set; + = censored observation; SAS = supplemental analysis set; SD = standard deviation.

Note: All end points were based on IRC assessments with a December 16, 2019 cut-off date.

^aEstimate based on Kaplan-Meier method.

Source: LIBRETTO-001 Clinical Study Report.¹⁸

Figure 5: Redacted

+ = censored observation.

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

Source: LIBRETTO-001 Clinical Study Report.¹⁸

Progression-Free Survival

PFS in patients with MTC in the PAS at the December 16, 2019 cut-off date had a median duration of follow-up of 16.7 months |||| |||| || ||||||. The median for PFS for the PAS population was not reached and the range went from | || |||| |||||| (Table 11 and Figure 6, Figure 7, and Figure 8). The rate of PFS at 12 months or more was ||||| of the population.

For the March 30, 2020 cut-off date, no patients in the groups evaluated (PAS, IAS, SAS) reached the median for PFS (range 0.0+ to 32.2+).

Figure 6: Kaplan-Meier Plot of PFS Based on IRC Assessments (Primary Analysis Set, N = 55)

IRC = independent review committee; PFS = progression-free survival; + = censored observation.

Source: LIBRETTO-001 Clinical Study Report.¹⁸

Figure 7: Redacted

+ = censored observation.

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

Source: LIBRETTO-001 Clinical Study Report.¹⁸

Figure 8: Redacted

+ = censored observation.

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

Source: LIBRETTO-001 Clinical Study Report,¹⁸

Response and Remission

Objective Response Rate

The percentage of patients reaching an ORR for the PAS population was 69.1% (95% CI, 55.2 to 80.9) as of the December 16, 2019 cut-off date and, overall, it was similar across the different sets. Similarly, for the March 30, 2020 cut-off date, results for ORR were 69.1% for the PAS population and similar across other sets (Table 12).

Duration of Response

At the cut-off date of December 16, 2019, the DOR had a median follow-up of 14.06 months (||| || || ||||) in the PAS, and the median DOR was not reached in any analysis set, except for SAS 1 (21.9 months, ||||| ||| || ||). For the March 30, 2020 cut-off date, the results were similar, except for the SAS 1 group, where the DOR reached a median of 21.9 months (range, 1.5 to 24.1) but with a median follow-up of 9.26 months (Table 12, Figure 9).

The total percentage of patients reaching a DOR for more than 12 months was || ||||| || ||| |||| ||||| || ||| |||| ||||| || ||||| ||| || || |||| for the December 16, 2019 cut-off date. For the March 30, 2020 cut-off date, the percentage of patients reaching a DOR for more than 12 months was 68.4% in the PAS group (Table 12).

Figure 9: Kaplan-Meier Plot of DOR Based on IRC Assessments (Primary Analysis Set)

DOR = duration of response; IRC = independent review committee.

Source: LIBRETTO-001 Clinical Study Report.¹⁸

Health-Related Quality of Life

EORTC QLQ-C30

EORTC QLQ-C30 was measured as an exploratory end point in a specific analysis set of the MTC population (Table 13). No patients were able to complete the pediatric questionnaire for HRQoL; hence, no results are provided on this measurement. Patients completed the EORTC QLQ-C30 version 3.0 at baseline (cycle 1, day 1, before study treatment) and approximately every 8 weeks thereafter, corresponding to imaging assessments (approximately every other cycle) until cycle 13.

Data from the December 16, 2019 cut-off date was obtained from a publication by the sponsor,¹⁷ where a change in global health status/QoL or functional subscale score was considered an improvement if it increased from baseline by 10 or more points and considered a worsening if it decreased from baseline by 10 or more points. Conversely, a decrease from baseline of 10 or more points in symptom subscale score was considered an improvement, and an increase from baseline of 10 or more points in symptom subscale score was considered a worsening. Patients who met the threshold for either improvement or worsening in change from baseline subscale score, without further changes of 10 or more points reversing that change, were considered to have a definite improvement or definite worsening, respectively. Functional subscale values lower than the established thresholds were considered clinically meaningful: physical function scores less than 83, emotional function less than 71, role function less than 58, cognitive function less than 75, and social function less than 58. Conversely, symptom subscale values higher than the established thresholds were considered clinically meaningful: fatigue score greater than 39, pain greater than 25, diarrhea greater than 17, dyspnea greater than 17, appetite loss greater than 50, insomnia greater than 50, constipation greater than 50, and financial difficulties greater than 1.

Data from the publication¹⁷ included 88 patients (41.5%) who were treatment-naive (with either vandetanib or cabozantinib) and 124 patients (58.5%) who had previously received these MKIs at study entry. Baseline physical function subscale scores were 80.9 (SD = 20.0) overall, 85.2 (SD = 18.2) for patients who were treatment-naive, and 75.4 (SD = 21.9) for patients with previous treatment. All of these baseline values met a clinically meaningful threshold for reduced physical function (score below 83). Most patients improved or remained stable on the physical function subscale at each cycle during study treatment with selpercatinib. Of all patients, 18.7% (36 out of 193) met the criteria for a definite improvement and 13.0% (25 out of 193) met the criteria for a definite worsening in physical function. Baseline physical function subscale scores were 80.9 (SD = 20.0) overall, 85.2 (SD = 18.2) for patients who were treatment-naive, and 75.4 (SD = 21.9) for patients with previous treatment. Most patients improved or remained stable on the physical function subscale at each cycle during study treatment with selpercatinib. Of all patients, 18.7% (36 out of 193) met the criteria for a definite improvement and 13.0% (25 out of 193) met the criteria for a definite worsening in physical function. Among the treatment-naive and previous treatment subgroups, respectively, 10.5% and 22.5% met the criteria for a definite improvement and 14.5% and 11.3% met the criteria for a definite worsening in physical function.

For global health status, the mean baseline global health status/QoL subscale scores were 65.1 (SD = 23.8) overall, and 68.5 (SD = 23.7) and 60.6 (SD = 23.5) for patients who were treatment-naive or previously treated, respectively. Most patients improved or remained stable on the global health status/QoL subscale at each cycle. Of all patients, 29.0% (56 out of 193) met the criteria for a definite improvement in global health status/QoL and 13.0% (25 out of 193) met the criteria for a definite worsening in global health status/QoL. Among the treatment-naive and previously treated subgroups, respectively, 26.3% and 31.3% met the criteria for definite improvement and 17.1% and 12.5% met the criteria for a definite worsening in global health status (QoL). The median time to first improvement was 5.6 months (95% CI, 3.7 to not reached) for those in the treatment-naive subgroup and 3.6 months (95% CI, 2.0 to 7.4) for patients with previous treatment exposure.

Bowel Diaries

In the same published study, of the 123 English-speaking patients who completed the mSTIDAT at baseline (cycle 1), 99 (80.4%) reported experiencing diarrhea at study entry. The patient-reported severity of diarrhea at baseline was minimal among 22 patients (22.2%), moderate among 48 patients (48.5%), and severe among 25 (25.3%) patients reporting diarrhea. Less than half of all patients reported diarrhea at each assessment after cycle 2 (range, 33.3% to 48.3%) of treatment, with fewer patients than at baseline (range, 0% to 17.2%) reporting the severity to be severe. The impact of diarrhea reported on the mSTIDAT ranges from 0 (no impact) to 10 (extreme impact on family life, social life, and overall QoL). At baseline, the mean impact of diarrhea was 2.7 (SD = 3.0) for family life, 3.6 (SD = 3.2) for social life, and 3.5 (SD = 2.8) for overall QoL. Patients reported little impact of diarrhea on any of these aspects of daily living during study treatment with selpercatinib.

Sensitivity analyses based on IRC and investigator-evaluated end points were similar overall and robust between assessments. Subgroups described in the Clinical Study Report for the PAS were small in sample size (n = 55) and not determined to be examined a priori. In a visual assessment, no meaningful differences were noted between the subgroups presented (age, sex, race, ECOG PS, RET mutation type, metastatic disease, prior systemic therapies, and RET molecular assay).

Harms

Harms are summarized from the safety population of the LIBRETTO-001 study (cut-off date December 16, 2019), and only those harms of interest identified in the review protocol are reported subsequently. AEs in the LIBRETTO-001 study were defined as any unfavourable medical occurrence in a patient who had been administered the drug under investigation, i.e., selpercatinib, with the occurrence not necessarily related to the intervention. An SRC was in charge of overseeing the safety aspects from phase I to complete the dose-escalation assessments.

Adverse Events

The AEs are summarized in Table 14. Investigators graded the severity of AEs from grade 1 (mild), to grade 5 (fatal) according to the Common Terminology Criteria for Adverse Events version 4.03.³¹

Among the 299 patients with RET-mutant MTC included in the safety population, ||| ||||||| ||||||||| || ||||| ||| ||| |||| ||||| ||| || with grade 3 or 4 and grade 5 AEs, respectively. A total of || |||||||| |||||| had AEs and discontinued the drug.

The most commonly reported AEs (> 20% of patients with at least 1 of these) included hypertension, diarrhea, constipation, fatigue, headache, peripheral edema, nausea, and abdominal pain.

Serious Adverse Events

SAEs occurred in || ||||||| of the 299 patients in the safety population, with || |||||| categorized as being related to selpercatinib. Among these, |||| patients had a fatal AE. The most common SAEs were |||||||||| ||||||||||||| ||| ||||||||||||| ||||| |||| ||||||| || ||||| ||||| ||| || of patients, respectively (Table 14).

Mortality

As of the December 16, 2019 cut-off date, among the 299 patients in the safety population with RET-mutant MTC, | |||||| |||||| |||||||| |||||| || |||| || |||| |||| || ||||||||||||| || ||| || ||||||| |||||||||||| | ||| || ||||||| |||||||| ||| || |||||| |||||||| |||| |||| || |||| ||||| ||| |||| ||||| || |||||| ||| || ||||||| |||||||||||| | ||| || ||||||| ||||||| | ||| || ||||| |||||| ||||||||||.

AEs were reported at the March 30, 2020 cut-off date, although not broken down by diagnosis populations but rather as the totality of patients included in the LIBRETTO-001 trial (MTC, NSCLC, DTC; N = 746). Of these, the most frequently reported drug-related TEAEs (reported in at least 20% of participants) were similar to the previous cut-off date in the MTC, i.e., dry mouth (35.5%) ALT increased (26.4%), AST increased (26.3%), hypertension (25.5%), and diarrhea (21.8%). Most AEs related to the study intervention were grade 1 (||||||||||||||| ||||||| grade 2 |||| ||||||||||||| ||||||| and grade 3 |||| ||||||||||||| |||||). For these cut-off dates, there were | | ||||||||| | |||| | || | || | |||||||| | | || | |||||| | |||||| | ||| | | | |||| | | || | | || | || | | ||| | ||||||||||||.

Notable Harms

Harms of special interest stated in the protocol for this review included diarrhea, bleeding, hepatotoxicity (AST or ALT increase), QTc prolongation, hypertension, and photosensitivity.

Elevations of liver enzymes occurred frequently, with || ||||||| ||| || ||||||| patients with ALT and AST elevations, respectively, although most were low grade (Table 14). Hypertension was reported (as TEAE by preferred term) in ||| ||||||| of patients. Diarrhea was present in || ||||||| of patients at any point, and hypersensitivity was rare (| ||||||||).

A common concern among clinicians was QTc prolongation, which was reported in ||| ||||||| of patients, with values that had increased by more than 30 ms from baseline, and || |||||||| ||||||| with values that had increased by more than 60 ms.

The harms events for the March 30 2020 cut-off date were similar to the harms events for the December 16, 2019 cut-off date, with a total of 313 (99.4%) AEs, and 97 patients (30.8%) with at least 1 SAE. At this cut-off, 28 out of 315 (8.9%) deaths occurred within 28 days of the last dose of selpercatinib (18 due to disease progression, 8 due to AEs, and 2 due to other), and no death occurred more than 28 days after the last dose. The most common AEs (> 5%) included dry mouth |||||, diarrhea |||||, hypertension |||||, fatigue ||||||, constipation (|||), increased AST (|||), increase ALT (|||), peripheral edema (|||), nausea (|||), increased blood creatinine level (|||), abdominal pain (|||), QT interval prolonged on ECG (|||), arthralgia (|||), cough (|||), and rash (|||). Safety data were analyzed by grade and SAEs.

Critical Appraisal

Internal Validity

The LIBRETTO-001 study is a single-arm, open-label, phase I and phase II study. As such, the study is descriptive in nature, as it did not evaluate the primary or secondary end points (e.g., ORR, DOR, OS, PFS) formally with adjustments for multiple comparisons. These limitations stem from the single-arm design and lack of comparator groups and constrain the estimation of the relative effects of treatment with selpercatinib.

An open-label design may also increase uncertainty in patient-reported outcomes (HRQoL) introducing bias due to the inherent subjectivity of the outcome in an unblinded assessor. This bias would be less likely in more objective outcomes, such as ORR, OS, or PFS if evaluated against a properly a priori set hypothesis. Furthermore, HRQoL outcomes were evaluated as exploratory end points and with no adjustment for multiplicity.

Anti-cancer treatments and prior cancer-related surgery were commonly observed at baseline (which occurred in 85% to 90% of the included patients). Any magnitude of effect that these interventions could have on the outcomes evaluated in patients who received selpercatinib is uncertain, given the lack of comparators.

Sensitivity analyses based on IRC versus investigator assessments were similar overall in their results. The sponsor provides information on different subgroups (for age, sex, race, ECOG PS, RET mutation type, metastatic disease, prior systemic therapies, and RET molecular assay) in the ORR end point; however, the sample size was small, and the end point was evaluated as an exploratory outcome. Hence, evidence is limited for identifying potential subgroup effects in this population.

As of the December 16, 2019 cut-off date, ||||| of patients discontinued the study drug and ||||| discontinued from the study, mostly due to disease progression and death, respectively. At the March 30, 2020 cut-off date, the discontinuation rates remained consistent (17.1% of patients discontinued treatment and 12.7% discontinued from the study, with 7.9% and 4.4% of patients discontinuing treatment due to PD and AEs, respectively). The sponsor evaluated all 226 patients in the efficacy population and all 299 patients in the safety population for the primary and secondary end points.

External Validity

There were fewer concerns about the generalizability of the population included and about the effects on survival and response. According to the clinical experts consulted by CADTH, except for the proportion of females, the baseline characteristics of the population included in the LIBRETTO-001 study were representative overall of the population of patients with RET-mutant MTC seen in Canadian clinical practice. Age, ECOG PS, initial disease stage, cancer history, RET mutation types, and prior therapies were similar to those expected in clinical practice. The inverse ratio of female to male patients being lower than expected was noted by the clinical experts, although they did not consider it to be a concern for applicability.

Most patients had good baseline performance status (e.g., low number of patients with an ECOG PS of 2 or higher), suggesting that the included population might be healthier when compared with Canadian clinical practice; however, the clinical experts did not consider it highly different from what is expected.

All outcomes measured in the LIBRETTO-001 study are of clinical relevance and, according to the clinical experts, important for patients and well known and used by clinicians in Canada. The only concern was the limitation of the follow-up, i.e., that it might be considered too short for assessing longer periods of observations for those patients continuing the study and for assessing OS.

Table 15 summarizes the generalizability of the evidence.

Table 15: Assessment of Generalizability of Evidence for Selpercatinib

DOR = duration of response; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; HRQoL = health-related quality of life; MTC = medullary thyroid cancer; ORR = objective response rate; OS = overall survival; PedsQL = Pediatric Quality of Life Inventory; PFS = progression-free survival; RET = rearranged during transfection.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

Selpercatinib has been previously assessed in a single-arm randomized controlled trial. However, no head-to-head evidence of selpercatinib compared against other relevant treatments for advanced RET mutation–positive MTC was available for this review. Due to this gap in evidence, the sponsor submitted an ITC for CADTH to review. Electronic databases including MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL), were searched using a combination of MeSH and keywords. Websites of professional organizations, including the European Society for Medical Oncology, International Association for the Study of Lung Cancer, ClinicalTrials.gov, and the International Clinical Trials Registry Platform, were searched to identify relevant conference abstracts. Retrieval was not limited by publication date or by language. Titles, abstracts, and full-text articles were screened for inclusion by 1 reviewer based on population and disease condition, interventions, comparators, outcomes, and study types (PICOS criteria). CADTH also conducted a literature search to identify other potentially relevant ITCs.

One sponsor-submitted ITC was summarized and critically appraised. This ITC was used to inform the pharmacoeconomic model.

Description of Indirect Comparison(s)

The overall objective of the sponsor-submitted ITC was to estimate the treatment effect for selpercatinib versus cabozantinib, vandetanib, and BSC (including placebo) in all lines of treatment for RET-mutation MTC. The outcomes analyzed were OS, PFS, and ORR. The population, intervention, comparators, outcomes, and design of studies included in the sponsor’s ITC are provided in Table 16.

Methods of ITC 1

Objectives

The efficacy of selpercatinib was evaluated in a single-arm trial, LIBRETTO-001. Indirect comparisons were conducted for selpercatinib versus relevant comparators for the treatment of advanced RET mutation–positive MTC as head-to-head trials did not exist.

Study Selection Methods

The sponsor conducted a systematic literature review of published clinical studies to identify comparators for selpercatinib for the treatment of patients with MTC or PTC. The literature search was conducted on September 30, 2019. In total, 44 publications were identified that included patients with thyroid cancer, of which 16 were primary studies. Of the 16 studies, 11 were trials that included patients with MTC, 3 included patients with PTC, and 2 included patients with both MTC and PTC. Among these 16 primary studies, 2 were for advanced RET mutation–positive MTC and 2 for advanced RET fusion–positive thyroid cancer. The outcomes analyzed were OS, PFS, and ORR.

The trial characteristics, patient demographics, treatment history, treatment outcomes, and interventions found in the included clinical trials were extracted from the full-text publications. Resources retrieved from websites were printed to preserve a record of information in the event that the information on the websites changes or becomes unavailable. References to other publications within a trial were backtracked to the original sources, where appropriate.

Data were extracted by 1 researcher using Microsoft Excel and all data were quality-validated by an independent reviewer, who performed a verification of the data from the original source. Data were quality-checked before their use in the ITC.

For each eligible trial, a quality assessment was performed to the standards recommended by the National Institute of Health and Care Excellence (NICE). At the time of the review, no validated tool to assess the quality of single-arm trials existed; thus, the Critical Appraisal Skills Programme cohort study checklist was used to assess the quality of all single-arm trials.

ITC Analysis Methods

Because the LIBRETTO-001 trial is a single-arm trial and does not have a control arm, it was not possible to perform a network meta-analysis or an anchored ITC to estimate the relative efficacy of selpercatinib versus relevant comparators. As such, an unanchored matching-adjusted ITC (an unanchored MAIC) comparing LIBRETTO-001 with the EXAM trial was conducted to estimate the relative efficacy of selpercatinib versus cabozantinib and placebo.

The sponsor compared selpercatinib in the LIBRETTO-001 trial (including all patients previously treated with cabozantinib, vandetanib, or both, and all cabozantinib and vandetanib treatment-naive patients) against placebo from the intention-to-treat population of the EXAM trial, and against patients treated with cabozantinib in the RET mutation–positive and RET M918T subgroups from the EXAM trial.

An unanchored adjusted ITC was conducted using individual patient-level data from the LIBRETTO-001 trial and summary statistics from the EXAM trial. MAICs were conducted for PFS and OS in which outcomes in the LIBRETTO-001 trial using propensity score weighting.

Kaplan-Meier curves were not available for OS for the RET mutation–positive subgroup treated with cabozantinib or placebo from the EXAM trial. Therefore, the unweighted curves for the RET M918T–positive patients receiving cabozantinib or placebo in the EXAM trial were digitized from Schlumberger 2017³³ and compared with the weighted curve for the any-line LIBRETTO-001 population. Propensity score matching was performed using the LIBRETTO-001 data and the EXAM trial data such that the LIBRETTO-001 outcomes were adjusted to reflect the EXAM trial population characteristics for the RET mutation–positive subgroup treated with cabozantinib.

For PFS, the unweighted curves for the RET mutation–positive population receiving cabozantinib or placebo in the EXAM trial were digitized from Sherman 2016³⁴ and compared with the weighted curve for the LIBRETTO-001 population. Propensity score matching was performed using LIBRETTO-001 data and data from the EXAM RET mutation–positive subgroup treated with cabozantinib.

The MAIC was adjusted for baseline characteristics; known or potential associations with the efficacy outcomes were reported in both the LIBRETTO-001 trial and EXAM trial publication. Re-weighting of selpercatinib data (LIBRETTO-001 trial) was based on baseline characteristics of the cabozantinib arm (EXAM trial, RET mutation–positive subgroup only). However, a comparison of adjusted selpercatinib outcomes data was conducted for both the placebo and cabozantinib arms independently. Baseline characteristics between LIBRETTO-001 and EXAM before and post matching were obtained from a logistic regression model. Only baseline characteristics with complete data were adjusted and they included |||| ||||||| |||| ||||||||||| ||||||| |||| ||||||| ||||||| ||||| ||| |||||||| ||| ||| ||||| |||||||| |||||||

To balance the baseline characteristics between LIBRETTO-001 and EXAM, data from LIBRETTO-001 patients were assigned weights such that:

• weighted mean baseline characteristics of LIBRETTO-001 patients exactly matched those reported for patients in the RET mutation–positive subgroup treated with cabozantinib in the EXAM trial

• the weight for each patient was equal to the patient’s estimated propensity weight of being in LIBRETTO-001 versus EXAM (RET mutation–positive subgroup treated with cabozantinib), and

• weights satisfying these conditions were obtained from a logistic regression model for the propensity of inclusion in the LIBRETTO-001 trial versus the EXAM study (RET mutation–positive subgroup treated with cabozantinib), with all matched-on baseline characteristics included as predictor variables in the model.

The logistic regression model was estimated using the method of moments because only summary statistics for baseline characteristics were available from the EXAM study. Using the method of moments estimates, the baseline means were exactly matched after weighting. The distribution of weights was investigated for potential extreme values, which can indicate poor overlap in the distributions of patient characteristics across trial populations.

Results of ITC 1

Summary of Included Studies

The process of study selection was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The searches identified a total of 7,142 records of which 3,390 met the eligibility criteria. Of these, 44 publications from 16 trials were identified that included patients with thyroid cancer. Of the 16 unique studies, 11 were trials including patients with MTC, 3 included patients with PTC, and 2 included patients with both MTC and DTC.

Three trials investigating selpercatinib, cabozantinib, and vandetanib at their recommended doses in patients with MTC were identified by the systematic literature review and deemed evaluable in the feasibility assessment. The 3 trials are LIBRETTO-001, EXAM, and ZETA. The key differences between trial design and reported outcomes are presented subsequently:

• Crossover from placebo to vandetanib was permitted in the ZETA trial at disease progression. This is anticipated to improve the OS of the placebo arm and to bias the estimates of relative efficacy. In the EXAM trial, crossover was not permitted. As a result, there is uncertainty in the comparability of the placebo arms between ZETA and EXAM.

• Outcomes available in EXAM:

  • PFS: Hazard ratio (HR) and Kaplan-Meier curve in ITT population, RET mutation–positive, RET M918T

  • OS: HR, Kaplan-Meier curve in ITT population, RET mutation–positive, RET M918T

  • ORR: ITT population, RET mutation–positive

• Outcomes available in ZETA:

  • PFS: HR in ITT population

  • OS: HR and Kaplan-Meier curve in ITT population

  • ORR: RET mutation–positive, ITT population, and RET M918T

The EXAM trial reported hazard ratios for both PFS and OS in the RET mutation–positive subgroup and included Kaplan-Meier curves for PFS in the RET mutation–positive and for both PFS and OS in M918T subgroups. These data are comparable to LIBRETTO-001, which included patients with RET mutation–positive MTC. In the ZETA trial, the only outcome reported for the RET mutation–positive subgroup is ORR.

Key differences in the patient population characteristics across the 3 trials include:

• The LIBRETTO-001 trial population is slightly older than the EXAM and ZETA trial populations.

• The percentage of male patients in LIBRETTO-001 is slightly lower than in EXAM and higher than in ZETA.

• A higher proportion of patients had an ECOG PS of 1 or 2 in the LIBRETTO-001 trial than in the EXAM and ZETA trial populations.

• The proportion of patients in the LIBRETTO-001 trial with prior anti-cancer therapy was substantially higher than in the EXAM trial and slightly higher than in the ZETA trial.

• The proportion of patients in the LIBRETTO-001 trial with prior TKI therapy was significantly higher than in the EXAM trial (data not reported for the ZETA trial).

• The proportion of patients in the LIBRETTO-001 trial who never smoked was higher than in the EXAM trial (data not reported for the ZETA trial).

Due to these issues with patient heterogeneity, it was deemed infeasible to include the ZETA trial in the comparison.

Results

MAIC Comparison of Baseline Characteristics Between the LIBRETTO-001 and EXAM Trials

Only results for the comparison of selpercatinib and placebo from the MAIC were presented, since cabozantinib was not identified as a comparator of interest in our protocol.

Table 16 presents the comparison of baseline characteristics before and post matching for the datasets from LIBRETTO-001 and the RET mutation–positive subgroup treated with cabozantinib in EXAM. The MAIC adjusted for |||| ||||||| |||| ||||||||||| ||||||| |||| ||||||| ||||||| ||| ||| ||||| |||||||| ||||||. The effective sample size for LIBRETTO-001 after weighting was ||||| |||||| || ||| |||||||| |||||| |||| |||| ||||||||||||||. Distribution of weights in the MAIC indicate no evidence of extreme weights.

The weighted comparisons of efficacy outcomes between selpercatinib in the LIBRETTO-001 trial and placebo in EXAM are presented in Table 18. For PFS, the HRs and corresponding 95% CIs were estimated from a weighted Cox proportional hazards model with ||||||||| ||||||||| as to the only covariate. For OS, the HRs and corresponding 95% CIs were estimated from a weighted Cox proportional hazards model with ||||||||| ||||||||| ||| ||| ||||| |||||| as covariates. After weighting, there was a statistically significant improvement in PFS for selpercatinib versus placebo ||| ||||| ||| ||| ||||| ||||| |||||||||. There was also a statistically significant improvement in OS for selpercatinib versus placebo ||| ||||| ||| ||| ||||| ||||| |||||||||.

Table 18: Comparison of PFS and OS for Selpercatinib Versus Placebo Before and After Propensity Score Matching

CI = confidence interval; HR = hazard ratio; OS = overall survival; PFS = progression-free survival.

Source: Sponsor-submitted indirect treatment comparison.

Critical Appraisal of ITC 1

The sponsor’s rationale for conducting the ITC and the objectives of the ITC were clearly reported. A comprehensive systematic review was performed with a 2-stage dual-selection process, which was considered appropriate. The language of publication was not restricted, thereby minimizing publication bias. The clinical efficacy outcomes assessed were OS, PFS, and ORR.

The key limitation of the sponsor-submitted ITC was that no randomized clinical trial evidence was available for selpercatinib versus any comparator due to the LIBRETTO-001 trial being a single-arm design.

According to the clinical expert consulted by CADTH for this review, cabozantinib is not a relevant comparator for this evaluation but is included in the ITC. The estimation of the relative treatment effect of selpercatinib is based on the comparison between selpercatinib and cabozantinib for the survival outcomes.

In the weighting process of the MAIC used to estimate the relative treatment efficacy on the survival outcomes, only the baseline prognostic factors that were reported in LIBRETTO-001 and EXAM were included. Consequently, other potential prognostic factors and effect modifiers were not accounted for in the MAIC. As such, the MAIC and its treatment effect estimates are subject to potential bias due to latent or unmeasurable confounding. It is unlikely for an unanchored MAIC to account for all prognostic factors and effect modifiers.

Heterogeneity across the prognostic factors, effect modifiers, and other baseline characteristics was assumed, but specific baseline characteristics where excess heterogeneity was of concern were not identified, described, or addressed. The potential effect of such heterogeneity on the quality and reliability of the MAIC was not discussed. The risk of bias on the estimated relative treatment effects due to the exclusion of key factors in the weighting process was not discussed. Due to the absence of a reported assessment of residual bias, the sponsor-submitted unanchored MAIC is considered to have a high risk of residual bias.³⁵

OS Kaplan-Meier data were not available from the EXAM trial for the RET mutation–positive subgroup to allow for evaluation of the data. The Kaplan-Meier curves for patients in the EXAM trial with RET M918T–positive MTC who received placebo were used instead. These data were compared using a propensity score-weighted approach for the LIBRETTO-001 population. The assumption was made that the OS rates for these different groups were sufficiently similar, but this is unknown.

Baseline characteristics were not reported for the ||| ||||| |||||||| |||||||| so, notwithstanding comparing with the outcomes of this subgroup, the LIBRETTO-001 trial data were matched and weighted to the broader RET mutation–positive cabozantinib arm in the EXAM trial. The assumption was made that the baseline characteristics of these patient groups were equivalent, but this is unknown.

Some relevant outcomes identified in the CADTH systematic review protocol were not assessed in the ITC, including DOR, HRQoL, and safety, so the comparative efficacy and safety of relevant treatments included remain unknown.

As part of the unanchored MAIC, the weights that were used to match patients in the LIBRETTO-001 and EXAM trials for the selpercatinib versus cabozantinib comparison were also used for the selpercatinib versus placebo comparison. The recommended methodological approach is to generate separate weights for these comparisons since they involve different patient subgroups. Although these randomized studies generally have a good balance in baseline characteristics between the 2 study arms, the cabozantinib group consists only of patients who are RET mutation–positive, whereas the placebo group consists of the entire ITT sample, which includes patients with RET mutation–positive and RET mutation–negative disease. As such, there may be important differences between these 2 patient groups that were not accounted for by the weights used in the MAIC, in addition to the other differences observed. Some of the characteristics used by the MAIC were not reported for the placebo arm. The inclusion of patients with RET mutation–positive and those with RET mutation–negative disease in the placebo comparison is another source of heterogeneity that was not accounted for in the MAIC.

Summary

The sponsor-submitted ITC included a systematic review and used a matching-adjusted, unanchored, ITC to evaluate the relative clinical efficacy of selpercatinib versus other comparators for the treatment of advanced RET mutation–positive MTC. Three outcomes were analyzed, including OS, PFS, and ORR.

The sponsor-submitted ITC reported that, after weighting, there was a statistically significant improvement in PFS for selpercatinib versus placebo ||| ||||| ||| ||| ||||| ||||| |||||||| and a statistically significant improvement in OS for selpercatinib versus placebo ||| ||||| ||| ||| ||||| ||||| ||||||||.

The sponsor-submitted ITC had several limitations, including that the following:

• not all prognostic factors and effect modifiers were included in the MAIC weighting process, which leads to a high risk of residual confounding

• the MAIC weights calculated for 1 comparison were used for another comparison that involves a different patient population

• there was heterogeneity between the patient populations used in different components of the ITC.

Given these limitations, there is uncertainty around the relative treatment effects estimated by the MAIC, which undermines the internal and external validity of the ITC. However, given the magnitude of the difference in the results between selpercatinib and placebo, selpercatinib is likely more effective than BSC on patient survival, but there is no reliable estimate of how much more effective it is.

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.

In addition to the pivotal trial LIBRETTO-001, 3 ongoing studies were considered relevant for this report: LIBRETTO-531,¹⁶ LIBRETTO-321,³⁶ and LIBRETTO-121.³⁷ No complete results are currently available; rather, details of each trial are presented, as they provide additional context for the decision-making process.

LIBRETTO-531

LIBRETTO-531¹⁶ is a phase III, randomized, multi-centre, open-label study comparing selpercatinib with a physician’s choice of cabozantinib or vandetanib in adult and pediatric patients with progressive, advanced, kinase inhibitor–naive, RET-mutant MTC. Patients will be enrolled in approximately 158 sites in 21 countries across the Americas (including Canada) and in Asia, Europe, and Oceania. Refer to Table 19 for more details.

This study is currently recruiting participants, with a planned enrolment of approximately 400 patients. The estimated primary completion date (the date on which the last participant in a clinical study was examined or received an intervention so as to collect final data for all the primary outcome measures) and study completion date (the date on which the last participant in a clinical study was examined or received an intervention or treatment so as to collect final data for the primary and secondary outcome measures, as well as final data on AEs at the last participant’s last visit) are May 20, 2024, and November 13, 2026, respectively. Patients will be randomized 2:1 to selpercatinib (160 mg twice a day) versus the physician’s choice of cabozantinib (140 mg daily) or vandetanib (300 mg daily). Stratification factors are mutation (M918T versus other) and Intended treatment If randomized to active comparators (cabozantinib versus vandetanib).³⁸ For patients in the active comparator arms, crossover to selpercatinib is allowed at progression. The primary end point is treatment failure–free survival by blinded independent committee review (BICR). The secondary end points include PFS by BICR, ORR by BICR, DOR by BICR, OS, PFS2 (second disease progression or death) by investigator, Functional Assessment of Cancer Therapy–General item GP5 (side effects), and concordance between the local laboratory and the central laboratory RET results.

LIBRETTO-321

LIBRETTO-321³⁶ is a phase II, single group assignment, open-label study in China to assess the efficacy and safety of selpercatinib in participants with RET fusion–positive solid tumours, MTC, and other tumours with RET activation. Patients will be enrolled from multiple sites in China. Refer to Table 19 for more details.

The study is active but not currently recruiting, with a planned enrolment of approximately 75 patients. The actual primary completion date (the date on which the last participant in a clinical study was examined or received an intervention to collect final data for all the primary outcome measures) and the estimated study completion date (the date on which the last participant in a clinical study was examined or received an intervention or treatment to collect final data for the primary and secondary outcome measures as well as final data on AEs at the last participant’s last visit) are March 25, 2021, and November 20, 2025, respectively. All patients enrolled were given selpercatinib 160 mg orally twice daily in a 28-day cycle. Cohort 1 (n = 30) comprised patients with advanced RET fusion–positive solid tumours who had progressed on or were intolerant to 1 or more prior standard first-line therapies or those who had declined or were not suitable to receive standard frontline therapy. Cohort 2 (n = 26) enrolled patients with advanced RET-mutant MTC who either had or had not received previous systemic therapy. Lastly, those enrolled in cohort 3 (n = 21) had advanced RET-altered solid tumours that met the requirements for cohorts 1 or 2 but who did not have measurable disease, those with a RET-altered solid tumours or a RET alteration or activation that did not meet the criteria for cohorts 1 or 2, and those with circulating tumour DNA that is positive for a RET alteration that was not known to be present in their tumour.³⁹ The primary end point is ORR by IRC. The secondary end points include DOR by IRC, time to response by IRC, clinical benefit rate, PFS by IRC, OS, and area under the concentration versus time curve (AUC).

LIBRETTO-121

LIBRETTO-121³⁷ is a phase I and II, single group assignment, multi-centre, open-label study to find the appropriate dose of, as well as to assess safety and efficacy of selpercatinib in pediatric participants with an activating RET alteration and an advanced solid or primary CNS tumour. Patients will be enrolled in approximately 25 study locations in 10 countries across North America, Europe, Asia, and Oceania. Refer to Table 19 for more details.

This study is currently recruiting participants, with a planned enrolment of approximately 100 patients. The estimated primary completion date (the date on which the last participant in a clinical study was examined or received an intervention to collect final data for all the primary outcome measures) and study completion date (the date on which the last participant in a clinical study was examined or received an intervention or treatment to collect final data for the primary and secondary outcome measures, as well as final data on AEs at the last participant’s last visit) are March 26, 2023, and March 26, 2024, respectively. All patients enrolled were given selpercatinib orally (capsule or liquid suspension) twice daily continuously. Dosing started at the adult RP2D equivalent, 92 mg/m² twice daily, to confirm RP2D in patients aged 2 years and older and older than 2 years.⁴⁰ The primary end points in phase I are DLTs in pediatric participants with advanced solid tumours and those with primary CNS tumours. For phase II, the primary end points are ORR per RECIST 1.1 and RANO by IRC. Secondary end points for phase I include plasma concentration, AUC_{0 to 24} (from 0 to 24 hours), C_max (maximum concentration),T_max (time to maximum concentration), MTD, preliminary antitumour activity of selpercatinib in pediatric participants with tumours harbouring an activating RET alteration, as determined by ORR per RECIST 1.1, change from baseline in pain (Wong-Baker FACES Scale), and change from baseline HRQoL (Pediatric Quality of Life Inventory core module). The phase II secondary end points are AUC_{0 to 24} (AUC from 0 to 24 hours), C_max, T_max, ORR per RECIST 1.1 and RANO by investigator, DOR by investigator and IRC, PFS by investigator and IRC, OS, clinical benefit rate by investigator and IRC, frequency of AEs, concordance between a prior molecular test that detected a RET alteration within the participant’s tumour and the diagnostic tests by the sponsor, post-operative stage, surgical margin status, and descriptive analyses of pre-treatment surgical and post-treatment plans.

The sponsor submitted preliminary results for this study as a conference abstract.⁴⁰ As of October 2, 2020, 11 patients (6 male) aged 2 to 20 years (MTC, n = 8; PTC, n = 2; osteosarcoma, n = 1) had been treated (phase I, n = 4; phase II, n = 7). At baseline, 7 patients had measurable disease. Prior therapies included surgery (n = 8), chemotherapy (n = 1), vandetanib (n = 1), and radiotherapy (n = 3), while 3 patients were previously untreated. Time on selpercatinib ranged from 0.9 to13.4 months and 9 patients remain on treatment. One patient experienced a dose reduction and 2 experienced dose interruptions due to TEAEs (elevated ALT and bilirubin). There were no TEAEs that led to the discontinuation of selpercatinib. TEAEs in greater than 15% of patients included elevated alkaline phosphatase, constipation, headache, elevated AST, diarrhea, hyperphosphatemia, hypoalbuminemia, hypothyroidism, nausea, pyrexia, urinary tract infection, vomiting, and weight gain. Best response was unconfirmed PRs in 4 patients, stable disease in 6 patients (2 lasting ≥ 16 weeks) and PD in 1 patient.

New Data for Request for Reconsideration

The sponsor requested an expansion of the initiation condition for selpercatinib to include only adults (18 years of age and older) with unresectable advanced or metastatic RET-mutant MTC in the first-line setting and has provided submitted data from a new cut-off date of June 15, 2021, as part of a request for reconsideration to CADTH on May 19, 2022.

Figure 10: Cut-Off Dates and Accrual of Patients With RET-Mutant MTC Included in the LIBRETTO-001 Study Up to the June 15, 2021 Cut-Off Date

Cab = cabozantinib; IAS = integrated analysis set; MTC = medullary thyroid cancer; NMD = non-measurable disease; RET = rearranged during transfection; SAS1 = supplemental analysis set 1; Van = vandetanib.

^a Defined as those with at least 1 dose of selpercatinib and 6 months of follow-up.

Source: LIBRETTO-001 Clinical Study Report.¹⁸

The new data submitted focus on the SAS 1 population (n = 142), i.e., in patients with treatment-naive RET-mutant MTC (Figure 10).

The data from a new cut-off were derived from cohorts of patients with RET-mutant MTC in LIBRETTO-001. The June 15, 2021 data cut-off consisted of the latest analyses and the interim Clinical Study Report and provides additional evidence with a focus on the cabozantinib- and vandetanib-naive (SAS 1) population, since that is the population of interest in the reconsideration request.

As of June 15, 2021, the median age of patients with RET-mutant MTC in all efficacy-eligible patients was 58.0 years, and in the overall safety population, 59.0 years (range, 15 years to 92 years). In addition, 140 patients (98.6%) were 18 years of age or older. The majority of the patients were male (60.5% in the efficacy set; 51.0% in the safety set), White (88.2% in the efficacy set; 68.5% in the safety set) and had an ECOG PS score of 1 (56.4% in the efficacy set; 56.4%; 58.3% in the safety set). At the time of enrolment, 97.5% of patients had a history of metastatic disease. For patients with MTC not previously treated with cabozantinib and/or vandetanib, the median time between initial diagnosis and metastatic disease was 54.4 months and 43.3 months, respectively; for patients with MTC previously treated with cabozantinib and/or vandetanib, the median was 70.9 months and 53.9 months, respectively.

Efficacy

Of the 142 patients in SAS 1, 115 (81%) were treatment-naive and 27 (19%) had been treated with a prior systemic therapy other than cabozantinib and vandetanib. At the time of data cut-off, the ORR by IRC assessment in SAS 1 was 81.0% (95% CI, 73.6 to 87.1), which is similar to but numerically higher than the ORR observed at the previous data cut-off (Table 20). With a median follow-up of 20.3 months, the median DOR by IRC assessment was not evaluable ( | |||| | ||| | |||). However, | ||| of responders were still on treatment with no documented disease progression by IRC assessment at the time of data cut-off.

For OS, the median by IRC assessment was not reached, with a median duration of follow-up of 26.3 months (interquartile range ||||| |||| || ||||| (Table 21). The maximum range for OS was |||| |||||| ||| ||||||||||. The rate of survival at 12 months or more and 24 months or more were ||||| and 95.0%, respectively.

For PFS, 83.1% of the patients remained alive and progression-free at the time of data cut-off, with a median duration of follow-up of 24.8 months (|||| |||| || ||||). The median PFS by IRC assessment was not reached at the time of data cut-off, and the maximum range for PFS was |||| |||||| ||| |||||||||| (Table 22). The rate of PFS at 12 months or more and 24 months or more were ||||| ||| ||||||, respectively (Figure 11 in Appendix 7). With the additional follow-up, the majority of the patients continue to remain alive and progression-free.

Harms

Within the total MTC safety analysis set (N = 319), harm events at the June 15, 2021 data cut-off were similar to the events presented at the March 30, 2020 data cut-off (Table 30). Of the AEs, only |||| of patients had a serious TEAE related to selpercatinib. At the time of data cut-off, |||||| |||||| |||||| |||||||| |||||| || |||| || |||| |||| || ||||||||||||| || ||| || ||||||| |||||||||||| || ||| || ||||||| ||||||| ||| | ||| || ||||||| ||| |||||| |||||| |||||||| |||| |||| || |||| ||||| ||| |||| |||| ||| ||| || ||||||| |||||||||||| | ||| || ||||||| ||||||| ||| | ||| || ||||||. Similar to the March 30, 2020 data cut-off, AEs with a frequency of 20% or greater, in decreasing order, include diarrhea, hypertension, dry mouth, fatigue, constipation, AST increased, peripheral edema, nausea, headache, ALT increased, blood creatine increased, abdominal pain, arthralgia, hypocalcemia, vomiting, QT prolonged on ECG, cough, back pain, rash.

This new cut-off date information provides more data to supplement the immature evidence seen in the initial cut-off dates. The results from this later cut-off date were consistent for each end point (OS, PFS, ORR, harms) with the results from the initial cut-off date. There is still an unmet need for patients with MTC who have PD despite initial treatments as well as patients who are treatment-naive. The population assessed in this new cut-off date can be considered generalizable to the Canadian clinical landscape, since this group is mostly treatment-naive and would be similar to the population indicated in the reimbursement conditions discussed in this reconsideration (i.e., selpercatinib as first-line therapy). Overall, this is considered an improvement in terms of applicability.

Despite the new information, there is still uncertainty in the evidence supporting the use of selpercatinib due to the single-arm unblinded design of the LIBRETTO-001 study and imprecision due to the small number of patients and events, as stated in the critical appraisal section of this report.

Discussion

Summary of Available Evidence

One clinical study was included in this report evaluating the use of selpercatinib in patients with RET-mutant advanced (unresectable) or metastatic MTC.

The LIBRETTO-001 trial is a single-arm, open-label, phase I and II study being conducted in several countries (including Canada). The population integrated in the study consists of patients with RET-mutant advanced MTC who were eligible from a broader population, including those with DTC and NSCLC. The population as of the December 16, 2019 cut-off date was the main population used for the analyses and this report since it was the pre-planned analysis. This analysis provides 6 months of additional follow-up information for patients enrolled as of the initial data cut-off of June 17, 2019, and was the information used for the Health Canada submission. Further information was provided by the sponsor for safety and efficacy end points with a March 30, 2020 cut-off date. Patients were eligible if they presented with metastatic or locally advanced disease; had an ECOG PS of 0, 1, or 2; and were aged 12 years and older. The primary objective of phase I of the study was to find the MTD and RP2D. The recommended dose from the dose-escalation process from phase I was reached at 160 mg. At phase II, the primary end point was to evaluate the ORR based on RECIST criteria, with DOR, PFS, OS, safety, PK, and change in tumour size as secondary end points. Biomarker changes and HRQoL assessments were exploratory end points. CADTH identified 3 ongoing studies relevant to this submission. LIBRETTO-531 (phase III RCT of selpercatinib versus cabozantinib or vandetanib), LIBRETTO-321 (phase II conducted in China), and LIBRETTO-121 (phase I and II study in a pediatric population), none of which (except for LIBRETTO-121 presented as a conference abstract) have data available at this time. All are expected to be completed by 2026, 2025, and 2024, respectively.

New data were submitted by the sponsor for a June 15, 2021 cut-off date, as part of a request for reconsideration to CADTH, requesting to include only adults (18 years of age and older) with unresectable advanced or metastatic RET-mutant MTC in the first-line setting.

One sponsor-submitted ITC used a matching-adjusted, unanchored ITC to evaluate the relative clinical efficacy of selpercatinib compared with placebo (BSC) and against vandetanib for the treatment of advanced RET mutation–positive MTC. Three outcomes were analyzed: OS, PFS, and ORR.

Interpretation of Results

Efficacy

The LIBRETTO-001 study evaluated end points for efficacy (such as ORR and DOR), survival (such as PFS and OS), and HRQoL. All of these end points were considered by the clinical experts consulted by CADTH to be critical for clinical decision-making and relevant to the Canadian landscape according to other stakeholders, such as patient groups and the drug programs. The primary (ORR) and secondary and exploratory end points (including OS, PFS, DOR, and HRQoL measures) in LIBRETTO-001 were evaluated but not formally adjusted for multiple comparisons.

The results from the LIBRETTO-001 trial on its primary end point of ORR reached a value of 69.1% in its PAS, which was considered by the clinical experts of clinical significance and better than expected for patients with metastatic or unresectable MTC. These values were similar when evaluating the later cut-off dates of the study. Similarly, the DOR was of particular clinical significance since, at a median follow-up of 14 months, the patients in the PAS had not reached the median DOR.

In terms of survival, || ||| ||||| ||||| ||| || ||| |||||||||| |||||| ||| |||||||| || ||| ||| |||||| ||| || || ||||||| at the December 16, 2019 data cut-off. At a later cut-off date (March 30, 2020), OS reached 33.2 months (range, 0.4 months to 33.3 months) in patients previously treated with vandetanib or cabozantinib and “not reached” in treatment-naive patients. An OS of 12 months or more was reassuring for the clinical experts consulted by CADTH, observing that ||||| of patients survived 12 months or more at the December16 2019 cut-off date, and more than 88% survived 12 months or more at the March 30 2020 cut-off date.

These numbers were considered by the clinical experts to indicate an improvement and meaningful effects above the expected level, based on their experience. When comparing selpercatinib with best standard of care and/or with vandetanib (the only funded intervention in Canada), the experts considered the value that patients put on HRQoL outcomes and indicated that selpercatinib has the potential to fulfill an unmet need, as available treatment options are currently limited. Although the estimates of HRQoL, as with the rest of the outcomes, have the same methodological limitations associated with a single-arm trial plus the limitations associated with an open-label design, these estimates were still considered relevant by the clinical experts when considering issues commonly cited by patients such as diarrhea and the need for further treatment options, as both issues were brought up frequently in the patient group input.

An update on the data that extended the follow-up, now with a median of 26.3 months for OS and 24.5 months for PFS (previous cut-off medians for both end points were not reached), denotes an improvement in the immature data observed in the analyses at the initial cut-off dates, and there is agreement between the base case and subsequent analyses.

One sponsor-submitted ITC reported 3 end points (OS, ORR, PFS) considered important by the experts and patient groups. After weighting, there was a statistically significant improvement in PFS for selpercatinib versus placebo and a statistically significant improvement in OS for selpercatinib versus placebo. Similarly, the ITC reported improvements in the ORR when compared with vandetanib. However, the ITC has serious limitations since it considers single-arm evidence against aggregated data in a MAIC with a high possibility of residual confounding and clinical and/or population heterogeneity, as well as limitations in the assumptions of similar OS among populations and use of surrogate weights from 1 comparison to another.

Overall, the uncertainty in this body of evidence in the context of the scarcity of comparative (randomized) evidence reflects the challenges for conducting phase III studies in rare and indolent conditions such as MTC.

Harms

AEs were reported in all but 2 patients taking selpercatinib. The most common AEs (i.e., > 20% of patients with at least 1 of these) were hypertension, diarrhea, constipation, fatigue, headache, peripheral edema, nausea, and abdominal pain.

Overall, there were no major concerns from the LIBRETTO-001 study related to harms at either the evaluated cut-off points or at the later cut-off point (June 15, 2021). While SAEs occurred in | | of the safety population |||||||||| ||| ||||||||||||| ||||| |||| ||||||| || |||| ||| || || |||||||| ||||||||||||), all AEs of concern, such as hypertension, diarrhea, QTc prolongation, and elevations of liver enzymes, were considered by the experts consulted by CADTH to be manageable in the clinical setting and would not impact the use of the drug, as many of the precautions taken during the administration of selpercatinib are familiar and in common use among physicians and other health professionals.

Conclusions

Evidence from a single-arm, open-label, unblinded study (LIBRETTO-001) suggests that treatment with selpercatinib is associated with survival and response end points (OS, PFS, ORR, DOR, HRQoL) that were considered relevant to both patients and clinicians when compared with the typical effects and clinical evolution observed by clinical experts among patients with RET-mutant, advanced and/or metastatic MTC after surgery. Overall, the clinical experts deemed the harms and safety profile of selpercatinib to be better than the undesirable effects usually seen in clinical practice with vandetanib or cabozantinib.

However, major limitations generate uncertainty around any effect estimates due to immature data, lack of comparative evidence, a high risk of bias (no blinding, attrition), no adjustment for multiple comparisons, and imprecision in time-to-event outcomes.

Evidence from a sponsor-submitted ITC is also associated with major limitations for the comparison between selpercatinib and BSC due to residual confounding (i.e., incomplete inclusion of prognostic factors and effect modifiers), surrogate use of weights for comparisons, and heterogeneity among the included populations.

Overall, there is uncertain evidence that selpercatinib provides clinical benefits with similar or lower risks of harms (i.e., toxicity) when compared with what is expected with relevant comparators.

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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: November 24, 2021

Alerts: Bi-weekly search updates until project completion

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

Limits:

• Conference abstracts: excluded

Table 23: Syntax Guide

Multi-Database Strategy

1. (selpercatinib* or Retevmo* or Retsevmo* or LOXO-292 or LOXO292 or ARRY-192 or ARRY192 or LY3527723 or LY-3527723 or WHO-10967 or WHO10967 or CEGM9YBNGD).ti,ab,kf,ot,hw,rn,nm.

2. 1 use medall

3. *selpercatinib/

4. (selpercatinib* or Retevmo* or Retsevmo* or LOXO-292 or LOXO292 or ARRY-192 or ARRY192 or LY3527723 or LY-3527723 or WHO-10967 or WHO10967).ti,ab,kf,dq.

5. 3 or 4

6. 5 use oemezd

7. 6 not (conference abstract or conference review).pt.

8. 2 or 7

9. remove duplicates from 8

Clinical Trials Registries

ClinicalTrials.gov

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

• [Search -- (selpercatinib OR retevmo OR retsevmo OR LOXO-292 OR LOXO292)]

WHO ICTRP

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

• [Search terms -- selpercatinib OR retevmo OR retsevmo OR LOXO292 OR LOXO-292]

Health Canada’s Clinical Trials Database

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

• [Search terms -- selpercatinib, retevmo, retsevmo, LOXO-292, LOXO292]

EU Clinical Trials Register

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

• [Search terms selpercatinib, retsevmo OR retevmo OR LOXO-292 OR LOXO292]

Grey Literature

Search dates: November 17 to 24, 2021

Keywords: selpercatinib, retevmo, retsevmo, LOXO-292, LOXO292, thyroid cancer

Limits: None

Updated: Search updated before the completion of stakeholder feedback period

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)

• Internet Search

Appendix 2: Excluded Studies

Note that this appendix has not been copy-edited.

Table 24: Excluded Studies

Appendix 3: Changes to the Protocol

Note that this appendix has not been copy-edited.

Table 25: Summary of Major Changes to the Protocol