Reimbursement Review

Lurbinectedin (Zepzelca)

Sponsor: Jazz Pharmaceuticals Canada Inc.

Therapeutic area: Metastatic small cell lung cancer

What Is Small Cell Lung Cancer?

• Small cell lung cancer (SCLC) is a fast-growing type of lung cancer that predominantly affects people with a history of smoking tobacco. SCLC is classified as metastatic when the cancer cells have spread from the lungs to other parts of the body such as the brain, bones, or liver.

• In 2024, an estimated 32,100 Canadians were expected to be diagnosed with lung cancer, with SCLC accounting for 10% to 15% of these diagnoses.

What Are the Treatment Goals and Current Treatment Options for Metastatic SCLC?

• Prolonging survival, stopping or delaying disease progression, and maintaining quality of life with reduced symptoms are the most important outcomes for patients. As survival outcomes, measured as overall survival (OS) or progression-free survival (PFS), are not always available, overall response rate and duration of response (DoR) were also selected as relevant outcomes as they are considered to be surrogate outcomes for survival.

• Current treatment options for patients with stage III or metastatic SCLC that progressed during or after receiving platinum-containing therapy include rechallenging with platinum-based chemotherapy (if the progression occurred more than 3 months after the last platinum dose), topotecan, irinotecan with or without platinum-based chemotherapy, and combination treatment with cyclophosphamide, doxorubicin, and vincristine (CAV).

What Is Zepzelca and Why Did Canada’s Drug Agency Conduct This Review?

• Zepzelca is a drug that is administered by IV infusion. Health Canada has approved Zepzelca for the treatment of adult patients with stage III or metastatic SCLC “who have progressed” (term used in the source) on or after platinum-containing therapy.

• Canada's Drug Agency (CDA-AMC) reviewed Zepzelca to inform a recommendation to the participating public drug programs on whether Zepzelca should be reimbursed for the second-line treatment of adult patients with stage III or metastatic SCLC who have progressed on or after a platinum-containing therapy. The sponsor is seeking reimbursement for this patient population.

  • CDA-AMC has reviewed Zepzelca in 2023 and issued a recommendation not to reimburse. New, relevant evidence has since become available, and a time-limited recommendation (TLR) pathway has been established.

Considerations for a TLR

• A TLR is a recommendation by a CDA-AMC expert committee to publicly fund a drug or drug regimen for a certain period of time on the condition that the sponsor will conduct 1 or more clinical studies that address uncertainty with the clinical evidence. CDA-AMC will subsequently conduct a reassessment of the additional evidence and issue a final reimbursement recommendation within a defined period. Based on the preliminary assessment by CDA-AMC, Zepzelca meets the requirements to be considered by the expert committee for a TLR recommendation. This is because:

  • Zepzelca received a Notice of Compliance with conditions from Health Canada on September 29, 2021.

  • The planned phase III trial (the LAGOON study) is being conducted with the same target population as the reimbursement request, and the anticipated completion date of the trial is within 3 years of the expert committee meeting.

  • The sponsor has committed to filing a reassessment application with CDA-AMC in accordance with the time frames specified for TLR procedures.

  • The evidence generated in the planned phase III trial is expected to address the gaps in evidence identified by the expert committee.

How Did CDA-AMC Evaluate Zepzelca?

• Zepzelca for SCLC received a “do not reimburse” recommendation from the pan-Canadian Oncology Drug Review Expert Review Committee (pERC) in January 2023. This present review consists of a resubmission of Zepzelca for consideration through the TLR pathway. pERC will examine the previously submitted evidence as well as any new evidence submitted by the sponsor.

• CDA-AMC reviewed the clinical evidence on the beneficial and harmful effects of Zepzelca versus other treatments used in Canada for the treatment of adult patients with stage III or metastatic SCLC who have progressed on or after platinum-containing therapy, as well as the economic evidence. Cisplatin or carboplatin plus etoposide, topotecan, irinotecan with or without cisplatin or carboplatin, and CAV were considered relevant treatments for comparison with Zepzelca when reviewing the clinical evidence.

• CDA-AMC identified equity and ethical considerations relevant to Zepzelca and metastatic SCLC.

• The review was informed by materials submitted by the sponsor, which included clinical and economic evidence.

• The review was also informed by 1 patient group submission, 2 clinician group submissions in response to our call for input, and input from the participating public drug programs around issues that may impact their ability to implement a recommendation.

• Two medical oncologists, with representation from Atlantic Canada and British Columbia, were consulted as part of the review process.

What Were the Findings?

Clinical Evidence

• Studies included in the previous review, which remain unchanged according to the sponsor, and were therefore not reappraised in this current review, included 1 phase II trial (B-005) reporting on the efficacy and safety of Zepzelca and 3 indirect treatment comparisons (ITCs) comparing Zepzelca to a basket of second-line treatments (e.g., platinum rechallenge, platinum with etoposide, CAV, topotecan, or other), topotecan, and carboplatin plus etoposide. Evidence from the initial review was considered by the expert committee during their deliberations. The Executive Summary of the Clinical Review of the initial submission can be found in Appendix 3 of the Supplemental Material document.

• In the current report, CDA-AMC reviewed the following clinical evidence:

  • 1 new ITC of Zepzelca versus topotecan

  • 1 real-world observational study comparing Zepzelca with other second-line treatments.

• For the comparison of Zepzelca versus topotecan based on the ITC reviewed as part of this resubmission:

  • The effect of Zepzelca on OS, PFS, overall response rate, and DoR were too uncertain to determine any effects due to the unanchored naive comparison, generalizability concerns, and overlapping 95% confidence intervals (CIs).

• For the comparison of Zepzelca versus other second-line treatments (including platinum rechallenge, platinum with etoposide, topotecan, immunotherapy, and others) based on the real-world observational study:

  • Zepzelca may result in little to no difference in real-world response rate and real-world PFS at 6 months compared to other second-line treatments. The evidence is very uncertain due to wide CIs that include important benefit from either the sponsor’s drug or the comparison treatment, and due to the risk of bias.

  • All other results, including real-world DoR and results across chemotherapy-free interval stratifications, were too uncertain to determine any effects due to wide CIs or small sample sizes.

  • The clinical experts consulted for this review indicated that the data presented did not raise any new concerns about the safety profile of Zepzelca and that the observed adverse events were consistent with what is expected with the drug.

• Results from the ITC do not adequately address any of the gaps identified by pERC in the initial submission. The real-world observational study offered some comparative data on the efficacy and safety of Zepzelca versus a basket of relevant comparators in this setting, but most outcomes were too uncertain to determine and OS — the outcome most important to patients — was not reported.

• How Zepzelca impacts health-related quality of life, an outcome important to patients and clinicians, is still unknown. There is also no evidence to show how Zepzelca directly compares with CAV or irinotecan with or without platinum-based chemotherapy.

Economic Evidence

• Zepzelca is available as lyophilized powder for IV infusion (4 mg per vial). At the submitted price of $12,565.25 per vial, the per 28-day cycle cost of Zepzelca is expected to be $33,507 per patient (21-day cycle = $25,130), based on the Health Canada–recommended dosage.

• Key clinical efficacy data used in the economic analysis (PFS, OS) for Zepzelca was derived from the single-arm B-005 study. The 2023 CADTH Clinical Review reported that, although the evidence submitted by the sponsor indicates objective responses were observed in some patients, PFS and OS results could not be interpreted due to a lack of direct evidence for the relative efficacy of Zepzelca compared with other treatments in adult patients with stage III or metastatic SCLC. Though the sponsor submitted 1 new ITC and 1 real-world observational study as part of this resubmission, the data were not used in the economic model. The ITC was affected by methodological limitations that precluded determining any effects on the efficacy and safety of Zepzelca versus topotecan. Results from the real-world observational study suggest that treatment with Zepzelca may result in little to no difference in PFS at 6 months compared with other second-line treatments. Further, OS was not assessed in this real-world observational study. A number of internal and external validity concerns were identified by CDA-AMC (refer to the Clinical Review section). These concerns preclude the use of the ITC or the real-world observational study to inform decision-making regarding treatment with Zepzelca versus comparators.

• In the economic model, comparative clinical efficacy comparing Zepzelca with topotecan, CAV, real-world evidence (RWE), and synthetic comparators was based on naive comparisons between B-005 study data for Zepzelca versus published literature and RWE for all comparators. Because of these naive comparisons, it is not possible to determine if any observed differences in PFS or OS are due to the effect of treatment or due to bias or confounding. Consequently, the comparative effectiveness of Zepzelca and other currently available treatments is highly uncertain.

• Based on the submitted price for Zepzelca, which equates to $33,507 per patient per 28 days, Zepzelca is expected to increase health care system costs if reimbursed by public drug plans. However, there is insufficient evidence to suggest that Zepzelca provides greater health benefit to patients than topotecan, CAV, RWE, or synthetic comparators. If there are no differences in health outcomes between Zepzelca and comparators, then the total cost of Zepzelca to the health system should not exceed that of any comparator for the treatment of adult patients with stage III or metastatic SCLC who have progressed on or after platinum-containing therapy.

• CDA-AMC estimates that the budget impact of reimbursing Zepzelca for the indicated population will be approximately $98.8 million over the first 3 years of reimbursement compared to the amount currently spent on comparators, with an estimated expenditure of $107.3 million on Zepzelca over this period. The actual budget impact of reimbursing Zepzelca will depend on the number of treatment cycles received, the number of people eligible for treatment, and the uptake of Zepzelca.

Background

Introduction

Context for the Review

In 2022, the sponsor filed the initial submission for lurbinectedin (Zepzelca) for consideration by the pan-Canadian Oncology Drug Review Expert Review Committee (pERC). The reimbursement request was the same as the Health Canada indication, which is for the treatment of adult patients with stage III or metastatic small cell lung cancer (SCLC) “who have progressed” (term used in the source and retained throughout this report) on or after platinum-containing therapy. In 2023, pERC reviewed the initial submission and recommended that the public drug plans not reimburse lurbinectedin. The rationale included the following:

• The lack of a control group limited the interpretation of the results from the basket phase II trial (B-005) and led to uncertainty in the magnitude of any clinical benefit of treatment with lurbinectedin.

• Although submitted indirect treatment comparisons (ITCs) compared treatment with lurbinectedin versus IV topotecan, carboplatin plus etoposide, and a mixture of post–platinum-based systemic therapies in settings within Canada, the numerous limitations in the analyses meant that conclusions could not be drawn on the efficacy and safety of lurbinectedin versus relevant comparators.

• Health-related quality of life (HRQoL), an outcome that is important to patients, was not assessed in the B-005 trial. The effect on HRQoL of lurbinectedin treatment compared with other available treatments remains unknown.

• Patients identified a need for treatments that improve survival, delay disease progression, relieve cancer symptoms, minimize side effects, and maintain or improve quality of life, but pERC could not conclude from the trial and ITC evidence that lurbinectedin treatment meets any of these needs.

In the present resubmission, the sponsor changed the reimbursement request for lurbinectedin (refer to the project website) to focus only on second-line treatment and requested that the file be considered through the time-limited recommendation (TLR) pathway. The sponsor submitted the previously reviewed evidence as well as new evidence from real-world settings and an ITC to address gaps identified by pERC in the initial submission. The objectives of this report are as follows:

• Review and critically appraise the new evidence submitted by the sponsor on the beneficial and harmful effects of lurbinectedin, 3.2 mg/m² by IV infusion, in the second-line treatment of adult patients with stage III or metastatic SCLC who have progressed on or after a platinum-containing therapy. The focus is on comparing lurbinectedin to relevant comparators in clinical practice in Canada and identifying gaps in the new evidence. This focus is outlined in Table 1.

• Review and critically appraise the new economic information submitted by the sponsor, including a cost-effectiveness analysis and budget impact analysis. The focus of the Economic Review aligns with the scope of the Clinical Review, unless otherwise stated. For most reviews, a Canada’s Drug Agency (CDA-AMC) base case is developed, informed by clinical expert input, the available clinical evidence, and the best interpretation of the economic evidence based on the information provided by the sponsor.

• In addition to this report, the 2023 clinical report will be provided in order for pERC to consider the totality of the available evidence.

Table 1: Information on the Application Submitted for Review and the CDA-AMC Review

AE = adverse event; CAV = cyclophosphamide, doxorubicin, and vincristine; CDA-AMC = Canada's Drug Agency; DoR = duration of response; HRQoL = health-related quality of life; NOC = Notice of Compliance; NOC/c = Notice of Compliance with conditions; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; SAE = serious adverse event; SCLC = small cell lung cancer; WDAE = withdrawal due to adverse event.

^aThe economic review aligns with the scope of the clinical review, unless otherwise stated.

^bThese comparators align with those considered in the initial submission. The clinical experts consulted for this present review indicated that these comparators were still the most relevant in Canada.

^cThese outcomes were identified as being of particular importance to patients in the input received in the previous review. These outcomes were also identified as important by the patient and clinician groups consulted for this present review.

Considerations for a TLR

A TLR is a recommendation by a CDA-AMC expert committee to publicly fund a drug or drug regimen for a certain period of time on the condition that the sponsor will conduct 1 or more clinical studies that address uncertainty with the clinical evidence. CDA‑AMC will subsequently conduct a reassessment of the additional evidence and issue a final reimbursement recommendation within a defined period of time. Based on the preliminary assessment (in Appendix 1 of the Supplemental Material document), lurbinectedin meets the criteria to be considered by the expert committee for a time-limited reimbursement recommendation. In brief:

• Lurbinectedin received a Notice of Compliance with conditions from Health Canada on September 29, 2021.

• The planned phase III trial (the LAGOON study) is being conducted with the same target population as the reimbursement request, and the anticipated completion date is within 3 years of the expert committee meeting.

• The sponsor has committed to filing a reassessment application with CDA-AMC in accordance with the time frames specified for TLR procedures (i.e., within 270 calendar days after the completion date of the phase III trial).

• The evidence generated in the planned phase III trial is expected to address the gaps in evidence identified by pERC.

Submission History for the Drug Under Review

CDA-AMC has not reviewed lurbinectedin for other indications through the Reimbursement Review process.

Sources of Information

The contents of the Reimbursement Review report are informed by materials submitted by the sponsor, input from interested parties (patient groups, clinician groups, and drug programs), and input from clinical experts consulted for this review.

Calls for patient group and clinician group input are issued for each Reimbursement Review. One joint patient group submission from Lung Cancer Canada (LCC), Lung Health Foundation, and Canadian Cancer Survivor Network was received. Two clinician group submissions from the Ontario Health (Cancer Care Ontario) Lung and Thoracic Cancer Drug Advisory Committee (Lung DAC) and the LCC Medical Advisory Committee (MAC) were received. The same 2 clinician groups provided input in the previous review of lurbinectedin. The patient group submission gathered information through interviews with 3 patients who were receiving or had recently received treatment with lurbinectedin, testimonies from 5 patients and caregivers who provided input for the initial submission, input from caregivers, and a cross-Canada survey including 5 respondents (7% of 75 respondents) with extensive or metastatic SCLC that had progressed after platinum-based chemotherapy. Lung DAC gathered information for their submission via email correspondence (n = 5 clinicians), whereas the LCC MAC submission was based on publicly available sources, such as published manuscripts and conference presentations, and the clinical experiences of LCC MAC members (n = 19 clinicians). The full submissions received for this resubmission are available on the project landing page in the consolidated input document. The drug programs provide input on each drug being reviewed through the Reimbursement Review process by identifying issues that may impact their ability to implement a recommendation.

Input from patient and clinician groups is considered throughout the review, including in the selection of outcomes to include in the Clinical Review and in the interpretation of the clinical and economic evidence. Relevant patient and clinician group input is summarized in the Disease Background, Current Management, and Unmet Needs and Existing Challenges sections.

Each review team includes at least 1 clinical expert 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. Two medical oncologists with expertise in the diagnosis and management of SCLC participated as part of the review team, with representation from Atlantic Canada and British Columbia.

Disease Background

In 2024 alone, doctors were expected to diagnose an estimated 32,100 cases of lung cancer in Canada, and the disease was projected to cause around 20,700 deaths — making lung cancer the most commonly diagnosed cancer and leading cause of cancer-related deaths in Canada.¹ Lung cancer predominantly affects older adults, with 98% of cases occurring in individuals aged 50 years and older.² SCLC accounts for 10% to 15% of all lung cancers.¹ It is characterized by rapid growth, early dissemination, and high rates of acquired drug resistance.¹ Smoking tobacco is the strongest risk factor for SCLC and contributes to most of the SCLC diagnoses.¹

SCLC is classically staged into limited stage (LS), which means the cancer is confined to 1 hemithorax that can be encompassed into a single radiation field, and extensive stage (ES), which means the cancer has spread beyond the boundaries of LS disease.³ In most patients, LS disease is stage III and ES disease is stage IV (metastatic).⁴ Metastatic SCLC means the cancer has spread to other parts of the body.³ Approximately two-thirds of patients present with metastatic ES disease, and the median survival of patients with ES SCLC is 7 to 11 months.^1,4,5 Following relapse, outcomes remain poor with a median survival of 1 to 8 months.⁶

The initial symptoms of SCLC are nonspecific and include cough, chest pain, trouble breathing, wheezing, hoarseness, loss of appetite, weight loss, and fatigue.⁷ According to the clinical experts consulted by CDA-AMC for this review, following development of symptoms or an abnormal chest X-ray, patients are referred to a cancer centre or peripheral hospital where, based on biopsy and imaging findings, SCLC is diagnosed by a team of specialists (pulmonologist, medical oncologist, radiation oncologist, pathologist, radiologist, and thoracic surgeon).

Patient group input: Patients highlighted the physical burden of the disease, which includes fatigue, breathlessness, persistent cough, pain, nausea, and rapid functional decline. The impact of late diagnosis, worry about disease progression, and distress regarding the limited treatment options available contribute to the emotional burden of SCLC. Patients highlighted the impact on families, with family members often taking on full-time caregiving roles, as well as the lack of independence for patients who rely on others for their daily tasks and struggle to maintain employment. This input aligns with the initial submission for lurbinectedin.

Current Management

Treatment Goals

Patient group input: Patients emphasised that, in addition to improving survival by stopping or delaying disease progression, managing side effects (like fatigue and trouble breathing) and maintaining quality of life are important outcomes. Patients considered it important to be able to preserve independence in terms of engaging in everyday activities such as driving, shopping, cooking, and working. Limiting time spent away from home and family and fewer hospital visits for treatment were also important to patients. These treatment goals were consistent with the initial submission for lurbinectedin.

Clinician input: The clinical experts consulted for this review and the clinician groups agreed that the most important treatment goals for adult patients with SCLC that progressed during or after platinum-containing therapy and who are ineligible for treatments with curative intent are to delay disease progression and prolong survival while maintaining a high quality of life with improved symptoms. These goals align with those identified as most important in the initial submission for lurbinectedin.

Current Treatment Options

The choice of SCLC treatment depends on the stage of the disease, patients’ overall health, and personal preferences.⁵ In rare cases, first-line treatment options for LS SCLC may include surgery with or without adjuvant chemotherapy and radiation (typically for patients with stage I to IIA disease).^3,5,8 Some of these patients may go on to receive prophylactic cranial irradiation to prevent the spread of cancer to the brain.^3,8 According to the clinical experts consulted for this review, the more common first-line treatment for patients with LS (including stage III) SCLC is 4 to 6 cycles of platinum-based chemotherapy (cisplatin or carboplatin) with radiotherapy given during the first cycle.^3,5,8 Immunotherapy (durvalumab) may be offered for 2 years following the completion of at least 4 cycles of first-line platinum-based chemoradiotherapy.^3,5,8 First-line treatment for patients with ES SCLC is platinum-based chemotherapy (cisplatin or carboplatin) plus etoposide for 4 to 6 cycles with an immunotherapy drug (durvalumab or atezolizumab) starting in the first or second cycle and continuing until progression.^3,5,8,9

The choice of second-line treatment options typically depends on the chemotherapy-free interval (CTFI) since the last dose of platinum in first-line treatment. If disease progression occurs more than 3 months after the last platinum dose, rechallenging with platinum-based chemotherapy with or without etoposide is typically the preferred second-line treatment option.^3,8,9 If progression occurs within 3 months of the last platinum dose, second-line treatment options include:^3,9

• topotecan

• irinotecan with or without platinum-based chemotherapy

• combination treatment with cyclophosphamide, doxorubicin, and vincristine (CAV).

Ontario Health (Cancer Care Ontario) guidelines now support the use of lurbinectedin for second-line treatment in both patients with a CTFI of less than 90 days and in patients with a CTFI of 90 days and longer.⁹ The Canadian Consensus Recommendations on the Management of Extensive-Stage Small-Cell Lung Cancer indicate that lurbinectedin could be considered for second-line treatment in patients with ES SCLC who experience disease progression on or within 3 months of completing first-line chemotherapy.¹⁰

Key characteristics of lurbinectedin and other second-line treatments available for stage III or metastatic SCLC are summarized in the Supplemental Material document (available on the project landing page), in Table 2, Appendix 2.

Unmet Needs and Existing Challenges

Patient group input: Patients noted that although current chemotherapy regimens can provide short-term disease control, they are harsh treatments that do not control disease for long and are associated with heavy side effects. Patients describe current treatments as exhausting, with recurrent nausea and fatigue, which have a big impact on a person’s independence, including the ability to maintain employment and perform activities of daily living. Radiation can also be painful, and nausea can last for weeks after treatment. Patients noted that there are few treatments available after first-line immunotherapy (atezolizumab) alongside chemotherapy. Patients and their families agree that harsh treatments with poor outcomes can leave them feeling hopeless and that there is a need for more safe, tolerable, and effective second-line options. These sentiments were echoed in the first submission for lurbinectedin. The patients providing input for this submission stated that only the results from the B-005 trial showed particularly meaningful results in the treatment of this aggressive and treatment-resistant disease. Patients with experience with lurbinectedin indicated that the treatment addressed some of the unmet needs in terms of disease response, manageable side effects, and ability to perform daily activities.

Clinician input: The clinical experts consulted for this review and clinician group input agreed that while patients with stage III or metastatic SCLC manifest rapid responses to first-line chemotherapy, these responses are not sustained. Clinicians indicated that, following relapse, patients often have SCLC that is refractory to currently available second-line treatment options, which are associated with common and severe adverse events (AEs) and are inconvenient for patients (i.e., require frequent visits to clinics and sometimes inpatient admissions for treatment), and that brain and bone metastases remain common. The experts noted that there remains a substantial unmet need for a well-tolerated (i.e., low toxicity), convenient, and effective drug in the second-line SCLC treatment setting. These unmet needs align with those identified in the initial submission.

Considerations for Using the Drug Under Review

Contents within this section have been informed by input from the clinical experts consulted for this review and from clinician groups. The implementation questions from the public drug programs and corresponding responses from the clinical experts consulted for this review are summarized in Table 3, Appendix 2 of the Supplemental Material document available on the project landing page. The following has been summarized by the review team.

Place in Therapy

The clinical experts consulted for this review and the clinician groups indicated that lurbinectedin would offer an alternative second- and third-line treatment option for patients with SCLC following first-line platinum-containing chemotherapy. This aligns with the anticipated place in therapy from the initial submission. Third-line therapy is not included in the present reimbursement request.

For patients with a CTFI of less than 90 days, the clinical experts considered that second-line treatment with lurbinectedin would be preferable to treatment with topotecan, CAV, or irinotecan because of the reduced time burdens associated with lurbinectedin treatment and the improved toxicity profile. For patients with a CTFI of 90 days and longer, the experts indicated that the decision to treat with lurbinectedin versus rechallenging with platinum-based chemotherapies to be clinician-dependent and influenced by the progression-free interval, previous response to treatment, and patient preference.

Patient Population

The clinical experts consulted for this review stated that all patients with SCLC need more effective treatment options and that this is particularly necessary for those who are not candidates for rechallenge with platinum-based chemotherapy (including those with a CTFI of less than 3 months or disease progression on initial treatment). The clinical experts and LCC MAC considered that all patients with SCLC that progressed after platinum-based chemotherapy with or without immunotherapy and with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2 should be eligible for treatment with lurbinectedin. In contrast, Lung DAC indicated that only patients who are not candidates for rechallenge with platinum-based chemotherapy and etoposide should be considered for second-line treatment with lurbinectedin. The clinical experts indicate that some patients with an ECOG PS of 3 would be suitable for second-line treatment with lurbinectedin and that the decision to treat should be up to the treating clinician and the patient. All the experts stated that there was no known predictive biomarker.

As eligibility of treatment with lurbinectedin is contingent on receipt of first-line treatment, the clinical experts consulted for this review and the clinician groups noted that patients would already have received a diagnosis of SCLC and be under the care of a medical oncology team.

This patient population aligns with those identified in the initial submission.

Assessing the Response to Treatment

The clinical experts consulted for this review recommended that patients receive clinical evaluations and laboratory tests (such as complete blood count, creatinine) before each treatment to assess the safety, tolerability, and response to treatment. It was noted that in clinical practice, cross-sectional imaging (typically CT scans of the chest, abdomen, and pelvis, and MRI or CT of the brain) are usually performed every 2 to 3 months. The experts stated that a clinically meaningful response to treatment would entail at least 1 of the following: improvement in symptoms, maintained quality of life, or improvement in time to clinical deterioration. The clinical experts consulted for this review considered that if a patient has a clinical response to treatment with radiographic progression, they could continue treatment beyond progression and undergo more frequent scans with or without treatment of progressive disease. The clinician groups agreed that response to treatment would be assessed via clinical evaluations and imaging. The method and frequency of assessing response to treatment was similar in the initial submission.

Discontinuing Treatment

The clinical experts stated that lurbinectedin should be discontinued if there is clinical deterioration, intolerance, or upon the patients’ request. This aligned with the clinician group input and the input received in the initial submission.

Prescribing Considerations

According to the clinical experts consulted for this review, lurbinectedin should be administered in an outpatient setting and be ordered by a medical oncologist, which aligns with the prescribing conditions noted in the initial submission. Lung DAC considered that a pulmonologist trained in systemic therapy for lung malignancies could manage lurbinectedin administration.

Additional Considerations

One of the clinician groups, LCC MAC, noted that due to comorbidities and other patient factors (e.g., frequent smoking of tobacco) and prior IV treatments, eligible patients may require central venous access regardless of the regimen selected for second-line treatment.

Clinical Review

The objective of this clinical review report is to review and critically appraise new evidence submitted by the sponsor on the beneficial and harmful effects of lurbinectedin, 3.2 mg/m² IV infusion, for the treatment of adult patients with stage III or metastatic SCLC who have progressed on or after platinum-containing therapy. The focus will be placed on how new evidence addresses any gap(s) identified by pERC during the initial submission.

According to the sponsor, the previously reviewed pivotal trial and indirect evidence remain unchanged from the initial submission. The patient population in the previously reviewed pivotal trial aligns with the new reimbursement request (i.e., for the second-line treatment of patients with stage III or metastatic SCLC who have progressed on or after platinum-containing therapy). Consequently, no reappraisal of the evidence in the initial submission was conducted. The Executive Summary of the Clinical Review of the initial submission can be found in Appendix 3 of the Supplemental Material document.

The review team selected outcomes (and follow-up times) for review based on the initial submission, clinical expert input, and patient and clinician group input. Included outcomes are those considered relevant to expert committee deliberations, and they were selected in consultation with committee members. Outcomes considered important for this review included overall survival (OS), HRQoL, progression-free survival (PFS), overall response rate (ORR), duration of response (DoR), cancer symptoms, AEs, serious AEs, withdrawals due to AEs, mortality, and notable harms (myelosuppression, hepatotoxicity, peripheral neuropathy). OS and PFS were selected as they address the main treatment goals for SCLC. As these outcomes were not always reported, ORR and DoR were selected as they are considered important surrogate outcomes for OS. HRQoL, cancer symptoms, and harms are considered important to patients, according to patient and clinician input.

Given that this is a resubmission of a file that was reviewed before the adoption of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology by CDA-AMC, certainty of the new evidence will not be ascertained using this tool.

Clinical Evidence

Two studies submitted by the sponsor were deemed to potentially address the gaps identified by pERC in the initial review. These studies were included and appraised in this review. The studies included:

• 1 ITC,¹¹ and

• 1 real-world observational study addressing gaps in the evidence.¹²

One additional observational study assessing the efficacy and safety of lurbinectedin in the real world, the Jazz EMERGE 402 study, was submitted by the sponsor.¹³ The aim of this study was to evaluate the effects of treatment with lurbinectedin in the real-world setting. Like the B-005 trial in the initial submission, the Jazz EMERGE 402 study is a single-arm study and does not provide comparative evidence. It was therefore not appraised by the CDA-AMC review team in the context of this resubmission as it does not address any of the gaps identified by pERC.

Pivotal Trials

No new pivotal trials were submitted by the sponsor.

Long-Term Extension Studies

No long-term extension studies were submitted by the sponsor.

Indirect Evidence

In the initial submission, pERC noted the numerous limitations associated with the submitted ITCs, which meant that conclusions could not be drawn regarding the efficacy and safety of lurbinectedin versus relevant comparators. A new ITC was reviewed as part of this present resubmission to potentially address the gap in the evidence.

Description of the ITC

One published indirect external control study was submitted by the sponsor to determine the comparative effectiveness and safety of lurbinectedin versus topotecan for the treatment of patients with metastatic SCLC with disease progression after receiving platinum-containing therapy.¹¹ The included population was limited to patients with a CTFI of 30 days or more and no central nervous system (CNS) metastases.

Study Selection and Review Methods

Two trials, the B-005 trial and the ATLANTIS trial, were selected to inform the indirect external control. No explanations of study selection methods, feasibility assessments, or data extraction methods were given. The same sponsor conducted both studies and had access to the full study dataset for each.

ITC Analysis Methods

Lurbinectedin and comparison groups were generated by applying 2 inclusion criteria from the selected studies to both of the studies because individual patient data (IPD) were available for both. These criteria were the requirement for a CTFI of at least 30 days in the ATLANTIS trial (already a requirement in the B-005 trial) and the exclusion of patients with CNS metastases in the B-005 trial (already a requirement in the ATLANTIS trial). No further adjustments were made for potential confounders (imbalances in prognostic factors or treatment-effect modifiers); thus, this was a naive comparison. Outcomes from the cohorts were then summarized.

Quality or risk of bias assessments of included studies were not performed by the sponsor.

Summary of Included Studies

Study Characteristics

Both trials were multicentre, open-label studies with adult patients with SCLC that progressed after treatment with a platinum-containing regimen.

The B-005 trial was a single-arm study assessing the efficacy and safety of lurbinectedin 3.2 mg/m² by IV infusion every 3 weeks (N = 105).

The ATLANTIS trial was a randomized controlled trial assessing the efficacy and safety of lurbinectedin and doxorubicin versus the physician’s choice of control therapy (CAV or topotecan). This phase III trial did not provide a direct comparison of lurbinectedin monotherapy versus topotecan, as the experimental arm was a combination of lurbinectedin at a reduced dose (2.0 mg/m²) and doxorubicin 40 mg/m². Topotecan was administered in the control arm (N = 122) by IV infusion daily on days 1 to 5 every 3 weeks at a dose of:

• 1.50 mg/m² in patients with calculated creatinine clearance greater than or equal to 60 mL/min

• 1.25 mg/m² in patients with calculated creatinine clearance of 40 to 59 mL/min

• 0.75 mg/m² in patients with calculated creatinine clearance of 30 and 39 mL/min.

Relevant outcomes included OS, PFS, ORR, DoR, and harms (AEs, AEs leading to dose reduction, AEs leading to treatment discontinuation, AEs leading to death). In both studies, all efficacy outcomes were confirmed according to investigator assessment; PFS, ORR, and DoR were also confirmed via an independent review committee (IRC). No assessment of the comparability of outcome definitions and time points was provided.

Patient Characteristics

Twenty-two patients were excluded from the B-005 trial due to a CTFI of less than 30 days (n = 21) and treatment with CNS metastases present at baseline (protocol deviation; n = 1). In the topotecan arm of the ATLANTIS trial, 24 patients were excluded due to a CTFI of less than 30 days (protocol deviation; n = 1), CNS metastases (n = 22), and randomized to receive topotecan but treated with lurbinectedin plus doxorubicin (major protocol deviation; n = 1).

A summary of the baseline characteristics of the ITC populations is provided in Table 2. Notable differences included a higher percentage of patients in the ATLANTIS ITC population:

• identifying as white (89.8% versus 79.5% in the B-005 ITC population)

• with bulky disease (36.7% versus 27.7% in the B-005 ITC population)

• with stable disease following platinum-based therapy (21.4% versus 14.5% in the B-005 ITC population).

A higher percentage of patients in the B-005 ITC population had:

• ES SCLC (100% versus 87.8% in the ATLANTIS ITC population)

• lymph nodes (80.7% versus 70.4% in the ATLANTIS ITC population)

• partial response to platinum-based therapy (73.5% versus 65.3% in the ATLANTIS ITC population)

• prior radiotherapy prophylactic cranial irradiation (69.9% versus 51.0% in the ATLANTIS ITC population).

Table 2: Summary of Baseline Characteristics Before and After Adjusting for ITC Inclusion Criteria

CTFI = chemotherapy-free interval; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ITC = indirect treatment comparison; NA = not applicable; ULN = upper limit of normal.

Note: Racial categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Source: Peters S, Trigo J, Besse B, et al. Lurbinectedin in patients with small cell lung cancer with chemotherapy-free interval ≥ 30 days and without central nervous metastases. Lung Cancer. 2024;188:107448. doi:10.1016/j.lungcan.2023.107448 Reprinted in accordance with Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0): https://creativecommons.org/licenses/by-nc-nd/4.0/

Critical Appraisal of the ITC

The most notable appraisal point of this ITC is the unanchored and naive nature of the comparison. The lack of a common comparator and failure to adjust for cohort differences result in a high risk of bias.

The selection of studies was likely based on the availability of IPD to the sponsor, which would affect the results due to selection bias. However, as the exact method for study selection was not provided, the potential bias is uncertain. Further, as no registered protocol was supplied by the sponsor, there is a risk that the reported results were selected from multiple analyses of the data (i.e., on the basis of a favourable direction and/or magnitude of effect).

The adjustment of the cohorts based on differences in inclusion criteria in the 2 trials was an acceptable first step. The clinical experts consulted for this review considered CTFI to be the most important variable to include in matching, which was considered in this ITC. However, 2 of the ITCs in the initial submission identified age, sex, ECOG PS, and disease stage as important treatment-effect modifiers, based on the literature. Failure to adjust for these measured differences and other known or unknown prognostic and treatment-effect modifiers increases the possibility of biased estimates, and observed differences in treatment effects may be driven by underlying patient characteristics rather than the treatment itself.

The experts noted that patients with CNS metastases and CTFI of less than 30 days typically have a worse prognosis. Consequently, the ITC likely overestimates the treatment effect compared to the population relevant to the reimbursement request. After applying the additional inclusion criteria to the study cohorts, the B-005 trial sample was reduced by 21% and the ATLANTIS trial sample by 20% from their original sizes. This raises concerns regarding the generalizability of results because the population in the ITC does not match the population of interest to this reimbursement request.

Despite the contributing trials being performed in similar geographic locations and periods of times, differences in baseline characteristics were observed. For example, a higher percentage of patients in the ATLANTIS-matched ITC population identified as white (89.8%) compared to the B-005 ITC population (79.5%). Although, the clinical experts considered that the differences between the treatment arms would not meaningfully influence the results in the indirect comparison, the amount of bias in results of unanchored ITCs is likely to be substantial. The National Institute for Health and Care Excellence (NICE) suggests methods to quantify the systematic error in unanchored ITCs that were not done for this ITC.¹⁴

The outcomes selected for the indirect comparison generally aligned with those deemed important by patient and clinician groups. One notable exception was HRQoL; although deemed important by patients and clinicians, it was not included in this indirect comparison because it was not appraised in the index trials.

No formal comparison of outcome definitions was provided across the trials. Based on a CDA-AMC review of the source publications, differences appear to exist in how partial response was defined — which affects both ORR and DoR. In addition, the time frame during which PFS was measured differed across the trials. In the ATLANTIS trial, PFS was measured from the date of randomization, while in the B-005 trial, it was measured from the date of first infusion. As no information was provided regarding any adjustments to account for these differences, it remains uncertain whether these discrepancies were addressed in the analysis.

Investigator-assessed outcomes are highly susceptible to bias when investigators know the treatment received, as in single-arm or open-label randomized controlled trials. This is because investigators are often optimistic about the investigational product, which can skew results. Therefore, when both investigator and IRC assessments are available, IRC outcomes are preferred because they are less prone to bias; IRCs are therefore the focus of this assessment.

While the point estimates of efficacy results appeared to favour the lurbinectedin group, all 95% confidence intervals (CIs) overlapped. Further, as no between-group effect estimates were reported, the precision of the observed effect could not be judged. While AEs appear to have occurred more frequently in the patients receiving topotecan, between-group effect estimates were also not reported for these outcomes, thereby limiting the ability to judge the precision of the observed effect.

Efficacy and Harms Results of the ITC

Key efficacy results of the ITC are presented in Table 3 and key harms results in Table 4.

Table 3: Summary of Efficacy Results From the B-005 (Lurbinectedin) and ATLANTIS (Topotecan) Trials in the ITC Population

CI = confidence interval; DoR = duration of response; IA = investigator assessment; IRC = independent review committee; ITC = indirect treatment comparison; ORR = overall response rate; OS = overall survival; PFS = progression-free survival.

Source: Peters S, Trigo J, Besse B, et al. Lurbinectedin in patients with small cell lung cancer with chemotherapy-free interval ≥ 30 days and without central nervous metastases. Lung Cancer. 2024;188:107448. doi:10.1016/j.lungcan.2023.107448 Reprinted in accordance with Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0): https://creativecommons.org/licenses/by-nc-nd/4.0/

Table 4: Summary of AEs From the B-005 (Lurbinectedin) and ATLANTIS (Topotecan) Trials in the ITC Population

AE = adverse event; ITC = indirect treatment comparison; NR = not reported.

^aPrimary growth colony-stimulating factor prophylaxis was mandatory in the ATLANTIS trial.

Source: Peters S, Trigo J, Besse B, et al. Lurbinectedin in patients with small cell lung cancer with chemotherapy-free interval ≥ 30 days and without central nervous metastases. Lung Cancer. 2024;188:107448. doi:10.1016/j.lungcan.2023.107448 Reprinted in accordance with Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0): https://creativecommons.org/licenses/by-nc-nd/4.0/

Studies Addressing Gaps in the Evidence

In the initial submission, pERC noted the lack of a control arm in the B-005 trial and numerous limitations associated with the submitted ITCs, which precluded reaching conclusions on the efficacy and safety of lurbinectedin versus relevant comparators. To address this gap, 1 new real-world observational study reporting on the comparative effectiveness and harms of second-line lurbinectedin treatment was included in this review and is summarized in this section.¹²

The sponsor submitted 1 additional single-arm observational study assessing the efficacy and safety of lurbinectedin in the real world.¹³ The efficacy and safety of lurbinectedin was established in the single-arm B-005 trial appraised by CDA-AMC during the initial submission. Further, pERC did not identify the performance of lurbinectedin in the real-world setting as a gap in the initial submission. Therefore, this single-arm real-world observational study was not included by the CDA-AMC review team in this resubmission.

Description of Studies

Study Characteristics

The aim of this retrospective observational real-world study was to evaluate clinical outcomes of lurbinectedin monotherapy and other second-line treatments in patients with previously treated ES SCLC, and conduct a subgroup analysis by platinum sensitivity status. Deidentified data from US-based electronic medical record (EMR)-derived Flatiron Health Enhanced Datamart were used. The Flatiron Health Enhanced Datamart is a curated real-world dataset from 260 outpatient cancer clinics in the US with diverse geography and payers. In addition to structured data such as diagnoses and laboratory values, the real-world study includes unstructured data such as information from physician notes and radiology and pathology reports that underwent manual review, facilitated by software, by trained human abstractors. An algorithm developed by the sponsor was used to determine line of therapy, rather than the established Flatiron Health algorithm.

Eligible patients were aged 18 years or older, with a histologically confirmed diagnosis of SCLC, who had started second-line treatment following disease progression during or after first-line platinum-based chemotherapy. Patients who received second-line lurbinectedin monotherapy between June 15, 2020 (the approval date for lurbinectedin in the US), and December 31, 2021, or a basket of other second-line treatments between March 18, 2019 (the approval date for atezolizumab for ES SCLC in the US), and December 31, 2021, were eligible for inclusion. Following the selection of patients, abstraction and curation of an additional 500 patients receiving lurbinectedin who were not previously included in the standard SCLC Flatiron Health Enhanced Datamart due to random sampling were added to the data. Patients who received investigational treatments in first- or second-line settings or had previously received lurbinectedin were excluded from the study. Patients with missing key covariates and outcomes data were excluded. Other exclusion criteria included gaps of greater than 120 days in structured clinical activity (as measured by medication administrations, vital visits, or lab results) from SCLC diagnosis to the index date, no radiographic evidence of disease progression before second-line treatment, and missing laboratory values in the 30 days before the initiation of second-line treatment.

The comparative evidence from the propensity score–weighted analysis provides information related to 1 of the gaps identified by pERC and is therefore the focus of this review.

Propensity score models were fitted via logistic regression using a list of covariates known at the study index date (start of observation for outcomes) deemed to be confounders a priori. The final covariates selected for the model were age, sex, race, practice type, ECOG PS, CTFI, stage, radiation, prophylactic cranial irradiation, time since last line and initial diagnosis, first-line treatment received (e.g., platinum with etoposide, topotecan monotherapy), and number of office visits. After the propensity score model was fitted and each patient was assigned a propensity score, overlap weighting was used. Each patient’s overlap weight represented the probability of receiving the opposite treatment on the index date. Scores near 0.5 made the largest contribution to the effect estimate; patients with propensity scores near 1 or 0 were down-weighted and made smaller contributions to the effect estimate. All efficacy and safety results were reported in the overall propensity score–weighted population and stratified by CTFI of less than 90 days and 90 days or longer. An additional analysis was performed in the cohort with a CTFI of 180 days or longer: the propensity score model was refitted with a smaller set of covariates (age, ECOG PS, stage at diagnosis, and type of treatment received in the first line [e.g., platinum with etoposide, topotecan monotherapy]) due to the smaller sample size.

All eligible patients were indexed on initiation of second-line treatment and included in this study. The baseline period, defined as the time between initial SCLC diagnosis and the index date, was used to leverage all available baseline data. The follow-up period was outcome-specific and defined separately for each outcome as the time from the index date (inclusive) until:

• the occurrence of the outcome

• the end of the study period (March 31, 2022)

• a gap in structured clinical activity (as measured by vital visits, medication administrations, and lab results) greater than 90 days

• death

• the start of third-line treatment (for response rate, DoR, and safety outcomes only).

The following efficacy outcomes were assessed and are relevant for this review:

• Real-world PFS (rwPFS), defined as the time from the initiation of second-line treatment until the first occurrence of documented disease progression or death, as determined by EMR review.

• Real-world response rate (rwRR), defined as the proportion of patients with a best overall response of complete response or partial response to second-line treatment. Response was assessed 29 days after the index day until censoring.

• Real-world DoR (rwDoR), defined as the time from first complete or partial response until the first documented progressive disease event. DoR was assessed from the index date until censoring.

• Safety assessments included the proportion of patients with adverse events of special interest (AESIs) and the frequency of outpatient visits (all cancer treatment-related visits). AESIs included febrile neutropenia, neutropenia, anemia, and thrombocytopenia. AESIs were assessed using laboratory values, except for febrile neutropenia, which was curated via chart abstraction.

Descriptive statistics (counts and percentages) were used for analyses of binary or categorical variables, as well as continuous variables (mean, standard deviation [SD], median, 95% CI, and interquartile range). Kaplan-Meier methods were used to estimate the rwPFS during the follow-up period and hazard ratios (HRs) were assessed using the Cox proportional hazards model. RwRR was assessed in each treatment group and was presented as a percentage, accompanied by the relative risk and a 95% CI.

Baseline Characteristics

Baseline characteristics for the overall population are presented in Table 5 and by CTFI in Appendix 8 of the Supplemental Material document.

After propensity score–overlap weighting, the baseline demographics and characteristics of the overall population were well-balanced across the treatment groups. Of the patients in both groups:

• About half were male (51.0% in both groups).

• About half had an ECOG PS of 1 (53.1% in both groups).

• Most had been diagnosed with ES SCLC (78.7% in both groups).

• Less than half had a CTFI of 90 to less than 180 days (42.2% in both groups).

• Most had received immunotherapy as first-line treatment (77.0% in both groups).

Table 5: Baseline Characteristics From the Flatiron Health 2025 Study

BMI = body mass index; CTFI = chemotherapy-free interval; ECOG PS = Eastern Cooperative Oncology Group Performance Status; IQR = interquartile range; SCLC = small cell lung cancer.

^aAll numbers are weighted values and do not represent the numbers of individual patients.

^bBMI calculated as weight (in kilograms) divided by height (in metres).²

^cECOG PS assessed as the most recently recorded value from 30 days before index date through index date (inclusive).

^dCTFI calculated as time in days from last administration of platinum in first-line treatment before disease progression (exclusive) to disease progression (inclusive).

^eUpfront refers to first course of treatment after initial diagnosis of SCLC.

Source: Flatiron Health, 2025 Clinical Study Report.¹⁵

Exposure to Study Treatments

Not reported.

Critical Appraisal

Internal Validity

The Guidance for Reporting Real-World Evidence outlines the foundations for the transparent reporting of real-world evidence (RWE) studies; adherence facilitates appraisal by CDA-AMC.^16,17 However, this study did not provide the following, which hindered the CDA-AMC appraisal: the justification for the generalizability of US data to the context in Canada; the decisions behind the selection of potentially confounding variables; the selection of study participants (in addition to random sampling); the quality of the data specifications (access, cleaning, curation, expected completeness of mortality data at time of analysis); and a data dictionary to provide information on the validity of relevant variables. The Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool and the Appraisal of Potential for Bias in Real-World Evidence Studies (APPRAISE) tool were used to guide the critical appraisal.^18,19

The objective of this RWE study was to describe treatment patterns, effectiveness, and safety of lurbinectedin as second-line therapy; it was not designed to make causal inferences regarding comparative effectiveness or to assess noninferiority.

The time periods studied for lurbinectedin and comparisons were sufficiently contemporaneous to avoid bias due to changes in standard of care. The effectiveness outcomes (rwPFS, rwRR, and rwDoR) and safety measures were clinically relevant, and the methods used to derive these outcomes from EMR-derived data were reasonable given the constraints of real-world data. The study did not use Response Evaluation Criteria in Solid Tumours (RECIST) criteria to define tumour response, and the clinicians assessing patients were not blinded to treatment; thus the study may be subject to variability and subjectivity, although it is unknown whether this would bias the findings in a specific direction.

Potential confounding was addressed using propensity score–overlap weighting, an accepted method. The clinical experts confirmed that the covariates included for the full analysis were appropriate and identified no omissions. However, residual confounding from unmeasured factors may remain, and could produce results driven by those factors rather than true differences in treatment effects. Excluding patients with missing covariates could also bias results if data were not missing at random. For the subgroup with CTFI of 180 days or more, a reduced covariate set was used due to the small sample size, which increases the risk of residual confounding and biased results.

More patients were censored due to study completion in the lurbinectedin weighted cohort than in the comparison cohort (Table 6). The comparison cohort also had an enrolment period about 10 months longer. Without information on the duration of treatment exposure in each group, it is difficult to determine whether the differences in progression events reflect bias from varying enrolment periods or in the timing of enrolment relative to study completion.

The study is at risk of selection bias. While it was appropriate to obtain a random sample of patients with SCLC from Flatiron Health and may be appropriate to enrich this sample with an additional 500 patients receiving lurbinectedin when random sampling did not deliver sufficient numbers, no information was provided on how the additional patients were identified and it is not possible to assess whether systematic bias was introduced. After applying inclusion criteria, 65% of patients receiving lurbinectedin and 30% of patients receiving comparison treatment remained (Appendix 8 of the Supplemental Material document). While many exclusion criteria were reasonable, the differential impact indicates potential bias. Much of the loss was from missing response data or a mismatch between the sponsor’s and the Flatiron Health line of therapy designation (Table 6). Because the sponsor grouped reporting, the contribution from each criterion is unclear; however, the sponsor’s algorithm for determining line of therapy, which differed from the Flatiron Health algorithm, was a contributing factor and may have introduced systematic bias. By design, all the patients receiving lurbinectedin had curated response data, but only a portion of patients in the comparison group did; the curation criteria for the comparison group were not well-defined and were influenced by whether the line of therapy from the sponsor’s algorithm was concordant with the Flatiron Health line of therapy, which may have introduced systematic bias. Ensuring curated data for all comparator candidates may have avoided the differential exclusion of patients in the 2 cohorts. Information on excluded comparator candidates or sensitivity analyses may have reduced uncertainty.

Improving survival was identified as the most important treatment goal by patients and clinicians. The sponsor reports mortality as a composite in the rwPFS events and rwDoR outcome measures, but not on its own. The FDA suggests that tumour measures such as PFS and ORR can serve as surrogate end points for OS.²⁰ However, no correlation between OS and either rwPFS or rwRR has been established in the real-world setting, where the rigour of rwPFS measures lacks blinding or objective criteria such as RECIST. Thus it remains unknown if rwPFS or rwRR are valid surrogate end points for OS in this setting. In addition, there is a lag in updating death data in the Flatiron database. While the sponsor provided provided the results of sensitivity and specificity analyses of their mortality data, they did not identify what lag should be used to achieve the metrics provided (e.g., analysis 24 months after the last date of observation); nor did they explain the timing of the study in relation to the last day of observation in the study.^12,15 Therefore, the completeness of death data is unknown and it is not possible to assess whether this lack of completeness would bias the findings in a specific direction. No justification was given as to why mortality (OS) was not reported as an outcome outside the rwPFS and rwDoR composite end points or if the described timing issues would have been limiting factors in this situation.

External Validity

The clinical experts consulted by CDA-AMC indicated that the study population was generally comparable to the patients they would expect to see in practice in Canada, based on the reported baseline characteristics. However, they noted that the study included a higher-than-expected percentage of patients with CTFI of less than 90 days and a lower-than-expected percentage of patients receiving first-line immunotherapy compared to clinical practice in Canada, where more than an estimated 90% of patients would receive first-line immunotherapy (compared to 77% in the study).

The comparisons used were considered reasonable for the context in Canada. Although some treatments in the comparator arm, such as immunotherapy, are not typically used as second-line therapy in clinical practice in Canada, they were used in a relatively small percentage of patients in the comparator arm. The clinical experts noted that despite this difference, they considered the results generalizable to the context in Canada. Grouping multiple therapies into a single comparison category may obscure differences between individual treatments; however, clinical experts stated that there is clinical equipoise regarding the alternative therapies included.

The sponsor stated that due to the scarcity of SCLC data in Canada, they relied on US rather than Canadian data sources. A recent study of non–small-cell lung cancer suggested that survival estimates from US clinical practice may be appropriate for decision-making in Canada;²¹ however, there is no evidence supporting such a claim for SCLC. Further, patients in the Flatiron database are largely from community oncology settings, while oncology care in Canada is more centralized, with academic centres playing a larger role.²² Additional differences in health system structure, treatment availability, and supportive care may affect the generalizability of these findings to the context in Canada. The sponsor did not indicate whether obtaining Canadian data was considered or explain why a study could not be conducted in Canada.

Results

Efficacy

Efficacy results for the overall population are presented in Table 6 and by CTFI in Appendix 8 of the Supplemental Material document.

• The median rwPFS among patients receiving lurbinectedin was 2.7 months (95% CI, 2.3 months to 3.3 months) compared to 2.5 months (95% CI, 2.2 months to 3.0 months) among patients receiving other treatments; the HR was 0.9 (95% CI, 0.8 to 1.2). The between-group difference in the percentage of patients remaining progression-free at 6 months was 1.5% (95% CI, −6.1% to 9.1%). RwPFS was similar between treatment groups in patients with a CTFI of less than 90 days (HR = 1.0 [95% CI, 0.8 to 1.4]). Among patients with a CTFI of 90 days or longer and 180 days or longer, patients receiving lurbinectedin had a numerically longer median rwPFS than patients receiving other treatment (CTFI ≥ 90 days lurbinectedin median rwPFS = 3.6 [95% CI, 2.8 to 4.1], other treatments median rwPFS = 3.0 [95% CI, 2.4 to 3.8], HR = 0.9 [95% CI, 0.7 to 1.2]; CTFI ≥ 180 days lurbinectedin median rwPFS = 5.7 [95% CI, 4.0 to 6.8], other treatments median rwPFS = 3.6 [95% CI, 2.1 to 5.0], HR = 0.6 [95% CI, 0.4 to 1.1]).

• The rwRR was 30.9% among patients receiving lurbinectedin and 31.8% among patients receiving other treatments; the relative risk was 1.0 (95% CI, 0.7 to 1.3). The between-group difference in the percentage of patients achieving an overall response was −0.9% (95% CI, −9.4% to 7.6%). Among patients with a CTFI of less than 90 days, the rwRR was 20.5% in patients receiving lurbinectedin and 26.1% in patients receiving other treatments; relative risk of 0.8 (95% CI, 0.5 to 1.3). Among patients with a CTFI of 90 days or longer and 180 days or longer, a numerically higher percentage of patients receiving lurbinectedin had a response (CTFI ≥ 90 days relative risk = 1.1 [95% CI, 0.8 to 1.5]; CTFI ≥ 180 days relative risk = 1.3 [95% CI, 0.7 to 2.4]).

• The median rwDoR among patients receiving lurbinectedin was 4.8 months (95% CI, 4.2 months to 5.5 months) compared to 5.6 months (95% CI, 4.8 months to 6.2 months) among patients receiving other treatments; the HR was 1.5 (95% CI, 1.1 to 2.1). The between-group difference in the percentage of patients still responding to treatment at 6 months was −12.7% (95% CI, −28.4% to 3.0%). Similar results were observed across stratifications by CTFI (CTFI < 90 days HR = 1.6 [95% CI, 1.0 to 2.8], CTFI ≥ 90 days HR = 1.4 [95% CI, 1.0 to 2.2], and CTFI ≥ 180 days HR = 1.4 [95% CI, 0.7 to 2.8]).

Table 6: Summary of Key Efficacy Results From the Flatiron Health 2025 Study

CI = confidence interval; EMR = electronic medical record; rwDoR = real-world duration of response; rwPFS = real-world progression-free survival; rwRR = real-world response rate.

^aEMR-derived effectiveness end points were used.

^bAll numbers are weighted values and do not represent the numbers of individual patients.

^cEstimated using the Kaplan-Meier method.

^dAssessed using the Cox proportional hazards model.

^eDefined as patients with a best overall response of complete response or partial response to second-line therapy.

^fEstimated among patients with a best response of complete or partial response during second-line therapy (n = 74 in the lurbinectedin group and n = 68 in the other treatments group).

^gCensoring events include end of study period, 90-day gap in clinical activity, and start of new line of therapy. In the absence of an event (i.e., progressive disease event, death), patients were censored on the date of their last recorded evaluable response (complete response, partial response, stable disease).

^hCalculated using the log-log transformation.

Source: Flatiron Health, 2025 Clinical Study Report.¹⁵

Harms

Harms data are presented in Table 7.

• The percentage of patients with febrile neutropenia and grade 3 or greater neutropenia was similar among patients receiving lurbinectedin and patients receiving other treatments. This trend remains across all stratifications by CTFIs.

• The percentage of patients with grade 3 or greater thrombocytopenia and grade 3 or greater anemia was lower among patients receiving lurbinectedin than patients receiving other treatments. This trend remains across all stratifications by CTFIs.

• The mean number of outpatient visits per person-year of follow-up was lower among patients receiving lurbinectedin (21.4 [SD = 19.2]) than among patients receiving other second-line treatments (62.9 [SD = 70.8]), across all stratifications by CTFIs.

Table 7: Summary of Key Harms Results From the Flatiron Health 2025 Study — Overall Propensity Score Population and by CTFI

CTFI = chemotherapy-free interval; ECOG PS = Eastern Cooperative Oncology Group Performance Status; SD = standard deviation; SoW = sum of weights.

^aIncludes patients with a CTFI of 90 days and longer (including 180 days and longer).

^bThe propensity score model was refitted with a smaller set of covariates (age, ECOG PS, stage at diagnosis, and type of first-line treatment received [e.g., platinum with etoposide, topotecan monotherapy]) due to the smaller sample size.

^cAll numbers are weighted values and do not represent individual patients.

^dOutpatient visits were defined as a treatment visit at a clinic in the Flatiron Health network; a maximum of 1 treatment visit per day was counted.

Source: Flatiron Health, 2025 Clinical Study Report.¹⁵

Discussion

In the 2023 recommendation against the reimbursement of lurbinectedin for the treatment of adult patients with stage III or metastatic SCLC who have progressed on or after platinum-containing therapy, pERC noted the following limitations in the available evidence:

• The lack of a control group in the B-005 trial led to uncertainty in the magnitude of any clinical benefit with lurbinectedin.

• Limitations in the ITCs meant that conclusions could not be drawn on the efficacy and safety of lurbinectedin versus relevant comparators.

• Uncertainty in the effects on HRQoL of lurbinectedin versus other available treatments.

• The inability to conclude, based on evidence from the B-005 trial and the ITC, if lurbinectedin meets any of the needs identified by patients.

In this resubmission, the sponsor changed the reimbursement request to focus only on second-line treatment and submitted 1 new ITC and 1 new real-world observational study that provide new evidence on the comparative efficacy and safety of lurbinectedin. While these new studies potentially address some of the limitations identified by pERC, there is still no evidence on the effect on HRQoL of treatment with lurbinectedin.

Efficacy

The patient group input collected for this review highlighted that the key treatment goals for adults with SCLC that progressed during or after platinum-containing therapy are to improve survival, delay progression, manage side effects, and maintain quality of life. Time spent away from home and their families with fewer hospital visits for treatment were also important to patients. The ITC reviewed as part of this resubmission evaluated the effects of lurbinectedin compared to topotecan, while the real-world observational study evaluated lurbinectedin compared to a basket of other second-line treatments (including platinum therapy, platinum with etoposide, topotecan, immunotherapy, and others). Both studies evaluated the effect of lurbinectedin versus the comparator through the assessment of PFS, ORR, DoR, and harms. The ITC also assessed OS.

The ITC informing the comparison of lurbinectedin to topotecan was an unanchored naive comparison — which results in a high risk of bias — using IPD from the B-005 (lurbinectedin) and the ALTANTIS (topotecan) trials. To generate cohorts with greater similarity for comparison, patients with a CTFI of less than 30 days or with CNS metastases were excluded from both trials. However, this ITC did not adjust for known confounders identified in the initial submission. Failure to account for these and other prognostic or treatment-effect modifiers increases the risk of biased estimates, and observed differences in treatment effects may be driven by underlying patient characteristics rather than the treatment itself. Further, the exclusion of patients with a CTFI of less than 30 days or with CNS metastases limits the generalizability of results to the population of interest for this reimbursement request. Although differences in outcome definitions were identified across the trials, no information was provided on any adjustments to account for these discrepancies. Due to the limitations of this ITC, conclusions cannot be drawn on the efficacy and safety of lurbinectedin compared to topotecan.

In the retrospective observational study that used US-based EMR-derived data from Flatiron Health, second-line treatment with lurbinectedin monotherapy or other second-line treatments were evaluated. The patient population included adults with SCLC who had started second-line treatment after progression during or after first-line platinum-based chemotherapy, which aligns with the reimbursement request under review. According to the clinical experts consulted for this review, there were some generalizability concerns (e.g., some treatments in the comparator arm are not relevant to settings in Canada, more patients had a CTFI of less than 90 days, and fewer patients received immunotherapy as first-line treatment than would be expected in Canada), though the experts considered that the results from this study could still be applied to the context in Canada. Further, despite the lower rate of first-line immunotherapy treatment in the Flatiron Health study population (77% of patients) than in current clinical practice in Canada (more than 90%, according to the experts), this rate is substantially greater than in the B-005 trial, where only 7.6% of patients received first-line immunotherapy. Compared to other second-line treatments, treatment with lurbinectedin did not result in significant differences in rwRR and rwPFS at 6 months, but the results are very uncertain due to wide CIs that include benefit from either the sponsor’s drug or the comparison treatment, and risk of bias. All other results, including those stratified by CTFIs, were too uncertain to determine any effects due to wide CIs or small sample sizes. All results are at risk of bias due to the potential systematic exclusion of some patients.

Although no new data were submitted on the effects of lurbinectedin treatment on time spent away from home or frequency of hospital visits, the clinical experts consulted for this review suggested that the administration schedule of once every 21 days (which is less onerous than most traditional chemotherapy regimens in this setting) and safety profile are likely to improve outcomes.

Harms

As noted in the Efficacy section, no conclusions can be drawn from the ITC due to methodological limitations.

In the Flatiron Health real-world observational study, similar percentages of patients receiving lurbinectedin and patients receiving other second-line treatments had febrile neutropenia and grade 3 or greater neutropenia. The percentage of patients with grade 3 or greater thrombocytopenia and grade 3 or greater anemia was lower among patients receiving lurbinectedin than among patients receiving other treatments. The same trends were observed across all stratifications by CTFIs. The clinical experts consulted for this review considered that the data from the real-world observational study did not raise any new concerns about the safety profile of lurbinectedin and that the observed events, including lower rates of anemia and thrombocytopenia, were consistent with what is expected with the drug.

The product monograph indicates that patients treated with lurbinectedin should be monitored for myelosuppression and injection site reactions. The use of a central venous catheter to reduce the risk of extravasation with lurbinectedin should also be considered. Due to the risk of embryofetal toxicity, the product monograph advises that people use effective contraception during treatment with lurbinectedin to prevent pregnancy.

Ethics and Equity Considerations

SCLC is predominantly experienced by people with a history of smoking. This was reflected in the study populations in the B-005 trial, the reviewed ITC, and the Flatiron Health study, where more than 90% of patients currently or previously smoked. The clinical experts indicated that the strong association between SCLC and smoking has led to significant stigma, which can impact patient care and public perception of the disease. This may be exacerbated in systemically marginalized and equity-deserving populations, where tobacco use is disproportionately higher, potentially contributing to their increased risk of developing this disease. Even if lurbinectedin were recommended for public reimbursement, it is unlikely that the stigma associated with increased risk of SCLC in these systemically marginalized and equity-deserving populations will be addressed as these are broader challenges requiring systemic and policy-level interventions.²³

The populations in the reviewed ITC and the Flatiron Health study predominantly identified as white. The clinical experts consulted for this review suggested that this reflects the demographics of patients seen in clinical practice in Canada. This raises the question about whether the findings can be confidently extended to racialized people or to those less well-represented in populations with SCLC.

Patient groups highlighted that many patients have SCLC that is refractory to current second-line treatment options. Currently available treatments are also associated with toxicities leading to treatment withdrawal and lower chances of being declared fit enough to receive third-line therapies. Some treatments, such as topotecan, require frequent clinic visits, which can be burdensome for patients and caregivers. The consulted clinical experts indicated that the administration schedule and safety profile of lurbinectedin are likely to improve these outcomes, though there is currently no evidence to support this claim.

Other Considerations

In the initial submission for lurbinectedin, in 2022, the reimbursement request was the same as the Health Canada indication. In the present resubmission, the reimbursement request was narrowed to focus only on the use of lurbinectedin in the second-line setting. Beyond the generalizability concerns identified in the initial review, the CDA-AMC review team did not identify any additional generalizability concerns related to the population described in the changed reimbursement request and the studies initially reviewed.

Conclusion

In this resubmission for lurbinectedin, CDA-AMC reviewed 1 ITC and 1 real-world observational study that investigated the efficacy and safety of lurbinectedin compared to topotecan and to a basket of other second-line treatments, respectively. The methodological limitations in the ITC resulted in an inability to determine any effects on the efficacy and safety of lurbinectedin compared to topotecan. Results from the real-world observational study suggested that, compared to other second-line treatments, treatment with lurbinectedin may result in little to no differences in rwRR and rwPFS at 6 months, but the results are very uncertain due to wide CIs that include benefit from either the sponsor’s drug or the comparison treatment, and due to the risk of bias. All other results, including those stratified by CTFIs, were too uncertain to determine any effects due to wide CIs or small sample sizes. Further, OS — the most important outcome for patients and clinicians — was not assessed in this real-world observational study. The CDA-AMC review team acknowledges the value of evidence from observational studies that provides insights into the comparative effectiveness and safety of lurbinectedin versus other second-line treatments in a real-world setting. However, most of the evidence was subject to uncertainty due to low precision and a number of internal and external validity concerns. Therefore, most of the gaps identified by pERC in the initial review remain to be addressed. The new reimbursement request aligns with the inclusion criteria from the B-005 trial and ITCs submitted during the initial review. Consequently, the previously submitted evidence was not reappraised by the review team. The totality of the evidence will be presented to pERC for consideration through the TLR pathway.

Economic Review

Methods

The review team appraised the pharmacoeconomic evidence submitted by the sponsor on the cost-effectiveness and budget impact of lurbinectedin compared to other treatment regimens for the treatment of adult patients with stage III or metastatic SCLC who have progressed on or after platinum-containing therapy. The sponsor also submitted analyses that assessed the cost-effectiveness of lurbinectedin in the requested reimbursement population (i.e., for the second-line treatment of adult patients with stage III or metastatic SCLC who have progressed on or after platinum-containing therapy), which is narrower than the Health Canada indication.

Summary of the Submitted Economic Evaluation

The sponsor submitted a cost-utility analysis to estimate the cost-effectiveness of lurbinectedin from the perspective of a public health care payer in Canada over a lifetime horizon (25 years). The modelled population comprised adults with SCLC who have previously received 1 chemotherapy-containing line of therapy, which is narrower than the Health Canada indication and was based on the participants in the B-005 trial. The sponsor’s base-case analysis included costs related to drug acquisition, administration, subsequent treatment, health care resource use, AEs, and mortality.

In the sponsor’s base case, lurbinectedin was associated with incremental costs of $82,343 and 0.20 incremental quality-adjusted life-years (QALYs) relative to CAV. This resulted in an incremental cost-effectiveness ratio of $403,454 per QALY gained. Of the incremental benefit compared to CAV (0.20 incremental QALYs), all QALYs were accrued during the B-005 trial period (41 months). 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 information about the sponsor’s submission is summarized in Appendix 11 of the Supplemental Material document. Treatment with lurbinectedin was both more costly and produced more QALYs than all comparators, of which RWE, synthetic comparator (SYNTH), and CAV remained on the frontier.

CDA-AMC identified several key issues with the sponsor’s analysis (refer to Table 8; full details are provided in Appendix 12 of the Supplemental Material document).

Table 8: Key Issues With the Sponsor’s Economic Submission

CDA-AMC = Canada’s Drug Agency; OS = overall survival; PFS = progression-free survival; PSM = partitioned survival model; vs. = versus.

Note: Full details of the issues identified by CDA-AMC are provided in Supplemental Materials, Appendix 11.

CDA-AMC Assessment of Cost-Effectiveness

The 2023 CADTH Clinical Review of the single-arm B-005 study found that treatment with lurbinectedin resulted in objective responses in some patients that persisted for several months; however, 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. Though the sponsor submitted 1 new ITC and 1 real-world observational study as part of this resubmission, the data from these were not used in the economic model. The clinical review of the newly submitted ITC and real-world observational study determined the safety and efficacy of lurbinectedin compared with topotecan to be inconclusive due to methodological limitations. In addition, lurbinectedin may result in little to no difference in PFS at 6 months compared with other second-line treatments. Further, OS — the most important outcome for patients and clinicians — was not assessed in this real-world observational study. The internal and external validity concerns (i.e., wide CIs, small sample sizes, low precision, risk of confounding, and risk of bias) identified by CDA-AMC preclude the use of the ITC or the real-world observational study to inform decision-making regarding treatment with lurbinectedin versus the comparators.

Estimates of relative efficacy for the economic evaluation were based on naive comparisons of lurbinectedin versus published literature and RWE for all modelled comparators. The sponsor’s model predicts that the majority (63%) of QALYs gained with lurbinectedin treatment are accrued in the postprogression health state (i.e., after discontinuation of lurbinectedin), which is not supported by data from clinical trials. Because of the use of naive comparisons, it is not possible to determine if any observed differences in PFS or OS are due to the effect of treatment, bias, or confounding. Consequently, the incremental QALYs with lurbinectedin predicted by the submitted model are highly uncertain. Further, the sponsor assumed that all patients will receive lurbinectedin in 4 treatment cycles, regardless of disease progression or toxicity, which does not align with the Health Canada–recommended dosing strategy.²⁴ Based on these limitations, no definite conclusions could be drawn on the cost-effectiveness of lurbinectedin versus topotecan, CAV, RWE, and SYNTH for the second-line treatment of adult patients with stage III or metastatic SCLC who have progressed on or after platinum-containing therapy. No reanalyses were performed as there is insufficient evidence to reliably inform the incremental differences between lurbinectedin and relevant comparators. Lurbinectedin was associated with higher 28-day cycle drug acquisition costs compared to all other comparators (refer to Supplemental Materials, Appendix 9, Table 8).

Summary of the Budget Impact

The sponsor submitted a budget impact analysis to estimate the 3-year (2026 to 2028) budget impact of reimbursing lurbinectedin for use in the requested reimbursement population. The sponsor assumed that the payer would be CDA-AMC–participating public drug plans and derived the size of the eligible population using an epidemiologic approach. The price of lurbinectedin was aligned with the price included in the sponsor’s economic evaluation, while the prices of comparators were based on the publicly available list prices. Additional information pertaining to the sponsor’s submission is provided in Supplemental Materials, Appendix 13.

CDA-AMC identified a number of issues with the sponsor’s estimated budget impact and made changes to model parameters and assumptions in consultation with clinical experts to derive the CDA-AMC base case (Supplemental Materials, Appendix 13). CDA-AMC estimated that 1,353 patients would be eligible for lurbinectedin over a 3-year period (year 1 = 445; year 2 = 451; year 3 = 457), of whom 723 are expected to receive lurbinectedin (year 1 = 197; year 2 = 245; year 3 = 281). The estimated incremental budget impact of reimbursing lurbinectedin is predicted to be approximately $98.8 million over the first 3 years, with an expected expenditure of $107.3 million on lurbinectedin. The actual budget impact of reimbursing lurbinectedin will depend on the number of lurbinectedin treatment cycles received, the number of people eligible for treatment, and the uptake of lurbinectedin.

Conclusion

Estimates of relative efficacy for the economic evaluation were based on naive comparisons of lurbinectedin with topotecan, CAV, RWE, and SYNTH using published literature and RWE for all comparators. The sponsor’s model predicts that the majority (63%) of QALYs gained with lurbinectedin treatment are accrued in the postprogression health state (i.e., after discontinuation of lurbinectedin). This prediction is not supported by data from clinical trials. Due to the use of naive comparison, it is not possible to determine if any observed differences in PFS or OS are due to the effect of treatment or due to bias or confounding. Consequently, the incremental QALYs with lurbinectedin predicted by the submitted model are highly uncertain. Given the uncertainty in the comparative clinical evidence, there is insufficient evidence to determine whether lurbinectedin provides greater health benefit than any comparator. Lurbinectedin was associated with higher 28-day cycle drug acquisition costs than all other comparators (refer to Table 8 in the Supplemental Materials document, Appendix 9). If there are no differences in health outcomes between lurbinectedin and comparators, the total cost of lurbinectedin to the health system should not exceed that of any comparator used for the second-line treatment of adult patients with stage III or metastatic SCLC who have progressed on or after a platinum-containing therapy.

The budget impact of reimbursing lurbinectedin to the public drug plans in the first 3 years is estimated to be approximately $98.8 million. The 3-year expenditure on lurbinectedin (i.e., not accounting for current expenditure on comparators) is estimated to be $107.3 million. The estimated budget impact is uncertain due to the uncertainty in the number of lurbinectedin treatment cycles that will be received, the number of people eligible for treatment, and the uptake of lurbinectedin.

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