CADTH Reimbursement Review

Lurbinectedin (Zepzelca)

Sponsor: Jazz Pharmaceuticals Inc.

Therapeutic area: Metastatic small cell lung 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.

Table 1: Submitted for Review

NOC/c = Notice of Compliance with conditions; SCLC = small cell lung cancer.

Source: Sponsor’s submission for lurbinectedin (Zepzelca).¹

Introduction

Small cell lung cancer (SCLC) accounts for 10% to 15% of all lung cancers.² SCLC is classically staged as limited-stage (LS) or extensive-stage (ES) disease; approximately two-thirds of patients present with metastatic ES disease at diagnosis and approximately one-quarter present with stage III LS disease.^2,3 The initial symptoms of SCLC are nonspecific and include cough, chest pain, trouble breathing, wheezing, hoarseness, loss of appetite, weight loss, and fatigue.⁴ The physical, emotional, and social toll of an SCLC diagnosis negatively impacts patient health-related quality of life (HRQoL).⁵ For patients with metastatic ES disease, median overall survival (OS) is less than 1 year, and the 5-year survival rate is approximately 5%.^6,7 The sponsor estimated that there would be 521 patients per year (as of 2022) receiving second-line or third-line therapy for SCLC (238 with platinum-resistant disease, defined as a chemotherapy-free interval [CTFI] shorter than 90 days) who would be eligible to receive lurbinectedin.

According to the clinical experts consulted by CADTH for this review, standard first-line systemic therapy for patients with LS (stage III or earlier) or ES (metastatic) SCLC is a platinum-containing drug (cisplatin or carboplatin) plus etoposide for 4 to 6 cycles.⁸ Since 2021, standard first-line therapy for patients with ES disease has included platinum doublet therapy plus durvalumab.⁹ Second-line treatment options in Canada for patients with ES or LS disease include rechallenge with platinum plus etoposide (if progression occurs after an interval of approximately 3 months from the last dose of first-line chemotherapy), topotecan, and cyclophosphamide plus doxorubicin and vincristine (CAV). Third-line treatment options include topotecan and CAV (if not used as second-line therapy), as well as irinotecan with or without a platinum-containing drug. According to the clinical experts consulted by CADTH for this review, response rates decrease as line of therapy advances, and many of the second-line and third-line treatment options are difficult to tolerate; therefore, there is a high need for additional treatment options. The clinical experts stated that the goal of treatment for stage III or metastatic SCLC is to prolong survival while maintaining HRQoL.

Lurbinectedin is an alkylating drug that is indicated for the treatment of adult patients with stage III or metastatic SCLC who have progressed on or after platinum-containing therapy. Lurbinectedin received advance consideration from Health Canada under a Notice of Compliance with conditions; these conditions were to conduct timely, well-designed studies to verify the clinical benefit of the drug; to provide appropriate educational materials; and to comply with any postmarket surveillance commitments and advertising, labelling, and distribution requirements placed on the drug. The drug is supplied as a 4 mg vial and administered at a dose of 3.2 mg/m² by IV infusion over 60 minutes, repeated every 21 days.

The objective of this report was to perform a systematic review of the beneficial and harmful effects of lurbinectedin (3.2 mg/m² by IV infusion over 60 minutes, repeated every 21 days) for the treatment of adult patients with stage III or metastatic SCLC who have progressed on or after platinum-containing therapy.

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 from clinical experts consulted by CADTH for the purpose of this review.

Patient Input

Two patient groups provided input for this review: Lung Cancer Canada (LCC); and the Lung Health Foundation (LHF), previously known as the Ontario Lung Association. LCC conducted phone interviews with 2 patients in Canada with SCLC (1 with localized and 1 with metastatic disease) and environmental scans with 1 patient and 2 caregivers of patients in the US with metastatic SCLC in March 2022; all had experience with lurbinectedin. LHF conducted an online survey (2 respondents; no demographic or disease information collected) and phone interviews (3 patients in Canada with lung cancer; type and stage not reported) from September to December 2021 and collected input from 2 additional individuals (1 registered nurse and 1 certified respiratory educator); none had experience with lurbinectedin. Patients highlighted the nonspecific early symptoms of SCLC, which led to delays in diagnosis, as well as the physical (e.g., shortness of breath, cough, fatigue, pain), emotional, and social toll of an SCLC diagnosis. Patients acknowledged that although existing treatments for SCLC (e.g., surgery, radiation, chemotherapy, targeted therapy, immunotherapy) prolong survival and delay disease progression, the side effects of currently available second-line and third-line chemotherapies for metastatic SCLC (e.g., nausea, fatigue, weight, and hair loss) were sometimes severe and negatively impacted HRQoL, employment, and the ability to perform activities of daily living. Patients identified an unmet need for additional second-line treatment options for metastatic SCLC that can prolong survival, delay disease progression, manage cancer symptoms, and maintain HRQoL with minimal side effects. Patients emphasized that stopping or delaying disease progression was the most important factor when choosing treatments, and they were more receptive to the potential side effects of efficacious therapies. Patients who had experience with lurbinectedin felt that the drug had reduced or stabilized tumour size, delayed disease progression, helped them continue or resume activities of daily living, including employment, and led to more manageable side effects and a shorter recovery time compared with other SCLC therapies they had received.

Clinician Input

Input From Clinical Experts Consulted by CADTH

Two clinical specialists with expertise in the diagnosis and management of stage III and metastatic SCLC provided input for this review. According to the clinical experts, patients with stage III or metastatic SCLC manifest rapid responses to first-line chemotherapy, but these are not sustained. Currently available second-line chemotherapy options (e.g., topotecan, CAV, irinotecan) have significant drawbacks, including toxicity and inconvenience (e.g., topotecan has a dosage regimen of 5 consecutive days of IV treatment every 3 weeks). The clinical experts stated that lurbinectedin would be used as second-line or third-line therapy for patients with stage III or metastatic SCLC after first-line platinum plus etoposide therapy and potential rechallenge; if progression following first-line therapy occurred after a relatively long interval (e.g., 6 to 12 months), many clinicians would rechallenge with platinum plus etoposide as a second-line option before using lurbinectedin. The clinical experts emphasized that all patients with ES SCLC need additional treatment options to prolong survival and maintain HRQoL. According to the clinical experts, the patient population best suited to treatment with lurbinectedin includes patients with ES SCLC who progress after treatment with platinum plus etoposide with or without durvalumab; patients with poor performance status (e.g., Eastern Cooperative Oncology Group [ECOG] performance status [PS] score of 3 or greater) or limited organ function are least suitable for treatment with lurbinectedin. According to the clinical experts, assessment of response to lurbinectedin would involve imaging scans (approximately every 3 months), clinical improvement, and laboratory markers. Clinically meaningful responses to treatment would be manifested by an improvement in symptoms and improvement or stabilization in HRQoL. The clinical experts stated that lurbinectedin should be discontinued when disease progression or unacceptable toxicities occur or by patient choice. The clinical experts stated that lurbinectedin would be administered in an outpatient setting and would be ordered by a medical oncologist.

Clinician Group Input

Two clinician groups, the LCC Medical Advisory Committee (10 medical oncologists, 2 respirologists, 1 thoracic surgeon, and 1 pathologist) and the Ontario Health-Cancer Care Ontario Lung Cancer Drug Advisory Committee (5 medical oncologists), provided input for this review. No major contrary views were presented. Clinician groups echoed the high unmet need for additional efficacious second-line treatment options for stage III and metastatic SCLC that have fewer side effects and are more convenient to administer. The clinician groups noted that some clinicians would perform imaging evaluations slightly more frequently than others (every 2 to 3 cycles or 6 to 9 weeks versus every 3 months), and that in addition to improvement or stabilization of symptoms and HRQoL, clinically meaningful responses to lurbinectedin would be manifested as tumour shrinkage observed on imaging scans. In addition, the clinician groups noted that it was not yet clear if re-treatment with platinum plus etoposide would be the preferred option for patients with platinum-sensitive disease who have treatment-free periods beyond some cut-off (e.g., 6 months).

Drug Program Input

The Provincial Advisory Group identified the following jurisdictional implementation issues: relevant comparators, considerations for initiation of therapy, considerations for prescribing of therapy, funding algorithm, care provision issues, and system and economic issues. The clinical experts consulted by CADTH for this review weighed evidence from the included study and other clinical considerations to provide responses to drug program implementation questions.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

One phase II, multicentre, OL, basket trial (study B-005)¹⁰ designed to evaluate the efficacy and safety of lurbinectedin in previously treated patients with advanced solid tumours provided evidence for this review; only data for the SCLC cohort (N = 105) are described in this report. The primary objective of the study was to assess the objective response rate (ORR) per investigator assessment (IA) of lurbinectedin in patients with advanced SCLC who had received 1 prior line of systemic therapy. Secondary objectives included ORR per independent review committee (IRC), duration of response (DOR) per IA and IRC, clinical benefit rate per IA and IRC, progression-free survival (PFS) per IA and IRC, and OS. Adult patients (aged 18 years and older) with SCLC who had received 1 previous line of systemic therapy for advanced disease and met the eligibility criteria were enrolled at 1 of 26 sites, primarily in Europe (predominantly Spain; no sites in Canada). Patients were treated with lurbinectedin (3.2 mg/m² on day 1 of a 21-day treatment cycle) until disease progression or unacceptable toxicity.

Adult patients (aged 18 years and older) with SCLC, an ECOG PS score of 2 or lower, and measurable disease who had received 1 prior line of systemic therapy for advanced disease were eligible if they did not have central nervous system (CNS) involvement identified by CT or MRI, did not have serious comorbidities, and had not received chemotherapy in the previous 3 weeks. The median age at study entry was 60 years. Most patients (56.2%) had an ECOG PS score of 1, roughly one-third (36.2%) had an ECOG PS score of 0, and only 7.6% (8 patients) had an ECOG PS score of 2. Most patients (93.3%) had ES disease at study entry; only 2 patients (1.9%) had nonmetastatic disease at study entry. Nearly all patients (93.3%) had received 1 line of prior systemic therapy (platinum-containing drugs: 100.0%; etoposide: 99.0%); only 7.6% of patients had received prior immunotherapy. Based on their CTFIs, 42.9% of patients had platinum-resistant disease (CTFI < 90 days, including both refractory disease [CTFI < 30 days = 20.0%] and resistant disease [CTFI 30 to 89 days = 22.9%]), whereas 57.1% of patients had platinum-sensitive disease (CTFI ≥ 90 days, including both sensitive disease [CTFI 90 to 179 days = 38.1%] and very sensitive disease [CTFI ≥ 180 days = 19.0%]).

Lurbinectedin (3.2 mg/m²) was administered as a 1-hour IV infusion on day 1 of a 3-week treatment cycle. The dose was capped at a body surface area of 2.0 m² (6.4 mg). Treatment was continued until disease progression (per IA), unacceptable toxicity, a treatment delay of 3 weeks or longer (except in the case of clear clinical benefit with sponsor’s approval), the requirement for more than 2 dose reductions, intercurrent illness of sufficient magnitude to preclude safe continuation of the study, a major protocol deviation that could affect the risk-to-benefit ratio for the participating patient, investigator decision, noncompliance with study requirements, or patient refusal. During the treatment period, tumour response was evaluated for all original sites of disease involvement at baseline, every 2 cycles until cycle 6, and then every 3 cycles thereafter.

Efficacy Results

Key efficacy results of study B-005 are summarized in Table 2.

Overall Survival

Median OS was 9.3 months overall (95% confidence interval [CI], 6.3 to 11.8 months). Median OS among patients with a CTFI shorter than 90 days and 90 days or longer was 5.0 months (95% CI, 4.1 to 6.3 months) and 11.9 months (95% CI, 9.7 to 16.2 months), respectively.

Progression-Free Survival

Median PFS per IA was 3.5 months overall (95% CI, 2.6 to 4.3 months). Median PFS per IA among patients with a CTFI shorter than 90 day and 90 days or longer was 2.6 months (95% CI, 1.3 to 3.9 months) and 4.6 months (95% CI, 2.8 to 6.5 months), respectively.

Median PFS per IRC was 3.5 months overall (95% CI, 2.6 to 4.2 months). Median PFS per IRC among patients with a CTFI shorter than 90 days and 90 days or longer was 1.4 months (95% CI, 1.3 to 3.5 months) and 4.3 months (95% CI, 3.0 to 6.3 months), respectively.

Objective Response Rate

The ORR per IA was 35.2% overall (95% CI, 26.2% to 45.2%). The ORR per IA among patients with a CTFI shorter than 90 days and 90 days or longer was 22.2% (95% CI, 11.2% to 37.1%) and 45.0% (95% CI, 32.1%, 58.4%), respectively.

The ORR per IRC was 30.5% overall (95% CI, 21.9%, 40.2%). The ORR per IRC among patients with a CTFI shorter than 90 days and 90 days or longer was 13.3% (95% CI, 5.1%, 26.8%) and 43.3% (95% CI, 30.6%, 56.8%), respectively.

Duration of Response

Median DOR per IA in patients who had a confirmed complete response or partial response as best overall response was 5.3 months overall (95% CI, 4.1 to 6.4 months). Median DOR per IA among patients with a CTFI shorter than 90 days and 90 days or longer was 4.7 months (95% CI, 2.6 to 5.6 months) and 6.2 months (95% CI, 3.5 to 7.3 months), respectively.

Median DOR per IRC in patients who had a confirmed complete response or partial response as best overall response was 5.1 months overall (95% CI, 4.9 to 6.4 months). Median DOR per IRC among patients with a CTFI shorter than 90 days and 90 days or longer was 4.8 months (95% CI, 2.4 to 5.3 months) and 5.3 months (95% CI, 4.9 to 7.0 months), respectively.

Harms Results

Key harms results of study B-005 are summarized in Table 2. Adverse events (AEs) occurred in most patients (98.1%), serious adverse events (SAEs) occurred in 32.4% of patients, AEs leading to dose reduction occurred 26.3% of patients, and withdrawal due to AEs occurred in 3.8% of patients. Sixty-six patients (62.9%) died during the study, all due to progressive disease. Among CADTH protocol-defined notable harms, the most common myelosuppression-associated AEs in study B-005 were anemia (95.2%), lymphopenia (85.7%), leukopenia (79.0%), neutropenia (71.4%), and thrombocytopenia (43.8%). Febrile neutropenia occurred in 4.8% of patients. The most common hepatotoxicity-associated AEs were alanine aminotransferase (ALT) increase (71.8%), gamma-glutamyl transferase increase (65.0%), asparagine aminotransferase (AST) increase (44.7%), and alkaline phosphatase increase (33.0%). Peripheral neuropathy and peripheral sensory neuropathy occurred in 2 patients (1.9%).

Table 2: Summary of Key Results From Study B-005 (Treated Patients)

AE = adverse event; ALT = alanine aminotransferase; AP = alkaline phosphatase; AST = asparagine aminotransferase; CI = confidence interval; CPK = creatine phosphokinase; CTFI = chemotherapy-free interval; DOR = duration of response; GGT = gamma-glutamyl transferase; IA = investigator assessment; IRC = independent review committee; NR = not reported; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

Notes: Treatment-emergent AEs reported in this table were defined as any untoward medical occurrence after administration of the first dose of study drug and within 30 days of the last dose of study drug. AEs were coded using MedDRA version 21.0 and graded according to NCI-CTCAE version 4.

For biochemical parameters that were measured in fewer than 105 patients, the denominator is indicated.

^aFrom Kaplan-Meier analysis.

Source: B-005 Clinical Study Report.¹¹

Critical Appraisal

The major limitations of study B-005 were its single-arm, noncomparative design and its relatively small size, with associated uncertainty in the estimation of effect sizes. Other potential internal validity concerns included potential for bias in outcome assessment (e.g., tumour response) because of the single-arm, OL study design and the descriptive nature of efficacy analyses and absence of formal statistical hypothesis testing (other than ORR per IA).

The clinical experts consulted by CADTH for this review considered the demographic and disease characteristics of patients in study B-005 to be broadly reflective of adult patients with advanced SCLC who have received prior platinum-based doublet therapy in Canada. However, the clinical experts felt that patients in study B-005 were slightly younger, in better health, and more treatment-seeking than the general population of SCLC patients. Patients with CNS involvement, who would be expected to have worse prognoses, were excluded from study B-005; however, patients with a short CTFI, who are excluded from many trials due to their poor prognoses, were included. Although the study assessed lurbinectedin in the second-line treatment setting, the clinical experts felt that the study results could be generalized to the third-line treatment setting as well. Stabilization of HRQoL and cancer symptoms, which were identified as important outcomes to patients and goals of treatment by the clinical experts consulted by CADTH for this review, were not assessed in study B-005.

Indirect Comparisons

Description of Studies

Three sponsor-submitted indirect treatment comparisons (ITCs) are included in this CADTH report. The first ITC study evaluated the treatment landscape and comparative efficacy of lurbinectedin in the treatment of patients in Alberta with advanced SCLC following exposure to platinum-based therapy, who were diagnosed with SCLC (any stage) and who initiated a post–platinum-based systemic therapy to build a synthetic control arm (SCA) to evaluate aggregate trial-level data for comparison to the phase II B-005 study.¹²

The second ITC was a simulated treatment comparison (STC) that facilitated the indirect comparison of lurbinectedin (using individual patient data from the B-005 trial) to topotecan IV (using aggregated data from the von Pawel et al. [2014]¹³ randomized controlled trial [RCT]) in patients with relapsed or refractory SCLC.¹⁴

The third ITC was a matching-adjusted indirect comparison (MAIC) created to be used with a network meta-analysis (NMA) to compare the efficacy and safety of lurbinectedin with competing interventions (including topotecan IV and carboplatin plus etoposide) among patients with SCLC receiving second-line treatment with respect to ORR, DOR, OS, and PFS, as well as hematological AEs of grade 3 and 4 (including anemia, thrombocytopenia, neutropenia, and febrile neutropenia).¹⁵

Efficacy Results

The first ITC, the SCA analysis, was descriptive in nature, but also provides a comparison of lurbinectedin (Study B-005) against the SCA stratified by CTFI and stage at initial diagnosis. The median OS in this adjusted population analysis of the SCA reached 5.8 months (95 CI, 5.1 to 6.9 months), and the median OS in the B-005 trial was 9.3 months (95% CI, 6.3 to 11.8). The unadjusted OS reached a median of 6.58 months (95% CI, 5.75 to 7.46 months). The SCA was subsequently updated to align more closely with the B-005 trial population by excluding patients who developed brain metastasis after diagnosis but before initiating post–platinum-based therapy. The median OS in this adjusted population analysis of the updated SCA reached 6.1 months (95% CI, 5.4 to 7.7 months) and the unadjusted OS reached a median of 6.7 months (95% CI, 6.0 to 7.7 months).

In the second ITC, the STC evaluated OS and PFS. Adjusted estimates showed the median OS was 10.0 months (95% CI, 8.5 to 11.6 months) and 7.8 months (95% CI, 6.6 to 8.5 months) in the lurbinectedin and topotecan trials, respectively, with a mean difference of 2 months (95% CI, 0.4 to 4.0 months). For PFS, adjusted estimates were obtained, with a median PFS of 3.4 months (95% CI, 3.0 to 3.9 months) and 3.5 months (95% CI, 2.9 to 4.2 months) in the lurbinectedin and topotecan trials, respectively, with a mean difference of –0.10 months (95% CI, –0.89 to 0.69 months).

The third ITC provided results of an MAIC and an NMA that evaluated OS, PFS, ORR, DOR, and harms.

For OS, from the MAIC evaluation, the hazard ratio (HR) for lurbinectedin versus carboplatin plus etoposide was 0.42 (95% CI, 0.27 to 0.65). In the base-case NMA for OS, lurbinectedin had an HR of 0.43 (95% credible interval [CrI], 0.26 to 0.70) against IV topotecan, and 0.42 (95% CrI, 0.30 to 0.58) against carboplatin plus etoposide.

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For ORR, when assessing the MAIC base case, no evidence of difference was detected between lurbinectedin and carboplatin plus etoposide (███ █ ████ █ ███ █ █ ████ █ █ █ █ ██ █ ███ █ █ █ ████). In the NMA, no evidence of difference was detected between lurbinectedin and IV topotecan (odds ratio [OR] = 2.36; 95% CrI, 0.89 to 6.23) or between lurbinectedin and carboplatin plus etoposide (OR = 0.85; 95% CrI, 0.40 to 1.83).

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Harms Results

Harms were only directly evaluated in the third ITC (MAIC and NMA).

Anemia of grade 3 or 4 in MAIC estimates had lower odds in the lurbinectedin arm compared with the carboplatin plus etoposide arm (█ █ █ ████ █ ██ █ ██ █ ███ █ █ █ ████). The NMA estimates also showed lower odds in the lurbinectedin arm compared with the carboplatin plus etoposide arm (OR = 0.22; 95% CrI, 0.08 to 0.61) and the IV topotecan arm (OR = 0.21; 95% CrI, 0.06, 0.74), with consistent results in the sensitivity analyses.

MAIC estimates for grade 3 or 4 thrombocytopenia also showed lower odds in the lurbinectedin arm than in the carboplatin plus etoposide arm (█ █ █ ████ █ ██ █ ██ █ ███ █ █ █ ████), and results were similar across sensitivity analyses. Similarly, in the NMA assessing thrombocytopenia of grade 3 or 4, the base-case analysis showed lower odds (OR = 0.23; 95% CrI, 0.08 to 0.69), and results were consistent with the sensitivity analyses.

However, in the MAIC, the odds of neutropenia of grade 3 or 4 (█ █ █ ████ █ ██ █ ██ █ ███ █ █ █ █████) was higher with lurbinectedin compared with carboplatin plus etoposide, but this effect was the opposite when lurbinectedin was compared with IV topotecan in the group of patients with any platinum sensitivity (sensitivity analysis) (█ █ █ ████ █ ██ █ ██ █ ███ █ █ █ ████) and when observing the patients with sensitive disease, involving a CTFI longer than 90 days (█ █ █ ████ █ ██ █ ██ █ ███ █ █ █ ████). In the NMA, the results were similar, with increased odds in the lurbinectedin arm compared with the carboplatin plus etoposide arm (OR = 7.05; 95% CrI, 3.09 to 16.11), but not in the lurbinectedin arm compared with the IV topotecan arm (OR = 1.19; 95% CrI, 0.45 to 3.17). The reason for these differences in neutropenia rates was deemed to be explained by differences in the requirements for prophylaxis with granulocyte colony-stimulating factor (G-CSF) across studies.

Critical Appraisal

The results from all ITCs have uncertainty due to imprecision in effect estimates, risk of confounding, and risk of bias in the body of evidence (e.g., violation of proportional hazards, intransitivity, poor overlap of covariates in the MAIC weighting process, use of observational data from the single-arm, nonrandomized trial connected through a MAIC to each NMA) with sparsity of the formed network used for the NMAs. The ORR and DOR were also uncertain, with no evidence of better ORR odds for lurbinectedin compared with carboplatin plus etoposide or to topotecan IV and incomplete evidence for evaluating the DOR. The maturity of data for evaluating long-term outcomes was also uncertain.

Generalizability issues arose because some arms included in the third ITC evaluated drugs not used in Canada (e.g., oral topotecan) and some variables considered important by clinical experts could not be included.

Other Relevant Evidence

No other relevant evidence was identified for this review.

Conclusions

Evidence from study B-005 suggested that administration of lurbinectedin in patients with SCLC who received 1 prior line of platinum-containing chemotherapy resulted in objective responses in some patients that persisted for several months. In the absence of a control group, PFS and OS results could not be interpreted, and there was no direct evidence to inform the relative efficacy of lurbinectedin compared with other treatment options. Indirect evidence (3 sponsor-submitted ITCs) suggested that lurbinectedin treatment may result in improved OS and/or PFS compared with IV topotecan, and compared with carboplatin plus etoposide, albeit with a high risk of bias (due to unanchored comparisons and limited ability to adjust for variability in prognostic factors and treatment-effect modifiers) and a sparse dataset. In study B-005, the main toxicity of lurbinectedin, reversible myelosuppression, was considered acceptable and manageable with dose reductions and appropriate transfusion and growth-factor support. The indirect evidence also suggested that lurbinectedin was associated with lower frequencies of grade 3 or 4 anemia and thrombocytopenia compared with oral topotecan and carboplatin plus etoposide, again with high uncertainty. The indirect evidence was aligned with some outcomes identified as important to patients with SCLC, who are seeking additional second-line and third-line treatment options that prolong survival, delay disease progression, and maintain HRQoL and that have acceptable toxicity profiles.

Introduction

Disease Background

SCLC accounts for 10% to 15% of all lung cancers and is characterized by rapid growth, early dissemination, and high rates of acquired drug resistance.² Smoking tobacco is the strongest risk factor for SCLC and contributes to most SCLC diagnoses.² SCLC is classically staged as LS or ES disease; although there is no direct correspondence with tumour, node, and metastasis staging, in most patients, LS disease is stage III and ES disease is stage IV (metastatic).³ Approximately two-thirds of patients present with metastatic ES disease at diagnosis, approximately one-quarter present with stage III LS disease, and very few patients (less than 5%) present with stage 0 to II disease.^2,3 The initial symptoms of SCLC are nonspecific and include cough, chest pain, trouble breathing, wheezing, hoarseness, loss of appetite, weight loss, and fatigue.⁴ Nevertheless, the physical, emotional, and social toll of a SCLC diagnosis negatively impacts patient HRQoL.⁵

Based on estimates of the population of Canada,¹⁶ the annual incidence of lung cancer (97 per 100,000 population),⁶ the proportion of SCLC among all lung cancers (12.1%),^6,17 the proportions of patients diagnosed with LS (stage III) and ES (metastatic) disease (25% and 67%, respectively),⁶ the proportions of patients (any stage) receiving first-line platinum-containing chemotherapy (54.6%) and subsequent lines of systemic therapy (28.4%),^1,12 the sponsor calculated that in 2022 there would be 420 patients receiving second-line therapy and 101 patients receiving third-line therapy in Canada, outside of Quebec, who would be eligible to receive lurbinectedin. In this calculation, it was assumed that SCLC incidence was equivalent to prevalence, as most patients discontinue treatment and/or die in the year after diagnosis. Approximately 80% of patients were estimated to have platinum-sensitive disease (CTFI ≥ 90 days), whereas approximately 20% were estimated to have platinum-resistant disease (CTFI < 90 days).^10,12 For patients with metastatic ES stage, median OS is less than 1 year, and the 5-year survival rate is approximately 5%.^6,7 Most patients with LS disease will relapse after potentially curative first-line therapy, with a median OS of approximately 2 years and a 5-year survival of approximately 25%.^6,7

According to the clinical experts consulted by CADTH for this review, after the development of symptoms or an abnormal chest X-ray, patients are referred to a cancer centre, where the diagnosis of SCLC can be made by a team of specialists (pulmonologist, medical oncologist, radiation oncologist, pathologist, radiologist, and thoracic surgeon) based on biopsy and imaging findings.

Standards of Therapy

According to the clinical experts consulted by CADTH for this review, standard first-line systemic therapy for patients with LS (stage III or earlier) or ES (metastatic) SCLC is a platinum-containing drug (cisplatin or carboplatin) plus etoposide for 4 to 6 cycles.⁸ Patients with LS disease are treated with chemotherapy combined with thoracic radiation and prophylactic cranial irradiation as part of potentially curative first-line therapy. Until recently, thoracic radiation and prophylactic cranial irradiation were optionally given to patients with ES disease who had stable disease or better after chemotherapy. However, since 2021, standard first-line therapy for patients with ES disease and without contraindications has included durvalumab (added starting at the first or second chemotherapy cycle and continuing until progression);⁹ no thoracic radiation or prophylactic cranial irradiation is given in patients receiving immunotherapy.

The clinical experts consulted by CADTH for this review explained that patients with LS disease who relapse 3 months or more after potentially curative first-line therapy receive the standard first-line treatment in the metastatic setting (platinum doublet plus durvalumab), as well as other second-line options; those who relapse more rapidly would typically receive other, non–platinum-based, second-line options. Second-line treatment options available to patients with ES or LS disease in Canada include rechallenge with platinum plus etoposide (if progression occurs more than 3 months after the last dose of first-line chemotherapy), topotecan (used off-label in patients who progress in the 60 days after initiation of first-line therapy), and CAV. Third-line treatment options include topotecan and CAV (if not used as second-line therapy) and irinotecan with or without a platinum-containing drug. Oral etoposide may also be used in a small number of patients. According to the clinical experts consulted by CADTH for this review, ORRs and DOR decrease with as the line of therapy advances, and many of the second-line and third-line treatment options are difficult to tolerate; therefore, there is a high need for additional treatment options. The clinical experts stated that the goal of treatment for stage III or metastatic SCLC is to prolong survival while maintaining HRQoL.

Drug

Key characteristics of lurbinectedin are shown in Table 3. Lurbinectedin is an alkylating drug with a mechanism of action that involves binding to DNA, inhibition of transcription, and induction of apoptosis. The Health Canada–recommended dosage is 3.2 mg/m² by IV infusion over 60 minutes, repeated every 21 days until disease progression or unacceptable toxicity. Lurbinectedin is indicated for the treatment of adult patients with stage III or metastatic SCLC who have progressed on or after platinum-containing therapy. The drug is not approved in Canada for other indications and has not been previously reviewed by CADTH. Lurbinectedin received advance consideration from Health Canada under a Notice of Compliance with conditions; these conditions were to conduct timely, well-designed studies to verify the clinical benefit of the drug, to provide appropriate educational material, and to comply with any postmarket surveillance commitments and advertising, labelling, and distribution requirements placed on the drug. The sponsor’s reimbursement request is aligned with the Health Canada indication.

Table 3: Key Characteristics of Chemotherapy Drugs for the Treatment of Patients With SCLC

CAV = cyclophosphamide, doxorubicin, and vincristine; LVEF = left ventricular ejection fraction; NSCLC = non–small cell lung cancer; SCLC = small cell lung cancer.

^aHealth Canada–approved indications.

^bIn the SCLC protocol, carboplatin is dosed at an area under the concentration, taking renal function into account, on day 1 of a 21-day treatment cycle.

^cIn the SCLC protocol, cisplatin is dosed at 25 mg/m² per day on days 1 to 3 of a 21-day treatment cycle.

^dIn the SCLC protocol, IV etoposide is dosed at 100 mg/m² per day on days 1 to 3 of a 21-day treatment cycle.

^eIn the SCLC protocol, oral etoposide is often dosed at 50 mg/m² to 100 mg/m² per day over 3 to 5 days of a 21-day week treatment cycle. However, other schedules, including more prolonged administration, are also used.

^fIn the SCLC protocol, the CAV regimen is administered at doses of 1,000 mg/m² cyclophosphamide, 50 mg/m² doxorubicin, and 1.4 mg/m² vincristine, all on day 1 of a 21-day cycle.

^gIn the SCLC protocol, irinotecan is often dosed at 50 mg/m² weekly on a 3-week or 4-week cycle, but other variations are also used.

Sources: Product monographs for lurbinectedin,¹⁸ carboplatin,¹⁹ cisplatin,²⁰ etoposide,²¹ topotecan,²² cyclophosphamide,²³ doxorubicin,²⁴ vincristine,²⁵ and irinotecan.²⁶

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The original patient group submissions can be found at the end of this report.

Two patient groups provided input for this review: LCC and the LHF, previously known as the Ontario Lung Association. LCC conducted phone interviews with 2 patients in Canada with SCLC (1 with localized and 1 with metastatic disease) and environmental scans with 1 patient and 2 caregivers of patients with metastatic SCLC in the US in March 2022; all had experience with lurbinectedin. The LHF conducted an online survey (2 respondents; no demographic or disease information collected) and phone interviews (3 patients in Canada with lung cancer; type and stage not reported) from September to December 2021, and collected input from 2 additional individuals (1 registered nurse and 1 certified respiratory educator); none had experience with lurbinectedin. Patients highlighted the nonspecific early symptoms of SCLC that led to delays in diagnosis, as well as the physical (e.g., shortness of breath, cough, fatigue, pain), emotional, and social toll of an SCLC diagnosis. Patients acknowledged that although existing treatments for SCLC (e.g., surgery, radiation, chemotherapy, targeted therapy, immunotherapy) prolong survival and delay disease progression, the side effects of currently available second-line and third-line chemotherapies for metastatic SCLC (e.g., nausea, fatigue, weight, and hair loss) were sometimes severe and negatively impacted HRQoL, employment, and the ability to perform activities of daily living. Patients identified an unmet need for additional second-line treatment options for metastatic SCLC that can prolong survival, delay disease progression, manage cancer symptoms, and maintain HRQoL and that have minimal side effects. Patients emphasized that stopping or delaying disease progression was the most important factor in choosing treatments, and they were more receptive to potential side effects of efficacious therapies. Patients who had experience with lurbinectedin felt that the drug had reduced or stabilized tumour size, delayed disease progression, helped them continue or resume activities of daily living, including employment, and had more manageable side effects and a shorter recovery time compared with other SCLC therapies they had received.

Clinician Input

Input From Clinical Experts Consulted by CADTH

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

Unmet Needs

The clinical experts consulted by CADTH for this review stated that patients with stage III or metastatic SCLC generally manifest rapid responses to first-line chemotherapy (although these are not usually sustained) and that there are currently no biomarkers for response to immunotherapy. Brain and bone metastases are common in this population. Currently available second-line chemotherapy options (e.g., topotecan, CAV) have significant drawbacks, including toxicity and inconvenience (e.g., topotecan has a dosage regimen of 5 consecutive days of IV treatment every 3 weeks).

Place in Therapy

According to the clinical experts consulted by CADTH for this review, lurbinectedin would be used as second-line or third-line therapy for stage III or metastatic SCLC (after first-line platinum plus etoposide therapy and potential rechallenge). The clinical experts stated that if progression occurred a relatively long interval after first-line therapy (e.g., 6 to 12 months), many clinicians would rechallenge with platinum plus etoposide as a second-line option before using lurbinectedin.

Patient Population

The clinical experts consulted by CADTH for this review emphasized that all patients with ES SCLC need additional treatment options to prolong survival and maintain HRQoL. The patient population best suited to treatment with lurbinectedin would be patients with ES SCLC who progress after treatment with platinum plus etoposide with or without durvalumab. Such patients are followed by a medical oncologist and would be identified at the time of progression. Patients with a poor performance status (e.g., ECOG PS score of 3 or greater) or limited organ function would be least suitable for treatment with lurbinectedin. Apart from these factors, it is not currently possible to identify patients who would be most likely to respond to lurbinectedin.

Assessing Response to Treatment

According to the clinical experts consulted by CADTH for this review, assessment of response to lurbinectedin therapy would involve imaging scans (CT or MRI), clinical improvement, and laboratory markers (e.g., liver function tests, lactate dehydrogenase levels, carcinoembryonic antigen levels). Clinically meaningful responses to treatment would manifest as improvement in symptoms and improvement or stabilization of HRQoL. Response to treatment is assessed with clinical examinations, imaging scans, laboratory assessments, and evaluation of patient-reported outcomes. All of these except imaging would be assessed on the same schedule as treatment cycle length (3 weeks). Imaging would be assessed before each cycle via chest X-ray when appropriate and with imaging scans approximately every 3 months.

Discontinuing Treatment

The clinical experts stated that lurbinectedin should be discontinued in patients who progress according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria, when unacceptable toxicities occur, or by patient choice.

Prescribing Conditions

The clinical experts stated that lurbinectedin would be given in an outpatient setting and would be ordered by a medical oncologist.

Additional Considerations

The clinical experts emphasized the unmet need for better second-line and third-line treatment options for patients with stage III or metastatic SCLC.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups. The original clinician group submissions can be found in the Stakeholder Input section at the end of this report.

Two clinician groups, the LCC Medical Advisory Committee (10 medical oncologists, 2 respirologists, 1 thoracic surgeon, and 1 pathologist) and the Ontario Health-Cancer Care Ontario Lung Cancer Drug Advisory Committee (5 medical oncologists), provided input for this review. No major contrary views were presented. Clinician groups echoed the unmet need for additional efficacious second-line treatment options for patients with stage III or metastatic SCLC that have fewer side effects and are convenient to administer. The clinician groups noted that some clinicians would perform imaging evaluations slightly more frequently than others (every 2 to 3 cycles [6 to 9 weeks] versus every 3 months) and that in addition to improvement or stabilization of symptoms and HRQoL, clinically meaningful responses to lurbinectedin would be manifested as tumour shrinkage observed on imaging scans. In addition, the clinician groups noted that it was not yet clear if re-treatment with platinum plus etoposide would be the preferred option for patients with platinum-sensitive disease who have treatment-free periods beyond some cut-off (e.g., 6 months).

Drug Program Input

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 4.

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

CAV = cyclophosphamide plus doxorubicin and vincristine; CTFI = chemotherapy-free interval; CNS = central nervous system; CYP3A4 = cytochrome P450 family 3 subfamily A member 4; ES = extensive stage; LS = limited stage; PAG = Provincial Advisory Group; pERC = CADTH pan-Canadian Oncology Drug Review Expert Review Committee.

Clinical Evidence

The clinical evidence included in the review of lurbinectedin is presented in 2 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 that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor. No other relevant evidence was identified for this review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of lurbinectedin (3.2 mg/m² by IV infusion over 60 minutes, repeated every 21 days) for the treatment of adult patients with stage III or metastatic SCLC who have progressed on or after platinum-containing therapy.

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 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 5: Inclusion Criteria for the Systematic Review

AE = adverse event; CTFI = chemotherapy-free interval; DOR = duration of response; HRQoL = health-related quality of life; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; SAE = serious adverse event; SCLC = small cell lung cancer; WDAE = withdrawal due to adverse event.

^aThese outcomes were identified as being of particular importance to patients in the input received by CADTH from patient groups.

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.²⁷

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946—) via Ovid and Embase (1974–) via Ovid. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Zepzelca and lurbinectedin. The following clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.²⁷ No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results.

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.²⁸ Included in this search were the websites of regulatory agencies (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.

See Appendix 1 for the detailed search strategies. The initial search was completed on March 24, 2022. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Review Expert Review Committee (pERC) on July 13, 2022.

The searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts.

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

Findings From the Literature

Three reports of a single study were identified from the literature^10,29,30 and 1 report of the same study was identified from other sources¹¹ for inclusion in the Systematic Review (Figure 1). The included studies are summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of the Included Study (B-005)

ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = asparagine aminotransferase; CNS = central nervous system; CPK = creatine phosphokinase; DBIL = direct bilirubin; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group performance status; IA = investigator assessment; IRC = independent review committee; NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; OL = open label; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics; RBC = red blood cell; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; SCLC = small cell lung cancer; TBIL = total bilirubin; ULN = upper limit of normal.

Note: One additional report was included (B-005 Clinical Study Report).

^aNumbers of patients reflect only those with SCLC.

^bDate of first and last patient registrations.

^cDose was capped at a body surface area of 2.0 m² (6.4 mg).

Source: B-005 Clinical Study Report.¹¹

Description of Studies

Study B-005¹⁰ was a phase II, single-arm, multicentre, OL, basket trial designed to evaluate the efficacy and safety of lurbinectedin in previously treated patients with advanced solid tumours. Only data for the SCLC cohort (N = 105) are described in this report. The primary objective of the study was to assess ORR by IA of lurbinectedin in patients with advanced SCLC who had received 1 prior line of systemic therapy. Secondary objectives included ORR per IRC, DOR per IA and IRC, clinical benefit rate per IA and IRC, PFS per IA and IRC, and OS.

Adult patients (aged 18 years and older) with SCLC who had received 1 previous line of systemic therapy for advanced disease and met the eligibility criteria were enrolled at 26 sites (primarily in Europe, predominantly Spain; no sites in Canada) from October 21, 2015, to October 15, 2018. Patients were treated with lurbinectedin (3.2 mg/m² on day 1 of a 21-day treatment cycle) until disease progression or unacceptable toxicity. The data cut-off date was January 15, 2019, at which point the study was ongoing and patients were still being treated and followed. For SCLC patients, survival follow-up was every 6 months until death or study termination. The study was funded by PharmaMar, a Spanish pharmaceutical company that entered into an exclusive licensing agreement with the sponsor in 2019 for commercialization of lurbinectedin in North America.

Populations

Inclusion and Exclusion Criteria

Adult patients aged 18 years and older with SCLC, an ECOG PS score of 2 or less, and measurable disease who had received 1 prior line of systemic therapy for advanced disease were eligible if they had not been previously treated with lurbinectedin or trabectedin and did not have known CNS involvement identified on CT or MRI. In addition, patients with serious comorbidities (e.g., cardiac problems, breathing difficulties, infections, wounds) and patients who had received chemotherapy within 3 weeks of cycle 1 day 1 were excluded.

Baseline Characteristics

The baseline demographic characteristics of patients in the B-005 study are shown in Table 7. More than 3-quarters of patients were white, 60.0% were male, and the median age was 60 years. Most patients (56.2%) had an ECOG PS of 1, roughly 36.2% had an ECOG PS score of 0, and only 7.6% (8 patients) had an ECOG PS score of 2. Almost all patients (92.4%) were current or former smokers. Approximately one-third (30.5%) of patients were diagnosed with LS disease; the rest (69.5%) were diagnosed with ES disease. However, only 7 patients (6.7%) had LS disease at study entry and only 2 patients (1.9%) had nonmetastatic disease at study entry. Almost all patients (98.1%) had lung disease at baseline, most (81.9%) had lymph node involvement, and nearly half (41.0%) had liver involvement. Very few patients had received prior potentially curative or palliative surgery (1.0% each), whereas most had received external radiotherapy (71.4%) or prophylactic cranial irradiation (58.1%). Nearly all patients (93.3%) had received 1 line of prior systemic therapy (100.0% received platinum-containing drugs and 99.0% received etoposide), whereas only 7.6% of patients had received prior immunotherapy. Based on their CTFIs, 42.9% of patients had platinum-resistant disease (CTFI < 90 days, including both refractory disease [CTFI < 30 days = 20.0%] and resistant disease [CTFI 30 to 89 days = 22.9%]), whereas 57.1% of patients had platinum-sensitive disease (CTFI ≥ 90 days, including both sensitive disease [CTFI 90 to 179 days = 38.1%] and very sensitive disease [, CTFI ≥ 180 days = 19.0%]).

Table 7: Summary of Baseline Demographic and Disease Characteristics in Study B-005 (Treated Patients)

BSA = body surface area; CNS = central nervous system; CTFI = chemotherapy-free interval; ECOG PS = Eastern Cooperative Oncology Group performance status; IMRT = intensity-modulated radiotherapy; LDH = lactate dehydrogenase; PARPi = poly(ADP-ribose) polymerase inhibitor; ULN = upper limit of normal.

^aPatients recruited in France and Belgium did not have race information available due to ethical requirements in those countries.

^bOne patient had no LDH data at baseline.

^cOne patient with CNS metastases at baseline was treated (reported as a protocol deviation). The other 3 patients did not have CNS involvement at study entry.

^dSyndrome of inappropriate antidiuretic hormone secretion (n = 6), Cushing’s syndrome (n = 2), and paraneoplastic syndrome not specified (n = 1).

^eFive patients were treated with nivolumab, 1 patient was treated with carboplatin plus etoposide (rechallenge plus atezolizumab), and 1 patient was treated with an investigational drug.

^fOne patient received platinum plus gemcitabine as first-line therapy.

^gFive patients received nivolumab as second-line therapy, 2 patients received platinum and etoposide plus atezolizumab as first-line therapy, and 1 patient received platinum and etoposide plus atezolizumab as second-line therapy.

^hTwo patients received carboplatin plus etoposide plus veliparib as first-line therapy.

Source: B-005 Clinical Study Report.¹¹

Interventions

Lurbinectedin (3.2 mg/m²) was administered as a 1-hour IV infusion on day 1 of a 3-week treatment cycle. The dose was capped at a body surface area of 2.0 m² (6.4 mg). Infusions were administered at hospitals and cancer centres in an outpatient setting. Treatment was continued until disease progression (per IA), unacceptable toxicity, a treatment delay of 3 weeks or longer (except in the case of clear clinical benefit with sponsor’s approval), the need for more than 2 dose reductions, intercurrent illness of sufficient magnitude to preclude safe continuation of the study, major protocol deviation that may affect the risk-to-benefit ratio for the participating patient, investigator decision, noncompliance with study requirements, or patient refusal.

All patients received antiemetic prophylaxis before each lurbinectedin infusion, including corticosteroids, serotonin antagonists, dexamethasone, and metoclopramide. Allowed medications included therapies for pre-existing and treatment-emergent medical conditions (including pain management), blood products and transfusions, bisphosphonates, secondary prophylaxis and/or symptomatic treatment for emesis, G-CSF for therapy and for secondary prophylaxis, erythropoietin, and anticoagulation therapy. Use of other antineoplastic therapies (except somatostatin analogues for neuroendocrine tumours), radiotherapy, other investigational drugs, aprepitant and related drugs, immunosuppressive therapies (other than corticosteroids for antiemetic prophylaxis and/or pain control), and primary G-CSF prophylaxis was forbidden.

To continue treatment, patients had to fulfill the following re-treatment criteria at each cycle: ECOG PS score of 2 or less, hemoglobin of 8 g/dL or greater, absolute neutrophil count of 1.5 × 10⁹/L or greater, platelet count of 100 × 10⁹/L or greater, AST and ALT of 3.0 × upper limit of normal (ULN) or lower, total bilirubin of 1.5 × ULN or lower or direct bilirubin of 1.0 × ULN, albumin of 3 g/dL or higher, serum creatinine of 1.5 × ULN or lower, or creatinine clearance of 30 mL/min or higher. In addition, active infections (including sepsis) and/or bleeding (any grade) had to be absent, and the following AEs must have resolved before re-treatment: grade 1 or lower creatinine phosphokinase elevation, grade 1 or lower nonhematological drug-related AEs (except isolated increased gamma-glutamyl transferase and/or alkaline phosphatase, grade 2 asthenia, constipation, alopecia, peripheral neuropathy, or nonoptimally treated nausea and/or vomiting). Patients who did not meet these requirements on day 1 of a cycle were reassessed at least every 2 to 3 days; after a maximum delay of 3 weeks, patients were withdrawn from the study. Dose reduction was implemented after recovery from the following AEs: grade 3 or higher treatment-related nonhematological toxicity (except grade 3 or 4 nausea and/or vomiting not optimally treated, grade 3 asthenia lasting 3 days or less, grade 3 diarrhea lasting 2 days or less or not optimally treated, grade 3 transient ALT and/or AST elevations that were rapidly reversible and did not lead to subsequent delays, and nonclinically relevant biochemical abnormalities), grade 4 thrombocytopenia, or grade 3 thrombocytopenia with grade 3 or 4 bleeding, grade 4 neutropenia, any grade of febrile neutropenia or neutropenia associated with infection and/or sepsis, and frequent or prolonged (longer than 1 week) dose delays due to any treatment-related AEs. Dose reduction occurred stepwise from 3.2 mg/m² to 2.6 mg/m² and then to 2.0 mg/m²; up to 2 dose reductions were allowed per patient, and dose was not re-escalated under any circumstances. Patients who experienced grade 3 or 4 hypersensitivity reactions were withdrawn from treatment. Patients who continued to experience treatment-related toxicity and/or frequent dose delays could continue receiving the study medication if objective clinical benefit was adequately documented by the investigator, and upon agreement with the sponsor.

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 8. These end points are further summarized subsequently.

Table 8: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

DOR = duration of response; IA = investigator assessment; IRC = independent review committee; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1.

Source: B-005 Clinical Study Report.¹⁰

OS, PFS, ORR, and DOR are standard and broadly accepted outcome measures in oncology trials for the treatment of SCLC (refer to Table 8 and Table 9 for outcome definitions and censoring rules). Involvement of all measurable sites of disease, as well as nonmeasurable sites of disease, was evaluated by CT or MRI at baseline (in the 28 days before cycle 1 day 1). During the treatment period, tumour response was evaluated for all original sites of disease involvement at baseline every 2 cycles until cycle 6, and then every 3 cycles thereafter. Imaging evaluations were repeated at the end-of-treatment visit, if not previously done, and if the reason for treatment discontinuation was not disease progression. The same imaging modality was used for each patient throughout the study. Anonymized copies of all scans were sent to the sponsor and subsequently for evaluation by an IRC. Whether or not the IRC was blinded to the nature of the study and intervention was not stated.

Tumour response was assessed using RECIST 1.1.³¹ Progressive disease was defined as a predefined increase in the sum of diameters of target lesions (at least 20%), taking as reference the smallest sum of diameters on study, in target lesions or new nontarget lesions; the sum must also have demonstrated an absolute increase of at least 5 mm. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete response was defined as the disappearance of all target lesions with a reduction of the short axis of any pathological lymph nodes to less than 10 mm. Stable disease was defined as neither sufficient shrinkage (compared to baseline) to qualify for partial response nor sufficient increase (taking as reference the smallest sum diameters while on study) to qualify for progressive disease. An initial indication of response per IA was confirmed 4 or more weeks later (also by IA).

Decisions to discontinue protocol therapy due to progressive disease were made by the investigator, based on local imaging scans and clinical evaluation to assess clinical deterioration in the absence of radiological evidence. Patients who discontinued treatment without documented progressive disease continued to have radiological assessments every 2 months for the first 6 months, and every 3 months thereafter, until progressive disease, start of new antitumour therapy, death, or the date of study termination. Following disease progression, patients were followed up for survival on the same schedule (in person or by phone call) until death.

Harms outcomes included treatment-emergent AEs, SAEs, AEs requiring dose reduction, withdrawals due to AEs, and deaths. AEs that began or worsened on or after the start of protocol therapy were captured until 30 days after the last dose of study drug. AEs were defined as any untoward medical occurrence and were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) version 21.0³² and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.³³

Statistical Analysis

Statistical analyses in study B-005 are summarized in Table 9. The sample size for each tumour type (9 cohorts in total) was based on an adaptive design. Up to 25 evaluable patients for each tumour type were to be recruited to test the null hypothesis that 1% of patients or fewer with each tumour type achieve an objective response to lurbinectedin and the alternative hypothesis that at least 10% of patients achieve an objective response. The variance of the standardized test was based on the null hypothesis. The type I error associated with this 1-sided test was 0.025 and the type II error was 0.2 using a normal approximation (approximately 0.3 if using an exact binomial distribution); hence, the statistical power was 80% using a normal approximation (approximately 70% if using an exact binomial distribution). Under these assumptions, if the number of patients who achieve a confirmed objective response was 2 or more, this would allow rejection of the null hypothesis.

An interim analysis to reject H₀ (nonbinding) or to reject H₁ (futility) was planned after the recruitment of 15 evaluable patients in each cohort; if the number of responding patients was 2 or more at the interim analysis, then recruitment had to continue up to 25 evaluable patients. A gamma family boundary would be used to control for the type I error, the parameter to reject H₀ was fixed as –1 and the parameter to reject H₁ was fixed as 0. If none of the first 15 evaluable patients in a specific tumour cohort had a confirmed response, the alternative hypothesis would be rejected, according to boundaries and sample size assumptions, and recruitment would be stopped. If the number of responding patients was already 2 or more at the interim analysis, then H₀ could be rejected and the study would have sufficient power to be stopped. In contrast, if there was 1 confirmed response, recruitment would be continued to up to 25 evaluable patients for the relevant tumour type.

In the SCLC and endometrial carcinoma cohorts, the analysis at 25 evaluable patients would serve as the second interim analysis to decide on continuation of recruitment. Two confirmed responses would be required to expand accrual up to 100 (SCLC) and 50 (endometrial carcinoma) evaluable patients. For the SCLC cohort, expanded recruitment was not preplanned and occurred as a result of 2 protocol amendments: the first, in July 2016, permitted enrolment of up to 50 patients based on results of the PM1183-A-003-10 study, which showed responses to lurbinectedin plus doxorubicin; and the second, in March 2017, permitted enrolment of up to 100 patients based on early results of study B-005 and to support the ATLANTIS trial. For the SCLC cohort, a type I or II error would be controlled for with a gamma family boundary (–1 to reject H₀, 0 to reject H₁). For the endometrial carcinoma cohort, a type I or II error would be controlled for with a gamma family boundary (–1 to reject H₀, –3 to reject H₁)

The sample size for the SCLC cohort of was to be increased to 100 evaluable patients if the success boundary (at least 2 confirmed responses) was reached in the first 25 evaluable patients. Type I and type II errors were to be controlled for with a gamma family boundary (–1 to reject H₀, 0 to reject H₁). These additional patients were to be recruited to test the null hypothesis that 15% of patients or less achieve objective responses to lurbinectedin and the alternative hypothesis that at least 30% of patients achieve objective responses. The variance of the standardized test was based on the null hypothesis. The type I error associated with this 1-sided test was 0.025 and the type II error was 0.051 (normal approximation; approximately 0.05 if exact binomial distribution); hence, statistical power was 95% (normal approximation; approximately 95% if exact binomial distribution). Under these assumptions, if the number of patients who achieve a confirmed objective response was at least 23, the null hypothesis could be rejected. With the sample size of 100 evaluable SCLC patients, the CIs for outcomes would be narrower, and their half-widths would be confined to ± 15%.

For the primary analysis of ORR per IA among all treated patients, the ORR and its exact 95% binomial CI were calculated. The same approach was used for the secondary outcome of ORR per IRC. PFS per IA and IRC, DOR per IA and IRC, and OS functions among all treated patients were estimated using the Kaplan-Meier product limit method; 2-sided 95% CIs for median PFS, DOR, and OS were obtained with log-log transformation. PFS and OS rates at fixed time points and their 95% CIs were derived from a Kaplan-Meier analysis. No hypothesis tests of secondary outcomes were conducted, and no multiplicity adjustment was performed.

No adjustment factors were included in the statistical analyses. Missing data were accounted for in the Kaplan-Meier analyses of OS, PFS, and DOR with censoring. For analyses of ORR, patients with unknown or missing response data were classified as nonresponders. A sensitivity analysis of ORR per IA was conducted among all evaluable patients. Subgroup analyses by CTFI (using a 90-day cut-off, as well as by refractory [CTFI < 30 days], resistant [CTFI 30 to 89 days], sensitive [CTFI 90 to 179 days], and very sensitive [CTFI ≥ 180 days] disease) were prespecified for all outcomes; however, hypothesis tests for deviation from threshold values were not conducted and multiplicity was not taken into account. In addition, prespecified subgroup analyses for efficacy by sex (male versus female), age (younger than 65 years versus 65 years and older), race (white versus other), number of prior lines of therapy (1 versus 2 or more), body surface area (1.8 m² or less versus greater than 1.8 m²), ECOG PS (0 versus 1 versus 2), geographic area (Europe versus US), and alpha-1 acid glycoprotein level were performed for the primary efficacy end point (ORR by IA).

Table 9: Statistical Analysis of Efficacy End Points in Study B-005

CI = confidence interval; DOR = duration of response; IA = investigator assessment; IRC = independent review committee; KM = Kaplan-Meier; ORR = objective response rate; OS = overall survival; PFS = progression-free survival.

Source: B-005 Clinical Study Report.¹⁰

Analysis Populations

The set of all included patients refers to all patients recorded in the trial database, regardless of whether they received the study drug; this set was not used for any efficacy analyses. The set of all treated patients was defined as all included patients who received at least 1 partial or complete infusion of lurbinectedin.

The set of all evaluable patients (for efficacy) was defined as all included patients who had received at least 1 complete infusion of lurbinectedin and either had at least 1 postbaseline tumour assessment per RECIST 1.1 or were categorized as treatment failures. Patients who discontinued treatment because of treatment-related toxicity before tumour assessment was performed, patients who died early from malignant disease, and patients in whom treatment was withdrawn because of clinical progression and/or symptomatic deterioration with no tumour assessments were classified as treatment failures and considered nonevaluable for objective tumour response (not included in the denominator for evaluation of response); these patients were still considered evaluable for efficacy. Separate sets of evaluable patients were defined per IA and per IRC.

The set of all responding patients was defined as all evaluable patients who had a confirmed complete response or partial response as best overall response according to RECIST 1.1. Separate sets of responding patients were defined per IA and per IRC. All treated patients were considered evaluable for safety.

Results

Patient Disposition

Patient disposition in study B-005 is summarized in Table 10. In total, 110 patients were screened for participation in the study, of whom 105 (95.5%) were treated with lurbinectedin. The 5 patients who were not treated did not meet various eligibility criteria (e.g., ECOG PS, albumin levels, CNS involvement, dyspnea, and ALT levels). Most patients (89.5%) discontinued lurbinectedin during the study; the most common reason for treatment discontinuation was disease progression (80.0%). Four patients (3.8%) discontinued treatment due to investigator decision and 2 patients (1.9%) refused treatment. Only 2 patients (1.9%) discontinued treatment due to treatment-related AEs. Only 1 patient (0.9%) was lost to follow-up. In total, 104 (94.5%) of patients were considered evaluable for efficacy per IA and 98 (89.1%) were considered evaluable for efficacy per IRC.

Major protocol deviations (those that might affect the risk-to-benefit ratio of the clinical trial by study investigators) in study B-005 are summarized in Table 11. Fifteen patients (13.6%) had assessments not performed per protocol (primarily missing biochemical and/or coagulation tests required for lurbinectedin re-treatment), 10 patients (9.1%) had protocol deviations related to treatment noncompliance (primarily failure to reduce or delay doses in patients meeting protocol requirements), 9 patients (8.2%) had protocol deviations related to eligibility (primarily missing data on hematological and/or organ function and a washout period from prior monoclonal antibody therapy of less than 4 weeks), and 2 patients (1.8%) had protocol deviations related to issues with the informed-consent form.

Table 10: Patient Disposition in Study B-005

AE = adverse event; IA = investigator assessment; IRC = independent review committee.

^aIncludes 2 patients with symptomatic deterioration or clinical disease progression (without radiological evidence of progressive disease).

^bInvestigator decision was related to persistent asthenia not meeting preplanned criteria for treatment discontinuation (n = 2), clinical deterioration (n = 1), and not specified (n = 1).

^cOne patient had grade 4 febrile neutropenia, grade 3 thrombocytopenia, and grade 3 anemia reported as SAEs, and 1 patient had worsening of peripheral neuropathy.

^dOne patient withdrew consent and 1 patient refused treatment because of bone radiotherapy for pain control but allowed follow-up.

^eAll deaths were due to disease progression.

^fOne patient was lost to follow-up on February 1, 2016, with stable disease as best response to treatment and progressive disease at last assessment (January 15, 2016).

^gTwo patients were treated but not evaluable due to early death, 2 patients were treated but did not have radiologically documented progressive disease (symptomatic deterioration or clinical progressive disease), and 1 patient was treated but refused to undergo disease measurement after having received 2 cycles of lurbinectedin.

^hSeven patients were not evaluable by RECIST per IRC because of missing imaging data at baseline or during treatment.

Source: B-005 Clinical Study Report.¹⁰

Table 11: Major Protocol Deviations in Study B-005 (Included Patients)

Source: B-005 Clinical Study Report.¹⁰

Exposure to Study Treatments

Exposure to lurbinectedin in study B-005 is summarized in Table 12. The median number of cycles administered was 4 (range, 1 to 24 cycles), and the median time on treatment was 14.0 weeks (range, 1.1 to 85.0 weeks). The median relative dose intensity was 97.4% (range, 65.2% to 104.3%). Lurbinectedin was administered during clinic visits so adherence was not a relevant consideration.

For OS analyses, 66 patients (62.9%) died and 39 (37.1%) were censored; the median follow-up time was 17.1 months (95% CI, 8.9 to 22.5 months). For PFS analyses per IA, 90 patients (85.7%) experienced disease progression or death and 15 (14.3%) were censored; the median follow-up time was 14.5 months (95% CI, 14.5 months to not reached). For PFS analyses per IRC, 81 patients (77.1%) experienced disease progression or death and 24 (22.9%) were censored; the median follow-up time was 16.2 months (95% CI, 6.0 months to not reached).

Table 12: Treatment Exposure in Study B-005 (Treated Patients)

^aCalculated as date of last infusion plus 30 days, or date of death or subsequent therapy (whichever comes first) minus date of first infusion.

^bCalculated as the cumulative dose divided by the number of weeks of treatment.

^cCalculated as the ratio of absolute dose intensity divided by the intended dose intensity.

Source: B-005 Clinical Study Report.¹⁰

Concomitant transfusion and growth-factor support in study B-005 were as follows: 9 patients (8.6%) received transfusion support (red blood cells: 7.6%; platelets: 2.9%), 2 patients (1.9%) received erythropoietin, and 23 patients (21.9%) received G-CSF (secondary prophylaxis: 8.6%; therapeutic: 11.4%; both secondary prophylaxis and therapeutic: 1.9%).

Anticancer therapies received subsequent to study treatment discontinuation in study B-005 are summarized in Table 13. Forty-seven patients (44.8%) received subsequent systemic anticancer therapy and 20 patients (19.0%) received subsequent radiotherapy. The most common subsequent systemic drugs were carboplatin (15.2%), etoposide (14.3%), paclitaxel (12.4%), and topotecan (12.4%).

Table 13: Subsequent Therapies in Study B-005 (Treated Patients)

^aThree patients received lurbinectedin as further treatment and 2 patients received rovalpituzumab tesirine. Seven patients received immunotherapy: 3 received ipilimumab and nivolumab, 1 received nivolumab monotherapy, 1 received nivolumab with chemotherapy, 1 received pembrolizumab monotherapy, and 1 received atezolizumab with chemotherapy.

Source: B-005 Clinical Study Report.¹⁰

Efficacy

Only efficacy outcomes and analyses of subgroups identified in the review protocol are reported here.

Datasets Analyzed

Data for all patients were reviewed for outcome assessment per IA and per IRC. Of the 105 included patients, 104 were evaluable for efficacy per IA (1 patient withdrew consent before the first postbaseline tumour assessment). Of the 105 included patients, 98 were evaluable for efficacy per IRC (1 patient withdrew consent before the first postbaseline tumour assessment; 2 patients died during the first cycle before tumour assessments were done; 2 patients had symptomatic deterioration or clinical progressive disease during the first cycle before tumour assessments were done; and 2 patients did not have baseline imaging available for IRC review).

Of the 105 included patients, 100 were evaluable for tumour response per IA (1 patient withdrew consent before the first postbaseline tumour assessment; 2 patients died during the first cycle before tumour assessments were done; and 2 patients had symptomatic deterioration or clinical progressive disease during the first cycle before tumour assessments were done). Of the 105 included patients, 98 were evaluable for tumour response per IRC for the same reasons as for evaluability for efficacy.

Overall Survival

OS results among all treated patients in study B-005 are summarized in Table 14, Figure 2, and Figure 3. Median OS was 9.3 months overall (95% CI, 6.3 to 11.8 months). Median OS among patients with a CTFI shorter than 90 days and 90 days or longer was 5.0 months (95% CI, 4.1 to 6.3 months) and 11.9 months (95% CI, 9.7 to 16.2 months), respectively. Median OS among patients with a CTFI shorter than 30 days, 30 to 89 days, 90 to 179 days, and 180 days or longer was 4.7 months (95% CI, 1.6 to 6.3 months), 6.2 months (95% CI, 4.1 to 7.6 months), 11.8 months (95% CI, 7.8 to 15.8 months), and 16.2 months (95% CI, 9.6 months to not calculable), respectively.

Table 14: OS in Study B-005 (Treated Patients)

CI = confidence interval; CTFI = chemotherapy-free interval; NC = not calculable; OS = overall survival.

^aFrom Kaplan-Meier analysis.

Source: B-005 Clinical Study Report.¹⁰

Figure 2: Kaplan-Meier Plot of OS in Study B-005 (Treated Patients)

OS = overall survival.

Source: B-005 Clinical Study Report.¹⁰

Figure 3: Kaplan-Meier Plot of OS in Study B-005 (Treated Patients With a CTFI < 90 Days or ≥ 90 Days)

CTFI = chemotherapy-free interval; OS = overall survival.

Source: B-005 Clinical Study Report.¹⁰

Health-Related Quality of Life

HRQoL was not assessed in study B-005.

Progression-Free Survival

PFS results per IA and IRC among all treated patients in study B-005 are summarized in Table 15, Figure 4, and Figure 5. Median PFS per IRC was 3.5 months overall ███ █ ██ █ ██ █ █ █ ██ █ ███████. Median PFS per IRC among patients with CTFI less than 90 days and 90 or more days was ██ █ █████ █ ███ █ ██ █ ██ █ █ █ ██ █ ███████ and ██ █ █████ █ ███ █ ██ █ ██ █ █ █ ██ █ ███████, respectively. Median PFS per IRC among patients with CTFI less than 30 days, 30 to 89 days, 90 to 179 days, and 180 or more days was ██ █ █████ █ ███ █ ██ █ ██ █ █ █ ██ █ ███████ █ ██ █ █████ █ ███ █ ██ █ ██ █ █ █ ██ █ ███████ █ ██ █ █████ █ ███ █ ██ █ ██ █ █ █ ██ █ ███████ █ ██ █ ██ █ █████ █ ███ █ ██ █ ██ █ █████ █ █ █ ██ █ ████████ respectively.

Table 15: PFS in Study B-005 (Treated Patients)

CI = confidence interval; CTFI = chemotherapy-free interval; IA = investigator assessment; IRC = independent review committee; PFS = progression-free survival.

^aFrom Kaplan-Meier analysis.

Source: B-005 Clinical Study Report.¹⁰

Figure 4: Kaplan-Meier Plot of PFS in Study B-005 (Treated Patients)

IA = investigator assessment; IRC = independent review committee; PFS = progression-free survival.

Source: B-005 Clinical Study Report.¹⁰

Figure 5: Kaplan-Meier Plot of PFS per IRC in Study B-005 (Treated Patients With a CTFI < 90 Days or ≥ 90 Days)

CTFI = chemotherapy-free interval; IRC = independent review committee; PFS = progression-free survival.

Source: B-005 Clinical Study Report.¹⁰

Objective Response Rate

ORR results per IA and IRC among all treated patients in study B-005 are summarized in Table 16. The ORR per IA was 35.2% overall (95% CI, 26.2% to 45.2%). The null hypothesis that no more than 15% of patients achieved objective responses to lurbinectedin was rejected, as the number of patients with objective responses exceeded the minimum number needed (23 of 100 patients). The ORR per IA among patients with a CTFI shorter than 90 days and 90 or more days was 22.2% (95% CI, 11.2% to 37.1%) and 45.0% (95% CI, 32.1%, 58.4%), respectively. The ORR per IA among patients with a CTFI shorter than 30 days, 30 to 89 days, 90 to 179 days, and 180 or more days was ████ █ ███ █ ██ █ ███ █ █ █ ██████ █ ████ █ ███ █ ██ █ ████ █ █ █ ██████ █ ████ █ ███ █ ██ █ ████ █ █ █ ███████ and 60.0% (95% CI, 36.1%, 80.9%), respectively. All confirmed responses were partial responses. A sensitivity analysis of ORR per IA among all evaluable patients showed results similar to the primary analysis of ORR per IA among all included and treated patients. A subgroup analysis showed that ORR per IA among all treated patients who had received 1 line of prior systemic therapy (n = 98) was ████ █ ███ █ ██ █ ████ █ █ █ ██████, whereas among all treated patients who had received 2 or more lines of prior systemic therapy (n = 7), it was ████ █ ███ █ ██ █ ███ █ █ █ ██████.

The ORR per IRC was 30.5% overall (95% CI, 21.9% to 40.2%). The ORR per IRC among patients with a CTFI shorter than 90 days and 90 or more days was 13.3% (95% CI, 5.1% to 26.8%) and 43.3% (95% CI, 30.6% to 56.8%), respectively. The ORR per IRC among patients with a CTFI shorter than 30 days, 30 to 89 days, 90 to 179 days, and 180 or more days was 9.5% (95% CI, 1.2% to 30.4%), 16.7% (95% CI, 4.7% to 37.4%), 40.0% (95% CI, 24.9% to 56.7%), and 50.0% (95% CI, 27.2%, 72.8%), respectively.

Table 16: ORR in Study B-005 (Treated Patients)

CI = confidence interval; CTFI = chemotherapy-free interval; IA = investigator assessment; IRC = independent review committee; ORR = objective response rate.

^aStable disease category includes 4 patients with partial response not confirmed.

^bOne patient was not evaluable because of patient refusal to have disease measurement. Four patients were not evaluable per RECIST: 2 patients had early death considered related to malignant disease occurring 28 days and 18 days after the first infusion, respectively; and 2 patients had symptomatic deterioration due to progressive disease during cycle 1 without any radiological assessment performed.

Source: B-005 Clinical Study Report.¹⁰

Duration of Response

DOR results per IA and IRC among all responding patients in study B-005 are summarized in Table 17, Figure 6, and Figure 7. Median DOR per IRC was 5.1 months overall (95% CI, 4.9 to 6.4 months). Median DOR per IRC among patients with CTFIs shorter than 90 days and 90 or more days was ██ █ █████ █ ███ █ ██ █ ██ █ █ █ ██ █ ██████ █ ██ █ ██ █ █████ █ ███ █ ██ █ ██ █ █ █ ██ █ ███████, respectively. Median DOR per IRC among patients with a CTFI shorter than 30 days, 30 to 89 days, 90 to 179 days, and 180 or more days was ██ █ █████ █ ███ █ ██ █ ██ █ ███████████ █ ██ █ █████ █ ███ █ ██ █ ██ █ █ █ ██ █ ███████ █ ██ █ █████ █ ███ █ ██ █ ██ █ █ █ ██ █ ███████ █ ██ █ ██ █ █████ █ ███ █ ██ █ ██ █ █ █ ██ █ ███████, respectively.

Table 17: DOR in Study B-005 (Responding Patients)

CI = confidence interval; CTFI = chemotherapy-free interval; DOR = duration of response; NC = not calculable.

^aFrom Kaplan-Meier analysis.

Source: B-005 Clinical Study Report.¹⁰

Figure 6: Kaplan-Meier Plot of DOR in Study B-005 (Treated Patients)

DOR = duration of response; IA = investigator assessment; IRC = independent review committee.

Source: B-005 Clinical Study Report.¹⁰

Figure 7: Kaplan-Meier Plot of DOR per IRC in Study B-005 (Treated Patients With a CTFI < 90 Days or ≥ 90 Days)

CTFI = chemotherapy-free interval; DOR = duration of response; IRC = independent review committee.

Source: B-005 Clinical Study Report.¹⁰

Cancer Symptoms

Cancer symptoms were not assessed in study B-005.

Harms

Only harms identified in the review protocol are reported here. Refer to Table 18 for detailed harms data.

Adverse Events

Overall, 103 patients (98.1%) experienced AEs in study B-005. The most common AEs were fatigue (76.2%), nausea (37.1%), decreased appetite (33.3%), constipation (31.4%), dyspnea (29.5%), vomiting (21.9%), and diarrhea (20.0%).

Serious Adverse Events

SAEs occurred in 34 patients (32.4%) in study B-005. The most common SAEs were febrile neutropenia (4.8%), neutropenia (3.8%), and thrombocytopenia (3.8%).

Adverse Events Leading to Dose Reduction

AEs leading to dose reduction occurred in 25 patients (26.3%) in study B-005. The most common AEs leading to dose reduction were related to hematological toxicities (17.9%) or both hematological and nonhematological toxicities (4.2%).

Withdrawals Due to Adverse Events

Four patients (3.8%) withdrew from lurbinectedin treatment in study B-005 because of AEs. One patient discontinued treatment after the development of grade 4 febrile neutropenia, grade 3 thrombocytopenia, and grade 3 anemia. Another patient discontinued treatment because of peripheral neuropathy. For the remaining 2 patients, discontinuation was not considered to be treatment-related.

Mortality

Overall, 66 patients (62.9%) died during study B-005. All deaths were related to disease progression. Two deaths were associated with AEs (both grade 5 dyspnea related to progressive disease).

Notable Harms

Among CADTH protocol-defined notable harms, the most common myelosuppression-associated AEs in study B-005 were anemia (95.2%), lymphopenia (85.7%), leukopenia (79.0%), neutropenia (71.4%), and thrombocytopenia (43.8%). Febrile neutropenia occurred in 4.8% of patients. The most common hepatotoxicity-associated AEs were ALT increase (71.8%), gamma-glutamyl transferase increase (65.0%), AST increase (44.7%), and AP increase (33.0%). Peripheral neuropathy and peripheral sensory neuropathy occurred in only 2 patients (1.9%).

Table 18: Summary of Harms in Study B-005 (Treated Patients)

AE = adverse event; ALT = alanine aminotransferase; AP = alkaline phosphatase; AST = asparagine aminotransferase; CPK = creatine phosphokinase; GGT = gamma-glutamyl transferase; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

Notes: Treatment-emergent AEs reported in this table were defined as any untoward medical occurrence after administration of the first dose of study drug and in the 30 days after the last dose of study drug. AEs were coded using MedDRA version 21.0 and graded according to NCI-CTCAE version 4.

For biochemical parameters that were measured in fewer than 105 patients, the denominator is indicated.

^aAEs with frequency ≥ 10% are listed.

^bSAEs occurring in ≥ 2 patients are listed.

^cMost of these were not clinically significant creatinine increases; creatinine values were within normal range and grade 1 was due to creatinine increase > 1.5 × baseline, according to the NCI-CTCAE v.4 severity calculation. Using NCI-CTCAE v.3, only 25 patients (24.0%) would have a grade 1 or 2 creatinine increase.

Source: B-005 Clinical Study Report.¹⁰

Critical Appraisal

Internal Validity

Study B-005¹⁰ was a single-arm, phase II, basket trial in which a relatively small number of adult patients with SCLC (N = 105) were treated with OL second-line lurbinectedin following progression on or after platinum doublet therapy. In the absence of a randomized comparison with an alternative treatment, effect estimates are at high risk of bias, and causal inferences around the magnitude of the effect of the intervention cannot be made. The study results cannot be directly compared with those of prior or subsequent studies.

Because investigators (and potentially the IRC) were aware of treatment in this single-arm study, a potential source of bias in study B-005 was observer bias in outcome assessment (for ORR, PFS, and DOR per IA), as well as in investigator decisions to discontinue treatment due to progressive disease. Ten patients (9.5%) evaluated as having stable disease or a tumour response per IA but with progressive disease according to IRC review remained on protocol therapy; in addition, 4 patients who were discontinued from therapy after progressive disease per IA had stable disease per IRC. Protocol measures meant to control for bias in the interpretation of end points included standardized protocols for image acquisition, interpretation, and measurement of response and progression, and independent review of all images by an IRC. However, the organizational details and algorithm of the IRC were not provided. According to the clinical experts consulted by CADTH for this review, bias in favour of the drug would be more likely among investigators participating in single-arm oncology trials. Estimates of ORR per IRC were, in general, more conservative than those per IA. It was unclear whether the IRC was blind to the study and treatment, so the potential for observer bias in IRC review was unclear. Very few patients (2.8%) discontinued the study for reasons other than death after disease progression, so attrition biases were likely minimal.

The clinical experts consulted by CADTH for this review acknowledged that the protocol deviations in study B-005 related to missed assessments for lurbinectedin re-treatment, and failure to reduce or delay doses could have theoretically contributed to higher estimates of the drug’s efficacy. However, the experts emphasized that the impacts of these protocol deviations would be minor and unlikely to affect interpretation of the study results.

The outcomes used in study B-005 (OS, PFS, ORR, DOR) are standard in oncology trials and tumour responses were objectively evaluated using RECIST 1.1. Thus, there were no major concerns regarding the validity or measurement properties of outcomes, although in the absence of a comparator arm, interpretation of the efficacy results was limited. However, the analysis of OS would be influenced by subsequent therapies in the third line and later, which were received by nearly half (44.8%) of the patients. In addition, the potential for patient and/or investigator observer bias in harms outcome reporting is inherent in any single-arm, OL trial.

Several statistical issues should be noted when interpreting the results of study B-005. First, the OS data were relatively immature (median follow-up of 17.1 months, 37.1% censoring) and the results may differ in the final analysis when the study is completed. Second, although statistical methods were overall appropriate, all efficacy analyses were descriptive and no formal statistical hypothesis testing was conducted, except for the primary outcome of ORR per IA. For outcomes other than OS, missing data (PFS, 14.3% to 22.9% censoring; ORR, 4.8% to 6.7% not evaluable; DOR, 21.6% to 31.3% censoring) were primarily due to patients being progression-free and/or recurrence-free at the time of assessment, or to rapid progression or death without tumour assessments (for ORR). Missing data were accounted for appropriately using Kaplan-Meier methodology. Subgroup analyses by CTFI were prespecified but exploratory, with no formal hypothesis testing and no adjustment for multiplicity.

External Validity

According to the clinical experts consulted by CADTH for this review, the eligibility criteria for study B-005 would be expected to result in the recruitment of adult patients with stage III or metastatic SCLC representative of the Canadian patient population undergoing second-line treatment for advanced disease. However, the clinical experts noted that in practice, approximately 25% of patients with advanced SCLC undergoing second-line therapy would be expected to have CNS involvement; these patients generally have worse prognoses and were not included in the study. The expectations of the clinical experts with regard to CNS involvement were not aligned with the small number of screening failures in the study (5 of 110 patients), and the reasons for this discrepancy were unclear. The clinical experts also emphasized that study B-005 included patients with a short CTFI (platinum-refractory and platinum-resistant) who are excluded from many trials, which they felt was laudable; these patients generally have worse prognoses than those with platinum-sensitive disease. The clinical experts stated that the baseline characteristics of the B-005 study population were similar to those of patients with SCLC in Canada undergoing second-line chemotherapy for advanced disease, although trial participants were somewhat younger, with better performance status and overall health compared with the general population (as is the case in most oncology trials). The clinical experts also noted the relatively high proportion of patients in the study (approximately half) who went on to receive other systemic anticancer therapies in the third line and beyond, which they explained was higher than they would expect in clinical practice and potentially reflected the recruitment of a treatment-seeking trial population in better health than the general population.

The clinical experts consulted by CADTH for this review felt that the absence of Canadian sites in study B-005, which was conducted primarily in Europe, would not limit generalizability to patients in Canada. Moreover, although the study was conducted in the second-line setting, the clinical experts did not see any major issues with generalizing the study results to the third-line setting, although they noted the generally decreasing effectiveness of treatment with advancing lines of therapy.

Doses of lurbinectedin administered in study B-005 were aligned with the Health Canada–approved dosing. The clinical experts stated that the transfusion and growth-factor support received by patients in study B-005 was generally appropriate, and as expected. However, the clinical experts stated that because secondary G-CSF prophylaxis is not typically given in Canada in the metastatic setting, some harms outcomes (e.g., hematological toxicities) may have been underestimated compared with real-world clinical practice in Canada.

Input from patient groups for this review suggested that patients with SCLC desired new second-line treatment options that prolonged survival (OS) and delayed disease progression (PFS) while maintaining HRQoL and controlling disease symptoms, with an acceptable toxicity profile. ORR and DOR were not specifically mentioned as an outcome important to patients.

The duration of follow-up in study B-005 was adequate for assessment of ORR, DOR, and PFS ████ █ ████ █ ███ █ ████ █ ██ █ █ ███ █ █████ █ ███ █ █████ █ ███ █ ████ █ ██ █ ███ █ ████ █ ██████. Although OS data were not fully mature (median follow-up 17.1 months, 37.1% censoring), the duration of follow-up was probably adequate for estimation of median OS because of the relatively short survival expectations in this patient population.

According to the clinical experts, patients in study B-005 underwent imaging scans more frequently (every 2 cycles until cycle 6, and every 3 cycles thereafter) than many patients treated in clinical practice in Canada would. However, the clinical experts did not feel that this would limit the generalizability of the study findings.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

The objective of this section is to summarize and appraise evidence from ITCs for the relative effects and safety of lurbinectedin for the treatment of adult patients with stage III or metastatic SCLC who have progressed on or after platinum-containing therapy. The aim is to fill a gap created by the absence of trials directly comparing lurbinectedin to comparators relevant in the Canadian landscape, as stated in the protocol of this CADTH report.

A focused literature search for NMAs dealing with SCLC was run in MEDLINE All (1946–) on March 23, 2022. No limits were applied to the search. No published ITCs were found in the literature search from CADTH comparing lurbinectedin to comparators of interest based on inclusion criteria in this clinical report.

Three ITCs were submitted by the sponsor and are reviewed in this section: an SCA analysis, an STC, and an MAIC and NMA.

Description of Indirect Comparisons

The SCA analysis¹² aimed to evaluate the treatment landscape and efficacy of lurbinectedin in the treatment of patients with advanced SCLC after exposure to platinum-based therapy in Alberta. This study consisted of 2 phases: the first phase evaluated a real-world cohort of all individuals in Alberta diagnosed with SCLC at any stage from 2004 to 2019 and initiated a post–platinum-based systemic therapy and a second phase consisted of building (from the first phase population) an SCA for comparison with the SCLC cohort in the phase II B-005 (single-arm) study.

The second ITC¹⁴ was an STC to facilitate the indirect comparison of lurbinectedin (using individual patient data [IPD] from the B-005 study) to topotecan IV (using aggregated data [AD] from the von Pawel et al. [2014] RCT¹³) in patients with relapsed or refractory SCLC.

The third submitted ITC¹⁵ was an MAIC combined with an NMA to evaluate the efficacy and safety of lurbinectedin versus relevant comparators among patients with SCLC receiving second-line treatment with respect to ORR, DOR, OS, and PFS, as well as hematological AEs of grade 3 or 4 (including anemia, thrombocytopenia, neutropenia, and febrile neutropenia).

Synthetic Control Arm

Objectives

The objectives in the first phase of the study include defining the population of patients with SCLC who initiated a post–platinum systemic therapy and characterizing OS, time to next treatment (TTNT) or death, and frequency of hospitalization and emergency department visits in the 6 months after therapy (as proxy measures of SAEs) in this population.

For the second phase — the synthetic control, feasibility, and summary-level analyses — the primary objectives included:

• conduct a feasibility assessment to define trial eligibility and evaluate the distribution of prognostic variables in the patient population

• if feasible, identify a well-characterized SCA population in alignment with the SCLC cohort of the B-005 study

• estimate standardized rates for OS and TTNT in the SCA population that can be used as benchmarks for the B-005 study.

Patient Selection From Databases

In the first phase of the study, a streamlined process was used to access various provincial administrative databases maintained by the Alberta government using an Alberta unique lifetime identifier assigned to each person at birth or upon becoming a resident of the province, which captures all demographic information, health care encounters, and electronic medical records in the province. The database linkage and statistical analyses were conducted by a research group in charge of the study that de-identified and analyzed all data. The following databases were used and linked:

• Alberta Cancer Registry: captures information on all individuals diagnosed with cancer in Alberta (300,000+ cases), information related to cancer, and information on the date and cause of death and last known date of follow-up

• ARIA electronic medical records: a database of electronic medical records for all 17 provincial cancer centres (2 tertiary, 4 regional, and 11 community centres), covering 4.5 million residents of Alberta

• Discharge Abstract Database: captures information each time an individual is discharged from an inpatient hospital bed and information on the date and the duration of the hospitalization

• National Ambulatory Care Reporting System database: captures information on all inpatient and outpatient use of ambulatory care services

• Practitioner Claims database: captures physician and allied practitioner claims used for reimbursement and shadow-billing purposes that have been processed by the Alberta government

• population registry: includes information related to birth and death dates as well as migration out of province for all residents with Alberta Health Care Insurance Plan coverage.

The data collected and analyzed are population-based. This system of databases and registries captures more than 99% of cancers diagnosed in Alberta. Any loss to follow-up was expected to be noninformative because of the reliance on vital statistics and the population registry to identify the last known date of follow-up. In addition, data were linked via a chart review with administrative data at the population level due to the implementation of provincial electronic medical records in Alberta.

Potentially eligible subjects were identified from the Alberta Cancer Registry and then selected for inclusion based on the availability of administrative data sources with relevant data of interest. Because this is a population-based registry that captures all cases of cancer diagnosed in Alberta, no specific sampling techniques were employed, and all eligible individuals were included. Various administrative data algorithms were used to approximate different eligibility criteria, such as disease progression, adequate laboratory measures, impending need for radiotherapy, and high-grade toxicity.

The first phase of the study included patients aged 18 years and older who were diagnosed with SCLC (any stage) in Alberta from 2004 to 2019. Patients were followed until the end of 2020.

The second phase of this investigation involved a subset of the population identified in the first phase with the following additional eligibility criteria applied to approximate the eligibility criteria used in the B-005 trial:

• pretreatment with only 1 previous treatment line of systemic therapy (immunotherapy was allowed, combined with chemotherapy or alone)

• evidence of disease progression and adequate hematologic, renal, and liver function based on patients’ receipt of subsequent systemic therapy (defined as a systemic drug not in the original treatment regimen or a gap of more than 90 days between subsequent treatment dispensations)

• time from the end date of prior systemic treatment to initiation of subsequent treatment of at least 3 weeks for patients initially treated with chemotherapy alone, or 4 weeks for patients initially treated with immunotherapy or radiotherapy

• evidence of prior or concurrent malignant disease

• high-grade toxicity on first treatment (e.g., at least 1 hospitalization or emergency department visit)

• absence of brain metastases at initial diagnosis.

Patients who received radiation therapy after the end of the initial systemic treatment regimen and before subsequent systemic treatment were excluded from the second-phase analysis.

Outcomes

OS was defined as the time of initiation of subsequent systemic therapy administered after initial systemic therapy (used as proxy for disease progression) until death from any cause. Individuals lost to follow-up were censored. Meanwhile, TTNT was defined as the time of initiation of subsequent systemic therapy administered after exposure to platinum-based therapy until death from any cause or until initiation of subsequent systemic therapy. Individuals lost to follow-were censored.

High-grade AEs were defined as causing 1 or more hospitalizations or emergency department visits in the 6 months after initiation of systemic therapy. For the health care resource-use outcomes, the total number and mean encounters for each patient were reported in each year of follow-up, starting from the initiation of a subsequent line of therapy for hospitalizations, ambulatory care encounters, and physician visits.

Analysis Methods

For the first phase, baseline demographics were summarized and reported for the identified patient population using summary statistics (i.e., mean or median for continuous variables and proportion for categorical variables). Baseline characteristics reported were stratified by CTFI (CTFI < 90 days and CTFI ≥ 90 days). Kaplan-Meier plots of the survival function for OS and TTNT were provided, along with the median, 6-month interval survival, and corresponding 95% CI. High-grade AEs were assessed using (as a surrogate) the number and proportion of patients experiencing 1 or more hospitalizations or emergency department visits in the 6 months after the initiation of subsequent systemic therapy. For health care resource-use outcomes, the total count and the mean number of events per patient were reported in each year of follow-up, starting from the initiation of subsequent systemic therapy (i.e., number of hospitalizations, days hospitalized, encounters with ambulatory care services, and physician visits).

For the second phase, an SCA was identified by applying the aforementioned eligibility criteria to approximate that of the lurbinectedin trial (Study B-005). Baseline characteristics of the SCA were estimated and compared with those in the lurbinectedin trial. The magnitudes of differences in the mean and prevalence of baseline characteristics were assessed using standardized differences; values less than 0.1 were judged to be indicative of the balance achieved in a randomized trial, and values greater than 0.1 were considered to reflect a clinically meaningful imbalance. OS, TTNT, and high-grade AEs were estimated in the SCA using the methods described in the first phase. The study authors adjusted 2 prognostic variables (based on input from clinical experts): the stage at initial diagnosis (LS versus ES); and CTFI (90 days or shorter versus longer than 90 days). Estimates of median OS, median TTNT, and proportion who experienced a high-grade AE were generated within strata defined by stage and CTFI. The strata-specific estimates were pooled using weights defined by the distribution observed in the lurbinectedin trial where estimates can be provided for the lurbinectedin trial and where there is a sufficient sample size in the SCA. The 95% CI for the pooled estimates were generated using the percentile bootstrap method (1,000 iterations). Also, bootstrapping was used to obtain P values that assessed the 1-sided null hypothesis that OS in the SCA was equal to or greater than that of the B-005 trial.

Results of the SCA Analysis

For the first phase, an overview is presented of all individuals in Alberta who were diagnosed with SCLC (any stage) from 2004 to 2019 and who initiated a post–platinum-based systemic therapy (platinum regimen refers to carboplatin-containing or cisplatin-containing regimens). In total, 3,721 individuals were diagnosed with SCLC during the study period, 2,031 (55%) of whom initiated platinum-containing therapy. Of the 2,031 individuals who initiated platinum-based therapy, 577 (28%) subsequently initiated a post–platinum-based systemic therapy regimen.

The baseline characteristics of patients in the first and second phases (SCA) are presented in Table 19.

Table 19: Baseline Characteristics of Patients With SCLC Who Initiated Post–Platinum-Based Therapy in the SCA

CAV = cyclophosphamide + doxorubicin + vincristine; CTFI = chemotherapy-free interval; ES = extensive stage; IQR = interquartile range; LS = limited stage; NR = not reported; SCA = synthetic control arm; SCLC = small cell lung cancer; SD = standard deviation.

Source: Sponsor-submitted ITC1 report.¹²

In terms of OS in the first phase of the study, the median reached 6.67 months (95% CI, 6.08 to 7.2 months).

AEs were assessed indirectly as the proportion of patients who were hospitalized or who had at least 1 emergency department visit in the 6 months after initiation of post–platinum-based therapy. This was used as a proxy measure for serious treatment-related AEs. Overall, among the 577 included patients, 300 (52.0%) experienced at least 1 hospitalization in the 6 months after initiation of post–platinum-based therapy, 364 (63.1%) experienced at least 1 emergency department visit, and 388 (67.2%) experienced at least 1 hospitalization or emergency department visit.

Phase 2 originated from the initial 577 patients in the first phase who received post–platinum-based therapy. Of these, 224 (39%) were eligible for inclusion in the SCA for comparison with the phase II B-005 trial. An overview of the baseline characteristics of these patients is presented in Table 19. The vast majority of individuals had 1 prior line of therapy (fewer than 10 patients had 2 prior lines of therapy), and nearly all received platinum-based therapy in combination with etoposide as their first platinum-based therapy (fewer than 10 patients received platinum in combination with an alternative systemic drug). The majority of other post–platinum-based therapies were other platinum combinations (fewer than 10 patients received topotecan post–platinum-based therapy).

Overall Survival

OS estimates for the SCA are presented here as overall and as stratified by the CTFI and by stage at initial diagnosis. Estimates of OS simultaneous stratification (by both CTFI and stage) could not be obtained due to small cell counts (i.e., fewer than 10 patients in the SCA had a CTFI of less an 90 days and were LS at initial diagnosis).

Survival estimates are presented unadjusted and after adjustment for differences in the distribution of CTFI and stage at initial diagnosis. Specifically, the strata-specific estimates from the SCA were pooled using the weights estimated from the trial. This standardization provides an estimate of the outcome in the SCA if the SCA had the same distribution of CTFI and stage at initial diagnosis as the trial.

For the overall population, the unadjusted OS reached a median of 6.58 months (95% CI, 5.75 to 7.46 months). The median OS did not differ significantly between patients stratified in the ES group (OS = 5.75 months; 95% CI, 4.90 to 6.81 months) and those stratified in the LS group (OS = 7.63 months; 95% CI, 6.25 to 9.83 months). However, it differed when comparing the group of patients with a CTFI shorter than 90 days (median OS = 4.31 months; 95% CI, 3.29 to 6.74 months) and those with a CTFI of 90 days or more (median OS = 6.87 months; 95% CI, 3.29 to 6.74 months; P = 0.011).

In the adjusted population analysis, the OS reached a median of 5.8 months (95 CI, 5.1 to 6.9 months), whereas the median OS in the B-005 trial was of 9.3 months (95% CI, 6.3 to 11.8 months).

When comparing estimates of OS between the SCA and the phase II B-005 trial, the results favoured the B-005 trial arm, whether adjusted or unadjusted (see Table 20).

The SCA was subsequently updated to align more closely with the B-005 trial population by excluding patients who developed brain metastasis after diagnosis but before initiating post–platinum-based therapy. In the updated SCA, the unadjusted OS reached a median of 6.7 months (95% CI, 6.0 to 7.7 months). In the adjusted population analysis, the median OS reached 6.1 months (95% CI, 5.4 to 7.7 months). CADTH was unable to independently verify the methodological details of the analysis.

Table 20: Comparison of OS Between the Phase II B-005 Trial and the SCA (Unadjusted and Adjusted for CTFI and for Stage at Initial Diagnosis)

CI = confidence interval; CTFI = chemotherapy = free interval; OS = overall survival; SCA = synthetic control arm.

Source: Sponsor-submitted ITC1 report.¹²

Unadjusted and adjusted estimates were reported for the proportion of individuals who were hospitalized or admitted to the emergency department within 6 months after initiation of post–platinum-based therapy in the SCA. The adjusted analysis (stratified by stage and CTFI) showed that the proportion of individuals who were hospitalized or who had 1 or more emergency department visits in the months after initiation of post–platinum-based therapy was 64.9% (95% CI, 56.9% to 72.5%). The unadjusted analysis showed similar results (60.7%; 95% CI, 54.5% to 67.0%).

Critical Appraisal of the SCA Analysis

This submitted analysis assesses the treatment landscape of patients with advanced SCLC after exposure to platinum-based therapy in Alberta, and creates an SCA for comparison against the SCLC cohort in the phase II B-005 (single-arm) study.

There were several linked databases used for the first phase of the study. Although these seemed appropriate and thorough, it is possible that information on some patient groups might have been missing or underrepresented, and no specific techniques for sampling were used. Overall, the set of patients seemed generalizable to the population of patients with SCLC in Alberta and likely in the rest of the Canadian provinces and territories, according to the clinical experts consulted by CADTH. However, there are no data on other important patient and disease characteristics, such as ethnicity, socioeconomic status, and smoking status, that would help establish the generalizability of the results.

In the second phase of this analysis, the authors compared an SCA of patients selected from the first phase population with the SCLC cohort in the B-005 trial. In the SCA, the authors were unable to exclude patients who developed a brain metastasis after diagnosis but before initiation of post–platinum-based therapy, which may have resulted in an underestimation of survival in the SCA and a bias in favour of lurbinectedin. However, in the updated SCA analysis, this bias was accounted for by the exclusion of patients who developed brain metastases after diagnosis but before the initiation of post–platinum-based therapy.

Administrative data algorithms were used to assess and select SCA patients in alignment with B-005 eligibility criteria, such as disease progression, adequate laboratory measures, impending need for radiotherapy, and high-grade toxicity. The use of different administrative data algorithms may introduce potential inaccuracies in patient characteristics and outcomes to the analyses, which could result in misclassification. There is a lack of data on performance status and the presence of brain metastases at the time of disease progression. It was not possible to restrict selection to patients with an ECOG PS of 2 or less or who did not develop a brain metastasis after diagnosis, as was done in the B-005 trial, which also has the potential to produce a bias in favour of lurbinectedin.

The authors state that due to confidentiality regulations, they had to rely on aggregate-level data in the B-005 study during the second phase, so they could not adjust for more than 2 variables simultaneously, which could have implications on selection bias when estimating any treatment effects.

As the comparisons between the SCA and the B-005 trial rely on observational data in a nonrandomized fashion, there is high risk of bias related to residual confounding (unobserved or unmeasured variables that could have an effect on outcomes).

Simulated Treatment Comparison

The second ITC described in this CADTH report consists of an STC submitted by the sponsor¹⁴ and performed per the general guidelines of the Decision Support Unit Technical Support Document 18.³⁴ Furthermore, the authors used the information to assess the feasibility of conducting a population-matched ITC and to evaluate whether the important assumptions necessary for a matching are met.

Objectives

The main objective was to facilitate an ITC of lurbinectedin to topotecan in patients with SCLC who progress on or after platinum-containing therapy.

Study Selection Methods

A targeted literature search was used to obtain the relevant study with which to compare lurbinectedin with IV topotecan. It was determined that 1 study (von Pawel et al. [2014]¹³) represented the most recent data for the topotecan arm. No specific search strategy, study selection, data extraction, or study quality assessment was described in the report.

For the lurbinectedin arm, IPD from the B-005 study were used.¹⁰ The study design and eligibility criteria of the lurbinectedin and topotecan trials are presented in Table 21.

Table 21: Study Designs, Eligibility Criteria, and Population Baseline Characteristics of the Lurbinectedin and Topotecan Trial Arms

CNS = central nervous system; CTCAE = Common Terminology Criteria for Adverse Events; ECOG PS = Eastern Cooperative Oncology Group performance status; NA = not applicable; RECIST = Response Evaluation Criteria for Solid Tumours; SCLC = small cell lung cancer.

Source: Sponsor-submitted STC report.¹⁴

ITC Analysis Methods

After the main trials were selected, the feasibility of conducting an STC was assessed and the assumptions necessary for matching were evaluated. Because the included studies lacked a common control arm, the authors concluded that an unanchored STC was required.

The first step of the STC process included an outcome (regression) model, which was constructed for the lurbinectedin arm with covariates selected from a literature search for effect modifiers, prognostic variables, and an analysis of imbalances between studies.

The following covariates and evaluations were identified by the authors in the literature as prognostic factors of the outcomes:

• Stage — SCLC was classified as LS or ES disease. Patients with ES disease have a considerably worse 5-year prognosis of survival (2.2%) than those with LS disease (28.5%)

• Sex — Females were observed to have a higher 5-year prognosis of survival than males (4.7% to 7.7%)

• Age — Older age at diagnosis was negatively correlated with a worse 5-year prognosis of survival for patients (< 45 years = 13.4%; < 65 years = 8.3%; ≥ 65 years = 4.9%).

• ECOG PS — Even allowing for sex and stage of disease, ECOG PS scores have been shown to be independently prognostic of survival, with higher scores observed to be associated with a shorter median survival.

The following covariate was identified in the literature as a treatment-effect modifier:

• Response to prior first-line therapy — patients who, in response to a first-line platinum-containing therapy, achieve a CTFI of 90 days or longer are deemed to be sensitive as opposed to resistant (CTFIs shorter than 90 days) and are shown to achieve longer median OS and median PFS in the clinical trials of resistant or refractory SCLC.

For survival outcomes, a systematic model exploration was performed. Model analyses included tests of proportional hazards and accelerated failure time models for their model fit, visual comparability and comparisons of reasonable predictive ability, and estimates from the original Kaplan-Meier curve. Seven parametric model distributions were tested, both with full and stepwise covariate inclusion (exponential, Weibull, Gompertz, log-normal, log-logistic, generalized gamma, and simple gamma). Modelling was performed in statistical software R version 4.02, using the flexsurvreg survival function.

In the second step of the STC process, a prediction of transformed outcomes on treatment with lurbinectedin in the comparator trial using the outcome model was performed. Once lurbinectedin treatment-effect outcomes were predicted among the simulated comparator population, the authors proceeded to step 3 in the STC, which is a final ITC between the adjusted lurbinectedin outcome estimates and the published comparator results. The difference in efficacy between interventions is calculated as the difference between adjusted lurbinectedin and the comparator, and standard errors were calculated (step 4) by sampling randomly from the asymptotic normal distribution of the maximum-likelihood estimate, and then taking quantiles to calculate the CIs for the transformed outcome.

To provide evidence that absolute outcomes could be predicted with sufficient accuracy in relation to the relative treatment effects and present an estimate of the likely range of residual systematic error (step 5), during exploration to find the optimal models, sample methods were explored to estimate the likely range of residual systematic error. Model accuracy was considered with several model-fitting scenarios of prognostic variables and effect modifiers and was assessed with statistical fit and visual inspection of the curve with to regard consistency of estimates between models.

For step 6 — the transportation of the effect estimate (the difference between adjusted lurbinectedin and topotecan) into the target population for the decision — the authors described the representativeness of the matched comparison as observed in the differences between study designs, inclusion and exclusion criteria of each study, and baseline characteristic distributions (Table 22).

For the seventh (and final) step, model-fit statistics were used to confirm whether models were reasonably constructed after each parametric regression. Fit statistics included the Akaike information criterion and Bayesian information criterion (BIC), where lower values signify better fit prediction models. As adding additional covariates generally tends to improve model fit, BIC is assessed to take into account that it penalizes models for over-fitting. Log-likelihood and chi-square distribution values were also used to compare model significance between similar models.

Table 22: Patient Baseline Characteristics of the Lurbinectedin and Topotecan Trial Arms

CNS = central nervous system; CTFI = chemotherapy-free interval; ECOG PS = Eastern Cooperative Oncology Group performance status; IQR = interquartile range; LDH = lactate dehydrogenase; NA = not applicable; SCLC = small cell lung cancer.

^aMeaningful imbalances as assessed by the standardized difference and proportion of the variance of ≥ 0.2 (20%).

Source: Sponsor-submitted STC report.¹⁴

Baseline characteristics obtained from each arm trial (Table 22) were assessed and compared to address important imbalances. The standardized difference and proportion of the variance as explained by group variance were used to describe imbalances, considering a standardized difference of 0.2 (20%) to denote meaningful imbalances in baseline covariates.

The outcomes matched and evaluated in this comparison include survival analysis end points: median OS and median PFS.

OS is a time-to-event outcome defined as time from randomization to death from any cause. Each study estimated and reported median OS. The outcomes model to fit median OS used parametric survival analysis to estimate and adjust for imbalanced effect modifiers and prognostic variables. Similarly, PFS is a time-to-event end point defined as the time from randomization to death or progression, whichever happens first. PFS was measured using documentation of radiographic disease progression or death from any cause at the time of data cut-off. Each study estimated and reported median OS and PFS.

The PFS and OS outcomes models for the STC used parametric survival analysis to estimate median OS and PFS and adjust for imbalanced effect modifiers and prognostic variables. Each of the 7 parametric distributions were tested, presented based on the best statistical fit, and validated through visual inspection. The effects of the covariates estimated in the outcomes model were applied to calculate a conditional median (prediction) using the means and/or proportions of the matched comparators’ imbalanced baseline characteristics. The results are interpreted as a mean difference, with values greater than 0 favouring lurbinectedin and denoting longer median PFS, and values less than 0 favouring topotecan and denoting shorter median PFS.

Results of the STC

Characteristics and Differences of Included Studies

The 2 studies included in the ITC had similar definitions for OS and PFS, and these were the 2 outcomes addressed in the body of evidence. However, as described in Table 21, there were discrepancies observed in the ascertainment of end points; for example, in the topotecan trial, PFS was determined by the investigator (unblinded), whereas in the lurbinectedin trial, it was determined by the IRC (with IA available as well). Another example is the phase of the study; the topotecan trial is a phase III, randomized study, whereas B-005 is single-arm, OL study.

For eligibility criteria, both the lurbinectedin and topotecan trials had similar inclusion criteria, with 3 exceptions. Overall, there were differences in the ECOG PS inclusion criteria, with a maximum PS of 2 in the lurbinectedin trial and of 1 in the topotecan trial. The time from diagnosis and its impact on CTFI was also different; 20% of patients in the lurbinectedin arm had a CTFI shorter than 30 days, whereas no patients in the topotecan arm did. Therefore, the STC authors restricted the lurbinectedin sample to patients with a CTFI longer than 30 days to match the topotecan arm. For the ECOG inclusion threshold, despite differences in the topotecan study eligibility criteria, the distributions of patients with a ECOG PS of 2 were similar in the topotecan and lurbinectedin trials.

The lurbinectedin trial reported the stage of disease at diagnosis, whereas the topotecan publication reported the stage of disease at study enrolment. The stage of disease at study enrolment for lurbinectedin patients could retroactively be assigned from the B-005 Clinical Study Report, using information on the number of patients with disease restricted to ipsilateral hemithorax at study entry.

When assessing differences in baseline patient characteristics between the lurbinectedin and topotecan trials (as assessed by the standardized difference), potential clinically meaningful imbalances were observed in ECOG PS and disease stage at diagnosis.

Clinical Efficacy End Points

Results for OS and PFS are presented in Table 23.

For OS, unadjusted estimates showed a median of 10.9 months (95% CI, 7.8 to 14.9 months) and 7.8 months (95% CI, 6.6 to 8.5 months) in the lurbinectedin and topotecan trials, respectively, with a mean difference of 3.1 months (95% CI, –0.6 to 6.8 months). When adjusted estimates were obtained, median OS was 10.0 months (95% CI, 8.5 to 11.6 months) and 7.8 months (95% CI, 6.6 to 8.5 months) in the lurbinectedin and topotecan trials, respectively, with a mean difference of 2.0 months (95% CI, 0.4 to 4.0 months).

For PFS, unadjusted estimates showed a median of 4.1 months (95% CI, 2.8 to 5.2 months) and 3.5 months (95% CI, 2.9 to 4.2 months) in the lurbinectedin and topotecan trials, respectively, with a mean difference of 0.60 months (95% CI, –0.76 to 1.96). When adjusted estimates were obtained, median PFS was 3.4 months (95% CI, 3.0 to 3.9 months) and 3.5 months (95% CI, 2.9 to 4.2 months) in the lurbinectedin and topotecan trials, respectively, with a mean difference of –0.10 months (95% CI, –0.89 to 0.69 months).

When testing model fitness, the most suitable distribution for modelling OS was determined to be the log-logistic. This was validated after consideration of each of the statistical indices and further validated with visual inspection. For PFS, the most suitable distribution for modelling PFS was determined to be the generalized gamma, because it had the smallest BIC. This was also validated after consideration of each of the statistical indices and further validated with visual inspection of each of the 7 curves overlaid on the Kaplan-Meier curve. There was nonconvergence in exponential, Weibull, log-normal, log-logistic, Gompertz, and simple gamma as a result of time-varying hazards.

Table 23: OS and PFS in the STC of Lurbinectedin and Topotecan

CI = confidence interval; CTFI = chemotherapy-free interval; ECOG PS = Eastern Cooperative Oncology Group performance status; NA = not applicable; OS = overall survival; PFS = progression-free survival; SCLC = small cell lung cancer; STC = simulated treatment comparison.

^aValues are median except for the last column.

Source: Sponsor-submitted STC report.¹⁴

Critical Appraisal of the STC

The most notable appraisal point of this ITC is the unanchored nature of the comparison. Even after adjustment for prognostic variables and effect modifiers, the consistency of the absolute-effects assumption in an STC cannot be validated. Unaccounted patient covariates and the risk of residual confounding is present and generates uncertainty in the effect estimates. It is unclear what process was used to choose the comparator trial. The identification of covariates to include in the adjustments was obtained through a literature review, but more information from clinical experts could reinforce the appropriate use of these variables.

The lurbinectedin and topotecan trials had dissimilarities in their design and populations (i.e., differences in eligibility criteria, design, ECOG PS, and disease stage) that can also produce bias. The lurbinectedin study sample size is small and, therefore, there will be limitations in the ability to detect differences in the comparative efficacy of lurbinectedin and a comparator (i.e., imprecision in the effect estimates).

Ascertainment by investigator in the topotecan trial was unblinded and could systematically bias the ascertainment of progression and, as a consequence, the effect estimates from the STC. The direction of this bias is unknown. The IRC is a strength of the lurbinectedin study; a committee of independent reviewers was used to standardize assessments across trial sites and, therefore, more accurately assign the date of progression.

Only OS and PFS could be assessed in this ITC, but HRQoL and AEs are considered important and valued end points to patients, clinicians, and other decision-makers. Although the population included is overall generalizable to the Canadian landscape, the differences in the ECOG PS (stricter in the topotecan trial) mean that patients might have a more stable status and/or fewer toxicities, which adds some uncertainty in the applicability of results of this STC.

Combined MAIC and NMA

Objectives

The objective of this ITC was to compare the efficacy and safety of lurbinectedin versus relevant comparators among patients with SCLC receiving second-line treatment with respect to ORR, DOR, OS, PFS, and specific hematological AEs of grade 3 or 4 (anemia, thrombocytopenia, neutropenia, and febrile neutropenia).

Study Selection Methods

Systematic Literature Search

First, a systematic literature review of clinical efficacy and safety was conducted to capture any relevant published information available on the second-line treatment of SCLC. A comprehensive database search of MEDLINE, Embase, and the Cochrane Register of Controlled Clinical Trials was conducted to identify RCTs, nonrandomized prospective trials, and single-arm trials eligible for inclusion. Searches of the US National Institutes of Health Clinical Trial Registry and 3 relevant conferences (American Society of Clinical Oncology, American Association for Cancer Research, and the International Association for the Study of Lung Cancer World Conference on Lung Cancer) were also performed. Two reviewers, working independently, conducted abstract selection, full-text selection, and data extraction. RCTs that reported data on tumour response, DOR, survival (overall or progression-free), or AEs were included. Nonrandomized trials or single-arm trials were included only when comparative RCTs were unavailable for an intervention of interest. Results of the systematic literature review provided the foundation from which to assess the feasibility of performing an ITC.

After screening and excluding single-arm and non-RCT studies with available comparative studies for an intervention of interest, 20 citations (12 full-text publications, 3 conference abstracts, 3 registry listings, and 2 client-provided documents) evaluating 10 unique trials were included. The 10 trials consisted of 5 RCTs, 2 single-arm trials, 2 RCTs with only 1 arm of interest, and 1 trial that included both randomized and nonrandomized cohorts with only 1 arm of interest.

Feasibility Assessment

A feasibility assessment was conducted to determine the appropriateness of proceeding with an NMA. The feasibility assessment process included 5 steps: a determination of whether the RCT evidence for the interventions of interest formed 1 connected network for the overall population and each outcome of interest and an assessment of the distribution of trial characteristics across the network; an assessment of the distribution of treatments; an exploration of the distribution of baseline patient characteristics within and between comparisons to identify factors that may bias indirect estimates (i.e., identify effect modifiers); an assessment of outcome definitions and outcome availability; and an assessment of the variability in observed relative treatment effects.

The full evidence network of the included trials is shown in Figure 8: the lurbinectedin single-arm basket trial (study B-005); 4 RCTs with data available in publications (Baize [2020], O’Brien [2006], Eckardt [2007], von Pawel [2001]); 1 RCT with data available in the form of a registry listing [United Therapeutics (2017)]); 2 RCTs with only 1 arm of interest (Owonikoko [2019], CheckMate 331), 1 trial with both a randomized and nonrandomized cohort with only 1 arm of interest (CheckMate 032); and 1 single-arm trial (Smyth [1994]). Figure 8 also describes platinum-sensitivity status by study.

Figure 8: Network of Trials Included in the Feasibility Assessment

CTFI = chemotherapy-free interval; IPD = individual patient data; NR, not reported; PO = orally; RCT = randomized controlled trial.

Note: red text = trials excluded from analyses; blue text = trial excluded from base case but included in sensitivity analysis.

* United Therapeutics (2017) is a 2-part study; only part 2 is a relevant RCT (part 1 = dose escalation).

† Investigator’s choice: intervention considered not relevant, given that results are not stratified by treatment.

Source: Sponsor-submitted MAIC and NMA report.¹⁵

Among the 10 trials included in the feasibility assessment, there were some differences in overall study design, with a mix of RCTs (either OL or double-blind) and single-arm trials included in the evidence base. Eight of the 10 trials were international studies, Baize (2020) was conducted at multiple centres exclusively in France, and Smyth (1994) did not report study location. All trials included patients with limited or extensive disease, except for Smyth (1994), which was restricted to extensive disease only. Three trials were designed to enrol patients with sensitive disease (CTFI ≥ 90 days) (Baize [2020], Eckardt [2007], von Pawel [2001]), 6 trials recruited a mix of patients with sensitive (CTFI ≥ 90 days) and resistant (CTFI < 90 days) disease (O’Brien [2006], United Therapeutics [2017], Owonikoko [2019], CheckMate 331, CheckMate 032, study B-005), and the population type was unknown in 1 trial (Smyth [1994]). All trials focused on the second-line setting, except for CheckMate 032 (second-line and beyond) and Smyth (1994) (first-line and second-line).

Of the 10 trials in the evidence base, 5 RCTs formed a connected network (Baize [2020], O’Brien [2006], von Pawel [2001], Eckardt [2007], and United Therapeutics [2017]), 5 trials were disconnected (study B-005, Smyth [1994], Owonikoko [2019], CheckMate 032, and CheckMate 331)., The network of trials included in the final base-case ITC for patients with platinum-sensitive disease is depicted in Figure 9.

Figure 9: Network of Trials Included in the Base-Case ITC for Patients With Platinum-Sensitive Disease

CTFI = chemotherapy-free interval; IPD = individual patient data; ITC = indirect treatment comparison; PO = orally; RCT = randomized controlled trial.

* Based on the CTFI ≥ 90 days subgroup.

Source: Sponsor-submitted MAIC and NMA report.¹⁵

ITC Analysis Methods

After feasibility was confirmed, an unanchored MAIC was conducted to inform the NMA. Once study B-005 was connected to either Baize (2020) or Eckardt (2007), the MAIC-based relative treatment effect (i.e., effect of lurbinectedin relative to topotecan) was considered as if it was a direct estimate of the relative treatment effect (Figure 10).

Figure 10: Evidence Networks for Base-Case Analysis in Patients With Platinum-Sensitive Disease

ITC = indirect treatment comparison; MAIC = matching-adjusted indirect comparison; PO = orally.

Note: (A.) Network for ORR, OS, grade 3 or 4 anemia, grade 3 or 4 thrombocytopenia, and grade 3 or 4 neutropenia. (B.) Network for PFS and grade 3 or 4 for CTFI ≥ 90-day subgroup (n = 60). Orange node: index trial with IPD. Yellow in pie charts: sensitive disease (CTFI ≥ 90 days). Blue in pie charts: resistant disease (CTFI ≤ 90 days). Trial names in red italic represent trials used to connect study B-005 to the network via an MAIC.

* Based on the CTFI ≥ 90 days subgroup

Source: Sponsor-submitted MAIC and NMA report.¹⁵

The studies included in this network are described in Table 24.

Table 24: Summary of Study Characteristics of Included Trials in the Base-Case Analysis

CR = complete response; CTFI = chemotherapy-free interval; ECOG PS = Eastern Oncology Cooperative Group performance status; ES = extensive stage; LS = limited stage; NA = not applicable; NR = not reported; OL = open label; PR = partial response.

Source: Sponsor-submitted MAIC and NMA report.¹⁵

Unanchored MAIC

Since the intervention of interest is represented by 1 single-arm study, it cannot be connected to the network of RCT evidence, and there is no relative treatment-effect estimate to incorporate in an NMA. To address these deficiencies, for each of the end points of interest, an unanchored MAIC was conducted comparing study B-005 with the reference group of a trial that was already part of the network. This contrast was then connected to the network and the estimated treatment differences used in NMAs estimating relative treatment effects for all treatments in the network.

For the MAIC, propensity score weights were used to adjust for differences between the population in the index trial (i.e., study B-005) and the population in the external AD trial that was already part of the network and was used to link study B-005 to the network. The estimation of these propensity weights was performed using a modified likelihood reweighting approach, which estimates weights from a logistic regression model. The method-of-moments approach, outlined by Signorovitch, was used to balance the mean covariate values across populations. The weighting scheme was based only on the covariates included and was therefore independent of the outcome. To evaluate the distribution of the patient characteristics and the effect and appropriateness of the weighting process, the weights were rescaled relative to the unit weights of the original IPD dataset based on sample size, which facilitated the interpretation of the distribution of weights.

Potentially important treatment-effect modifiers were identified from a literature search that produced an evidence base of relevant publications. These initial variables included platinum sensitivity (sensitive versus resistant), disease stage (limited versus extensive), ECOG PS score (0 versus 1 versus 2), and race (Asian versus non-Asian).

Later, MAIC weights were generated for the index trial to match each of the external trials. Based on the availability of baseline characteristics from each study, the covariates of interest for the MAIC models were age, sex, ECOG PS score, and disease stage.

A measure of the extent of overlap between the index trial and the external AD trial of interest was represented by the effective sample size, an adjustment of the sample size that accounts for the weighting of the observations and the resulting correlations between estimated responses. Large reductions in the effective sample size are not desirable because they imply a poor overlap between IPD and AD studies and introduce uncertainty.

Differences between the index trial and the external trial for each covariate were measured using the standardized mean difference, which ranges from 0% to 100%, and allows for comparisons of covariates measured in different units (e.g., age in years versus percentage of males). For a dichotomized covariate, the standardized mean difference for naive comparisons was calculated. A large standardized difference denotes that there is poor overlap between the 2 trials. For MAIC, the patient weights were calculated such that the weighted covariate mean of the index trial matched the reported covariate mean of the external trial. An exact match equated to a difference of 0; however, not all MAIC weight models resulted in differences of 0 for each covariate. The standardized difference for weighted comparisons for binary covariates was therefore calculated; a covariate was considered balanced when the absolute standardized difference was less than or equal to 10%.

To quantify the improvement after applying MAIC weights across all covariates of interest, 2 diagnostic measures based on standardized difference were used: overall improvement across the covariates of interest; and the number of covariates with improved balance using 10% as the cut point. An external trial with a larger overall improvement, after applying weights, indicated its covariates had poorer overlap with the index trial, compared with another external trial with a smaller overall improvement. Based on this assessment, the external trial with the most overlap with the index trial population was selected for the base-case analysis.

Once the index trial (B-005) was connected to an external trial by applying MAIC weights, outcomes for the index treatment were predicted for the target population by reweighting the observed outcomes from the index trial. Treatment comparisons were then made based on differences between the weighted averages from the index trial and the observed outcome from the AD study evaluating the competitor in the target population. These treatment comparisons were then considered pseudodirect comparisons in the NMA.

Network Meta-Analysis

Once study B-005 was connected to either the Baize (2020) or Eckardt (2007) studies, the MAIC-based relative treatment effect (i.e., effect of lurbinectedin relative to topotecan) was considered as if it was a direct estimate of relative treatment effect.

Because there were no closed loops in any evidence networks, it was not feasible to assess the consistency between direct and indirect comparisons in the current NMA.

The deviance information criterion (DIC) (a measure of model fit that penalizes model complexity), in addition to an assessment of overall stability, was used to guide the identification of the appropriate model (i.e., fixed or random effects). A more complex model results in a better fit to the data, demonstrating a smaller residual deviance. Normal noninformative prior distributions of the parameters were used with a mean of 0 and a variance of 10,000. Both fixed and random-effects models were considered for each analysis. For the random-effects models, 1 parameter for the between-study heterogeneity was used, assuming that the between-study heterogeneity was the same for each intervention relative to the overall reference treatment of choice. Given the limited evidence base, random-effects models lead to unstable estimates; therefore, fixed-effects models were preferred.

For time-to-event data, the proportional hazard assumption regarding time-to-event outcomes for each individual trial was assessed using the Grambsch and Therneau test and visual inspection of log-log plots. The NMA of reported HRs in terms of OS (assuming proportional hazards between treatments) was performed using a regression model with a contrast-based normal likelihood for the log HR (and corresponding standard error) of each trial (or comparison) in the network. If a Kaplan-Meier curve was not presented in the AD study and a median survival was reported instead, the median survival was estimated from the IPD of the lurbinectedin study, before and after applying weights. Because a detailed distribution from AD was not available, no formal test was performed to assess the relative treatment effect.

For binary outcomes (ORR and grade 3 or 4 AEs), the number of patients with the event and the number without were used to determine the probability of an event in the target population. The NMA could then be performed based on the proportion of patients experiencing the event of interest using a logistic regression model with a binomial likelihood and logit link. Relative treatment effects were expressed as ORs. A regression model with a contrast-based normal likelihood for the log OR (and corresponding standard error) of each comparison in the network was performed. Similarly, safety outcomes NMAs were performed using OR as input data.

The base-case analyses included patients with platinum-sensitive disease (defined as CTFI longer than 90 days), and sensitivity analyses were based on patients with any platinum-sensitivity status. The outcomes assessed were OS, PFS, ORR, DOR (only MAIC performed because only median DOR reported in external studies), and harms (specific hematological AEs of grade 3 or 4 anemia, thrombocytopenia, neutropenia, and febrile neutropenia).

Results of the Combined MAIC and NMA

The baseline patient characteristics of interest for the MAIC were age, sex, ECOG PS, and disease stage; an additional variable of platinum sensitivity was considered when the full population of study B-005 was considered. The distribution of these variables is shown for the included studies in Table 25.

Table 25: Summary of Baseline Patient Characteristics in Study B-005 and RCTs in the Connected Network for the Platinum-Sensitive Disease Population

1L = first-line; 2L = second-line; ECOG PS = Eastern Cooperative Oncology Group performance status; ES = extensive stage; LS = limited stage, RCT = randomized controlled trial.

Source: Sponsor-submitted MAIC and NMA report.¹⁵

Overall Survival

The MAIC-adjusted HRs of OS for lurbinectedin compared with other treatments from an external trial of interest are presented in Table 26.

In the base-case NMA for OS (study B-005 sensitive subgroup connected to Baize [2020]), lurbinectedin had an HR of 0.43 (95% CrI, 0.26 to 0.70) against IV topotecan and of 0.42 (95% CrI, 0.30 to 0.58) against carboplatin plus etoposide. When study B-005 was connected to the Eckardt (2007) study (i.e., sensitivity analyses), the relative treatment effects of these comparisons were smaller (HR closer to 1) and no longer statistically significant whether lurbinectedin was compared to IV topotecan (HR = 0.75; 95% CrI, 0.56 to 1.03) or carboplatin plus etoposide (HR = 0.74; 95% CrI, 0.50 to 1.09).

Results from the random-effects models had similar HR estimates similar to the corresponding fixed-effect models, whereas the CrIs were much wider, as expected due to the small sample sizes that studies provided to the networks. The DIC for the random-effects models were slightly greater than those for the fixed-effect models (e.g., in the base case, DIC was 5.31 for the fixed-effects model versus 6.66 for the random-effects model).

Table 26: Results of MAIC for OS for Lurbinectedin (Study B-005) Versus Comparators (Baize [2020] or Eckardt [2007])

CI = confidence interval; CTFI = chemotherapy-free interval; ESS = effective sample size; HR = hazard ratio; MAIC = matched adjusted indirect comparison; NA = not applicable; OS = overall survival.

^aConsidered as pseudodirect evidence.

^bUsed as validation for NMA.

Source: Sponsor-submitted MAIC and NMA report.¹⁵

Progression-Free Survival

Among the connected RCTs, Baize (2020) reported PFS, whereas von Pawel (2001) and Eckardt (2007) only reported time to progression. The definitions for PFS and time to progression differed. Only studies that reported PFS were analyzed. The proportional hazard assumption was violated for Baize (2020) and Eckardt (2007). Fractional polynomial models were fitted to estimate time-varying HRs, instead of using the reported constant HR for the NMA. Weighted number at risk and weighted number of events from study B-005 and IPD reconstructed from external trial Kaplan-Meier curves were prepared as input for the NMA (rather than an MAIC), but further details were not provided.

The time-varying HR estimates indicated that carboplatin plus etoposide was associated with a higher HR for PFS than lurbinectedin at first (i.e., HR greater than 1), but the HR curve had a steep decline and by month 3, the direction of the HR changed (i.e., was less than 1), as shown in Table 27. From 6 months onward, PFS was longer with lurbinectedin than carboplatin plus etoposide, although HR estimates beyond 12 months were based on model extrapolation.

Table 27: Estimated PFS HRs Over Time for Lurbinectedin Versus Competing Interventions From Fixed-Effect Fractional Polynomial NMA

CrI = credible interval; HR = hazard ratio; NMA = network meta-analysis; PFS = progression-free survival.

Note: Cells shaded in grey indicate estimates based on model extrapolations.

Source: Sponsor-submitted MAIC and NMA report.¹⁵

Objective Response Rate

The MAIC-adjusted ORs of the ORR for lurbinectedin versus other treatments from an external trial of interest are presented in Table 28.

Table 28: Results of MAIC for ORR for Lurbinectedin (Study B-005) Versus Relevant Comparators (Baize [2020] or Eckardt [2007])

CI = confidence interval; CTFI, chemotherapy-free interval; ESS = effective sample size; MAIC = matching-adjusted indirect comparison; OR = odds ratio; ORR = objective response rate.

Note: For response outcomes, OR > 1 favours lurbinectedin.

^aConsidered to be pseudodirect evidence.

^bUsed as validation for NMA.

^cOne of 60 patients was not evaluable and was assumed to have no response.

^dFive of 105 patients were not evaluable and were assumed to have no response.

Source: Sponsor-submitted MAIC and NMA report.¹⁵

Similar to OS, because oral topotecan was the central node of the network, the ORs for lurbinectedin versus oral topotecan were used as input for the NMA. Results from the ORR fixed-effect NMA are presented.

In the base-case analysis (incorporating study B-005 sensitive subgroup via Baize [2020]), no evidence of difference was detected between lurbinectedin versus IV topotecan (OR = 2.36; 95% CrI, 0.89 to 6.23) or between lurbinectedin and carboplatin plus etoposide (OR = 0.85; 95% CrI, 0.40 to 1.83).

When study B-005 (in the any platinum-sensitivity subgroup) was connected to the network via Eckardt (2007) (i.e., sensitivity analyses), lurbinectedin demonstrated greater odds of an ORR than IV topotecan (OR = 2.71; 95% CrI, 1.46 to 4.96), but no difference was detected between lurbinectedin and carboplatin plus etoposide (OR = 0.96; 95% CrI, 0.38 to 2.46).

Similarly, lurbinectedin presented greater odds for an ORR in the sensitivity analysis of patients with platinum-sensitive disease connected via Eckardt (2007) when compared against IV topotecan (OR = 2.93; 95% CI, 1.54 to 5.6) but not against carboplatin plus etoposide (OR = 1.07; 95% CrI, 0.41 to 2.82).

When random-effects models were used to capture heterogenous between-trial treatment effects, the OR point estimates were comparable to the corresponding fixed-effect models; however, the CrIs were much wider, as expected. In addition, DICs for the random-effects models were slightly larger than those for the fixed-effect models (e.g., in the base case, DIC was 6.4 for the fixed-effect model versus 6.98 for the random-effects model).

Duration of Response

In the connected network of RCTs, only 3 trials reported median DOR (Baize [2020], von Pawel [2001] and Eckardt [2007]), with 1 providing 95% CIs and 2 providing ranges, but relative treatment-effect estimates (i.e., HR) or Kaplan-Meier curves were not available. Only an unanchored MAIC was performed for DOR, and only treatment-level data were reported, as no relative treatment effects could be estimated.

When the study B-005 sensitive subgroup was considered as the third arm of the Baize (2020) study, the median DOR for lurbinectedin was ██ █ █████ █ ███ █ ██ █ ███ █ █ █ ███ █ ███████, whereas the median DOR for carboplatin plus etoposide was ██ █ █████ █ ███ █ ██ █ ██ █ █ █ ██ █ ███████ with overlapping 95% CIs (see Table 29).

When the study B-005 full population was connected to Eckardt (2007) (sensitivity analysis 1), the median DOR for lurbinectedin was ███ █ █████ █ ███ █ ██ █ ███ █ █ █ ███ █ ███████. Similarly, when the study B-005 platinum-sensitive subgroup was connected to Eckardt (2007) (sensitivity analysis 2), the median DOR for lurbinectedin was ██ █ █████ █ ███ █ ██ █ ███ █ █ █ ███ █ ███████; the DOR estimate was similar regardless of the external study used to connect study B-005 to the network.

Harms

To present an overall description of the harms outcomes of interest in each study included in the NMAs, Table 30 depicts a summary of data across the trials included.

Table 29: Results of MAIC for DOR for Lurbinectedin (Study B-005) Versus Comparators (Baize [2020] or Eckardt [2007])

DOR = duration of response; MAIC = matching-adjusted indirect comparison.

Note: Only median DOR was available for Baize (2020) and Eckardt (2007), and comparative estimates could not be generated.

^aPatients with sensitive disease (CTFI ≥ 90 days) and study B-005 connected via Baize (2020).

^bPatients with any platinum-sensitivity status and study B-005 connected via Eckardt (2007).

^cPatients with sensitive disease (CTFI ≥ 90 days) and study B-005 connected via Eckardt (2007).

Source: Sponsor-submitted MAIC and NMA report.¹⁵

Table 30: Summary of Harms Outcomes Across Trials Included in the NMA

CTFI = chemotherapy-free interval; IPD = individual patient data; ITT = intention-to-treat; NA = not available; NMA = network meta-analysis.

Note: Either treatment-related or any hematological AEs were extracted.

^aApproximately 10% of patients in both treatment groups had a CTFI < 90 days at study entry.

^bApproximately 2% of patients in both treatment groups had a CTFI < 90 days at study entry.

Source: Sponsor-submitted MAIC and NMA report.¹⁵

MAIC Estimates

MAIC estimates of harms in the lurbinectedin arm compared to relevant comparators are presented in Table 31. When observing the MAIC estimates (ORs) for harms in the base-case analysis, lurbinectedin was associated with a lower incidence of grade 3 or 4 anemia compared with carboplatin plus etoposide (█ █ █ ████ █ ██ █ █ █ ████ █ ████). Similarly, the adjusted estimates for grade 3 or 4 thrombocytopenia for lurbinectedin versus carboplatin plus etoposide showed lower odds of harm (OR = 0.23; 95% CI, 0.06 to 0.95).

For grade 3 or 4 thrombocytopenia, lurbinectedin showed lower odds when compared with carboplatin plus etoposide (█ █ █ ████ █ ████ █ ███ █ █ █ ████), and odds were similar across sensitivity analyses.

However, lurbinectedin had higher odds of neutropenia grade 3 or 4 (█ █ █ ████ █ ██ █ █ █ ████ █ █████) when compared to carboplatin plus etoposide, but this effect was the opposite when lurbinectedin was evaluated against IV topotecan in the group of patients with any platinum sensitivity (sensitivity analysis) (█ █ █ ████ █ ██ █ █ █ ████ █ ████) and when the patients with sensitive disease (CTFI > 90 days) were observed (█ █ █ ████ █ ██ █ █ █ ████ █ ████). These differences in neutropenia rates were deemed by the authors to be related to differences in the requirements for prophylaxis with G-CSF across studies (i.e., primary prophylaxis with G-CSF was not permitted in study B-005 or in Eckardt [2007], but was recommended for all patients in Baize [2020]; thus, grade 3 or 4 neutropenia rates were lower in Baize [2020]).

Table 31: Results of MAIC for Harms of Lurbinectedin (Study B-005) Versus Comparators (Baize [2020] or Eckardt [2007])

CI = confidence interval; ESS = effective sample size; MAIC = matching-adjusted indirect comparison; NA = not available; NMA = network meta-analysis; OR = odds ratio.

Note: All analyses are base case.

Source: Sponsor-submitted MAIC and NMA report.¹⁵

NMA Estimates

The NMA estimates for grade 3 or 4 anemia in the base-case analysis showed lower odds of harm in the lurbinectedin arm than in the carboplatin plus etoposide arm (OR = 0.22; 95% CrI, 0.08 to 0.61) and than in the IV topotecan arm (OR = 0.21; 95% CrI, 0.06 to 0.74), with consistent results in the sensitivity analyses.

Similarly, for thrombocytopenia grade 3 or 4, the base-case analysis showed lower odds (OR = 0.23; 95% CrI, 0.08 to 0.69), and odds were consistent in the sensitivity analyses.

For the end point of neutropenia grade 3 or 4, higher odds were observed in the lurbinectedin arm than in the carboplatin plus etoposide arm (OR = 7.05; 95% CrI, 3.09 to 16.11), but not than in the IV topotecan arm (OR = 1.19; 95% CrI, 0.45 to 3.17). In the sensitivity analyses (patients with any platinum sensitivity and patients with platinum-sensitive disease), the odds of neutropenia were lower in the lurbinectedin arm than in the carboplatin plus etoposide arm, as described in the MAIC analysis.

Critical Appraisal of the Combined MAIC and NMA

A systematic literature process is defined in a separate technical report. Overall, the methods for the systematic literature search and study selection were well described and appropriate, including the search strategy, screening process, and quality assessment of individual studies.

This ITC represents 2 connected evidence syntheses. First, IPD from 2 different analysis populations from study B-005 (platinum-sensitive subgroup and full population of patients with any platinum-sensitivity status) were used to perform the unanchored MAICs to connect the lurbinectedin arm and AD from 1 of 2 other trials that included relevant comparators (either Baize [2020] or Eckardt [2007], depending on the outcome evaluated). Second, estimates of treatment effect from the MAIC were included in the NMA, with the rest of the studies by essentially treating it as direct evidence. The validity of this technique is unknown. The main concern is the inclusion of uncertainty due to lack of holding the transitivity assumptions. Sparsity of the network is also a concern, together with concerns about important differences between included studies.

In an unanchored MAIC, for the approach to be a valid comparison, the investigators would need to achieve balance on all prognostic factors and all effect modifiers between each arm of treatment by including all such factors in a weighting process to make the population similar for the evaluation of efficacy and safety end points. The effective sample size in different analyses presents moderate to large decreases from the original data, which suggests an inadequate overlap of covariate distribution between studies. The choice of covariates for the MAIC models was limited by the availability of baseline patient characteristics in the external RCTs. It was not feasible to adjust for covariates that were not reported or unknown in the external studies, and it was not feasible to adjust for differences in study design or location. These covariates of interest (age, sex, ECOG PS, disease stage, and platinum sensitivity) were selected based on those reported in the trials, rather than a comprehensive literature search and/or clinical expert advice. For instance, the presence of CNS metastases was considered important for inclusion in the overall MAIC analysis by experts consulted by CADTH.

There were also uncertainties due to concerns about violations of the proportional hazards assumptions for the end points, although the authors attempted to address this issue by using fractional polynomials to model in situations where the proportional hazards assumptions did not match.

In the NMA, the first issue is the addition of a single-arm trial through an unanchored MAIC, which increases risk of bias due to loss of randomization benefits. Further strong assumptions were made to form this connected network (e.g., disease stage comparable across trials, no significant differences between IA or IRC assessment for tumour response). Despite performing an extensive feasibility assessment to carefully select the trials for inclusion in the network, the assumption of consistency may not hold. Furthermore, there were no closed loops in any evidence networks, so it was not feasible to assess the consistency between direct and indirect comparisons.

The analysis of DOR was limited by data availability in the external trials; no relative treatment effect (i.e., HR) or Kaplan-Meier curves was available. Although median DORs were reported, standard error for median DOR was unavailable for the external RCTs in the connected network. Therefore, only an unanchored MAIC was performed for this outcome, as strong assumptions would be required to incorporate these data into an NMA (e.g., assumptions that the difference in median DOR is normally distributed and that the standard error can be estimated correctly based on the ranges).

The population of the MAIC from the IPD arm (study B-005) is, overall, generalizable to the target population for the indication in this CADTH submission (i.e., patients with SCLC receiving second-line treatment); however, as noted, the populations from the comparator arms had differences that did not align with the target population of interest, such as ECOG PS, disease stage, and platinum-sensitivity status. Furthermore, some comparators relevant to this CADTH review explained in the protocol of this report (i.e., CAV, irinotecan) were not included in this MAIC and NMA.

Harms data could be of different maturity between trials and have an impact on the certainty on these effect estimates. For example, some differences noted (heterogeneity) between the effect estimates in different sensitivity analyses were detected in the neutropenia grade 3 or 4 end point. However, duration of treatment (median number of cycles administered) was similar across studies. Last, no information on HRQoL was assessed in this ITC, which was an important outcome for this CADTH report.

Other Relevant Evidence

No other relevant evidence was identified for this review.

Discussion

Summary of Available Evidence

One phase II, multicentre, single-arm, OL basket trial (B-005)³¹ designed to evaluate the efficacy and safety of lurbinectedin in previously treated adult patients with advanced solid tumours, including SCLC (N = 105), contributed evidence to this report. The study enrolled adult patients with SCLC who had received 1 prior line of chemotherapy for advanced disease, had an ECOG PS score of 2 or less, and did not have CNS involvement. Patients received OL lurbinectedin (3.2 mg/m²) until disease progression or unacceptable toxicity. The primary outcome of the study was ORR per IA; secondary outcomes included ORR per IRC, DOR per IA and IRC, PFS per IA and IRC, and OS. According to the clinical experts consulted by CADTH for this review, the baseline characteristics of the B-005 study population were broadly representative of patients with SCLC in Canada who have progressed on or after first-line platinum etoposide doublet therapy. The median age was 60 years, most patients had an ECOG PS of 0 (36.2%) or 1 (56.2%), and most patients had ES disease (93.3%) at study entry; according to the clinical experts consulted by CADTH for this review, the study population was younger and had better performance status than the general SCLC patient population, as expected for any clinical trial population. Proportions of patients with platinum-refractory or platinum-resistant disease (42.9% for CTFI < 90 days) and platinum-sensitive disease (57.1% for CTFI ≥ 90 days) were similar.

Three sponsor-submitted ITCs are included in this CADTH report. The first ITC evaluated treatment efficacy in patients with advanced SCLC after exposure to platinum-based therapy in Alberta, and used these data to build an SCA for comparison with the B-005 study population.¹² The second ITC is an STC that facilitates the indirect comparison of lurbinectedin (using IPD from the B-005 trial) with topotecan IV (using AD from the von Pawel et al. [2014] RCT publication¹³) in patients with relapsed or refractory SCLC.¹⁴ The third ITC is a series of combined MAICs and NMAs to evaluate the efficacy and safety of lurbinectedin compared with competing interventions among patients with SCLC receiving second-line treatment with respect to ORR, DOR, OS, and PFS, as well as hematological AEs of grade 3 or 4.¹⁵

Interpretation of Results

Efficacy

There was no direct comparative evidence available to inform the relative efficacy of lurbinectedin compared with other treatment options in the second-line or third-line treatment of SCLC. According to the clinical experts consulted by CADTH for this review, the ORRs (35.2% per IA and 30.5% per IRC in the overall study population) and median DORs (5.3 months per IA and 5.1 months per IRC) observed in study B-005 were encouraging in the second-line treatment setting. The clinical experts emphasized that the decreasing efficacy of lurbinectedin (and any drug) with shorter CTFIs was expected, and that the observation of any objective responses lasting several months in patients with a CTFI shorter than 90 days was promising. Spontaneous tumour regression would not be expected in this patient population. In agreement with guidance from the FDA, the clinical experts explained that in the absence of a control group, interpretation of OS and PFS results was unclear.³⁵ HRQoL and cancer symptoms, outcomes of importance to patients with SCLC, were not assessed in the study. The clinical experts stressed that despite the uncertainties regarding efficacy data from study B-005, available options for the second-line and third-line treatment of SCLC are not effective in many patients.

Regarding evidence from ITCs, the SCA analysis provides a comparison of lurbinectedin (study B-005) against the SCA based on real-world data adjusted by CTFI and stage at initial diagnosis, where a longer median OS in the lurbinectedin arm was observed. In the STC of lurbinectedin versus IV topotecan, adjusted estimates suggest longer median OS with lurbinectedin than with topotecan IV, although the results had limitations related to imprecision, risk of bias, and residual confounding. Results from the MAIC and NMA in the third ITC suggest that lurbinectedin improves median OS and PFS rates from 3 to 9 months compared with IV topotecan and carboplatin plus etoposide. However, results from the MAICs are limited by the imprecision, confounding, and risk of bias (e.g., violation of proportional hazards, intransitivity, poor overlap of covariates in the MAIC). ORR and DOR were uncertain, with no evidence of better ORR odds with lurbinectedin than with carboplatin plus etoposide or topotecan IV, and incomplete evidence for the evaluation the DOR. Overall, in the third ITC, there was too much uncertainty to draw conclusions because the NMA has limitations similar to those observed in the MAICs, which were used to include a single-arm trial in an already sparse network of studies.

Several phase III and phase IV studies investigating lurbinectedin for treatment of SCLC have been completed or are ongoing. The phase III ATLANTIS study is a randomized, OL trial of lurbinectedin plus doxorubicin versus investigator’s choice of CAV or topotecan in patients with SCLC who failed on prior line of platinum-containing chemotherapy (N = 613);³⁶ the study did not meet its primary end point and no OS benefit was observed for the lurbinectedin plus doxorubicin combination (NCT02566993). However, lurbinectedin was dosed at 2 mg/m² to mitigate toxicities of the combination regimen. The phase III LAGOON study is a randomized, OL trial comparing lurbinectedin monotherapy, lurbinectedin plus irinotecan, and investigator’s choice of irinotecan or topotecan in patients with SCLC who failed 1 line of platinum-containing chemotherapy (N = 705); results are not yet available (NCT05153239).³⁷ The phase IV EMERGE-402 study is an ongoing real-world observational study of lurbinectedin monotherapy in any line among patients with ES SCLC (N = 300); results are not yet available (NCT04894591).³⁸

Harms

The clinical experts consulted by CADTH for this review stressed that the potential importance of lurbinectedin for the treatment of patients with SCLC was tied closely to potentially improved tolerability compared with other treatment options in second-line and third-line settings. The clinical experts repeatedly stressed that the difficulties patients experience with available treatments in the second and subsequent lines, especially IV topotecan and CAV, are “terribly harsh.” Patient input also identified treatment options with improved toxicity profiles as important to patients with SCLC. Although roughly one-quarter of patients had dose reductions of lurbinectedin in study B-005, very few discontinued treatment due to AEs or unacceptable toxicity (3.8%). Moreover, SAEs related to hematological toxicities were relatively infrequent (neutropenia, febrile neutropenia, anemia, and thrombocytopenia all had frequencies of 5% or less), although the protocol did not include primary G-CSF prophylaxis. The clinical experts consulted by CADTH for this review felt that severe hematological toxicities occurred less frequently in patients receiving lurbinectedin in the B-005 study compared with their clinical experience with IV topotecan and CAV in the second-line and third-line settings.

Regarding the indirect evidence, harms were only evaluated through the MAIC and NMA. Overall, lurbinectedin was associated with a lower incidence of grade 3 or 4 anemia compared with carboplatin plus etoposide and a better profile for grade 3 to 4 thrombocytopenia. Lurbinectedin was associated with a greater incidence of grade 3 or 4 neutropenia in the base-case analysis. However, in the sensitivity analysis, a lower incidence of grade 3 or 4 neutropenia was observed with lurbinectedin compared with oral topotecan. These differences in neutropenia rates were deemed to be related to differences in the requirements for prophylaxis with G-CSF across studies. These harm-effect estimates suffer from the same limitations as the efficacy outcomes, although with better confidence in the generalizability of the results and ascertainment of the outcomes.

Conclusions

Evidence from study B-005 suggested that administration of lurbinectedin in patients with SCLC who received 1 prior line of platinum-containing chemotherapy resulted in objective responses in some patients that persisted for several months. In the absence of a control group, PFS and OS results could not be interpreted, and there was no direct evidence to inform the relative efficacy of lurbinectedin compared with other treatment options. Indirect evidence (3 sponsor-submitted ITCs) suggested that lurbinectedin treatment may result in improved OS and/or PFS compared with IV topotecan and carboplatin plus etoposide, albeit with a high risk of bias (due to unanchored comparisons and limited ability to adjust for variability in prognostic factors and treatment-effect modifiers) and a sparse dataset. In study B-005, the main toxicity of lurbinectedin, reversible myelosuppression, was considered acceptable and manageable with dose reductions and appropriate transfusion and growth-factor support. The indirect evidence also suggested that lurbinectedin was associated with lower frequencies of grade 3 or 4 anemia and thrombocytopenia compared with oral topotecan and carboplatin plus etoposide, again with high uncertainty. The indirect evidence was aligned with some outcomes identified as important to patients with SCLC, who are seeking additional second-line and third-line treatment options that prolong survival, delay disease progression, and maintain HRQoL while having acceptable toxicity profiles.

References

1.Drug Reimbursement Review sponsor submission: Zepzelca (lurbinectedin): lyphilized powder, 4 mg/vial, intravenous infusion [internal sponsor's package]. Mississauga (ON): Jazz Pharmaceuticals; 2022 Feb 24.

2.Rudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer. Nat Rev Dis Primers. 2021;7(1):3. PubMed

3.Kalemkerian GP, Gadgeel SM. Modern staging of small cell lung cancer. J Natl Compr Canc Netw. 2013;11(1):99-104. PubMed

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5.Bennett BM, Wells JR, Panter C, Yuan Y, Penrod JR. The Humanistic Burden of Small Cell Lung Cancer (SCLC): A Systematic Review of Health-Related Quality of Life (HRQoL) Literature. Front Pharmacol. 2017;8:339. PubMed

6.Canadian Cancer Statistics Advisory Committee. Canadian cancer statistics: A 2020 special report on lung cancer. 2020; https://www.cancer.ca/Canadian-Cancer-Statistics-2020-EN. Accessed May 5, 2021.

7.Doherty J, Dawe DE, Pond GR, Ellis PM. The effect of age on referral to an oncologist and receipt of chemotherapy among small cell lung cancer patients in Ontario, Canada. J Geriatr Oncol. 2019;10(3):449-458. PubMed

8.Sun A, Durocher-Allen LD, Ellis PM, et al. Initial management of small-cell lung cancer (limited- and extensive-stage) and the role of thoracic radiotherapy and first-line chemotherapy: a systematic review. Curr Oncol. 2019;26(3):e372-e384. PubMed

9.Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. PubMed

10.Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020;21(5):645-654. PubMed

11.Clinical study report: Study number PM1183-B-005-14. A multicenter phase II clinical trial of lurbinectedin (PM01183) in selected advanced solid tumours - small cell lung cancer (SCLC) cohort [internal sponsor's report]. Madrid (Spain): Pharma Mar S.A.; 2019 October 29.

12.Oncology Outcomes. Evaluating the Treatment Landscape and Comparative Efficacy of Lurbinectedin in the Treatment of Small Cell Lung Cancer (SCLC) Following Exposure to Platinum Therapy in Alberta, Canada: Phase One and Two Results [internal sponsor's report]. In: Drug Reimbursement Review sponsor submission: Lurbinectedin, 4mg single dose vial. Mississauga (ON): Jazz Pharmaceuticals; 2022. 2022.

13.von Pawel J, Jotte R, Spigel DR, et al. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol. 2014;32(35):4012-4019. PubMed

14.Purple Squirrel Economics. Simulated Treatment Comparisons of Survival Outcomes in Lurbinectedin and Topotecan Treated Relapsed / Refractory Small Cell Lung Cancer Patients. [internal sponsor's report]. In: Drug Reimbursement Review sponsor submission: Lurbinectedin, 4 mg single dose vial. Mississauga (ON): Jazz Pharmaceuticals. 2021.

15.precisionHEOR. Systematic Literature Review and Indirect Treatment Comparison of Lurbinectedin for the Second-Line Treatment of Small Cell Lung Cancer: Technical Report. [internal sponsor's report]. In: Drug Reimbursement Review sponsor submission: Lurbinectedin, 4 mg single dose vial. Mississauga (ON): Jazz Pharmaceuticals; 2022. 2021.

16.Canada S. Table 17-10-0005-01 Population Estimates on July 1st, by Age and Sex. 2021; https://www150.statcan.gc.ca/t1/tbl1/en/cv.action?pid=1710000501. Accessed May 5, 2021.

17.Brenner DR, Weir HK, Demers AA, et al. Projected estimates of cancer in Canada in 2020. CMAJ. 2020;192(9):E199-E205. PubMed

18.PrZepzelcaTM (lurbinectedin): lyophilized powder, 4 mg/vial, intravenous injection [product monograph]. Dublin (IE): Jazz Pharmaceuticals; 2021 Sep 29.

19.PrCarboplatin injection BP: sterile solution, 10 mg/mL (50 mg, 150 mg, 450 mg, 600 mg of carboplatin per vial), antineoplastic agent [product monograph]. Kirkland, QC: Pfizer Canada; 2022 March 29.

20.PrCisplatin injection BP: sterile solution, 1 mg/mL (50 mg and 100 mg f carboplatin per vial), antineoplastic agent [product monograph]. Kirkland, QC: Pfizer Canada; 2020 April 3.

21.PrEtoposide injection USP: sterile solution, 20 mg/mL (100 mg/5 mL, 200 mg/10 mL, 500 mg/2 mL, 1 g/50 mL), antineoplastic agent [product monograph]. Boucherville, QC: Sandoz Canada Inc.; 2015 May 21.

22.PrTopotecan hydrochloride for injection: sterile solution, 4 mg topotecan (as topotecan hydrochloride) per 4 mL, antineoplastic agent [product monograph]. Kirkland, QC: Pfizer Canada Inc.; 2018 January 5.

23.PrProcytox: cyclophosphamide tablets USP: 25 mg, 50 mg and cyclophosphamide for injection: 200 mg, 500 mg, 1000 mg, 2000 mg (powder for injection) per vial,, antineoplastic agent [product monograph]. Mississauga, ON: Baxter Corporation; 2012 September 7.

24.PrDoxorubicin: doxorubicin hydrochloride injection, preservative-free solution, 2 mg/mL, 10 mg (5 mL) and 50mg (25 mL), antineoplastic agent [product monograph]. Kirkland, QC: Pfizer Canada; 2021 September 30.

25.PrVincristine sulfate injection USP, 1 mg/mL, antineoplastic agent [product monograph]. Kirkland, QC: Pfizer Canada; 2021 July 26.

26.PrIrinotecan hydrochloride injection USP (irinotecan hydrochloride trihydrate), 20 mg/mL (40 mg/2 mL, 100 mg/5 mL, 500 mg/25 mL), antineoplastic agent [product monograph]. Kirkland, QC: Pfizer Canada; 2019 March 8.

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

29.Fernandez-Teruel C, Lubomirov R, Fudio S. Population Pharmacokinetic-Pharmacodynamic Modeling and Covariate Analyses of Neutropenia and Thrombocytopenia in Patients With Solid Tumors Treated With Lurbinectedin. J Clin Pharmacol. 2021;61(9):1206-1219. PubMed

30.Subbiah V, Paz-Ares L, Besse B, et al. Antitumor activity of lurbinectedin in second-line small cell lung cancer patients who are candidates for re-challenge with the first-line treatment. Lung Cancer. 2020;150:90-96. PubMed

31.Schwartz LH, Litiere S, de Vries E, et al. RECIST 1.1-Update and clarification: From the RECIST committee. Eur J Cancer. 2016;62:132-137. PubMed

32.Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. Geneva (CH): International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; 2018: https://www.meddra.org. Accessed 2022 Jan 1.

33.Common Terminology Criteria for Adverse Events (CTCAE v4.0: CTCAE v4.03. Bethesda (MD): National Cancer Institute; 2010: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. Accessed 2022 Jan 1.

34.Phillippo DM, Ades AE, Dias S, Palmer S, Abrams KR, Welton NJ. Methods for Population-Adjusted Indirect Comparisons in Health Technology Appraisal. Med Decis Making. 2018;38(2):200-211. PubMed

35.US FDA. Clinical trial endpoints for the approval of cancer drugs and biologics: Guidance for industry 2018; https://www.fda.gov/media/71195/download.

36.Farago AF, Drapkin BJ, Lopez-Vilarino de Ramos JA, et al. ATLANTIS: a Phase III study of lurbinectedin/doxorubicin versus topotecan or cyclophosphamide/doxorubicin/vincristine in patients with small-cell lung cancer who have failed one prior platinum-containing line. Fut Oncol. 2019;15(3):231-239. PubMed

37.ClinicalTrials.gov. Clinical trial of lurbinectedin as single-agent or in combination with irinotecan versus topotecan or irinotecan in patients with relapsed small-cell lung cancer (LAGOON). 2021; https:/www.clinicaltrials.gov/ct2/show/NCT05153239.

38.ClinicalTrials.gov. To assess the effectiveness and safety of Zepzelca in adult patients with extensive stage small cell lung cancer (SCLC). 2021; https:/www.clinicaltrials.gov/ct2/show/NCT04894591.

Appendix 1: Literature Search Strategy

Clinical Literature Search

Overview

Interface: Ovid

Databases:

• MEDLINE All (1946 to present)

• Embase (1974 to present)

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

Date of search: March 24, 2022

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 32: Syntax Guide

Multi-Database Strategy

1. (Zepzelca* or lurbinectedin or PM01183 or “PM 01183” or pm1183 or pm 1183 or WHO9397 or WHO 9397 or ly01017 or “ly 01017” or tryptamicidin* or zepsyre* or 2CN60TN6ZS).ti,ab,ot,kf,hw,nm,rn.

2. 1 use medall

3. *lurbinectedin/ or (Zepzelca* or lurbinectedin or PM01183 or “PM 01183” or pm1183 or pm 1183 or WHO9397 or WHO 9397 or ly01017 or “ly 01017” or tryptamicidin* or zepsyre*).ti,ab,kf,dq.

4. 3 use oemezd

5. 4 not (conference review or conference abstract).pt.

6. 2 or 5

7. remove duplicates from 6

Clinical Trials Registries

ClinicalTrials.gov

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

• Search -- Studies with results: Zepzelca/lurbinectedin AND SCLC

WHO ICTRP

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

• Search terms -- Zepzelca/lurbinectedin AND SCLC

Health Canada’s Clinical Trials Database

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

• Search terms -- Zepzelca/lurbinectedin AND SCLC

EU Clinical Trials Register

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

• Search terms -- Zepzelca/lurbinectedin AND SCLC

Grey Literature

Search dates: March 14 to 17, 2022

Keywords: Zepzelca, lurbinectedin, SCLC

Limits: Publication years: 1996-present

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)

Appendix 2: Excluded Studies

Table 33: Excluded Studies

Pharmacoeconomic Review

Executive Summary

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

Table 1: Submitted for Review

NOC = Notice of Compliance; NOC/c = Notice of Compliance with conditions; SCLC = small cell lung cancer.

Table 2: Summary of Economic Evaluation

CAV = cyclophosphamide + doxorubicin + vincristine; ICER = incremental cost-effectiveness ratio; LY = life-year; OS = overall survival; PFS = progression-free survival; QALY = quality-adjusted life-year; SCLC = small cell lung cancer; SYNTH = synthetic basket comparator derived from real-world evidence.

Conclusions

The sponsor’s economic model is informed by results from the PM1183-B-005-14 trial (hereafter referred to as the B-005 study), a single-arm, phase II trial that aimed to assess the efficacy and safety of lurbinectedin as a second-line treatment for patients with small cell lung cancer (SCLC). Quality of life (QoL) was not assessed in the B-005 trial. The CADTH clinical review concluded that data from the B-005 study were inadequate to interpret the overall survival (OS) and progression-free survival (PFS) findings because of the lack of a comparator group. Owing to the sponsor’s use of naive comparisons of lurbinectedin to all modelled comparators, it is not possible to determine if any observed differences in PFS, OS, or quality-adjusted life-years (QALYs) between treatments are due to the effect of treatment or are instead due to bias or confounding. As a result, the comparative effectiveness of lurbinectedin and other currently available treatments is highly uncertain.

Given the lack comparative data and critical limitations within the sponsor’s model, CADTH was unable to derive a reliable base-case estimation of the cost-effectiveness of lurbinectedin. Notably, the sponsor’s model predicts a survival benefit with lurbinectedin that has not been shown in clinical trials; further, the model predicts that the majority of the benefits of lurbinectedin are realized after patients discontinue treatment, which is not supported by data from clinical trials. In their analysis, the sponsor assumes that all patients receive lurbinectedin for four 21-day treatment cycles, which is not aligned with the monograph-recommended dosing and may underestimate drug acquisition costs. CADTH conducted an exploratory reanalysis to assess the effect of alternative extrapolation curves on PFS and OS; however, CADTH was unable to address critical limitations related to the absence of comparative clinical data in the pharmacoeconomic model or related to the structure of the sponsor’s model. Further, drug costs associated with lurbinectedin acquisition are likely underestimated, owing to the structure of the sponsor’s model.

The results of the CADTH exploratory analyses were consistent with those submitted by the sponsor: lurbinectedin is not cost-effective at a willingness-to-pay (WTP) threshold of $50,000 per QALY. Based on the CADTH exploratory analysis, a price reduction of at least 83% would be needed for lurbinectedin to be considered cost-effective at a WTP threshold of $50,000 per QALY, compared with the synthetic basket comparator derived by the sponsor from real-world data (SYNTH) (i.e., intended to reflect usual care for patients in Canada whose disease has progressed on or after platinum-based chemotherapy). However, this estimate is subject to the limitations discussed, including a lack of comparative clinical data and an underestimation of lurbinectedin acquisition costs. Additional uncertainty is introduced by the use of data from real-world clinical practice and from structured clinical trials. As such, a higher price reduction may be warranted.

CADTH notes that, among patients with platinum-resistant SCLC, lurbinectedin was less effective than the combination of cyclophosphamide, doxorubicin, and vincristine (CAV), and there is no price reduction that would make lurbinectedin cost-effective in this patient subgroup based on data submitted by the sponsor. In patients who have progressed on or after platinum-based chemotherapy, lurbinectedin is more costly than treatment with currently available comparators. There is no reliable information on the comparative clinical effects of lurbinectedin relative to any alternative treatment. As such, there is insufficient evidence to support a price premium over currently available treatments.

Stakeholder Input Relevant to the Economic Review

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

Patient input was received from the Lung Health Foundation and Lung Cancer Canada. The Lung Health Foundation collected perspectives through an online survey (2 patients) and interviews (3 patients) with patients with lung cancer. Lung Cancer Canada collected perspectives through interviews (2 patients) and environmental scans. Patients had experience with surgery, radiation, chemotherapy, targeted therapy, and immunotherapy, and noted that the side effects related to currently available treatments affect their QoL and their ability to work and perform activities of daily living; such side effects included fatigue, nausea, vomiting, mood changes, diminished appetite, weight loss, hair loss, anemia, and neuropathy. Some respondents noted the financial burden related to the high cost of treatment and travel-related expenses (i.e., to receive treatment), and the need for caregivers to take time off work to provide care. Patients expressed a desire for a treatment that would stop or slow disease, be effective in managing symptoms, have manageable side effects, and allow them to maintain their independence and QoL. Patients who have used lurbinectedin reported side effects such as fatigue, headache, nausea, shortness of breath, and gastrointestinal issues.

Clinician input received from Lung Cancer Canada and the Ontario Health (Cancer Care Ontario) Lung Cancer Drug Advisory Committee indicated that currently available treatments for patients with relapsed SCLC include re-treatment with platinum plus etoposide (for those with platinum-sensitive disease), CAV, topotecan, palliative radiation, supportive care, or clinical trial drugs. Clinicians noted that existing treatments for patients with relapsed SCLC are associated with short PFS and OS. Adverse events (AEs) associated with currently available treatments include nausea and vomiting, neutropenia, thrombocytopenia, infection, mucositis, and fatigue, and clinicians noted that treatments with improved AE profiles are needed. Clinicians noted that tumour shrinkage, PFS, OS, and improved patient-reported symptoms and QoL are key goals of treatment. Clinicians indicated that a clinically meaningful response to treatment would include a reduction in tumour size and an improvement in disease-related symptoms. Clinicians noted that lurbinectedin may be used as a second-line or third-line treatment.

Participating drug plans noted considerations related to clinical evidence, relevant comparators, and potential implementation factors (e.g., drug wastage). The plans noted that the relevant comparators depend on whether relapsed disease is platinum-sensitive or platinum-resistant or -refractory. Plans noted that comparators for platinum-sensitive disease include cisplatin plus etoposide and carboplatin plus etoposide. For platinum-refractory disease, plans noted that the relevant comparators are CAV, topotecan, cisplatin plus irinotecan, and carboplatin plus irinotecan. The plans highlighted that the pivotal trial, B-005, is a single-arm trial, so no comparators were included. The plans noted that, based on the recommended dosage of lurbinectedin, drug wastage is anticipated, and additional pharmacy resources will be required to assess potential drug interactions with lurbinectedin. Plans noted that all chemotherapy comparators have existing confidential negotiated prices in place.

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

• Subgroup analyses were provided to assess the cost-effectiveness of lurbinectedin among patients with platinum-sensitive and platinum-resistant disease.

• The use of a cost-utility approach accounts for some issues related to QoL; however, it is unclear if all QoL concerns noted to be important to patients were captured in the health state utility values adopted by the sponsor. QoL was not assessed in the B-005 trial.

• Wastage was considered in the sponsor’s analysis.

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

• Some comparators identified as being relevant by the drug plans (carboplatin or cisplatin plus irinotecan) could not be included, owing to a lack of clinical information and the structure of the sponsor’s model.

• Patients were assumed to discontinue lurbinectedin after 4 treatment cycles regardless of disease progression. This may underestimate drug costs.

Economic Review

The current review is for lurbinectedin (Zepzelca) for adults with SCLC who have received 1 prior chemotherapy-containing line of therapy.

Economic Evaluation

Summary of Sponsor’s Economic Evaluation

Overview

Lurbinectedin is indicated for the treatment of stage III or metastatic SCLC that has progressed on or after platinum-based chemotherapy in adult patients.¹ The sponsor submitted a cost-utility analysis (CUA) to assess the cost-effectiveness of lurbinectedin in this population and in 2 subgroups: patients without platinum-sensitive disease and patients with platinum-refractory disease.² The modelled population is consistent with the reimbursement request. In the full Health Canada–indicated population, lurbinectedin was compared to topotecan, CAV, and to 2 basket comparators: real-world evidence (RWE) comprised of topotecan, CAV, carboplatin plus etoposide, cisplatin plus etoposide, other platinum regimens, and other regimens; and SYNTH comprised of CAV, carboplatin plus etoposide, cisplatin plus etoposide, and other regimens. Among the platinum-sensitive patient subgroup, lurbinectedin was compared to topotecan, carboplatin plus etoposide, cisplatin plus etoposide, and carboplatin plus irinotecan. Among the platinum-refractory patient subgroup, lurbinectedin was compared to topotecan and CAV.

Lurbinectedin is available as a 4 mg vial, with a recommended dosage of 3.2 mg/m² by IV infusion once every 21 days, until disease progression or unacceptable toxicity.¹ At a submitted price of $6,470.00 per 4 mg vial, the 21-day drug cost of lurbinectedin was calculated by the sponsor to be $12,940. The drug costs of comparator regimens were as follows: CAV = $1,457; topotecan = $2,835; carboplatin plus etoposide = $1,360; cisplatin plus etoposide = $1,341; and carboplatin plus irinotecan = $1,326.

The clinical outcomes of interest were QALYs and life-years (LYs). The economic analysis was undertaken from the perspective of the publicly funded health care payer over a 25-year horizon. Discounting (1.5% per annum) was applied to both costs and outcomes. The sponsor assumed an inflation rate of 2.57%.

Model Structure

The sponsor submitted a partitioned survival model (PSM) that included 3 health states: Progression Free, Progressed Disease, and Death. The modelled time cycle was 1 month. The proportion of patients in the Progression-Free state, who moved to Progressed Disease or Death states at any time over the model’s time horizon was derived from nonmutually exclusive survival curves. All patients entered the model in the Progression-Free state. The proportion of patients in the Progressed Disease state was calculated as the proportion of patients alive (based on the OS curve) minus the proportion of patients alive and progression-free (based on the PFS curve). In the model, PFS was capped by OS. Patients in the Progression-Free state were assumed to receive treatment for a defined number of treatment cycles. After disease progression, 24% of patients were assumed to receive subsequent (i.e., third-line) treatment for 3 months. Disutility associated with AEs were assumed to last for 1 month.

Model Inputs

The modelled cohort’s characteristics were based on the B-005 trial (mean age = 60 years; 1.80 m² body surface area; 60% male). For lurbinectedin, PFS and OS data were obtained from the B-005 study, a single-arm, basket trial that enrolled 110 patients with SCLC. PFS and OS estimates for CAV, topotecan, carboplatin plus etoposide, cisplatin plus etoposide, and carboplatin plus irinotecan were obtained from the literature when available; otherwise, the sponsor assumed equivalence between treatments. For RWE and SYNTH, time to next treatment (as a proxy for PFS) and OS were derived from a retrospective cohort of SCLC patients in Alberta, from 2004 to 2019. The effectiveness of RWE was derived from 577 patients who received a systemic post–platinum-based treatment, and effectiveness of SYNTH was derived from a subset of 224 patients who additionally met the inclusion criteria of the B-005 study. The treatments included in the RWE and SYNTH baskets by the sponsor, and their relative frequencies, are shown in Appendix 3.

For lurbinectedin, Kaplan-Meier (KM) estimates of PFS and OS from the B-005 trial period were used to fit parametric survival curves to extrapolate the observed data beyond the trial period (piecewise model) (OS data were extrapolated from 42 months, PFS data were extrapolated from 19 months). Log-logistic distributions were adopted by the sponsor for lurbinectedin OS and PFS, whereas gamma distributions were adopted for OS and PFS for topotecan and CAV, with the choice between curves based on Akaike information criteria, Bayesian information criteria, and visual inspection. For RWE and SYNTH, KM estimates were used for OS and PFS without extrapolation.

Health state utility values were obtained for the progression-free state (on or off systemic treatment) and the Progressed Disease state from the literature,³ based on 5-Level EQ-5D data from a Canadian cohort of patients with advanced SCLC, valued using Canadian preference weights. The sponsor’s model included grade 3 and 4 AEs, with the prevalence of AEs and associated disutility values obtained from the literature.

The model included costs related to drug acquisition and administration, antiemetic treatments, febrile neutropenia prophylaxis, subsequent treatment after disease progression, AEs, health care resource use, and mortality costs. Drug acquisition costs for lurbinectedin were based on the sponsor’s submitted price, whereas the drug acquisition costs for comparators were obtained from a previous CADTH review.⁴ Each drug was assigned a risk of emesis (low, moderate, high) and febrile neutropenia (low, intermediate, high), with each risk level associated with a per-cycle treatment cost. Administration costs were assumed to be $223 per hour for drugs administered by IV infusion,⁵ with the duration of administration for each treatment obtained from Cancer Care Ontario and the literature. Total monthly treatment costs (includes drug acquisition costs, antiemetic and prophylactic febrile neutropenia costs, administration costs) included by the sponsor are as follows: lurbinectedin = $19,203; CAV = $3,701; carboplatin plus etoposide = $4,101; cisplatin plus etoposide = $4,719; carboplatin plus irinotecan = $4,214; topotecan = $6,392; RWE = $3,835; and SYNTH = $3,822. Subsequent treatment was assumed to consist of etoposide for 3 months. The cost of treating AEs was obtained from the Ontario Case Costing Initiative for hematologic and nonhematologic AEs. Health care resource use was assumed to include oncologist visits, imaging (CT, MRI, X-ray), and laboratory diagnostics, with the frequency of use assumed to vary depending on whether the patient was on treatment or under surveillance (stratified by limited-stage or extensive-stage disease) according to National Comprehensive Cancer Network guidelines.⁶ Mortality costs were assumed to include acute care and hospice care applied to the final 3 months of life.

Summary of Sponsor’s Economic Evaluation Results

All analyses were run probabilistically (5,000 iterations for the base-case and scenario analyses). The deterministic and probabilistic results were similar. The probabilistic findings are presented here. Additional results from the sponsor’s submitted economic evaluation base case are presented in Appendix 3.

The sponsor-provided base-case analyses were intended to reflect the B-005 trial population (including both platinum-sensitive and platinum-refractory patients), and subgroup analyses were intended to reflect platinum-sensitive and non–platinum-sensitive patients (hereafter referred to as resistant, which includes patients with platinum-resistant and platinum-refractory disease). As noted in the CADTH clinical review, the B-005 trial population includes platinum-sensitive (57.1%) and platinum-resistant patients (42.9%).

Base-Case Results

In the B-005 trial population, lurbinectedin was associated with estimated costs of $107,726 and QALYs gains of 0.67 over a 25-year time horizon (Table 3). Treatment with lurbinectedin was more costly and produced more QALYs than all comparators. Based on a sequential analysis, the incremental cost-effectiveness ratio (ICER) for lurbinectedin is $248,709 per QALY compared with CAV. At a WTP of $50,000 per QALY, the probability of lurbinectedin being considered the most likely cost-effective intervention was 0%.

Results were driven by the predicted differences in total LYs between lurbinectedin and comparators (incremental LYs versus CAV = 0.39 years) and increased drug acquisition costs associated with lurbinectedin (incremental costs versus CAV = $50,782). All QALYs were accrued during the B-005 trial period (i.e., none were accrued through extrapolation), and the sponsor’s model predicts that the majority (63%) of QALYs gained with lurbinectedin are accrued in the postprogression health state (i.e., after discontinuation of lurbinectedin treatment). Additional results from the sponsor’s submitted economic evaluation base case are presented in Appendix 3.

Table 3: Summary of the Sponsor’s Economic Evaluation Results — B-005 Trial Population