CADTH Reimbursement Review

Durvalumab (Imfinzi)

Sponsor: AstraZeneca Canada Inc.

Therapeutic area: Extensive-stage small cell lung cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Executive Summary

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

Introduction

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths in Canada.¹ Small cell lung cancer (SCLC) accounts for 12% to 15% of lung cancer cases.^2,3 Small cell lung cancer is characterized by a rapid growth rate, early metastasis to regional lymph nodes and/or distant sites, and an initial sensitivity to chemotherapy and radiotherapy.⁴ In Canada, the 5-year predicted net survival for SCLC is 7%.¹ Patients with tumour involvement that is more widespread in the lungs, and who may be diagnosed with malignant pleural or pericardial effusions or hematogenous metastases, are classified as having extensive-stage (ES) SCLC.⁴ Approximately two-thirds of SCLC patients have ES disease.³ According to the clinical experts consulted by CADTH, patients with ES-SCLC present as severely ill. A diagnosis of SCLC is made using a standard pathologic assessment of a tissue biopsy. Staging to determine whether the patient has ES-SCLC is done with radiology testing (e.g., CT, PET scan, bone scan, or brain MRI). The experts noted that patients who are diagnosed with SCLC are seen urgently by medical oncologists. All patients with ES-SCLC have a poor prognosis.

The clinical experts consulted by CADTH noted that current treatment options for ES-SCLC are limited and have not changed in 30 years. The vast majority of patients receive etoposide with either cisplatin or carboplatin (etoposide-platinum [EP] therapy) for 4 to 6 cycles as a first-line therapy. A small number of patients who are not candidates for platinum therapy or do not want to receive IV systemic therapy may be treated with oral etoposide. Although there is a high initial response rate to first-line treatment with EP therapy, most patients relapse within months. Patients derive limited benefit from second-line chemotherapy, and many patients are not well enough to receive second-line chemotherapy after relapse.

Durvalumab is a humanized immunoglobulin G1 (IgG1) kappa monoclonal antibody that selectively blocks the interaction of programmed cell death ligand 1 (PD-L1) with programmed cell death protein 1 (PD-1) and cluster of differentiation 80 (CD80).⁵ On September 21, 2020, durvalumab was approved by Health Canada for the first-line treatment of patients with ES-SCLC in combination with etoposide and either carboplatin or cisplatin.⁵ The reimbursement request for durvalumab by the sponsor is consistent with the Health Canada–approved indication. Durvalumab is available as a single-use vial and is administered as an IV infusion over 60 minutes.⁵ For the treatment of ES-SCLC in patients with a body weight of more than 30 kg, the recommended dosage is 1,500 mg in combination with etoposide and either carboplatin or cisplatin every 3 weeks for 4 cycles, followed by 1,500 mg every 4 weeks as monotherapy until disease progression or unacceptable toxicity. For patients with a body weight less than or equal to 30 kg, the recommended dosage is 20 mg/kg in combination with etoposide and either carboplatin or cisplatin every 3 weeks for 4 cycles, followed by 20 mg/kg every 4 weeks as monotherapy until disease progression or unacceptable toxicity.

The objective of the report is to perform a systematic review of the beneficial and harmful effects of durvalumab in combination with etoposide and either carboplatin or cisplatin for the first-line treatment of patients with ES-SCLC.

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

Patient Input

Two patient advocacy groups provide input regarding patients’ experiences, values, and preferences related to SCLC and its treatment: Lung Cancer Canada (LCC) and the Lung Health Foundation (LHF), previously known as the Ontario Lung Association. The LCC group is a registered national charity that focuses exclusively on lung cancer in Canada. The LHF is a registered charity that assists and empowers people living with or caring for others with lung disease, provides programs and services to patients and health care providers, invests in health research, and advocates for better policies on lung health.

According to the patient input received, a diagnosis of lung cancer and the subsequent treatment has a major impact on the life of the patient and their families. Many patients report issues with work, day-to-day chores, and socialization. Caregivers may need to take time off work to provide care, which affects work productivity and finances, and can cause mental stress. The emotional and physical toll during and after treatment may affect caregivers’ ability to fulfill their role in the family and at work and their ability to participate in activities they enjoy.

Key outcomes identified by the patient advocacy groups as important to patients include the following: control the cancer, improve symptoms, delay deterioration, have manageable side effects, be effective on the central nervous system, delay progression, extend survival with a good quality of life, and provide longer-lasting and durable treatment.

The patient groups reported poor numbers in terms of survival for ES-SCLC and a lack of treatment options. According to the patient input received, treatment for SCLC has not changed in the past 30 years, representing a significant unmet need.

Clinician Input

Input From Clinical Experts Consulted by CADTH

Input was provided by 2 clinical specialists with expertise in the diagnosis and management of ES-SCLC. The clinical experts consulted by CADTH indicated that there is a significant unmet need for a systemic therapy that can extend response to first-line treatment, prolong survival, and preserve the symptom and quality-of-life benefits.

The clinical experts indicated that they would administer durvalumab concurrently with first-line EP therapy, then as single-drug maintenance therapy. The clinical experts would offer durvalumab to all patients for whom EP therapy is planned, except for patients who have contraindications to immunotherapy (e.g., autoimmune disease, organ transplant recipient). The clinical experts stated that there are no known patient subgroups that would be more likely to benefit from durvalumab. No biomarkers or patient characteristics have been identified that can predict which patients are more likely to respond to durvalumab.

The clinical experts noted that treatment response in SCLC is assessed by physical examination, history of symptom burden, and serial radiography. The experts agreed that CT scans are usually made at the completion of 4 to 6 cycles of EP and then every 8 weeks to 12 weeks. Chest X-rays may also be taken more frequently between CT scans. The clinical experts agreed that they would discontinue durvalumab if a patient experienced disease progression, intolerable adverse events (AEs) or serious adverse events (SAEs), or the patient wishes to stop treatment.

The clinical experts consulted by CADTH emphasized that current treatment options for ES-SCLC are limited and have not changed in 30 years. The experts indicated that prolonged overall survival (OS) would be a clinically meaningful response to treatment. Delayed disease progression, reduced symptom burden, and improved Eastern Cooperative Oncology Group Performance Status (ECOG PS) are also clinically meaningful.

Clinician Group Input

Clinician group input was provided by Lung Cancer Canada and the Ontario Health Lung and Cancer Drug Advisory Committee. The views of the clinician groups were consistent with those of the clinical experts consulted by CADTH. Similar to the clinical experts consulted by the CADTH, the clinician groups reported that any improvement in the percentage of patients living beyond 18 months to 24 months is considered meaningful.

Drug Program Input

In response to the Drug Plan’s questions about administering durvalumab to patients in Canada, the clinical experts consulted by CADTH generally indicated that they would administer durvalumab according to the pivotal CASPIAN trial design and the product monograph. In response to questions regarding when to stop maintenance therapy with durvalumab, the clinical experts indicated that clinicians prefer to continue durvalumab maintenance therapy until a patient experiences disease progression, intolerable AEs or SAEs, or the patient wishes to stop treatment. The clinical experts indicated that it would be unlikely that patients would have difficulty tolerating 4 cycles of EP therapy when initiating treatment with durvalumab. If durvalumab was temporarily stopped due to an immune-mediated AE, the clinical experts agreed that it would be reasonable to restart durvalumab after the event had resolved. The clinical experts were not aware of evidence to support weight-based dosing of durvalumab in patients with ES-SCLC.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

The CASPIAN trial was an international multi-centre, phase III, open-label, randomized controlled trial (RCT) conducted to investigate the efficacy and safety of durvalumab, with or without tremelimumab, in combination with EP compared with EP alone as a first-line treatment regimen in adult patients with ES-SCLC (Figure 2). A total of 805 patients were randomized in a 1:1:1 ratio to 3 treatment arms: durvalumab with tremelimumab in combination with etoposide and either carboplatin or cisplatin (durvalumab + tremelimumab + EP), durvalumab in combination with etoposide and either carboplatin or cisplatin (durvalumab + EP), and etoposide and either carboplatin or cisplatin alone (EP). In the experimental treatment arms, patients received durvalumab, with or without tremelimumab, administered concurrently with first-line EP chemotherapy every 3 weeks for 4 cycles. After chemotherapy was completed, durvalumab was administered every 4 weeks as monotherapy until progressive disease (PD) was recorded. In the control arm, patients received 4 to 6 cycles of EP every 3 weeks and prophylactic cranial irradiation at the investigator's discretion. The type of platinum-based chemotherapy (cisplatin or carboplatin) used was the investigator’s choice. Randomization was stratified by the platinum-based chemotherapy planned for the first treatment cycle. The primary outcome was OS. Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and change in health-related quality of life (HRQoL) and symptoms as measured by 2 European Organisation for Research and Treatment of Cancer instruments: the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) version 3.0 and the 13-item Lung Cancer Quality of Life Questionnaire (QLQ-LC13).

Data for the durvalumab + tremelimumab + EP arm of the CASPIAN trial will not be presented in the systematic review because tremelimumab is not approved in Canada and the combination is not aligned with the Health Canada product monograph for durvalumab.

The CASPIAN trial enrolled adults with histologically or cytologically confirmed ES-SCLC who were suitable for platinum-based chemotherapy as first-line treatment. Brain metastases at baseline were allowed in the case of asymptomatic or treated and stable patients. Enrolment was limited to patients with an ECOG PS of 0 or 1. Most patients were male (71.6%), White (82.6%) smokers (93.5%) with a small cell carcinoma (combined) histology type (84.1%) and an ECOG PS of 1 (63.0%). The mean age of all patients was 62.6 years. Baseline characteristics were generally well balanced between the durvalumab + EP arm and the EP arm. A total of 7 patients (0.9%) had received previous chemotherapy and 27 (3.4%) had received previous radiotherapy.

A pre-specified interim analysis was planned for after approximately 318 OS events occurred between the durvalumab + EP and EP-alone arms (60% maturity).⁶ The interim analysis had a data cut-off date of March 11, 2019, at which point the OS data had reached 63% maturity (336 OS events from 537 patients) in the durvalumab + EP and EP-alone arms.⁶ The primary analysis of OS was planned to be carried out when approximately 425 OS events (80% maturity) were observed across the durvalumab + tremelimumab + EP arm and the EP-alone arm, and the durvalumab + EP arm and the EP-alone arm. The final analysis was conducted with a data cut-off date of January 27, 2020, at which point the OS data had reached 82% maturity (441 events from 537 patients) in the durvalumab + EP arm and the EP-alone arm.⁷

Efficacy Results

Efficacy results from the CASPIAN trial are summarized in Table 2.

The CASPIAN trial met its primary end point of OS at the pre-specified interim analysis (data cut-off date of March 11, 2019). Median OS was 13.0 months (95% confidence interval [CI], 11.5 to 14.8) in the durvalumab + EP arm compared to 10.3 months (95% CI, 9.3 to 11.2) in the EP arm (hazard ratio [HR] = 0.73; 95% CI, 0.59 to 0.91; P = 0.0047). There was a delay of approximately 6 months in separation of the Kaplan–Meier curves, and the associated log-log plot showed some evidence of non-proportionality of hazards. The post hoc Kaplan–Meier estimate of landmark OS at 12 months was 53.7% (95% CI, 47.4 to 59.5) in the durvalumab + EP arm compared to 39.8% (95% CI, 33.7 to 45.8) in the EP-alone arm. The pre-specified, exploratory subgroup analysis of OS showed that the treatment effect was consistent with the primary analysis across the patient subgroups of smoking status, baseline ECOG PS, and brain metastases at baseline.

As of the final analysis, the median OS was 12.9 months (95% CI, 11.3 to 14.7) in the durvalumab + EP arm compared to 10.5 months (95% CI, 9.3 to 11.2) months in the EP-alone arm (HR = 0.75; 95% CI, 0.625 to 0.910; nominal P = 0.0032). Kaplan–Meier curves are provided in Figure 5. The post hoc Kaplan–Meier estimate of landmark OS at 18 months was 32.0% (95% CI, 26.5 to 37.7) in the durvalumab + EP arm compared to 24.8% (95% CI, 19.7 to 30.1) in the EP-alone arm. The post hoc Kaplan–Meier estimate of landmark OS at 24 months was 22.2% (95% CI, 17.3 to 27.5) in the durvalumab + EP arm versus 14.4% (95% CI, 10.3 to 19.2) in the EP-alone arm.

As of the interim analysis, median PFS was 5.1 months (95% CI, 4.7 to 6.2) in the durvalumab + EP arm and 5.4 months (95% CI, 4.8 to 6.2) in the EP arm (HR = 0.78; 95% CI, 0.645 to 0.936; nominal P = 0.0078). There was a delay of approximately 6 months in separation of the curves, and the associated log-log plot showed some evidence of non-proportionality of hazards. Results from the pre-specified exploratory subgroup analysis of PFS showed that the treatment effect on PFS was consistent with the primary analysis across the patient subgroups of smoking status, baseline ECOG PS, and brain metastases at baseline.

As of the final analysis, median PFS was 5.1 months (95% CI, 4.7 to 6.2) in the durvalumab + EP arm and 5.4 months (95% CI, 4.8 to 6.2) in the EP-alone arm (HR = 0.80; 95% CI, 0.665 to 0.959; nominal P = 0.0157). The post hoc Kaplan–Meier estimate of landmark PFS at 18 months was 13.9% (95% CI, 10.0 to 18.4) in the durvalumab + EP arm compared to 3.4% (95% CI, 1.6 to 6.4) in the EP-alone arm. The landmark PFS at 24 months was 11.0% (95% CI, 7.5 to 15.2) in the durvalumab + EP arm versus 2.9% (95% CI, 1.2 to 5.8) in the EP-alone arm. The unconfirmed ORR was 79.5% and 70.6% in the durvalumab + EP and EP-alone arms, respectively (odds ratio [OR] = 1.61; 95% CI, 1.086 to 2.401; nominal P = 0.0177). The confirmed ORR was 67.9% and 58.0% in the durvalumab + EP and EP-alone arms, respectively (OR = 1.53; 95% CI, 1.078 to 2.185; nominal P = 0.0173). Duration of response was calculated post hoc in the subset of patients who had a confirmed response. At both the interim and final analyses, the Kaplan–Meier estimate of median confirmed DOR was 5.1 months (95% CI, 4.9 to 5.3) in the durvalumab + EP arm and 5.1 months (95% CI, 4.8 to 5.3) in the EP arm. The Kaplan–Meier estimates of the percentage of patients remaining in confirmed response at 24 months were 13.5% (95% CI, not reported) and 3.9% (95% CI, not reported) in the durvalumab + EP and EP-alone arms, respectively.

Health-related quality of life and symptoms assessed by the EORTC QLQ-C30 and QLQ-L13 scales were evaluated at the interim analysis.⁸ The EORTC QLQ-C30, which evaluates the quality of life of patients with cancer participating in clinical trials, consists of 5 functional scales, 3 symptom scales, and 6 single items. This instrument also includes global health status and overall quality of life. A higher score on a functional scale corresponds to a higher level of function, while a higher score in the symptom scale corresponds to a higher burden of symptoms.⁹ The QLQ-LC13 is a lung cancer–specific module that consists of lung cancer–related symptoms and treatment side effects.⁸

Median time to deterioration in global health status/quality of life was 8.4 months (95% CI, 7.3 to 11.5) in the durvalumab + EP arm compared to 7.2 months (95% CI, 6.3 to 9.0) in the EP arm (HR = 0.81; 95% CI, 0.626 to 1.054; nominal P = 0.1166). Time to deterioration analysis suggested that the addition of durvalumab to EP may be beneficial for function scales (physical, role, emotional, cognitive, and social) and the symptoms of dyspnea, insomnia, appetite loss, constipation, diarrhea, hemoptysis, chest pain, arm and/or shoulder pain, and other pain compared to EP alone.

The results from the mixed model for repeated measures (MMRM) analysis of EORTC QLQ-C30 and QLQ-LC13 key symptoms from baseline to PD or 12 months showed a statistically significant difference in appetite loss in favour of durvalumab + EP. The adjusted mean change from baseline in appetite loss score was −12.7 points in the durvalumab + EP arm, which is greater than the minimal important difference (MID), and the estimated difference between treatment arms was −4.5 points (95% CI, −9.04 to −0.04; P = 0.009). No statistically significant differences between treatment arms were observed for the symptoms of fatigue, cough, dyspnea, and chest pain.

Harms Results

Key harms reported in the CASPIAN trial as of the final analysis (data cut-off date January 27, 2020) are summarized in Table 2. A total of 260 patients (98.1%) in the durvalumab + EP arm and 258 patients (97.0%) in the EP arm experienced an AE. The most commonly reported AEs in the durvalumab + EP and EP-alone arms were neutropenia (41.9% and 46.6%, respectively), anemia (38.5% and 47.0%, respectively), nausea (33.6% and 33.5%, respectively), and alopecia (31.7% and 34.2%, respectively). Adverse events led to discontinuation of study treatment in 10.2% of patients in the durvalumab + EP arm and 9.4% of patients in the EP arm. Overall, 34% of patients in the durvalumab + EP and EP-alone arms of the CASPIAN trial experienced an SAE. A greater percentage of patients in the EP arm experienced an SAE compared to the durvalumab + EP arm (36.5% versus 32.1%, respectively). The most commonly reported SAEs in the durvalumab + EP and EP-alone arms were febrile neutropenia (4.5% and 4.5%, respectively), anemia (1.9% and 4.5%, respectively), pneumonia (2.3% and 3.4%, respectively), and thrombocytopenia (0.4% and 3.4%, respectively). As of the final analysis, 78.4% of patients in durvalumab + EP arm and 85.9% of patients in EP arm had died, with most deaths attributable to ES-SCLC.

Immune-related AEs were more frequent in the durvalumab + EP arm compared to the EP arm (53.2% versus 39.1%, respectively). The most commonly reported immune-related AEs in the durvalumab + EP arm were endocrine disorders (n = 75, 28.3%) and dermatitis/rash (n = 51, 19.2%). The most commonly reported immune-related AEs in the EP arm were diarrhea/colitis (n = 31, 11.7%) and dermatitis/rash (n = 25, 9.4%). A small number of patients in both treatment arms (durvalumab + EP and EP alone) experienced infusion-related reactions (1.9% and 1.1%, respectively) and hypersensitivity/anaphylactic reactions (1.1% and 0.8%, respectively). In the durvalumab + EP arm, 35.1% of patients experienced an infection compared to 30.8% of patients in the EP arm.

Critical Appraisal

The open-label design of the trial makes it prone to biases. The primary outcome of the CASPIAN trial, OS, is an objective outcome, and reporting of deaths is unlikely to be influenced. However, the way in which patients are treated throughout the study could be influenced by knowledge of treatment assignment and affect OS. The direction of this bias is unknown. Outcomes relying on investigator’s assessment (PFS, DOR, and ORR) may have been biased, but the direction of bias is unknown. The open-label design also may have affected AE reporting and patient-reported HRQoL and symptoms, but the direction of bias is unknown.

Subgroup analyses of OS and PFS (ECOG PS, smoking history, and brain metastases at baseline) were specified a priori. However, they were not adjusted for multiplicity and therefore considered exploratory. Treatment exposure was adequate to evaluate the safety and tolerability of durvalumab and EP, although there were high treatment discontinuation rates. There was extremely little loss to follow-up and patients were followed for survival for up to 2 years. Treatment groups were generally well balanced.

The interim analysis of the CASPIAN trial data was planned, and a multiple testing procedure was applied to control the overall type I error rate for OS and PFS at 5%. The CASPIAN trial met its primary end point for OS at the interim analysis. It was not possible to formally test PFS for statistical significance within the multiple testing procedure at either the interim or final analysis.

Four protocol amendments were implemented in the trial, including multiple changes to the primary objective and primary end points of the trial implemented after randomization of study patients was complete. Progression-free survival was originally a co-primary end point but was then changed to the key secondary end point. Blinded central review to determine PD for PFS was removed, and PD was then determined per investigator assessment. The changes in objectives and end points were accompanied by changes to the multiple testing procedure and alpha spending. The direction of the bias introduced by the protocol amendments is unclear.

Overall type I error was controlled for the MMRM analysis for 5 key symptoms assessed by the EORTC QLQ-C30 and QLQ-LC13. There was no adjustment for multiplicity for the other secondary efficacy outcomes (ORR, DOR, and time to deterioration in EORTC QLQ-C30 and QLQ-LC13 scores). Landmark OS, landmark PFS, and DOR were calculated post hoc. Interpretation of the HRQoL and symptom results was limited by the divergence in compliance rates between the treatment arms.

The enrolled study population is generally representative of Canadian patients with ES-SCLC, although there were some differences. Enrolment in the CASPIAN trial was limited to patients with an ECOG PS of 0 or 1, which does not reflect the Canadian ES-SCLC patient population, according to the clinical experts consulted by CADTH. The experts also noted that the study patient population included a greater proportion of non-smokers than is seen in Canadian clinical practice. The CASPIAN trial did not enroll any patients from Canada.

Indirect Comparisons

No indirect treatment comparisons were included in the sponsor’s submission to CADTH or identified in the literature search.

Other Relevant Evidence

No long-term extension studies or other relevant studies were included in the sponsor’s submission to CADTH.

Conclusions

One phase III, open-label, active-controlled RCT (CASPIAN) provided direct evidence regarding the efficacy and safety of durvalumab in combination with EP in adult patients with ES-SCLC relative to EP alone. Compared to patients treated with EP, those treated with durvalumab + EP showed benefits in OS. The difference in median OS between treatment arms (2.7 months) was considered statistically significant and clinically relevant by the clinical experts consulted by CADTH. The results suggest that the addition of durvalumab to EP was associated with an improvement in PFS compared to EP alone, but this finding is associated with substantial uncertainty because formal statistical testing was not possible due to the trial’s multiple testing procedure, evidence of non-proportionality of hazards, potential attrition bias, and introduction of bias by removing blinded independent central review after enrolment was complete. The effect of durvalumab on ORR and DOR is also uncertain due to the lack of control for multiplicity and that DOR was calculated post hoc in confirmed responders only when confirmation of response was not required by the study protocol. The results of the time to deterioration in HRQoL and symptoms suggest that durvalumab + EP may have a beneficial effect, but this remains uncertain due to a lack of control for multiplicity and differences between treatment arms in completion rates of the EORTC QLQ-C30 and QLQ-LC13. The results of the symptom analysis suggest that adding durvalumab to EP may have a benefit for appetite loss compared to EP alone. Almost all study participants reported treatment-emergent AEs. Durvalumab + EP was related to more immune-mediated AEs than was EP alone, although the profile and incidence rates of these AEs were expected, according to the clinical experts consulted by CADTH. Infusion-related and hypersensitivity/anaphylactic reactions were uncommon, and the incidence of infections was similar in both treatment arms.

Introduction

Disease Background

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths in Canada.¹ Survival from lung cancers of all stages and histologies is poor, with an overall 5-year net survival rate of 19%.¹ In 2020 alone, an estimated 29,800 new cases of lung cancer will be diagnosed and 21,200 deaths will be associated with lung cancer.¹ One in 17 Canadians is expected to die of lung cancer.¹⁰ Smoking remains the largest single risk factor for lung cancer, responsible for 90% of lung cancers in men and 80% of lung cancers in women in Canada.⁴ Lung cancer is classified into SCLC and non–small cell lung cancer (NSCLC). Small cell lung cancer accounts for 12% to 15% of lung cancer cases.^2,3 Nevertheless, this represents a significant health burden, with more than 4,000 cases reported annually across Canada.¹¹ Cases of SCLC are distinguished from NSCLC by a rapid growth rate, early metastasis to regional lymph nodes and/or distant sites, and initial sensitivity to chemotherapy and radiotherapy.⁴ In Canada, the 5-year predicted net survival rate for SCLC is 7%.¹ According to the clinical experts consulted by CADTH for this review, SCLC is strongly associated with smoking tobacco.

Small cell lung cancer is most commonly characterized according to 2 stages developed by the Veterans Affairs Lung Cancer Study Group: limited-stage or ES disease.¹² Patients with disease confined to 1 hemithorax, regional mediastinal lymph nodes, and ipsilateral supraclavicular lymph nodes are classified as having limited-stage SCLC.⁴ Patients with tumour involvement that is more widespread in the lungs, and may include malignant pleural or pericardial effusions or hematogenous metastases, are classified as having ES-SCLC.⁴ Approximately 2-thirds of SCLC patients have ES disease.³ In recent years, there was some movement toward anatomic staging using the tumour-node-metastasis staging system.¹³ However, according to the clinical experts consulted by CADTH, most clinical trials select patient populations based on the Veterans Affairs Lung Cancer Study Group classification, and most clinicians use this system in clinical practice.

According to the clinical experts consulted by CADTH, patients with ES-SCLC present as very ill. A diagnosis of SCLC is made using a standard pathologic assessment of a tissue biopsy. Staging to determine whether the patient has ES-SCLC is done with radiology testing (e.g., CT, PET scan, bone scan, brain MRI).

Standards of Therapy

In general, surgery does not have a major role in the management of SCLC,¹⁴ and most patients with ES-SCLC are treated with chemotherapy alone.¹⁵ Thoracic irradiation as primary treatment is not routinely recommended for patients with ES-SCLC.⁴ However, radiotherapy can be used for symptom control where appropriate.⁴

The majority of patients with ES-SCLC receive 4 to 6 cycles of a platinum drug (cisplatin or carboplatin) in combination with etoposide for first-line treatment, which has been the standard of care for several decades.^4,15-17 Cisplatin + etoposide is generally the preferred regimen in Canadian practice.⁴ Carboplatin may be used in place of cisplatin in patients who are frail or have significant hearing loss, peripheral neuropathy, decreased heart function, or abnormal renal function.⁴

Patients with ES-SCLC frequently develop brain metastases and may be offered prophylactic cranial irradiation (PCI).⁴ According to the clinical experts consulted by CADTH, the gains in OS from these treatments are modest and selection of patients that are most likely to benefit from PCI remains challenging.

Although SCLC is initially chemosensitive, the majority of patients will relapse within months after first-line therapy.⁴ Further chemotherapy is frequently given at the time of relapse. The preferred option for second-line therapy is EP.⁴ Topotecan or cyclophosphamide + doxorubicin + vincristine are also options for second-line therapy.⁴ Modest improvements in OS were observed in a trial of oral topotecan versus best supportive care.¹⁸ Additional drugs such as amrubicin have failed to produce any improvement in OS when compared with topotecan.¹⁹ There is no established third-line therapy for ES-SCLC.

Little progress has been made recently in the systemic treatment and outcomes for ES-SCLC.²⁰ A variety of strategies have been evaluated over the past 20 years, including the use of non–cross-resistant chemotherapy,²¹ intense weekly chemotherapy,^22,23 maintenance chemotherapy,²⁴ and high-dose chemotherapy with transplantation.²⁵ None of these strategies have resulted in clear improvements in OS for patients with SCLC, according to the clinical experts consulted by CADTH. Multiple trials of drugs targeting a variety of molecular abnormalities have all failed to result in any improvement in treatment outcomes for patients with SCLC.

Drug

Durvalumab is a fully IgG1 kappa monoclonal antibody that selectively blocks the interaction of PD-L1 with PD-1 and CD80.⁵ Expression of PD-L1 helps tumours evade detection and elimination by the immune system. When PD-L1 interacts with PD-1 and CD80, the PD-L1/PD-1 pathway decreases cytotoxic T-cell activity, proliferation, and cytokine production. By selectively blocking the interaction of PD-L1 with PD-1 and CD80, durvalumab inhibits the immunosuppressive effects of the PD-L1/PD-1 pathway, thereby enhancing antitumour immune responses.

On September 21, 2020, durvalumab was approved by Health Canada for first-line treatment of patients with ES-SCLC in combination with etoposide and either carboplatin or cisplatin.⁵ The reimbursement request for durvalumab by the sponsor is the Health Canada–approved indication.

Durvalumab is also indicated for the treatment of patients with locally advanced, unresectable, stage III NSCLC.⁵ Durvalumab has been previously reviewed by CADTH for the treatment of patients with locally advanced, unresectable NSCLC following curative intent, platinum-based chemoradiation therapy, for up to a maximum of 12 months.²⁶ In addition, durvalumab has received marketing authorization with conditions for the treatment of locally advanced or metastatic urothelial carcinoma, pending the results of clinical trials.⁵

Durvalumab is available as a single-use vial and is administered as an IV infusion for 60 minutes.⁵ For the treatment of ES-SCLC in patients with a body weight of more than 30 kg, the recommended dosage is 1,500 mg in combination with etoposide and either carboplatin or cisplatin every 3 weeks for 4 cycles, followed by 1,500 mg every 4 weeks as monotherapy until disease progression or unacceptable toxicity. For patients with a body weight less than or equal to 30 kg, the recommended dosage is 20 mg/kg in combination with etoposide and either carboplatin or cisplatin every 3 weeks for 4 cycles, followed by 20 mg/kg every 4 weeks as monotherapy until disease progression or unacceptable toxicity.

Stakeholder Perspectives

Patient Group Input

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

About the Patient Groups and Information Gathered

Two patient groups responded to the call from CADTH to provide input about patients’ experience, values, and preferences related to SCLC and its treatment.

Lung Cancer Canada is a registered national charity with an exclusive focus on lung cancer in Canada. The group provided information collected through environmental scans as well as interviews with 7 patients (1 male and 6 females, between 40 and 70 years of age) and their families and/or caregivers who reported their thoughts and experiences with SCLC. The information was accessed from November to December 2020.

The second group that provided information was the LHF, previously known as the Ontario Lung Association. It is a registered charity that assists and empowers people living with or caring for others with lung disease, provides programs and services to patients and health care providers, invests in health research, and advocates for better policies on lung health. This group provided information from online surveys completed by people living with lung cancer and through telephone interviews with 14 patients living in Ontario.

Disease Experience

The patient groups identified lung cancer as the most commonly diagnosed cancer with the highest mortality rate in Canada, accounting for 25% of all cancer deaths. The 5-year survival rate is just 19%, with lower rates for advanced cases. Cases of SCLC represent approximately 15% of lung cancer cases. They are strongly associated with a history of smoking and patients have a median age at diagnosis of 70 years. Small cell lung cancer has a more aggressive presentation, with a median survival of 7 to 11 months with treatment, and is usually diagnosed in the later stages, with a high tumour burden and more symptoms at presentation.

According to the patient input received, a diagnosis of lung cancer and the subsequent treatment has a major impact on the life of the patient and their loved ones. Many caregivers are involved in the care, well-being, and management of their loved ones. More than half of patient respondents from the LHF reported current issues with work, day-to-day chores, and socialization. Lung Cancer Canada reported that with certain treatments, such as chemotherapy and immunotherapy, caregivers need to take their loved ones to the hospital or specialized clinics for their treatments, and care for them afterward for varying periods of time. In some cases, caregivers may need to take time off work to provide this care, affecting work productivity and finances, and causing mental stress. The emotional and physical toll during and after treatment may affect the caregivers’ ability to fulfill their role in the family and at work and affect their ability to participate in activities they enjoy. Direct quotes from patients include:

• “My work was demanding, and it would be too stressful to continue with an incurable diagnosis over my head.”

• “It takes longer to do everything — getting dressed, doing my personal hygiene, and completing ‘normal’ daily tasks.”

• “I have lot of anxiety and sadness now.”

Experiences With Currently Available Treatments

The current therapeutic options for ES-SCLC are chemotherapy and immunotherapy.

According to the patient input received, chemotherapy continues to be a viable form of treatment for this type of cancer. This treatment has been shown to work well in this group of patients, resulting in improved symptoms and increasing patients’ quality of life. However, chemotherapy can lower a patient’s immunity and, in some cases, may result in an inability to return to normal activities, have visitors, or spend quality time with family and loved ones.

Patients reported that immunotherapy is a form of treatment that has allowed many patients to hope for improved outcomes and has been shown to improve quality of life with more manageable side effects. Patients report feeling better within days of their first treatment with immunotherapy. Because lung cancer patients, and SCLC patients in particular, have a high symptom burden, this is an important aspect of this form of treatment. Patients on immunotherapy reported side effects that were mild and easily managed. In a few cases, stronger side effects had to be managed with over-the-counter or prescription drugs. Most patients found that the treatment was tolerable and did not interfere with day-to-day life. Lung Cancer Canada emphasized that no form of immunotherapy has currently been approved for SCLC patients in Canada.

Improved Outcomes

Both groups mentioned outcomes that are considered important for patients. Based on their experience, they include:

• control the cancer

• improve symptoms and delay deterioration

• have manageable side effects

• be effective on the central nervous system

• delay progression

• extend survival with a good quality of life

• provide longer-lasting and durable treatment.

All of these align with patients’ values and preferences in the Canadian landscape.

Experience With Drug Under Review

Neither LCC nor the LHF was able to include patients’ experiences with durvalumab because the treatment is not currently accessible to SCLC patients in Canada, and there were no Canadian trial sites for the requested treatment. Lung Cancer Canada was able to look at the outcomes of SCLC patients treated with atezolizumab in combination with chemotherapy to highlight patients’ experiences with an immunotherapy similar to durvalumab. This combination was shown to work well for patients in terms of tolerability.

Additional Information

The groups highlighted the poor survival rates for ES-SCLC, which is reported to have a 2-year survival rate of less than 5%, and a 5-year survival rate of less than 2%. The patient input emphasized that SCLC is a devastating disease, with few treatment options. Treatment for SCLC has not changed in the past 30 years, and this puts these patients at a disadvantage. Patient groups identified an unmet need, unlike the situation for NSCLC patients, for whom a larger range of treatment options is available. Input from LCC emphasized that there is a need for treatment options and that there is no reason to delay SCLC patients’ access to this treatment.

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 ES-SCLC.

Unmet Needs

The clinical experts consulted by CADTH noted that current treatment options for ES-SCLC are limited and have not changed in 30 years. Most patients receive either cisplatin or carboplatin with etoposide (EP therapy) for 4 to 6 cycles as first-line therapy. A small number of patients who are not candidates for platinum therapy or do not want to receive IV systemic therapy may be treated with oral etoposide, which is considered an inferior therapy. Although there is a high initial response rate to first-line treatment with EP therapy, most patients relapse within months. Patients derive limited benefit from second-line chemotherapy, which is less effective at extending survival, reducing disease burden, and improving symptoms. In addition, many patients are not well enough to receive second-line chemotherapy after relapse. Patients with ES-SCLC have an OS of approximately 9 months to 1 year.

The experts identified a significant unmet need for a systemic therapy that can extend response to first-line treatment to prolong survival and preserve the symptom and quality of life benefits.

Place in Therapy

The clinical experts consulted by CADTH for this review anticipated that durvalumab would be delivered concurrently with first-line EP therapy, then administered as single-drug maintenance therapy. Durvalumab would address the underlying disease process by potentiating T cells that target the somatic mutations and neoantigens associated with SCLC and are related to tobacco consumption. Durvalumab would be offered to all patients for whom EP therapy is planned, except patients for whom immunotherapy is contraindicated (e.g., those with autoimmune disease).

Patient Population

The clinical experts noted that patients with ES-SCLC who are candidates for EP therapy and for whom immunotherapy is not contraindicated would be suitable for treatment with durvalumab. Contraindications would include severe or active autoimmune disease and organ transplant recipients.

The experts revealed that, to date, no biomarkers or patient characteristics have been identified that can predict which patients are more likely to respond to durvalumab. There are no known patient subgroups that are most likely to respond to durvalumab.

Assessing Response to Treatment

Treatment response is assessed by physical examination, history of symptom burden, and serial radiography (CT) scans at the completion of 4 to 6 cycles of EP and then every 8 weeks to 12 weeks. Chest X-rays may also be done more frequently between CT scans due to the aggressiveness of the disease and its propensity for rapid recurrence. Patients are assessed approximately every 8 weeks during follow-up.

The clinical experts indicated that a clinically meaningful response to treatment would be prolonged OS. Delayed disease progression, reduced symptom burden, and improved ECOG PS are also clinically meaningful.

Discontinuing Treatment

The clinical experts consulted by CADTH agreed that treatment with durvalumab should be discontinued if a patient experiences disease progression, intolerable AEs or SAEs (e.g., anaphylactic allergic reaction, grade 3 colitis, or myocarditis), or the patient wishes to stop treatment.

Prescribing Conditions

A diagnosis of ES-SCLC is made by pathologic assessment of a tissue biopsy by a respirologist/pulmonologist, thoracic surgeon, or interventional radiologist. Treatment should be prescribed and monitored by medical oncologists, general practitioners of oncology, or nurse practitioners who have been trained in oncology and immunotherapy. Treatment with durvalumab could be provided at any outpatient chemotherapy unit at a Canadian cancer centre or hospital.

Clinician Group Input

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

Input was received from 2 clinician groups:

• The Ontario Health (previously Cancer Care Ontario) Lung and Cancer Drug Advisory Committee. The Ontario Health– Cancer Care Ontario drug advisory committees provide timely evidence-based clinical and health-system guidance on drug-related issues in support of Cancer Care Ontario’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program.

• Lung Cancer Canada is a national charitable organization that serves as Canada’s leading resource for lung cancer education, patient support, research, and advocacy. Based in Toronto, Ontario, LCC has a wide reach that includes both regional and pan-Canadian initiatives. Lung Cancer Canada is a member of the Global Lung Cancer Coalition and is the only organization in Canada focused exclusively on lung cancer.

Unmet Needs

The clinician groups noted that SCLC accounts for approximately 15% of all lung cancers. It is seen mainly in the elderly population, and the median age at diagnosis is approximately 70 years. Patients present at a late stage, and less than 5% of SCLC is diagnosed at a stage that would be amenable to surgical resection. In two-thirds of patients, the cancer is ES and has spread outside the lung and regional lymph nodes. Treatment for ES-SCLC is standard around the globe and has not changed in 30 years. First-line treatment consists of 4 to 6 cycles of systemic chemotherapy with IV etoposide and a platinum compound, either cisplatin or carboplatin.

The clinician groups reported that, despite high response rates to initial therapy, many patients progress rapidly. Less than half the patients live beyond 1 year, with few surviving beyond 2 years. Therefore, there is a high unmet need for more effective therapies that result in longer disease control and better OS.

The clinician groups stated that all patients with ES-SCLC have high unmet needs. They reported that the only factors that predict worse outcome are those associated with a higher tumour burden, making it impossible to identify subgroups of greater need.

Place in Therapy

The clinician groups indicated that durvalumab would be used as initial systemic therapy in patients with ES-SCLC in combination with 4 cycles of platinum and etoposide, followed by maintenance durvalumab until disease progression. The goals of adding durvalumab to EP therapy would be to improve PFS and OS. In particular, the hope is that the addition of durvalumab will increase the proportion of patients living beyond 18 to 24 months.

The clinician groups reported that the current standard of care is platinum and etoposide. This has been the case for the last 3 decades. No other drugs apart from immune checkpoint inhibitors have demonstrated improved OS as first-line therapies for ES-SCLC. According to the clinician group input, it would not be appropriate to recommend the addition of other therapies apart from an immune checkpoint inhibitor such as durvalumab. Importantly, because chemotherapy and durvalumab have non-overlapping toxicity profiles, both components can be administered at full doses without unacceptable toxicity.

The clinician groups anticipated that first-line treatment for ES-SCLC would move from double chemotherapy with EP to a triplet therapy with etoposide-platinum-durvalumab. The clinician groups that provided input for this review stated that it would not be appropriate to recommend that patients try other treatments before initiating treatment with durvalumab in combination with chemotherapy as no more than half of patients are fit enough for second-line treatments if they fail to respond or relapse after first-line therapy.

The clinician groups noted that durvalumab is not currently approved as a second-line treatment for ES-SCLC. They reported that there are no trials demonstrating benefit from an immune checkpoint inhibitor as subsequent therapy. Therefore, the clinician groups did not anticipate that the addition of durvalumab to EP as first-line therapy would have any downstream impact on other treatment options. The groups anticipated that second-line therapy would remain either re-treatment with platinum and etoposide or cyclophosphamide + doxorubicin + vincristine (CAV). The clinician groups noted that topotecan is another option, although it is not funded in all jurisdictions.

Patient Population

The clinician groups reported that all patients with ES-SCLC need improved therapies and that it would not be possible to identify subgroups that are more likely to benefit from the addition of durvalumab as there are no predictive biomarkers of benefit for the addition of durvalumab to chemotherapy. Therefore, this treatment should be considered for any patient with ES-SCLC and an ECOG PS of 2 or greater. ES-SCLC is a common condition that medical oncologists see and treat on a regular basis. These patients would be identified at the time of initial consultation with a medical oncologist. The clinician groups did not identify any specific issues for consideration. All patients with ES-SCLC and an ECOG PS of 2 or greater could be candidates for therapy with EP and durvalumab unless immune checkpoint inhibitors are contraindicated. Patients with symptomatic brain metastases should be treated before commencing systemic therapy. Patients with severe or symptomatic autoimmune disorders should not be treated with durvalumab immunotherapy.

The clinician groups reported that all hospitals in Canada have the ability to undertake the pathologic, hematologic, biochemical, and radiologic tests necessary to diagnose and treat SCLC. The clinician groups thought that advanced molecular profiling is not necessary. Selection of SCLC patients for immunotherapy, including durvalumab, does not require any special testing.

Assessing Response to Treatment

The clinician groups reported that tumour shrinkage on imaging studies would typically be used to determine if a patient is responding to therapy. Improvement in the patient’s symptoms would also be used as a measure of treatment benefit. Any improvement in survival beyond 18 months is considered meaningful.

According to the clinician groups, numerous tumour markers have been evaluated in an attempt to select patients for immunotherapy, including PD-1 and PDL-1 inhibitors. Results have been variable and inconsistent across tumour types and within individual cancers. The most extensively studied markers in lung cancer are PD-L1 status assessed in tumour samples by immunohistochemistry, and tumour mutational burden assessed either in tumour samples or in peripheral blood cell-free DNA.

According to the clinician groups, patients are evaluated in clinical practice for response (and toxicity) before each cycle of therapy by history, physical examination, bloodwork and/or chest radiographs. CT and/or MRI scans are performed every 2 to 3 cycles of chemotherapy and always at the completion of chemotherapy. For patients receiving EP therapy and durvalumab, treatment would continue until disease progression. After 6 months or so, the frequency of imaging may be increased to every 4 cycles of therapy.

Discontinuing Treatment

The clinician groups indicated that EP chemotherapy is never given for more than 6 cycles, and usually only for 4 cycles. In clinical practice, the reasons to discontinue treatment would be unequivocal disease progression, the development of grade 3 immune-related AEs, or patient choice. In this setting of extensive SCLC, immunotherapy similarly continues until disease progression or recurrence, toxicity, or when the patient or physician decides to stop for other reasons.

Prescribing Conditions

The clinician groups anticipated that chemotherapy and durvalumab can be administered as an outpatient treatment. Treatment most often would be given in a specialized cancer hospital with chemotherapy and immunotherapy expertise. Treatment would be administered under the supervision of a medical oncologist, as is standard in most regions of Canada.

Additional Considerations

The clinician groups reported that there have been no significant treatment advances in ES-SCLC in more than 30 years. The addition of durvalumab represents a modest but real improvement in survival for a group of patients with high unmet needs.

Drug Program Input

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

Clinical Evidence

The clinical evidence included in the review of durvalumab is presented in the Systematic Review section, which includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies selected according to an a priori protocol. No indirect or other evidence was identified.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of durvalumab in combination with etoposide and either carboplatin or cisplatin for the first-line treatment of patients with ES-SCLC.

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.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the 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 Imfinzi (durvalumab) and small cell lung cancer (SCLC). Clinical trials registries searched were 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, the European Union Clinical Trials Register, and Canadian Partnership Against Cancer Corporation’s Canadian Cancer Trials.

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. See Appendix 1 for the detailed search strategies.

The initial search was completed on December 22, 2020. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee on May 13, 2021.

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 (https://www.cadth.ca/grey-matters).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.

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

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

A total of 5 reports presenting data from a single unique study were identified from the literature 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

Description of Studies

The CASPIAN trial was an international multi-centre, phase III, open-label, RCT conducted to investigate the efficacy and safety of durvalumab, with or without tremelimumab, in combination with etoposide and platinum-based chemotherapy compared to EP alone in adult patients with ES-SCLC.^6,7 A total of 805 patients were randomized from April 7, 2017, to May 29, 2018, in a 1:1:1 ratio to 3 treatment arms: durvalumab with tremelimumab in combination with etoposide and either carboplatin or cisplatin (durvalumab + tremelimumab + EP), durvalumab in combination with etoposide and either carboplatin or cisplatin (durvalumab + EP), and EP alone. The CASPIAN trial included a 3-week screening period to complete eligibility assessments. Patients were randomized from 209 sites in 23 countries. No Canadian sites participated in the CASPIAN trial. The type of platinum-based chemotherapy (cisplatin or carboplatin) used was the investigator’s choice. Randomization was stratified by the platinum-based chemotherapy planned for the first treatment cycle. The study design is depicted in Figure 2.

The primary end point of the CASPIAN trial was OS, and the key secondary end point was PFS as assessed by the investigator. Protocol-specified secondary end points included the PFS rate at 6 months after randomization, PFS rate at 12 months after randomization, ORR, and changes in symptoms and HRQoL using the EORTC QLQ-C30 and the QLQ-LC13. Tumour assessments by CT or MRI were performed at screening, week 6, and week 12 after randomization, and every 8 weeks until confirmed disease progression. Tumours were evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. A follow-up scan was requested after every radiological PD on study when possible.

Figure 2: Study Schema of the CASPIAN Trial

Durva = durvalumab; ES-SCLC = extensive-stage small cell lung cancer; EP = etoposide and platinum-based chemotherapy (consisting of etoposide 80 mg/m² to 100 mg/m² with either carboplatin area under the curve 5 mg/mL/min to 6 mg/mL/min or cisplatin 75 mg/m² to 80 mg/m²); OS = overall survival; PCI = prophylactic cranial irradiation; PD = progressive disease; PFS = progression-free survival; PS = performance status; Q3W = every 3 weeks; Q4W = every 4 weeks; RECIST = Response Evaluation Criteria in Solid Tumours; Treme = tremelimumab.

* Patients in arm 3 were permitted an additional 2 cycles of EP (up to 6 cycles total) per the investigator’s discretion.

‡ Patients received an additional dose of tremelimumab post-EP.

Source: Clinical Study Report.⁶

Data for the durvalumab + tremelimumab + EP arm of the CASPIAN trial will not be presented in the systematic review because tremelimumab is not approved in Canada and the combination is not aligned with the Health Canada product monograph for durvalumab. However, efficacy and harms data for the durvalumab + tremelimumab + EP arm are available in Appendix 3 for context.

Analyses and Data Cut-Offs

A pre-specified interim analysis was planned to be conducted after approximately 318 OS events occurred between the durvalumab + EP and EP-alone arms (60% maturity).⁶ The interim analysis had a data cut-off date of March 11, 2019, at which point the OS data had reached 63% maturity (336 OS events from 537 patients) in the durvalumab + EP and EP-alone arms.⁶ The CASPIAN trial met its primary end point under the statistical analysis plan at the interim analysis, and therefore statistical testing of OS for durvalumab + EP versus EP-alone was considered complete at this analysis.

A primary analysis of OS was planned to be conducted when approximately 425 OS events (80% maturity) were observed across the durvalumab + tremelimumab + EP and EP-alone arms, and the durvalumab + EP and EP-alone arms. The final analysis was conducted with a data cut-off date of January 27, 2020, at which point the OS data had reached 82% maturity (441 events from 537 patients) in the durvalumab + EP and EP-alone arms.⁷

Protocol Amendments

Four protocol amendments were implemented during the CASPIAN trial, which are summarized in Table 7.⁷ In the original study protocol, OS and PFS by blinded independent central review were co-primary end points, and the primary objective of the trial was to assess the efficacy of durvalumab + tremelimumab + EP compared with EP alone in terms of OS and PFS. The objective to assess the efficacy of durvalumab + EP efficacy compared with EP alone was originally a secondary objective. Amendments 2 to 4 implemented changes to the primary objective, secondary objectives, determination of PFS, and multiple testing procedure to control alpha spending after randomization of study participants was complete.

Populations

Inclusion and Exclusion Criteria

Key inclusion and exclusion criteria are described in Table 6. Briefly, the CASPIAN trial enrolled adults with histologically or cytologically confirmed ES-SCLC who were suitable for platinum-based chemotherapy as first-line treatment.^6,7 Brain metastases at baseline were allowed if patients were asymptomatic or treated and stable (off steroids and anticonvulsants for at least 1 month before study treatment). Enrolment was limited to patients with an WHO/ECOG performance status of 0 or 1. Patients were excluded if they had prior exposure to immune-mediated therapy, radiotherapy to the chest, or contraindications to immunotherapy (e.g., history of allogenic organ transplantation, autoimmune or inflammatory disorders).

Baseline Characteristics

Baseline characteristics in the intention-to-treat (ITT) population of the CASPIAN trial are summarized in Table 8. Most patients enrolled in the trial were male (71.6%), White (82.6%), smokers (93.5%) with a small cell carcinoma (combined) histology type (84.1%) and an ECOG PS of 1 (63.0%).⁷ The mean age of all patients was 62.6 years. Baseline characteristics were generally well balanced between the durvalumab + EP and EP-alone arms. A total of 7 patients (0.9%) had received previous chemotherapy and 27 patients (3.4%) had received previous radiotherapy.

Interventions

The CASPIAN trial was a randomized, open-label, 3-arm trial.^6,7 Patients were randomized in a 1:1:1 ratio to durvalumab + tremelimumab + EP, durvalumab + EP, or EP alone. The durvalumab + tremelimumab + EP arm is not included in the CADTH systematic review because this regimen is not approved by Health Canada.

Durvalumab + Etoposide-Platinum

During the chemotherapy phase, patients received 4 doses of 1,500 mg IV durvalumab co-administered with IV etoposide (80 mg/m² to 100 mg/m²) with either carboplatin (area under the curve 5 mg/mL per min to 6 mg/mL per min) or cisplatin (75 mg/m² to 80 mg/m²) every 3 weeks. Durvalumab was administered over 60 minutes and EP was administered over 120 minutes. Treatment with chemotherapy was limited to 4 cycles. After chemotherapy, patients received 1,500 mg IV durvalumab every 4 weeks until PD by RECIST version 1.1 (unconfirmed and confirmed) unless there was unacceptable toxicity or withdrawal of consent, or another discontinuation criterion was met. Other discontinuation criteria included an inability to reduce the corticosteroid dosage to no more than 10 mg of prednisone per day (or equivalent) within 12 weeks after the last dose of the study drug, recurrence of a previously experienced Grade 3 treatment-related AE following resumption of dosing, and severe immune-mediated AEs. If a patient’s weight fell to 30 kg or less, they received weight-based dosing equivalent to 20 mg/kg of durvalumab until the weight had improved to more than 30 kg, at which point the patient started receiving the fixed 1,500 mg dose of durvalumab.

Patients with PD who, in the investigator’s opinion, continued to receive a benefit from durvalumab treatment could continue to receive durvalumab for as long as they were demonstrating a clinical benefit. However, patients with rapid tumour progression or with symptomatic progression requiring urgent medical intervention were not eligible for continuing durvalumab treatment. Following disease progression as assessed by the investigator, standard chemotherapy was offered.

Etoposide-Platinum Alone

Patients received at least 4 doses of etoposide (80 mg/m² to 100 mg/m²) with either carboplatin (area under the curve 5 mg/mL per min to 6 mg/mL per min) or cisplatin (75 mg/m² to 80 mg/m²) every 3 weeks over 120 minutes. Patients could receive an additional 2 doses of EP (maximum of 6 cycles total) at the investigator’s discretion, if clinically indicated. Following disease progression as assessed by the investigator, standard chemotherapy was offered. Crossover to durvalumab monotherapy following PD was not permitted.

Concomitant Medications

The following concomitant medications were allowed in the CASPIAN trial^6,7: serotonin antagonists, glucocorticoids, colony-stimulating factors, proton pump inhibitors, propulsives, other antiemetics, sulfonamides, electrolyte solutions, anilides, fluoroquinolones, benzodiazepine derivatives, natural opium alkaloids, H₂ receptor antagonists, osmotically acting laxatives, selective beta-blocking agents, platelet aggregation inhibitors (excluding heparin), 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, penicillins, ACE inhibitors, and dihydropyridine derivatives.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 9. These end points are further summarized in the following section.

Overall Survival

Overall survival, which was the primary outcome of the CASPIAN trial, was defined as the time from the date of randomization until the date of death due to any cause.

Progression-Free Survival

In the original trial protocol, PFS was a co-primary end point, and disease progression was to be assessed by blinded independent central review per RECIST version 1.1. In the final protocol, PFS was designated the key secondary outcome of the CASPIAN trial, and defined as the time from the date of randomization until the date of disease progression or death by any cause (in the absence of progression). Disease progression for analysis of PFS was determined by the investigator’s RECIST version 1.1 assessments.

Duration of Response and Objective Response Rate

The ORR was defined as the percentage of patients with at least 1 visit response of complete response or partial response. Response was determined by the investigator using RECIST version 1.1 criteria. Confirmation of response was not required per the protocol, and both unconfirmed and confirmed ORRs were reported. Unconfirmed responses corresponded to a complete or partial response observed at 1 or more study visit. Confirmed responses corresponded to a complete or partial response observed at 1 or more study visit and a confirmatory scan at least 4 weeks after the initial response. The DOR was calculated post hoc using confirmed response.

Health-Related Quality of Life

Change in HRQoL using the EORTC QLQ-C30 and QLQ-LC13 was a secondary end point in the CASPIAN trial. A detailed discussion and critical appraisal of the outcome measures are provided in Appendix 4. The EORTC QLQ-C30 is a standardized, patient self-administered questionnaire for evaluating the quality of life of patients with cancer participating in clinical trials.³³ This questionnaire complements the lung cancer–specific questionnaire, the QLQ-LC13.⁸ The EORTC QLQ-C30 consists of 5 functional scales (physical, role, emotional, cognitive, and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). This instrument also includes global health status and overall quality of life. A higher score on a functional scale corresponds to higher level of function, while a higher score in the symptom scale corresponds to higher burden of symptoms.⁹ The QLQ-LC13 consists of lung cancer–related symptoms (e.g., coughing, hemoptysis, dyspnea, and pain) and treatment side effects (e.g., hair loss, neuropathy, sore mouth, and dysphagia).⁸

Time to deterioration of EORTC QLQ-C30 and QLQ-LC13 scores was assessed in patients whose baseline scores were at least 10 for functioning and global health status/QoL and no more than 90 for symptoms. The CASPIAN trial defined a clinically meaningful deterioration as an increase of at least 10 points from baseline for symptoms and a decrease of more than 10 points from baseline for function and global health status/quality of life. The MID reported in the literature varies depending on the improvement or deterioration among different items scales. In 1 study, estimates of the MID for the EORTC QLQ-C30 ranged from 9.1 units (cognitive functioning) to 23.5 units (pain), and a meaningful change for deterioration ranging from 7.2 units (physical functioning) to 13.5 units (role functioning).³⁴ In another study, the MID estimates for deterioration based on using WHO performance status and weight loss as anchors were 4 and 6 for physical; 5 and 5 for role; 7 and 9 for social; 4 and 4 for global health status; 6 and 11 for fatigue; and 3 and 7 for pain.³⁵

Time to deterioration was calculated as the time from randomization to the first clinically meaningful deterioration at a subsequent assessment, or death from any cause in the absence of clinically meaningful deterioration.

Symptoms

Change in symptoms using the EORTC QLQ-C30 and QLQ-LC13 was a secondary end point in the CASPIAN trial. The predefined key symptoms were cough, dyspnea, and chest pain (as assessed by the QLQ-LC13), and fatigue and appetite loss (as assessed by EORTC QLQ-C30). The CASPIAN trial defined a clinically meaningful difference as an absolute change in the score from baseline of at least 10 points. The MID reported in the literature varies depending on the improvement or deterioration among different items scales. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

Immune-Related Adverse Events

Immune-related AEs included AEs with a potential or likely inflammatory or immune-mediated pathophysiological basis and were recorded as AEs of special interest in the CASPIAN trial. Immune-related AE categories included, but were not limited to, diarrhea/colitis and intestinal perforation, pneumonitis/interstitial lung disease, hepatitis/transaminase increases, endocrinopathies (adrenal insufficiency, hyperthyroidism, hypothyroidism, hypophysitis/ hypopituitarism, and type I diabetes mellitus), nephritis/blood creatinine increases, rash/dermatitis, pancreatitis/serum lipase and amylase increases, myocarditis, myositis/polymyositis, neuropathy/neuromuscular toxicity (e.g., Guillain-Barre and myasthenia gravis), pericarditis, sarcoidosis, uveitis, and infusion-related/hypersensitivity/anaphylactic reactions.

Statistical Analysis

In general, descriptive statistics were reported by treatment arm.^6,7 For continuous variables, the mean, standard deviation, median, minimum, and maximum were presented. For categorical variables, counts and percentages were presented. Results of statistical analyses were presented using 95% CIs and 2-sided P values, unless otherwise specified. The planned statistical analysis of the efficacy outcomes of interest in the CADTH systematic review are summarized in Table 10. There were multiple comparisons and a planned interim analysis in this phase III trial.

Multiple Testing Procedure

A multiple testing procedure with a gatekeeping strategy was used to control the overall type I error for OS and PFS at 5% (2-sided).⁶ Hypotheses were tested in a predefined order with an alpha-exhaustive recycling strategy (Figure 3). The alpha level was controlled at the interim and final analysis time points using a Lan-DeMets spending function that approximates an O’Brien-Fleming approach. The overall 5% type I error was initially split between the analysis of OS for durvalumab + EP versus EP (which was allocated an alpha level of 4%), and the analysis of OS for durvalumab + tremelimumab + EP versus EP (an alpha level of 1%).

Figure 3: Multiple Testing Procedure for Controlling Type I Error of Overall Survival and PFS in the CASPIAN Trial

Combo = durvalumab + tremelimumab; CV = critical value; EP = etoposide-platinum; HR = hazard ratio; ITT = intention-to-treat; Mono = durvalumab; OS = overall survival; PFS = progression-free survival.

Note: Alpha recycling between the Mono + EP versus EP and Combo + EP versus EP OS comparisons.

Source: Clinical Study Report.⁶

Sample Size Determination

The CASPIAN trial planned to randomize 795 eligible patients.^6,7 The primary objective of the trial was to assess the efficacy of durvalumab + tremelimumab + EP treatment compared with EP alone and the efficacy of durvalumab + EP treatment compared with EP alone in terms of OS. To control for type I error, a significance level of 1% was used for the analysis of durvalumab + tremelimumab + EP versus EP alone, and a significance level of 4% was used for the analysis of durvalumab + EP versus EP alone. The trial would be considered positive if either of the OS analysis results were statistically significant.

The sample size calculation assumed a 3-month delay in separation of the OS and PFS curves between the immunotherapy arms versus EP alone, and a HR of 0.62 thereafter. The planned data cut-off for the primary analysis of OS was when approximately 425 OS events (80% maturity) were observed across the durvalumab + tremelimumab + EP and EP-alone arms, and the durvalumab + EP and EP treatment arms. If at the time of the primary analysis (425 OS events), the average true OS HR is 0.69, the study would have a 96% power to demonstrate a statistically significant difference at a 2-sided 3.57% significance level (for an overall alpha of 4%) for the comparison of durvalumab + EP versus EP.

Interim Analysis

The interim analysis was planned to be conducted after approximately 318 OS events (60% maturity) occurred between the durvalumab + tremelimumab + EP and EP-alone arms and approximately 318 OS events (60% maturity) occurred between the durvalumab + EP and EP-alone arms.

If the average true OS HR is 0.71 at the interim analysis, the study would have an estimated 48% power to demonstrate a statistically significant difference with a 2-sided 0.23% significance level (for an overall alpha of 1%) for the comparison of durvalumab + tremelimumab + EP versus EP alone, and a 71% power to demonstrate a statistically significant difference at a 2-sided 1.43% significance level (for an overall alpha of 4%) for the comparison of durvalumab + EP versus EP. The smallest treatment difference that would be statistically significant was estimated to be an average HR of 0.71 for durvalumab + tremelimumab + EP versus EP alone and 0.76 for durvalumab + EP versus EP alone.

The alpha level applied at the interim analysis depended upon the observed number of deaths and percent of maturity for OS at the time of interim analysis. At the interim analysis, a total of 336 deaths were observed across the durvalumab + EP and EP arms out of the 425 targeted for the final analysis. The boundary for declaring statistical significance for the analysis of OS for durvalumab + EP versus EP was 0.0178, for a 4% overall alpha.

Primary Outcome

A stratified log-rank test was performed to compare durvalumab + EP to EP alone, adjusting for the type of platinum therapy (carboplatin or cisplatin) planned in cycle 1. The effect of durvalumab + EP versus EP treatment was estimated by the HR together with its CI and P value. The HRs and CIs were estimated from the Cox proportional hazards model. The assumption of proportional hazards was assessed by examining plots of complementary log-log (event times) versus log (time). A Kaplan–Meier plot of OS was presented by treatment arm. A sensitivity analysis was planned to examine censoring patterns to rule out attrition bias, which was done by a Kaplan–Meier plot of time to censoring with the censoring indicator of OS reversed.

Subgroup analyses were planned for type of platinum therapy planned in cycle 1, age, gender, stage (III versus IV), ECOG PS at baseline, smoking status at screening, central nervous system metastasis at baseline, race, and geographical area. For each subgroup, the HR and 95% CI were calculated from an unstratified Cox proportional hazards model with treatment as the only covariate.

Additional exploratory, post hoc analyses were conducted to investigate PD-L1 expression and tumour mutational burden relative to OS. In the exploratory analysis, PD-L1 was analyzed as a continuous variable and expression cut-offs were not predefined.³²

Secondary Outcomes

Progression-free survival was the key secondary outcome in the CASPIAN trial, and it was planned to be analyzed in the same method as OS. However, PFS was not formally tested for statistical significance at the interim analysis nor the final analysis due to the multiple testing procedure.^6,7 Both the durvalumab + EP and durvalumab + tremelimumab + EP groups were required to achieve statistical significance for OS before stepping down to PFS according to the pre-specified multiple testing procedure, and this was not achieved. As a result, the PFS results and P values should be considered descriptive only.

The ORR was compared between treatment arms using logistic regression models adjusting for the planned type of platinum therapy (cisplatin or carboplatin). Results were presented as an OR together with its associated profile likelihood and 95% CI. An OR of at least 1 favours durvalumab + EP. The analysis of confirmed ORR was post hoc.

Duration of response was calculated post hoc using confirmed responses. Kaplan–Meier estimates with CIs derived using the Brookmeyer-Crowley method and a log-log transformation were presented.

Time to deterioration in EORTC QLQ-C30 and QLQ-LC13 scores was summarized using the same methods as the primary outcome. However, the time to deterioration in EORTC QLQ-C30 and QLQ-LC13 scores was not part of the multiple testing procedure. Kaplan–Meier plots were presented by treatment arm.

Change from baseline in the 5 pre-specified key symptom scores was analyzed using an MMRM analysis of all data from baseline up to PD or 12 months. The overall type I error (2-sided, 5%) was controlled across the 10 hypothesis tests of 2 treatment comparisons in the MMRM analysis for each of the key symptoms using a Bonferroni-adjusted 1% significance level and 99% CIs. The MMRM model included treatment, age, sex, smoking history, visit, and the interaction between treatment and visit interaction as fixed factors and baseline as a covariate, and adjusted for the interaction between baseline and visit. Restricted maximum likelihood estimation was used. An overall adjusted mean estimate was derived to estimate the average treatment effect over visits, giving each visit equal weight. For this overall treatment comparison, adjusted mean estimates per treatment group and corresponding 95% CIs were presented along with an estimate of the treatment difference, 95% CI, and P value.

Analysis Populations

The ITT population included all patients randomized. Generally, efficacy analyses used the ITT population, although DOR, HRQoL, and symptoms were analyzed in a subset of patients.

DOR was calculated post hoc in confirmed responders (i.e., patients with a response of complete or partial response at 1 or more study visit and a confirmatory scan no sooner than 4 weeks after the initial complete or partial response per investigator assessment).

Symptoms and HRQoL were assessed in the patient-reported outcome (PRO)-evaluable population,³⁰ which consisted of the ITT population minus patients whose PRO data could not be verified at 1 trial site.³⁰ Time to deterioration of QLQ-C30 and QLQ-LC13 scores was assessed in patients whose baseline scores were 10 or higher for functioning and global health status/quality of life and 90 or lower for symptoms.

The safety analysis set consisted of all patients randomized before the end of global recruitment who received at least 1 dose of study drug.

Results

Patient Disposition

Details of patient disposition in the CASPIAN trial are summarized in Table 11. A total of 972 patients were screened and 805 patients were randomized to receive durvalumab + tremelimumab + EP (N = 268), durvalumab + EP (N = 268), or EP alone (N = 269).⁷ A total of 156 patients (16.1%) were screen failures, 3 patients (0.3%) died before randomization, and 8 patients (0.8%) withdrew before randomization. A total of 797 patients (99.0%) were treated: 266 (99.3%) received durvalumab + tremelimumab + EP, 265 (98.9%) received durvalumab + EP, and 266 (98.9%) received EP alone. In the durvalumab + EP arm, 223 patients (84.2%) had completed EP and 233 patients (87.9%) had discontinued the durvalumab as of the final analysis. In the EP arm, 190 patients (71.4%) had completed EP treatment as of the final analysis.

As of the final analysis, a total of 662 patients (82.2%) had terminated the study: 212 (79.1%) in the durvalumab + tremelimumab + EP arm, 212 (79.1%) patients in the durvalumab + EP arm, and 238 patients (88.5%) in the EP arm.⁷ The main reason for study termination was death, and the percentage of patients who died was highest in the EP arm: 76.1% died in the durvalumab + tremelimumab + EP arm, 77.2% in the durvalumab + EP arm, and 83.6% in the EP-alone arm. At the time of the final data cut-off, 11.2% of patients in the durvalumab + tremelimumab + EP arm and 11.9% of patients in the durvalumab + EP arm were ongoing study treatment, whereas 0 patients in the EP arm were ongoing study treatment.

Exposure to Study Treatments

Exposure to durvalumab treatment as of the interim analysis is summarized in Table 12 and exposure to EP treatment is summarized in Table 13. As of the interim analysis, the median duration of exposure to durvalumab in the durvalumab + EP arm was 28 weeks (range = 0.3 to 94.3).⁶ Exposure to EP was greater in the EP arm compared to the durvalumab + EP arm. In the EP arm, the median numbers of treatment cycles received were 6.0, 6.0, and 4.0 for the etoposide, carboplatin, and cisplatin components, respectively. In the durvalumab + EP arm, the median number of treatment cycles received was 4.0 for all chemotherapy components.

As of the final analysis (data cut-off on January 27, 2020), mean number of durvalumab infusions was 10.2 (standard deviation = 7.96), and the median (minimum to maximum) number of durvalumab infusions was 7.0 (1 to 37).

As of the interim analysis, 3 patients in the durvalumab + EP arm required a durvalumab dose interruption.⁶ Two patients required an etoposide dose interruption, no patients required a carboplatin dose interruption, and 1 patient required a cisplatin dose interruption. All dose interruptions were due to an AE. A total of 149 (56.2%) patients had durvalumab dose delays, the majority of whom had 1 delay (n = 78, 29.4%). The most common reason for a durvalumab dose delay was AEs (n = 109, 41.1%). A total of 113 patients (42.6%) had dose delays for etoposide, 89 carboplatin-treated patients (42.8%) had dose delays for carboplatin, and 23 cisplatin-treated patients (35.4%) had dose delays for cisplatin. The most common reason for chemotherapy dose delays was an AE.

As of the interim analysis, 9 patients in the EP arm required a dose interruption (7 due to an AE and 2 due to other reasons), 3 patients required a carboplatin dose interruption (all due to AEs), and no patients required a cisplatin dose interruption.⁶ A total of 144 (54.1%) patients had dose delays for etoposide, 118 carboplatin-treated patients (56.7%) had dose delays for carboplatin, and 29 cisplatin-treated patients (43.3%) had dose delays for cisplatin. The most common reason for dose delays was an AE.

A total of 795 (98.8%) patients received allowed concomitant medications during study treatment.⁶ Concomitant medications received by patients in the durvalumab + EP and EP-alone arms are summarized in Table 14.

Subsequent therapies received by patients in the CASPIAN trial are summarized in Table 15.

Efficacy

Only those efficacy outcomes and analyses of subgroups for the intervention and comparator arms identified in the review protocol are reported below. See Appendix 3 for detailed efficacy data.

Overall Survival

The OS results of the CASPIAN trial for the durvalumab + EP and EP-alone arms are summarized in Table 16.

As of the interim analysis (data cut-off: March 11, 2019), 336 death events occurred, representing 62.6% maturity for OS overall.⁶ Median duration of follow-up in all patients was 10.58 months between both treatment groups: 11.30 months in the durvalumab + EP group and 9.86 months in the EP-alone group. Median OS was 13.0 months (95% CI, 11.5 to 14.8) in the durvalumab + EP arm compared to 10.3 months (95% CI, 9.3 to 11.2) the EP arm (HR = 0.73; 95% CI, 0.59 to 0.91; P = 0.0047). Kaplan–Meier curves are depicted in Figure 4. There was a delay of approximately 6 months in separation of the curves, and the associated log-log plot showed some evidence of non-proportionality of hazards. The post hoc Kaplan–Meier estimate of landmark OS at 12 months was 53.7% (95% CI, 47.4 to 59.5) in the durvalumab + EP arm compared to 39.8% (95% CI, 33.7 to 45.8) in the EP arm.

As of the follow-up final analysis (data cut-off: January 27, 2020), 441 deaths had occurred, representing 82.1% maturity for OS overall.⁷ The median duration of follow-up in censored patients was 25.20 months in the durvalumab + EP group and 23.24 months in the EP-alone group. The median duration of follow-up including patients who died was 12.68 months in the durvalumab + EP group and 10.18 months in the EP-alone group. Median OS was 12.9 months (95% CI, 11.3 to 14.7) in the durvalumab + EP arm compared to 10.5 months (95% CI, 9.3 to 11.2) in the EP arm (HR = 0.75; 95% CI, 0.625 to 0.910; nominal P = 0.0032). Kaplan–Meier curves are depicted in Figure 7 (Appendix 3). The post hoc Kaplan–Meier estimate of landmark OS at 18 months was 32.0% (95% CI, 26.5 to 37.7) in the durvalumab + EP arm compared to 24.8% (95% CI, 19.7, 30.1) in the EP arm. The post hoc Kaplan–Meier estimate of landmark OS at 24 months was 22.2% (95% CI, 17.3, 27.5) in the durvalumab + EP arm versus 14.4% (95% CI, 10.3, 19.2) in the EP arm.

Figure 4: Kaplan–Meier Curves of Overall Survival for the Durvalumab + EP and EP-Alone Arms — ITT Population, Interim Analysis (Data Cut-Off: March 11, 2019)

CI = confidence interval; DE = durvalumab in combination with etoposide and either carboplatin or cisplatin; E = etoposide and either carboplatin or cisplatin; OS = overall survival.

Note: A circle indicates a censored observation and 1 month = 30.4375 days.

^a Based on a Lan-DeMets alpha spending function with an O’Brien-Fleming boundary with the actual number of events observed; the boundaries for declaring statistical significance are 0.0178 for a 4% overall alpha. Corresponding 95% CIs are shown.

Source: Clinical Study Report.⁶

In addition, a planned sensitivity analysis was conducted using a Kaplan–Meier plot of time to censoring, with the censoring indicator of OS reversed to assess potential attrition bias. Early censoring (> 10 weeks before data cut-off) was observed for 2 patients (0.7%) in the durvalumab + EP arm compared to 8 patients (3.0%) in the EP arm. This suggests that the potential for attrition bias affecting OS is low.

Results from the pre-specified, exploratory subgroup analysis of OS are summarized in Table 17. The treatment effect on OS was consistent with the primary analysis across the 3 pre-specified patient subgroups of smoking status, baseline ECOG PS, and brain metastases at baseline.

Exploratory post hoc analyses of OS by PD-L1 expression and tumour mutational burden were conducted for the subset of patients with available and evaluable tissue samples.³² Regarding PD-L1 expression, tumour tissue samples were evaluable for a total of 277 patients (51.6%) in the durvalumab + EP and EP arms. Overall, 94.9% and 77.6% of patients had PD-L1 expression of less than 1% on tumour cells and immune cells, respectively. Due to low PD-L1 expression, a 1% cut-off was used in post hoc analyses. There was no evidence of a statistically significant interaction between PD-L1 expression and OS. Tissue tumour mutational burden was assessed in 283 patients, and results from the exploratory analysis suggested that tumour mutational burden was not predictive of an improvement in OS for durvalumab + EP versus EP alone. Additional data on PD-L1 expression and tumour mutational burden relative to OS are available in Appendix 3 (Figure 8 and Figure 9).

Progression-Free Survival

The investigator-assessed PFS periods in the CASPIAN trial for the durvalumab + EP and EP-alone arms are summarized in Table 18. Median PFS was similar at both the interim and final analysis. As of the interim analysis, median PFS was 5.1 months (95% CI, 4.7 to 6.2) in the durvalumab + EP arm and 5.4 months (95% CI, 4.8 to 6.2) in the EP arm (HR: 0.78; 95% CI, 0.645 to 0.936; nominal P = 0.0078). Kaplan–Meier curves as of the interim analysis are depicted in Figure 6. There was a delay of approximately 6 months in separation of the curves, and the associated log-log plot showed some evidence of non-proportionality of hazards.

As of the final analysis, median PFS was 5.1 months (95% CI, 4.7 to 6.2) in the durvalumab + EP arm and 5.4 months (95% CI, 4.8 to 6.2) in the EP arm (HR = 0.80; 95% CI, 0.665 to 0.959; nominal P = 0.0157). As of the final analysis, the post hoc Kaplan–Meier estimate of landmark PFS at 18 months was 13.9% (95% CI, 10.0 to 18.4) in the durvalumab + EP arm compared to 3.4% (95% CI, 1.6 to 6.4) in the EP arm. The landmark PFS at 24 months was 11.0% (95% CI, 7.5 to 15.2) in the durvalumab + EP arm versus 2.9% (95% CI, 1.2 to 5.8) in the EP arm.

Figure 5: Kaplan–Meier Curves of PFS for the Durvalumab + EP and EP-Alone Arms in the CASPIAN Trial — ITT Population, Interim Analysis (Data Cut-Off: March 11, 2019)

CI = confidence interval; DE = durvalumab in combination with etoposide and either carboplatin or cisplatin; E = etoposide and either carboplatin or cisplatin; PFS = progression-free survival.

Note: A circle indicates a censored observation and 1 month = 30.4375 days.

Source: Clinical Study Report.⁶

Sensitivity analyses were conducted to assess potential biases, including attrition bias. Fewer patients were censored for PFS in the durvalumab + EP arm (N = 42, 16%) compared to the EP arm (N = 36, 13%).⁶ The Kaplan–Meier plot of time to censoring showed that patients were censored for PFS earlier in the EP group than were those in the durvalumab + EP group. Eight (3%) patients were early-censored (> 10 weeks before data cut-off) in the durvalumab + EP arm compared to 29 (11%) patients in the EP arm.

Results from the pre-specified, exploratory subgroup analysis of PFS are summarized in Appendix 3 (Table 25). The treatment effect on PFS was consistent with the primary analysis across the 3 pre-specified patient subgroups of smoking status, baseline ECOG PS, and brain metastases at baseline.

Duration of Response

Duration of response was calculated post hoc in the subset of patients that had a confirmed response and results are summarized in Table 19. At both the interim and final analyses, the Kaplan–Meier estimate of median confirmed DOR was 5.1 months (95% CI, 4.9 to 5.3) in the durvalumab + EP arm and 5.1 months (95% CI, 4.8 to 5.3) in the EP arm.^6,7 At the final analysis, the Kaplan–Meier estimates of patients remaining in confirmed response at 12 months were 23.2% and 7.3% in the durvalumab + EP and EP-alone arms, respectively. The Kaplan–Meier estimates of patients remaining in confirmed response at 24 months were 13.5% and 3.9% in the durvalumab + EP and EP-alone arms, respectively. Variance was not calculated for the percentage of patients remaining in confirmed response at 12 months and 24 months.

Objective Response Rate

The investigator-assessed unconfirmed and confirmed ORRs were similar at the interim and final analyses.^6,7

As of the interim analysis, the unconfirmed ORRs were 79.5% and 70.3% in the durvalumab + EP and EP arms, respectively (OR = 1.64; 95% CI, 1.106 to 2.443; nominal P = 0.0137). The confirmed ORRs were 67.9% and 57.6% in the durvalumab + EP and EP-alone arms, respectively (OR = 1.56; 95% CI, 1.095 to 2.218; nominal P = 0.0136).

As of the final analysis, the unconfirmed ORRs were 79.5% and 70.6% in the durvalumab + EP and EP-alone arms, respectively (OR = 1.61; 95% CI, 1.086 to 2.401; nominal P = 0.0177). The confirmed ORRs were 67.9% and 58.0% in the durvalumab + EP and EP-alone arms, respectively (OR = 1.53; 95% CI, 1.078 to 2.185; nominal P = 0.0173).

Health-Related Quality of Life

Results from the EORTC QLQ-C30 and QLQ-L13 were analyzed at the interim analysis.⁶

Time to deterioration of EORTC QLQ-C30 and QLQ-LC13 scores was assessed in patients whose baseline scores were 10 or higher for functioning and global health status/quality of life and no more than 90 for symptoms. Time to deterioration was calculated as the time from randomization to the first clinically meaningful deterioration at a subsequent assessment, or death from any cause in the absence of clinically meaningful deterioration. The CASPIAN trial defined a clinically meaningful deterioration as an increase of at least 10 points from baseline for symptoms and a decrease of at least 10 points from baseline for function and global health status/quality of life. The MID reported in the literature varied depending on the improvement or deterioration among different items scales. The EORTC QLQ-C30 and QLQ-L13 are described in detail in Appendix 4.

The PRO-evaluable population consisted of 261 patients from the durvalumab + EP arm and 260 patients from the EP-alone arm.^6,30 Compliance was defined as the proportion of patients in the PRO-evaluable population for whom data were available at each time point. Compliance rates for EORTC QLQ-C30 and QLQ-L13 were highest at baseline (≥ 94%) and similar between the durvalumab + EP and EP-alone groups for the first 9 weeks (≥ 78%).⁶ Compliance rates for both groups decreased over time and were generally lower in the EP group. Compliance rates of greater than 60% were observed for up to 84 weeks in the durvalumab + EP group, and for up to 20 weeks in the EP group.

Baseline EORTC QLQ-C30 and QLQ-LC13 scores are summarized in Appendix 3 (Table 26). Baseline scores were comparable between study groups.⁶

Times to deterioration in EORTC QLQ-C30 and QLQ-L13 scales are summarized in Figure 6 and Appendix 3 (Table 27). Median time to deterioration nominally longer in the durvalumab + EP arm compared to the EP-alone arm were observed for all function scales (physical, role, emotional, cognitive, and social).⁶ Median time to deterioration was also nominally longer in the durvalumab + EP arm compared to the EP arm for the symptoms of dyspnea, insomnia, appetite loss, constipation, diarrhea, hemoptysis, chest pain, arm/shoulder pain, and other pain.

Figure 6: Forest Plot of Time to Deterioration of EORTC QLQ-C30 and QLQ-L13 Scores — PRO-Evaluable Population, Interim Analysis (Data Cut-Off: March 11, 2019)

Durva = durvalumab; EP = etoposide-platinum (carboplatin or cisplatin); PRO = patient-reported outcome; QLQ-C30 = 30-item Core Quality of Life Questionnaire, version 3; QLQ-LC13 = 13-item Lung Cancer Quality of Life Questionnaire; QoL = quality of life.

Source: Clinical Study Report.⁶

Symptoms

Results from the EORTC QLQ-C30 and QLQ-L13 were analyzed at the interim analysis.⁶

Table 21 presents the results from the MMRM analysis of EORTC QLQ-C30 and QLQ-LC13 key symptoms from baseline to PD or 12 months. The predefined key symptoms were cough, dyspnea, and chest pain (as assessed by EORTC QLQ-LC13), and fatigue and appetite loss (as assessed by EORTC QLQ-C30). The CASPIAN trial defined a clinically meaningful difference as an absolute change in the score from baseline of at least 10 points. The MID reported in the literature varies depending on the improvement or deterioration among different items scales. The EORTC QLQ-C30 and QLQ-L13 are described in detail in Appendix 4.

For appetite loss, the adjusted mean change from baseline in appetite loss score was −12.7 points in the durvalumab + EP arm.⁶ The estimated difference between treatment arms for appetite loss was −4.5 (95% CI, −9.04 to −0.04; P = 0.009) in favour of durvalumab + EP. No significant differences between treatment arms were observed for the symptoms of fatigue, cough, dyspnea, and chest pain.

Harms

Only those harms identified in the review protocol for the durvalumab + EP and EP-alone arms of the CASPIAN trial are reported below. See Table 22 for detailed harms data. Harms data for the durvalumab + tremelimumab + EP arm are available in Appendix 3 (Table 30).

Adverse Events

A total of 260 patients (98.1%) in the durvalumab + EP arm and 258 patients (97.0%) in the EP-alone arm experienced an AE.⁷ The most commonly reported AEs in the durvalumab + EP and EP-alone arms were neutropenia (41.9% and 46.6%, respectively), anemia (38.5% and 47.0%, respectively), nausea (33.6% and 33.5%, respectively), and alopecia (31.7% and 34.2%, respectively). A greater proportion of patients (≥ 5% difference between groups) in the durvalumab + EP arm compared to the EP-alone arm experienced hyperthyroidism (9.8% versus 0.4%, respectively), hypothyroidism (9.4% versus 1.5%, respectively), cough (12.5% versus 6.8%, respectively), and hyponatremia (9.8% versus 4.5%, respectively). Anemia was reported at a lower proportion in the durvalumab + EP arm compared with the EP-alone arm (38.5% versus 47.0%, respectively).

Serious Adverse Events

Overall, 34% of patients in the durvalumab + EP and EP arms of the CASPIAN trial experienced an SAE.⁷ A greater number of SAEs were reported in the EP arm (N = 97, 36.5%) compared to the durvalumab + EP arm (N = 84, 32.1%). The most commonly reported SAEs in the durvalumab + EP and EP-alone arms were febrile neutropenia (4.5% and 4.5%, respectively), anemia (1.9% and 4.5%, respectively), pneumonia (2.3% and 3.4%, respectively), and thrombocytopenia (0.4% and 3.4%, respectively).

Withdrawals Due to Adverse Events

Withdrawals specifically due to AEs were not reported.^6,7 Withdrawals due to AEs in general in the CASPIAN trial are summarized in Table 11. A total of 4 patients (1.5%) in durvalumab + EP arm and 12 patients (2.5%) in the EP arm left the study due to withdrawal.⁷ Adverse events led to discontinuation of study treatment in 27 (10.2%) patients in the durvalumab + EP arm and 25 (9.4%) patients in the EP arm.

Mortality

As of the final analysis, 210 patients (78.4%) in durvalumab + EP arm and 231 patients (85.9%) in EP arm had died.⁷ The majority of deaths were attributed to ES-SCLC in both treatment arms: 189 patients (71.3%) in the durvalumab + EP arm and 200 patients (75.1%) in the EP arm.

Notable Harms

As of the final analysis, 141 patients (53.2%) in the durvalumab + EP arm and 104 patients (39.1%) in the EP arm experienced an immune-related AE. The most frequently reported immune-related AEs in the durvalumab + EP arm were endocrine (n = 75, 28.3%) and dermatitis/rash (n = 51, 19.2%). The most frequently reported immune-related AEs in the EP arm were diarrhea/colitis (n = 31, 11.7%) and dermatitis/rash (n = 25, 9.4%). A greater proportion of patients (≥ 5% difference between groups) in the durvalumab + EP arm compared to the EP arm experienced hepatic (14.0% versus 7.9%, respectively), endocrine (28.3% versus 6.8%, respectively), and dermatitis/rash (19.2% versus 9.4%, respectively) immune-related AEs. Furthermore, a greater proportion of patients (≥ 5% difference between groups) in the durvalumab + EP arm compared to the EP-alone arm received systemic corticosteroids (11.7% versus 2.6%), high-dose steroids (8.3% versus 1.1%), and endocrine therapy (16.6% versus 3.4%).

Five patients in the durvalumab + EP arm and 3 patients in the EP arm experienced an infusion-related reaction. Three patients in durvalumab + EP arm and 2 patients in the EP arm experienced hypersensitivity/anaphylactic reactions.

Ninety-three patients (35.1%) in the durvalumab + EP arm and 82 patients (30.8%) in the EP arm experienced an infection.

Critical Appraisal

Internal Validity

In general, the CASPIAN trial was a well-designed and well-conducted RCT. The sample size was adequate, and a stratified randomization procedure based on the type of platinum-based chemotherapy was used. Most efficacy analyses (including OS and PFS) were conducted according to the ITT principle. Subgroup analyses of OS and PFS (ECOG PS, smoking history, and brain metastases at baseline) were specified a priori. However, they were not adjusted for multiplicity and should therefore be considered exploratory. Treatment exposure was adequate to evaluate the safety and tolerability of durvalumab and EP, although treatment discontinuation rates were high. There was extremely little loss to follow-up and patients were followed for survival for up to 2 years. Treatment groups were generally well balanced. The differences in prognostic baseline characteristics (e.g., brain metastases, ECOG PS) between the 3 treatment arms were considered minor and unlikely to have a significant effect on outcomes, according to the clinical experts consulted by CADTH. There was an imbalance in prior radiotherapy between groups. However, the clinical experts advised that this was unlikely to influence clinical outcomes due to the small numbers of patients relative to the study sample size.

Four protocol amendments were implemented in the trial, including multiple changes to the primary objective and primary end points of the trial after randomization of all study patients was complete. Progression-free survival was originally a co-primary end point but was then changed to the key secondary end point. This may have introduced bias into the trial. In addition, blinded central review to determine PD for PFS was removed, and PD was then determined by investigator assessment. Removal of a blinded review could introduce bias into a trial, particularly as it was done after enrolment. The changes in objectives and end points were accompanied by changes to the multiple testing procedure and alpha spending, which could have introduced further bias. The direction of the bias introduced by the multiple protocol amendments is unclear.

The open-label design of the trial makes it prone to different biases. The primary outcome of the CASPIAN trial, OS, is an objective outcome and reporting of deaths are unlikely to be influenced. However, the way in which patients are treated throughout the study could be influenced by knowledge of treatment assignment and impact OS. The direction of the effect of this potential bias on OS is unknown. In addition, the open-label design could potentially affect study conduct and secondary outcomes, such as investigator assessment of response and disease progression (PFS, DOR, and ORR), patient withdrawals, patient-reported symptoms, and HRQoL. Outcomes that rely on investigator assessments may have been biased, but the direction of bias is unknown. The open-label design also may have affected AE reporting, but the direction of bias is unknown. Despite this, the clinical experts consulted by CADTH noted that maintaining blinding can be challenging in immunotherapy trials because the profile of AEs (e.g., dermatitis/rash and thyroid dysfunction) can reveal which treatment the patient is receiving.

In the CASPIAN trial, a multiple testing procedure was applied to control the overall type I error rate for OS and PFS at 5%. The CASPIAN trial met its primary end point for OS at the interim analysis, which indicated a survival benefit with the addition of durvalumab to EP. The treatment effect of durvalumab on OS was generally observed across patient subgroups as well. Furthermore, the PFS results generally support the observed treatment effect of durvalumab on OS and the results of the subgroup analysis of PFS were also consistent. However, the PFS results are associated with substantial uncertainty. It was not possible to formally test PFS for statistical significance within the multiple testing procedure at either the interim or final analysis. The primary end point of OS was met for the durvalumab + EP versus EP-alone arm, but both this and the durvalumab + tremelimumab + EP versus EP-alone analysis needed to be significant before PFS could be tested. As the latter was not, the results for PFS must be considered with regards to potential type I error. In addition, sensitivity analyses of PFS indicated a potential effect of attrition bias. For the analysis of both OS and PFS, the HRs and CIs were calculated using a stratified Cox proportional hazards model, adjusting for planned platinum therapy (carboplatin or cisplatin) at cycle 1. Kaplan–Meier plots of OS and PFS showed a 6-month delay in separation of the curves, providing some evidence of non-proportionality. This affects the validity of the Cox regression models used to analyze OS and PFS in the trial. Furthermore, because landmark OS and PFS were calculated post hoc, these results should be considered exploratory.

After experiencing disease progression, patients were offered standard chemotherapy per study protocol. Patients may also have received subsequent anticancer treatments after discontinuing the study. The OS data could be confounded by subsequent treatments. Subsequent chemotherapy was balanced between the durvalumab + EP and EP-alone treatment arms. There is a potential confounding effect of PCI, which was permitted only in the EP arm. A greater proportion of patients in the EP arm received subsequent radiotherapy. The radiotherapy imbalance may have biased results in favour of the EP arm. However, the clinical experts consulted by CADTH indicated that the subsequent treatments were unlikely to have a significant effect on OS.

Symptoms and HRQoL were analyzed at the interim analysis only. Overall type I error was controlled using the Bonferroni-adjusted procedure for the MMRM analysis of 5 key symptoms (cough, dyspnea, chest pain, fatigue, and appetite loss) assessed by the EORTC QLQ-C30 and QLQ-LC13. Results showed a statistically significant difference in favour of durvalumab + EP for appetite loss, but not for the other symptoms. Because this analysis was controlled for multiplicity, the results can be regarded with greater confidence.

As the time to deterioration analysis of the EORTC QLQ-C30 and QLQ-LC13 subscales was not controlled for multiplicity, results for HRQoL must be considered with regards to potential type I error, although the time to deterioration analysis results generally suggest that the addition of durvalumab to EP was beneficial to delaying deterioration in HRQoL compared to EP alone. Interpretation of the HRQoL and symptom results is limited by the divergence in compliance rates (i.e., completion of the questionnaires) between the treatment arms. The sample size in the EP arm was markedly lower than that in the durvalumab + EP arm from approximately week 24 onward, although the direction of bias remains unclear.

Because there was no adjustment for multiplicity for ORR and DOR, results must be considered with regards to potential type I error. In addition, confirmation of response was not required by the study protocol, which limits interpretation of the ORR as this may have introduced bias into the results, although the direction of bias is unclear. This also affects DOR, which was calculated post hoc in confirmed responders only. As a result of these factors, substantial uncertainty is associated with the secondary outcome results and interpretation of the data is limited.

External Validity

The assigned treatment in the EP arm of the CASPIAN trial was an appropriate comparator because it is reflective of current Canadian practice. In the durvalumab + EP arm, the dosage and administration schedule of durvalumab + first-line EP aligns with the Health Canada–approved dosing and the anticipated use of durvalumab in clinical practice, according to the clinical experts consulted by CADTH. The platinum component of EP in both treatment arms of interest included either carboplatin or cisplatin, as chosen by the investigator, which also reflects Canadian practice. However, a greater proportion of CASPIAN patients received carboplatin than would be expected in Canadian practice, according to the clinical experts consulted by CADTH.

Duration of follow-up was adequate to evaluate the efficacy and safety of durvalumab and EP. The final analysis provides a median follow-up of greater than 2 years.

The enrolled study population is generally representative of Canadian patients with ES-SCLC. The CASPIAN trial included patients with brain metastases at baseline, which is common in patients with ES-SCLC. However, the clinical experts consulted by CADTH identified some differences between the study population and Canadian ES-SCLC patients. For example, the CASPIAN trial patient population included a greater proportion of non-smokers than is seen in Canadian clinical practice. In addition, enrolment was limited to patients with an ECOG PS of 0 or 1, which does not reflect the Canadian ES-SCLC patient population. The clinical experts advised that Canadian patients with ES-SCLC often have a higher ECOG PS (≥ 2) at baseline. As the CASPIAN study population had a lower ECOG PS at baseline, it is possible that these patients would have better outcomes than patients with higher baseline ECOG PS records. However, the clinical experts noted that classification of ECOG PS is subjective, and a patient’s ECOG PS often improves after the first cycle of chemotherapy. The CASPIAN trial did not enroll any patients from Canada.

Indirect Evidence

No indirect treatment comparisons were included in the sponsor’s submission to CADTH or identified in the literature search.

Other Relevant Evidence

No long-term extension studies or other relevant studies were included in the sponsor’s submission to CADTH.

Discussion

Summary of Available Evidence

The systematic review of durvalumab in combination with EP for the first-line treatment of ES-SCLC included a single phase III RCT. The CASPIAN study (N = 805) was an international, multi-centre, phase III, open-label, RCT conducted to investigate the efficacy and safety of durvalumab, with or without tremelimumab, in combination with EP compared to EP alone as a first-line treatment regimen in adult patients with ES-SCLC. Patients were randomized in a 1:1:1 ratio to 3 treatment arms: durvalumab + tremelimumab + EP, durvalumab + EP, and EP alone. Randomization was stratified by the planned platinum drug (i.e., cisplatin or carboplatin). Data for the durvalumab + tremelimumab + EP arm of the CASPIAN trial were not included in the CADTH systematic review because the combination is not aligned with the Health Canada product monograph. The primary outcome of the CASPIAN trial was OS, and the key secondary outcome was PFS. Secondary outcomes included DOR, ORR, and HRQoL/symptoms (assessed by the EORTC QLQ-C30 and QLQ-LC13).

Most patients enrolled in the CASPIAN trial were male, White, smokers with a small cell carcinoma (combined) histology type, and an ECOG PS of 1. The mean age of all patients was 62.6 years. Small proportions of patients had received previous chemotherapy and radiotherapy.

No indirect treatment comparisons or other evidence were included in the sponsor’s submission to CADTH or identified in the literature search.

Interpretation of Results

Efficacy

Overall survival was considered the most important outcome by the clinical experts and clinician groups consulted by CADTH. Prolonging survival is also important to patients. The CASPIAN trial met its primary end point of OS for durvalumab + EP versus EP at the planned interim analysis. Durvalumab + EP demonstrated a statistically significant improvement in OS versus EP. Median OS was 2.7 months longer in the durvalumab + EP arm compared to the EP arm, which was considered clinically meaningful by the clinical experts consulted by CADTH. Kaplan–Meier curves showed a delay of approximately 6 months in separation, providing some evidence of non-proportionality of hazards. This affects the validity of the Cox regression model used in the trial. The subgroup analysis (smoking status, ECOG PS at baseline, and brain metastases at baseline) of OS was consistent with the primary analysis. The final follow-up analysis continued to show a similar improvement in OS with durvalumab + EP compared to EP. The OS benefits were observed against those of a control group that allowed PCI and up to 6 cycles of EP, compared to the 4 cycles allowed in the durvalumab + EP arm, which may have biased results in favour of EP.

The clinical experts consulted by CADTH and the clinician groups reported that the tail end of the Kaplan–Meier survival curves and landmark survival rates were important to the interpretation of study results. Landmark survival was calculated post hoc. The results generally suggest that the addition of durvalumab to EP may be beneficial compared to EP alone. However, the landmark survival analyses in the CASPIAN trial are considered exploratory, and these end points are associated with uncertainty due to the small number of patients alive at these time points. Furthermore, there was no hypothesis testing of these time points. For these reasons, the landmark survival results should be interpreted with caution.

Progression-free survival was the key secondary outcome of the CASPIAN trial. The patient groups that provided input on this review reported that delaying disease progression and prolonging survival is important to patients. The multiple testing procedure required OS to reach statistical significance for the analysis of the durvalumab + EP arm versus the EP arm and for the durvalumab + tremelimumab + EP versus EP-alone arms before stepping down to PFS. Because the latter was not met, PFS was not formally tested for statistical significance and the results for PFS must be considered with regards to potential for type I error. In addition, Kaplan–Meier curves showed a delay of approximately 6 months in separation, suggesting non-proportionality of hazards, and sensitivity analyses indicated potential attrition bias. Therefore, PFS results are associated with substantial uncertainty and must be interpreted with caution. Although the PFS results are uncertain, they were generally congruent with the OS results and the HRs suggested that the addition of durvalumab may be beneficial over EP alone. The landmark PFS rates generally suggested that the addition of durvalumab to EP may be beneficial compared to EP alone, but these analyses are exploratory, associated with a substantial degree of uncertainty due to the small number of patients alive at these time points, and lack hypothesis testing.

Objective response rate and DOR were secondary outcomes in the CASPIAN trial. The patient groups that provided input on this review reported that patients want treatments that provide longer-lasting and durable disease response, which aligns with these outcomes. Median DORs were equal in both treatment arms at both analyses, although the percentage of patients remaining in response at 12 and 24 months suggests that durvalumab + EP may be beneficial compared to EP alone. The ORs calculated for the unconfirmed and confirmed ORRs at both analyses also suggest that the addition of durvalumab may be beneficial over EP alone. However, interpretation of the ORR and DOR is limited as they were not controlled for multiplicity, and analysis of the DOR was post hoc.

Symptoms and HRQoL were evaluated as secondary outcomes in the CASPIAN trial. The patient groups that provided input for this review identified improving symptoms and delaying deterioration in HRQoL as important. Symptoms and HRQoL were analyzed at the interim analysis only, and the MMRM analysis of the 5 key symptoms was controlled for type I error. In the durvalumab + EP arm, the adjusted mean change from baseline in the appetite loss symptom score met the MID, and the difference between treatment arms was statistically significant.

Analysis of the time to deterioration in the function and symptom scales of the EORTC QLQ-C30 and QLQ-LC13 suggests that the addition of durvalumab may be beneficial over EP alone. However, the lack of adjustment for multiplicity means this analysis should be considered exploratory and interpreted with caution. Interpretation of the HRQoL and symptom results is also limited by the divergence in compliance rates between the treatment arms.

Harms

Almost all study participants reported treatment-emergent AEs. The most common AEs in both the durvalumab + EP and EP arms were hematological events (neutropenia and anemia), nausea, and alopecia. The clinical experts consulted by CADTH indicated that these AEs were reflective of the EP component of treatment. A greater proportion of patients died in the EP arm compared to the durvalumab + EP arm. The frequency of SAEs was also greater in the EP arm. The clinical experts consulted by CADTH noted that the greater frequency of SAEs in the EP arm may have been due to the higher number of cycles received (i.e., up to 6 cycles of chemotherapy in the EP arm versus a maximum of 4 cycles in the durvalumab + EP arm).

Notable harms in the review included immune-related AEs, infusion-related reactions, hypersensitivity/anaphylactic reactions, and infections. Immune-related AEs were more frequent in the durvalumab + EP arm compared to the EP arm. The most common immune-related AEs were endocrine-related issues and dermatitis/rash, which is consistent with the safety and tolerability profile of durvalumab, according to the clinical experts. Furthermore, the clinical experts consulted by CADTH reported that the immune-related AE profile was expected and consistent with other immune checkpoint inhibitors. A small number of patients in each treatment arm experienced infusion-related reactions and hypersensitivity/anaphylactic reactions. More patients in the durvalumab + EP arm experienced infection.

Conclusions

One phase III, open-label, active-controlled RCT (CASPIAN) provided direct evidence regarding the efficacy and safety of durvalumab in combination with EP in adult patients with ES-SCLC relative to EP alone. Compared to EP, patients who were treated with durvalumab + EP showed benefits in OS. The difference in median OS between treatment arms (2.7 months) was considered statistically significant and clinically relevant by the clinical experts consulted by CADTH. The results suggest that the addition of durvalumab to EP was associated with an improvement in PFS compared to EP alone, but this finding is associated with substantial uncertainty because of the inability to conduct formal statistical tests within the trial’s multiple testing procedure, evidence of non-proportionality of hazards, potential attrition bias, and introduction of bias by the removal of blinded independent central review after enrolment was complete. The effects of durvalumab on the ORR and DOR are also uncertain due to the lack of control for multiplicity, and the DOR was calculated post hoc in confirmed responders only when confirmation of response was not required by the study protocol. The results of the time to deterioration in HRQoL and symptoms suggest that durvalumab + EP may have a beneficial effect, but this remains uncertain due a lack of control for multiplicity and differences in completion rates of the EORTC QLQ-C30 and QLQ-LC13 between treatment arms. The results of the symptom analysis suggest that adding durvalumab to EP may have a benefit in terms of appetite loss compared to EP alone. Almost all study participants reported treatment-emergent AEs. Durvalumab + EP was related to more immune-mediated AEs compared to EP alone, although the profile and incidence rates of these AEs was expected, according to the clinical experts consulted by CADTH. Infusion-related and hypersensitivity/anaphylactic reactions were uncommon, and the incidence of infections was similar in both treatment arms.

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Appendix 1: Literature Search Strategy

Note that this appendix has been formatted for accessibility but has not been copy-edited.

Clinical Literature Search

Overview

Interface: Ovid

Databases:

• MEDLINE All (1946-present)

• Embase (1974-present)

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

Date of search: December 22, 2020

Alerts: Weekly search updates until project completion

Study types: No filters were applied to limit retrieval by study type

Limits:

• Publication date limit: none

• Language limit: none

• Conference abstracts: excluded

Table 23: Syntax Guide

Multi-Database Strategy

1. (durvalumab* or imfinzi* or medi4736 or medi-4736 or 28X28X9OKV or L01XC28).ti,ab,kf,ot,hw,nm,rn.

2. Small cell lung carcinoma/

3. (SCLC or SCLCs or ESSCLC or ESSCLCs).ti,ab,kf,ot.

4. ((small or microcellular* or smallcell) adj5 (lung* or bronch* or pulmonar*) adj5 (cancer* or tumor* or tumour* or carcinoma* or neoplas*)).ti,ab,kf,ot.

5. (oat-cell adj3 (cancer* or tumor* or tumour* or carcinoma* or neoplas*)).ti,ab,kf,ot.

6. (Combined adj5 (small or smallcell) adj5 (cancer* or tumor* or tumour* or carcinoma* or neoplas*)).ti,ab,kf,ot.

7. or/2–6

8. 1 and 7

9. 8 use medall

10. *durvalumab/ or (durvalumab* or imfinzi* or medi4736 or medi-4736 or L01XC28).ti,ab,kw,dq.

11. Small cell lung cancer/

12. (SCLC or SCLCs or ESSCLC or ESSCLCs).ti,ab,kw,dq.

13. ((small or microcellular* or smallcell) adj5 (lung* or bronch* or pulmonar*) adj5 (cancer* or tumor* or tumor* or carcinoma* or neoplas*)).ti,ab,kw,dq.

14. (oat-cell adj3 (cancer* or tumor* or tumour* or carcinoma* or neoplas*)).ti,ab,kw,dq.

15. (Combined adj5 (small or smallcell) adj5 (cancer* or tumor* or tumour* or carcinoma* or neoplas*)).ti,ab,kw,dq.

16. or/11–15

17. 10 and 16

18. 17 use oemezd

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

20. 18 not 19

21. 9 or 20

22. remove duplicates from 21

Clinical Trials Registries

ClinicalTrials.gov

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

[Searched terms: Imfinzi/durvalumab, small-cell lung cancer (SCLC)]

WHO ICTRP

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

[Searched terms: Imfinzi/durvalumab, small-cell lung cancer (SCLC)]

Health Canada’s Clinical Trials Database

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

[Searched terms: Imfinzi/durvalumab, small-cell lung cancer (SCLC)]

EU Clinical Trials Register

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

[Searched terms: Imfinzi/durvalumab, small-cell lung cancer (SCLC)]

Canadian Cancer Trials

Produced by the Canadian Partnership Against Cancer Corporation. Targeted search used to capture registered clinical trials.

[Searched terms: Imfinzi/durvalumab, small-cell lung cancer (SCLC)]

Grey Literature

Search dates: October 16 to 23, 2020

Keywords: Imfinzi (durvalumab), small-cell lung cancer (SCLC)

Limits:

Updated: Publication years: none

Search updated prior to 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 (https://www.cadth.ca/grey-matters) were searched:

• Health Technology Assessment Agencies

• Health Economics

• Clinical Practice Guidelines

• Drug and Device Regulatory Approvals

• Advisories and Warnings

• Drug Class Reviews

• Clinical Trials Registries

• Databases (free)

• Internet Search

• Open Access Journals

Appendix 2: Excluded Studies

Note that this appendix has been formatted for accessibility but has not been copy-edited.

Table 24: Excluded Studies

Appendix 3: Detailed Outcome Data

Note that this appendix has been formatted for accessibility but has not been copy-edited.

Figure 7: Kaplan–Meier Curves of Overall Survival for the Durvalumab + EP and EP Arms — ITT Population, Final Analysis (Data Cut-Off: January 27, 2020)

CI = confidence interval; DE = durvalumab in combination with etoposide and either carboplatin or cisplatin; E = etoposide and either carboplatin or cisplatin; OS = overall survival.

Circle indicates a censored observation.

One month = 30.4375 days.

Source: Clinical Study Report⁷

Table 25: PFS Subgroup Analysis — ITT Population, Interim Analysis (Data Cut-Off March 11, 2019)

CI = confidence interval; EP = etoposide and either carboplatin or cisplatin; HR = hazard ratio; ITT = intention-to-treat.

^aHR < 1 favours durvalumab + EP to be associated with a longer PFS than EP. HR and 95% CI were calculated from an unstratified Cox proportional hazards model with treatment as the only covariate.

Source: Clinical Study Report⁶

Table 26: Baseline EORTC QLQ-C30 and QLQ-LC13 Scores — PRO-Evaluable Population, Interim Analysis (Data Cut-Off March 11, 2019)

EORTC = European Organisation for Research and Treatment of Cancer; EP = etoposide + carboplatin or cisplatin; QLQ-C30 = 30-item Core Quality of Life Questionnaire, version 3; QLQ-LC13 = 13-item Lung Cancer Quality of Life Questionnaire; SD = standard deviation.

Source: Clinical Study Report⁶

Table 27: Time to Deterioration of EORTC QLQ-C30 and QLQ-LC13 — PRO-Evaluable Population, Interim Analysis (Data Cut-Off March 11, 2019)

CI = confidence interval; EORTC = European Organisation for Research and Treatment of Cancer; EP = etoposide + carboplatin or cisplatin; HR = hazard ratio; PRO = patient-reported outcome; QLQ-C30 = 30-item Core Quality of Life Questionnaire, version 3; QLQ-LC13 = 13-item Lung Cancer Quality of Life Questionnaire; QoL = quality of life; SD = standard deviation.

^aAnalysis population is based on patients who have a baseline score ≥ 10 in the EORTC QLQ-C30 function scales and global health status/QoL (respectively ≤ 90 in the EORTC QLQ-C30 and EORTC QLQ-L13 symptom scales/items).

^bMedian time to deterioration calculated using the Kaplan–Meier technique. CI is derived based on Brookmeyer-Crowley method and using the log-log transformation.

^cThe HR and CIs were calculated using a stratified Cox proportional hazards model, adjusting for planned platinum therapy in cycle 1 (carboplatin or cisplatin), and ties handled by Efron approach.

^dHR < 1 favours durvalumab + EP to be associated with a longer time to deterioration than EP.

^eNominal P value (i.e., results are non-inferential). The analysis was performed using the stratified log-rank test, adjusting for planned platinum therapy in cycle 1 (carboplatin or cisplatin), and using the rank tests of association approach.

Source: Clinical Study Report⁶

Table 28: Duration of Exposure to Study Treatments in the Durvalumab + Tremelimumab + EP Arm of the CASPIAN Trial — Safety Population, Final Analysis (Data Cut-Off January 27, 2020)

EP = etoposide + carboplatin or cisplatin; Max = maximum; Min = minimum; SD = standard deviation.

Source: Clinical Study Report⁷

Table 29: Summary of Efficacy Outcomes of the Durvalumab + Tremelimumab + EP Arm in the CASPIAN Trial — Final Analysis (Data Cut-Off January 27, 2020)