Indication: Cemiplimab in combination with platinum-based chemotherapy for the first-line treatment of adult patients with non-small cell lung cancer (NSCLC) whose tumors have no epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) or c‐ROS oncogene 1 (ROS1) aberrations and is locally advanced where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC
Sponsor: sanofi-aventis Canada Inc.
Final recommendation: Reimburse with conditions
Summary
What Is the CADTH Reimbursement Recommendation for Libtayo?
CADTH recommends that Libtayo in combination with platinum-based chemotherapy be reimbursed by public drug plans for the first-line treatment of adults with non–small cell lung cancer (NSCLC) whose tumours have no EGFR, ALK, or ROS1 aberrations and is locally advanced where patients are not candidates for surgical resection or definitive chemoradiation, or for those with metastatic NSCLC, if certain conditions are met.
Which Patients Are Eligible for Coverage?
Libtayo in combination with platinum-based chemotherapy should only be covered to treat adults who have stage IIIB or IIIC NSCLC and are not suitable for curative surgery or definitive chemoradiation or have stage IV NSCLC and have not received prior systemic treatment. Patients’ tumours should have no EGFR, ALK, or ROS1 aberrations. Patients should have a good performance status.
What Are the Conditions for Reimbursement?
Libtayo should only be reimbursed in combination with platinum-based chemotherapy if prescribed by clinicians with expertise and experience in treating NSCLC. The treatment should be delivered in outpatient specialized oncology clinics with expertise in systemic therapy delivery and management of immunotherapy-related side effects. The price of Libtayo should be negotiated so that its use in combination with platinum-based chemotherapy does not exceed the total drug cost of treatment with the least costly immunotherapy reimbursed in the first-line setting.
Why Did CADTH Make This Recommendation?
Evidence from a clinical trial demonstrated that treatment with Libtayo in combination with platinum-based chemotherapy was better than treatment with platinum-based chemotherapy alone in allowing patients to live longer and delaying cancer progression.
Libtayo meets patient needs of delaying disease progression, prolonging survival, and offering an additional treatment option.
Based on CADTH’s assessment of the health economic evidence, Libtayo does not represent good value to the health care system at the public list price. The committee determined that there is not enough evidence to justify a greater cost for Libtayo in combination with platinum-based chemotherapy compared with pembrolizumab or nivolumab and ipilimumab in combination of platinum-based chemotherapy over the duration of treatment.
Based on public list prices, Libtayo in combination with platinum-based chemotherapy is estimated to cost the public drug plans approximately $5 million over the next 3 years.
Additional Information
What Is NSCLC?
NSCLC occurs when healthy cells in the lung become cancerous and is considered metastatic when cancer cells have spread to other parts of the body. NSCLC is the most common type of lung cancer, comprising about 80% of all lung cancer cases. Approximately 30,000 new cases of NSCLC are diagnosed each year in Canada.
Unmet Needs in NSCLC
Not all patients have a response to currently available treatments for advanced NSCLC and most patients will experience disease progression.
How Much Does Libtayo Cost?
Treatment with Libtayo in combination with platinum-based chemotherapy is expected to cost between $9,055 and $13,735 per 21-day course, depending on the chemotherapy combination of choice.
The pCODR Expert Review Committee (pERC) recommends that cemiplimab in combination with platinum-based chemotherapy (cemiplimab plus PBC) be reimbursed for the first-line treatment of adults with NSCLC whose tumours have no EGFR, ALK, or ROS1 aberrations and is locally advanced where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, only if the conditions listed in Table 1 are met.
One phase III, double-blind, placebo-controlled trial (EMPOWER-Lung 3; N = 466) demonstrated that cemiplimab plus PBC resulted in added clinical benefit in adults with advanced NSCLC whose tumours had no EGFR, ALK, or ROS1 aberrations, and who were not candidates for surgical resection or definitive chemoradiation, or those who had metastatic disease. The EMPOWER-Lung 3 trial demonstrated that, compared with placebo plus PBC, cemiplimab plus PBC resulted in a statistically significant and clinically meaningful improvement in median overall survival (OS) at the 16.4 month median follow-up time (21.9 months versus 13.0 months; hazard ratio [HR] = 0.71; 95% confidence interval [CI], 0.53 to 0.93; P = 0.0140). Two-year OS rates at the final analysis with a 28.4 month median follow-up time were 42.7% (95% CI, 36.9 to 48.4) and 27.2% (95% CI, 20.1 to 34.9) for the cemiplimab plus PBC and placebo plus PBC groups, respectively. Cemiplimab plus PBC also demonstrated statistically significant improvements in progression-free survival (PFS) (HR = 0.56; 95% CI, 0.44 to 0.70; P < 0.0001) and objective response rate (odds ratio [OR] = 2.7; 95% CI, 1.72 to 4.19; P < 0.0001) compared with placebo plus PBC. pERC considered the safety profile of cemiplimab plus PBC to be manageable and consistent with the known safety profiles of cemiplimab and PBC.
pERC reviewed the results of a sponsor-submitted indirect treatment comparison (ITC) comparing cemiplimab plus PBC to current treatment options, pembrolizumab plus PBC and nivolumab plus ipilimumab plus PBC. Due to limitations of the ITC, pERC was unable to draw definitive conclusions on the relative efficacy of cemiplimab plus PBC compared to other combination therapies.
Patients identified a need for effective treatment options that delay disease progression, improve quality of life, have fewer side effects and the potential for cure, and improved patient access. pERC concluded that, compared with placebo plus PBC, cemiplimab plus PBC met some of the patients’ needs as it delays disease progression, prolongs survival, and offers an additional treatment option. pERC noted that the fixed dose of cemiplimab plus PBC may improve patient accessibility in rural and remote regions by avoiding the need for vial sharing associated with weight-based dosing with other immunotherapy combinations. Although patients expressed an unmet need for treatments that improve quality of life, no definitive conclusion could be reached regarding the effects of cemiplimab plus PBC on health-related quality of life (HRQoL) due to a significant decline in the number of patients available to provide assessments over time and the descriptive nature of the analyses.
At the sponsor-submitted price for cemiplimab plus PBC and publicly listed price for all other comparators, cemiplimab plus PBC was more costly than pembrolizumab plus PBC when assumed to be similarly effective based on the economic evaluation. As there is no evidence to suggest that cemiplimab plus PBC is more effective than pembrolizumab plus PBC and nivolumab plus ipilimumab plus PBC, the total drug cost of cemiplimab plus PBC should not exceed the total drug cost of the least costly immunotherapy over the duration of treatment.
Table 1: Reimbursement Conditions and Reasons
Reimbursement condition | Reason | Implementation guidance |
|---|---|---|
Initiation | ||
1. Treatment with cemiplimab + PBC should be reimbursed in adults with squamous or nonsquamous NSCLC who meet the following criteria: 1.1. have stage IIIB or IIIC NSCLC and are not suitable for curative surgery or definitive chemoradiation, or have stage IV NSCLC 1.2. have had no prior systemic treatment. | Evidence from the EMPOWER-Lung 3 trial demonstrated that treatment with cemiplimab + PBC resulted in a clinical benefit in patients with these characteristics. | pERC noted that patients who progress at least 6 months after their last dose of adjuvant or neoadjuvant platinum-doublet chemotherapy and PD-1 or PD-L1 inhibitor should be eligible to receive cemiplimab + PBC, in line with the EMPOWER-Lung 3 trial criteria. |
2. Patients should have good performance status. | Patients with an ECOG PS of 0 or 1 were included in the EMPOWER-Lung 3 trial. | Treating patients with an ECOG PS of 2 may be at the discretion of the treating clinician. |
3. Patients must not have any of the following: 3.1. tumours with EGFR, ALK, or ROS1 aberrations 3.2. active or untreated brain metastases 3.3. prior neoadjuvant or adjuvant anti–PD-1 or anti–PD-L1 therapy within 6 months of treatment start or any prior anti–PD-1 or anti–PD-L1 therapy in the advanced disease setting. | There is no evidence to support a benefit of cemiplimab + PBC treatment in patients with these characteristics as they were excluded from the EMPOWER-Lung 3 trial. | — |
Renewal | ||
4. Reimbursement of cemiplimab should be renewed for patients who demonstrate a continued response to treatment defined as absence of disease progression. 4.1. Assessment for renewal should be based on clinical and radiographic evaluation every 3 to 4 months. | In clinical practice, treatment response is evaluated clinically at each visit, and radiologically approximately every 3 to 4 months. This is aligned with the frequency of radiographic evaluation in the EMPOWER-Lung 3 trial, which was performed every 9 weeks (3 cycles) until disease progression. | — |
5. Cemiplimab treatment should be reimbursed for a maximum of 108 weeks. | There is insufficient evidence to demonstrate a benefit of cemiplimab in patients treated beyond 108 weeks. Patients in the cemiplimab group of the EMPOWER-Lung 3 trial received cemiplimab for up to 108 weeks (36 treatment cycles). | — |
Prescribing | ||
6. Treatment with cemiplimab + PBC should be prescribed by clinicians with expertise and experience treating NSCLC. The treatment should be supervised and delivered in outpatient specialized oncology clinics with expertise in systemic therapy delivery and management of immunotherapy-related side effects. | This will ensure that treatment is prescribed only for appropriate patients and adverse effects are managed in an optimized and timely manner. | — |
7. Cemiplimab + PBC should only be reimbursed when started in combination. | There is no evidence from the EMPOWER-Lung 3 trial to support the efficacy and safety of cemiplimab + PBC when initiated in combination with additional anticancer drugs or when either component is initially used as monotherapy. | Cemiplimab can continue as monotherapy after 4 cycles of PBC. If a patient experiences a toxicity that is known to be associated with chemotherapy, chemotherapy treatment may be discontinued but cemiplimab treatment may be continued. |
Pricing | ||
8. The cost of cemiplimab should be negotiated so that it does not exceed the drug program cost of treatment with the least costly immunotherapy reimbursed for first-line treatment of adults with NSCLC whose tumours have no EGFR, ALK, or ROS1 aberrations and who have locally advanced NSCLC who are not candidates for surgical resection or definitive chemoradiation, or those who have metastatic NSCLC. | There is no clinical evidence to justify a cost premium for cemiplimab over the least costly immunotherapy reimbursed for the indicated population. | — |
ECOG PS = Eastern Cooperative Oncology Group Performance Status; NSCLC = non–small cell lung cancer; PBC = platinum-based chemotherapy; pERC = pCODR Expert Review Committee.
pERC noted that other combination therapies, such as pembrolizumab plus PBC or nivolumab plus ipilimumab plus PBC, are currently available for the requested patient population. pERC discussed the results of a sponsor-submitted ITC that compared cemiplimab plus PBC with pembrolizumab plus PBC and nivolumab plus ipilimumab plus PBC. pERC acknowledged several limitations with the submitted network meta-analysis (NMA), notably the small number of studies and heterogeneity across study designs and populations. Due to the limitations of the NMA, pERC could not draw definitive conclusions on the relative efficacy and safety of cemiplimab plus PBC versus other combination therapies.
pERC noted that patients with NSCLC identified a need for alternative treatment options with fewer side effects. Comparative safety from the EMPOWER-Lung 3 trial indicated that grade 3 or higher and serious adverse events (AEs) were more common in patients treated with cemiplimab plus PBC than those treated with placebo plus PBC. pERC heard from the clinical experts that a higher proportion of AEs was expected in the cemiplimab plus PBC group, given that a combination therapy was being evaluated in comparison to chemotherapy only. pERC could not draw conclusions regarding the safety of cemiplimab plus PBC compared to other combination therapies due to limitations of the submitted indirect evidence. However, pERC acknowledged clinical expert input that the safety profile of cemiplimab plus PBC appeared consistent with, and as manageable as, other currently available combinations of immunotherapy and PBC.
pERC discussed input from patient and clinician groups that highlighted the potential advantages with the fixed dose of cemiplimab plus PBC versus weight-based dosing, which is used for alternative combination therapies by some jurisdictions. According to stakeholder input, weight-based dosing may require vial sharing and patients to travel to larger hospitals for infusions, which may pose financial, emotional, and mental burdens to patients. A fixed dosing option, such as cemiplimab plus PBC, may help close an equity gap by avoiding the need for vial sharing and allowing treatment to be administered in community settings closer to patients’ homes, thereby reducing barriers to treatment access. pERC agreed that cemiplimab plus PBC may improve patient accessibility in rural and remote regions by avoiding the need for vial sharing.
Lung and bronchus cancer is the most commonly diagnosed cancer in Canada (excluding nonmelanoma skin cancers). In 2022, an estimated 30,000 people in Canada were diagnosed with lung and bronchus cancer, representing approximately 13% of all new cancer cases, and 20,700 people in Canada died from lung cancer, representing 24% of all cancer deaths in 2022. The risk factors include tobacco smoking, second-hand smoke, radon, asbestos, and other environmental exposures, with symptoms like cough, shortness of breath, and chest pain. Lung cancer is primarily divided into small cell lung cancer and NSCLC, with NSCLC found in almost 80% of lung cancer cases. The prognosis largely depends on the stage at diagnosis, with half of the cases being diagnosed at stage IV.
Treatment for early-stage NSCLC (i.e., stages I, II, some IIIA) typically involves surgical resection, often combined with chemotherapy and/or radiation. Advanced stages (i.e., IIIB and IIIC, IV) are treated with systemic therapies like immunotherapy, chemotherapy, or both, depending on factors like PD-L1 expression and the presence of specific genetic alterations. Platinum-based chemotherapy, once the mainstay, is now often combined with or replaced by targeted therapies and immunotherapies, especially for tumours without oncogenic alterations. In Canada, treatment strategies include targeted therapy for actionable genetic alterations, with immunotherapy and chemotherapy used in various combinations based on PD-L1 expression and other factors.
The heterogeneity of NSCLC, with its various subtypes and molecular profiles, means that some patients’ disease may not respond to available treatments or may develop a lack of response over time, leading to disease progression. The current mortality rate in NSCLC remains high; thus, there is a need for therapies that can offer a more durable response and ultimately improve survival rates. The toxicity associated with systemic therapies for NSCLC is a significant concern. Adverse effects can range from mild to severe and life-threatening. Therefore, there is a need for treatments that extend survival while minimizing treatment-related toxicity.
The cemiplimab for injection, 350 mg/7 mL (50 mg/mL), single-use vial for IV infusion is indicated in combination with platinum- based chemotherapy for the first-line treatment of adult patients with NSCLC whose tumours have no EGFR, ALK or ROS1 aberrations and is locally advanced where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC.
To make its recommendation, the committee considered the following information:
a review of 1 phase III trial randomized controlled trial (RCT) in patients with advanced NSCLC and 1 sponsor-submitted ITC
patients’ perspectives gathered by 3 patient groups, the Canadian Cancer Survivor Network (CCSN), Lung Cancer Canada (LCC), and the Lung Health Foundation (LHF)
input from public drug plans and cancer agencies that participate in the CADTH review process
input from 2 clinical specialists with expertise diagnosing and treating patients with NSCLC
input from 2 clinician groups, the LCC – Medical Advisory Committee (MAC) and the Ontario Health-Cancer Care Ontario (OH-CCO) Lung Cancer Drug Advisory Committee
a review of the pharmacoeconomic model and report submitted by the sponsor.
The information in this section is a summary of input provided by the patient and clinician groups that responded to CADTH’s call for input and from the clinical experts consulted by CADTH for the purpose of this review.
Three patient groups provided input to CADTH: CCSN (9 patients and 1 caregiver), LLC (4 patients), and LHF (15 patients and 1 caregiver). Input was gathered through surveys and discussions, focusing on experiences with lung cancer treatments, including cemiplimab. The input noted that the disease significantly impacts patients’ and families’ daily lives, causing physical and emotional strain. Key outcomes important to patients include symptom management, quality of life, and delay in disease progression. CCSN emphasized the challenges faced by patients and caregivers, including managing side effects and emotional burdens, with most patients reporting satisfactory access to existing treatments. LCC noted positive experiences with cemiplimab, particularly in symptom management and ease of use. LHF reported on the significant impact of symptoms on patients’ lives, the effectiveness of current treatments in symptom relief, and the desire for earlier biomarker testing. All groups underscored the need for treatments that effectively delay disease progression with minimal side effects.
According to clinical experts consulted by CADTH, unmet needs in NSCLC include improving survival and quality of life while minimizing treatment toxicity. Cemiplimab combined with platinum-based chemotherapy is seen as an alternative to existing first-line therapies for patients with advanced or metastatic NSCLC without specific driver mutations and with varying PD-L1 expression levels. The experts identified the most benefit for patients with high disease burden and least suitability for those with significant comorbidities or poor performance status. Response to treatment should be assessed clinically and radiologically, focusing on tumour shrinkage and quality of life. Discontinuation of treatment can be considered upon disease progression, unacceptable toxicity, or after 2 years of treatment. Treatment with cemiplimab is managed by a medical oncologist in outpatient settings.
CADTH received input from 2 clinician groups, LCC – MAC and the OH-CCO Lung Cancer Drug Advisory Committee. In total, 12 clinicians from LCC - MAC and 3 clinicians from the OH-CCO Lung Cancer Drug Advisory Committee provided input to the submissions. Clinician groups agreed that the first line of treatment is chemotherapy and immunotherapy, or pembrolizumab alone in patients with a PD-L1 status higher than 50%. For patients not eligible for immunotherapy, platinum-doublet chemotherapy remains an option. There was agreement among all clinicians that improvements in PFS, OS, and quality of life are treatment goals. LCC - MAC noted the benefits of cemiplimab having a flat dose of 350 mg, without a weight-based option. This clinician group felt that this would provide significant advantages in delivering treatment closer to home for many patients with lung cancer because vial sharing would not be required. Both clinician groups agreed that in terms of place in therapy, cemiplimab in combination with platinum-based chemotherapy would be an alternative first-line treatment.
Regarding eligibility criteria, other than incurable NSCLC, first-line therapy, and no EGFR, ALK, ROS1 alterations, the clinical expert consulted by CADTH noted any PD-L1 expression and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2, while LCC - MAC added that patients in rural areas will benefit more from cemiplimab because no vial sharing would be required.
Clinical and radiological assessments were noted as the best ways to determine whether a patient’s disease is responding to treatment. Disease progression, toxicity, patient preference, and certain AEs were factors to be considered when deciding to discontinue treatment.
It was agreed that outpatient clinics under the supervision of a medical oncologist are the appropriate setting for treatment with cemiplimab in combination with platinum‐based chemotherapy. LCC – MAC added that in many jurisdictions across Canada, particularly in more remote or rural communities, medical oncologists work in partnership with general practitioners in oncology to comanage patients.
Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The clinical expert consulted by CADTH provided advice on the potential implementation issues raised by the drug programs. Refer to Table 2 for details.
Table 2: Responses to Questions From the Drug Programs
Implementation issues | Response |
|---|---|
Relevant comparators | |
The EMPOWER-Lung 3 trial compared cemiplimab + PBC vs. PBC alone in patients with advanced NSCLC with no EGFR, ALK, ROS1 driver mutations, irrespective of PD-L1 status. More appropriate comparators include single-drug pembrolizumab (if PD-L1 ≥ 50%), ipilimumab + nivolumab + chemotherapy, pembrolizumab + pemetrexed + platinum (nonsquamous only), pembrolizumab + nonpemetrexed platinum (squamous). How does cemiplimab + PBC compare to these immunotherapy ± chemotherapy regimens? | No direct evidence from a clinical trial currently exists to compare cemiplimab + PBC to other immunotherapies given as monotherapy or in combination with chemotherapy. The clinical experts consulted by CADTH anticipated that 2-year overall survival and progression-free survival with cemiplimab + PBC are likely comparable to other immunotherapies in combination with chemotherapy. Furthermore, the clinical experts consulted by CADTH anticipated the toxicity profile of cemiplimab + chemotherapy to be similar to that of pembrolizumab + chemotherapy. pERC acknowledged the clinical experts’ response and noted that there is insufficient evidence to draw definitive conclusions on the relative efficacy and safety of cemiplimab + PBC vs. other combination therapies. |
Considerations for initiation of therapy | |
The trial included those who had never smoked, patients with treated brain metastases, and those with an ECOG PS of 0 or 1. Should cemiplimab + PBC be considered for patients with an ECOG PS of greater than 1? | pERC agreed with the clinical expert that patients with an ECOG PS of 2 are likely to benefit from cemiplimab + PBC and should be considered. |
Are patients who had previous adjuvant or neoadjuvant immunotherapy eligible for cemiplimab + PBC? If so, is there a minimum disease-free interval that must be met? | The clinical experts noted that patients with NSCLC who have previously received adjuvant or neoadjuvant immunotherapy may be considered for subsequent treatment with cemiplimab + PBC. The optimal disease-free interval remains a subject of clinical judgment in the absence of robust evidence. The decision should be individualized, taking into account the duration and type of prior immunotherapy, the patient's disease course, and the potential benefits and risks of re-treatment with immunotherapy-chemotherapy combinations. pERC noted that patients who progress at least 6 months after their last dose of adjuvant or neoadjuvant platinum-doublet chemotherapy and PD-1 or PD-L1 inhibitor should be eligible to receive cemiplimab + PBC, in line with the EMPOWER-Lung 3 trial criteria. |
If a patient receives 108 weeks of cemiplimab and their disease subsequently relapses, is there evidence to support re-treatment? If so, would there be a maximum duration? | pERC agreed with the clinical experts suggesting to align re-treatment eligibility of cemiplimab + PBC with other reimbursed combinations of immunotherapy and chemotherapy. pERC noted that patients who completed 2 years of cemiplimab treatment and had disease progression after the end of treatment should be eligible for re-treatment for up to 17 cycles (1 year). pERC agreed that patients who start re-treatment with cemiplimab may receive chemotherapy treatment at the discretion of the treating physician. |
Considerations for discontinuation of therapy | |
If a patient discontinues treatment before the completion of 108 weeks due to toxicity, but without disease relapse, could the patient restart and be treated to a maximum of 108 weeks? | Patients were allowed to resume therapy after resolution of toxicity in the EMPOWER-Lung 3 trial. pERC agreed with the clinical experts that these trial criteria were applicable to clinical practice. |
Considerations for prescribing of therapy | |
Although CADTH had issued a positive recommendation, single-drug cemiplimab remains unfunded as a national agreement could not be reached. The CADTH assessment needs to account for the initiation of this regimen as a combination regimen. | This was a comment from the drug programs to inform pERC deliberations. |
Funding algorithm | |
Cemiplimab + PBC would be an alternative treatment option to existing immunotherapy ± chemotherapy regimens that are already funded. Under what conditions would cemiplimab + PBC be preferred over pembrolizumab ± chemotherapy, or nivolumab + ipilimumab + chemotherapy? | pERC agreed with the clinical experts that cemiplimab + PBC may be a valuable addition to the treatment landscape but may not drastically change the current standard of care. Cemiplimab + PBC may expand the options available to patients who are not suitable candidates for other treatments and have disease that has progressed on other PD-1 or PD-L1 therapies in the advanced setting. |
System and economic issues | |
In certain jurisdictions that do not fund drug wastage, cemiplimab may be a preferred option given its flat dosing. The cost of cemiplimab + PBC should not exceed the drug program cost of the existing funded immunotherapy + chemotherapy regimens. | This was a comment from the drug programs to inform pERC deliberations. |
Confidential prices are in place for pembrolizumab and ipilimumab + nivolumab. | This was a comment from the drug programs to inform pERC deliberations. |
ECOG PS = Eastern Cooperative Oncology Group Performance Status; NSCLC = non–small cell lung cancer; PBC = platinum-based chemotherapy; pERC = pCODR Expert Review Committee.
One pivotal phase III RCT was included in the systematic review: EMPOWER-Lung 3 part 2. EMPOWER-Lung 3 is a 2-part, phase III clinical trial evaluating the efficacy and safety of cemiplimab in combination with PBC versus placebo plus PBC in patients with advanced NSCLC regardless of PD-L1 expression levels. EMPOWER-Lung 3 did not include sites in Canada and maintained separate protocols for parts 1 and 2. Part 2 of the study compared cemiplimab plus PBC to placebo plus PBC across different PD-L1 expression levels and is the focus of this report. Two data cut-off dates were reported for EMPOWER-Lung 3 part 2: the first on June 14, 2021 (prespecified second interim analysis) after a median follow-up of 16.4 months, and the second on June 14, 2022 (prespecified final analysis) after approximately 28.4 months of follow-up. As the efficacy boundary was crossed at the second interim analysis, no alpha was assigned to the prespecified final analysis for OS. The Independent Data Monitoring Committee (IDMC) recommended unblinding the study after the first data cut-off date when statistical significance for OS was achieved. The primary objective of part 2 was to assess OS differences between the cemiplimab plus PBC and placebo plus PBC groups in the first-line treatment of advanced NSCLC. Secondary objectives included PFS and objective response rate (ORR).
Patients were randomized in a 2:1 ratio to receive histology-specific platinum-doublet chemotherapy with cemiplimab or placebo, stratified by histology and PD-L1 expression levels. Treatment continued for up to 108 weeks or until disease progression or unacceptable toxicity, with mandatory pemetrexed maintenance for nonsquamous histology. The study design instituted caps on enrolment based on PD-L1 expression and histology. Eligible participants were adults with advanced squamous or nonsquamous NSCLC, with no prior systemic treatment for metastatic disease. Patients with certain genetic aberrations were excluded, as targeted therapies are the standard of care for those conditions. Enrolment was open to patients with adequately treated brain metastases and controlled viral infections, and without significant autoimmune diseases. The main intervention was cemiplimab or placebo, administered intravenously in combination with PBC every 3 weeks for 4 cycles. The primary outcome, OS, was defined as the time from randomization to death from any cause. PFS, a key secondary outcome, was the time to disease progression or death, assessed by an Independent Review Committee using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria. ORR was the proportion of patients with a confirmed complete or partial response, reported as a key secondary outcome. The study also used the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Version 3.0 (QLQ-C30) and Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13) questionnaires to measure HRQoL as other secondary outcomes.
At the secondary interim analysis (June 14, 2021, data cut-off date), cemiplimab plus PBC showed statistically significant improvements in OS, PFS, and ORR for patients with advanced NSCLC compared to placebo plus PBC. The results at the subsequent data cut-off date, June 14, 2022, including the final OS analyses, were consistent with the those seen at the previous data cut-off date.
At the June 14, 2022, data cut-off date, cemiplimab plus PBC showed improvements in OS and PFS for patients with advanced NSCLC compared to placebo plus PBC. Median OS was longer in the cemiplimab plus PBC group (21.1 months; 95% CI, 15.9 to 23.5) versus the placebo plus PBC group (12.9 months; 95% CI, 10.6 to 15.7) with a stratified HR of 0.645 (95% CI, 0.507 to 0.820; P = 0.0003) in favour of the cemiplimab plus PBC group. Survival probabilities at 12 months and 24 months were 66.4% and 42.7%, respectively, in the cemiplimab plus PBC group, and were 53.9% and 27.2%, respectively, in the placebo plus PBC group. The median PFS was 8.2 months (95% CI, 6.4 to 9.0) in the cemiplimab plus PBC group compared to 5.5 months (95% CI, 4.3 to 6.2) in the placebo plus PBC group. PFS probabilities at 12 months and 24 months were 38.7% and 19.7%, respectively, in the cemiplimab plus PBC group and 16.1% and 3.6%, respectively, in the placebo plus PBC group. The ORR was higher in the cemiplimab plus PBC group (43.6%; 95% CI, 38.0 to 49.3) than in the placebo plus PBC group (22.1%; 95% CI, 15.8 to 29.5).
The safety results from part 2 of EMPOWER-Lung 3 trial at the June 14, 2022, data cut-off date indicated that, overall, the safety profile of the combination treatment appeared consistent with the known safety profiles of cemiplimab and PBC individually. Similar proportions of patients in both treatment groups experienced AEs (96.5% in the cemiplimab plus PBC group and 94.8% in placebo plus PBC group). The most frequent AEs (cemiplimab plus PBC versus placebo plus PBC) included anemia (45.8% versus 39.9%), alopecia (37.2% versus 43.8%), nausea (25.3% versus 16.3%), hyperglycemia (18.3% versus 11.8%), and increased alanine transaminase (ALT) levels (17.6% versus 15.0%). A total of 48.7% of patients in the cemiplimab plus PBC group and 32.7% of patients in the placebo plus PBC group experienced at least 1 grade 3 or higher treatment-emergent adverse event (TEAE). The most common grade 3 or higher TEAEs experienced by 2% or more of patients within the cemiplimab plus PBC group (cemiplimab plus PBC versus placebo plus PBC) included anemia (10.9% versus 6.5%), neutropenia (6.4% versus 5.9%), decreased white blood cell count (|||| versus ||||), and thrombocytopenia (3.2% versus 1.3%). Numerically, a higher proportion of serious AEs were reported in the cemiplimab plus PBC group (30.1%) than in the placebo plus PBC group (24.2%), with comparable rates for the most commonly reported serious AEs (cemiplimab plus PBC versus placebo plus PBC): pneumonia (2.9% versus 2.0%), anemia (2.9% versus 1.3%), febrile neutropenia (1.3% versus 2.6%), and death (8.7% versus 9.2%). AEs of special interest were reported in |||| of patients in the cemiplimab plus PBC group and |||| in the placebo plus PBC group as of the June 14, 2022, data cut-off. The most frequent AE of special interest was ||||| | || |||||| |||||||||||||||| |||||||||, occurring in |||| of patients in the cemiplimab plus PBC group and |||| in the placebo plus PBC group. A total of ||| patients (||||) died due to TEAEs in the cemiplimab plus PBC group and ||| patient (||||) died due to TEAEs in the placebo plus PBC group.
The EMPOWER-Lung 3 part 2 study was a double-blind, placebo-controlled phase III RCT. The study's randomization was facilitated by an interactive web response system, stratified by histology and PD-L1 expression level. The study employed appropriate methods for time-to-event analysis, including the Kaplan-Meier method and Cox proportional hazard model.
Limitations in the EMPOWER-Lung 3 part 2 study included the higher percentage of subsequent anticancer therapies received by patients in the placebo plus PBC group compared to the cemiplimab plus PBC group, which may have introduced a confounding variable, potentially affecting the OS results. Furthermore, as the study was concluded at the secondary interim analysis, data between the interim analysis cut-off date of June 2021 and the final analysis cut-off date of June 2022 were collected from an unblinded period of the study, potentially introducing biases in subjective outcomes such as HRQoL and harms. In addition, the high rate of missing patient-reported outcomes data over time, especially in the placebo group, makes interpretation of patient-reported outcomes over time challenging and the results remain inconclusive.
The clinical experts noted that the study’s inclusion criteria and patient characteristics align with typical oncology trials and clinical practice in Canada and suggested that baseline demographic and tumour characteristics were generally consistent with an expected population of patients with NSCLC seen in their practices. A limitation to generalizability was the trial’s comparator (placebo plus PBC), which does not reflect current practice in Canada, where patients typically receive immunotherapy. No trial sites were located in Canada, excluding the representation of health care settings in Canada from the trial. The overall low rates of subsequent therapies in both groups reduces generalizability of the results to practice in Canada.
No long-term extension studies were submitted by the sponsor.
The ITC submitted by the sponsor aimed to assess the comparative efficacy of cemiplimab plus PBC versus other Health Canada–approved therapies for the first-line treatment of patients who have locally advanced or metastatic NSCLC. Outcomes of interest included OS, PFS, ORR, and certain harms. An systematic literature review (SLR) was conducted, with searches updated until March 2022, to identify RCTs for inclusion in an NMA. The SLR focused on trials from 2010 onward. The review process included independent reviewers and a PRISMA flow diagram documenting study selection. The feasibility of an NMA was assessed, considering the connectedness of evidence, similarity of comparators, and distribution of baseline characteristics. A Bayesian NMA was performed using both fixed and random-effects models, with a fixed-effect model considered the default base case.
The SLR identified 11 relevant RCTs, with 5 unique RCTs included in the NMA for any PD-L1 expression and any histology. The evidence network allowed for comparisons of cemiplimab plus PBC with pembrolizumab plus PBC, nivolumab plus ipilimumab plus PBC, and investigator’s choice of chemotherapy.
Cemiplimab plus PBC showed favourable OS (HR at 24 months = 0.66; 95% credible interval [CrI], 0.51 to 0.87), PFS (HR at 24 months = 0.61; 95% CrI, 0.48 to 0.78), and ORR (OR at 24 months = 2.76; 95% CrI, 1.79 to 4.37) compared to investigator’s choice of chemotherapy. This is consistent with the direct evidence established in part 2 of the EMPOWER-Lung 3 trial. Comparisons against other immunotherapy combinations are much less robust and cannot inform on the comparative efficacy of cemiplimab plus PBC against other immunotherapy combinations. Results for the indirect comparison of cemiplimab plus PBC against pembrolizumab plus PBC included an HR at 24 months for OS of 0.88 (95% CrI, 0.65 to 1.21), an HR at 24 months for PFS of 0.87 (95% CrI, 0.66 to 1.15), and an OR of 0.89 (95% CrI, 0.54 to 1.49) for ORR. The results for the indirect comparison of cemiplimab plus PBC against nivolumab plus ipilimumab plus PBC included an HR at 24 months for OS of 0.85 (95% CrI, 0.61 to 1.19), an HR at 24 months for PFS of 0.91 (95% CrI, 0.68 to 1.24), and an OR of 1.53 (95% CrI, 0.89 to 2.67) for ORR.
Due to the limited evidence base and small number of events, harms results are not reported.
The sponsor-submitted ITC was performed through an SLR, which systematically identified all the trials in the network, according to prespecified criteria.
However, there was a lack of reporting on the result of the quality assessment, even though it was stated that Cochrane risk of bias tool was used, and it was unknown how studies with high-risk of bias were handled, if applicable. Several limitations resulting from the sparse network might have contributed to high uncertainty in the results obtained. The small number of included studies in the network with Bayesian fixed-effect model mandated several untested assumptions, including the clinical homogeneity assumption. However, a significant concern is whether this assumption would have been held given there was significant heterogeneity across patient populations, highly varied subsequent therapies, and differences in the level of PD-L1 expressions, histology, metastasis sites and status, chemotherapy, and maintenance therapy across the included studies.
Considering the limitations related to sparse network and clinical heterogeneity across the included trials, it is not possible to conclude that cemiplimab plus PBC has similar effect as other immunotherapies in combination with PBC on OS, PFS, and ORR. Considering the consistency of the direction of the indirect results of cemiplimab plus PBC versus chemotherapy in the ITC with the direct and existing evidence in the form of part 2 of the EMPOWER-Lung 3 trial, the indirect results can be considered supportive of the trial’s findings.
For pivotal studies and RCTs identified in the sponsor’s systematic review, Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was used to assess the certainty of the evidence for the outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.
Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.
When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty of evidence assessment was the presence or absence of a clinically important effect for EORTC QLQ-C30 based on a threshold identified in the literature for this review. The target of the certainty of evidence assessment was the presence or absence of any (non-null) effect for OS, PFS, ORR, and harms.
Table 3 presents the GRADE summary of findings for cemiplimab plus PBC versus placebo plus PBC in patients with NSCLC.
Table 3: Summary Of Findings For Cemiplimab + PBC Versus Placebo + PBC For Patients With Advanced NSCLC Whose Tumours Have No EGFR, ALK, or ROS1 Aberrations
Outcome and follow-up | Patients (studies), N | Relative effect (95% CI) | Absolute effects | Certainty | What happens | ||
|---|---|---|---|---|---|---|---|
Placebo + PBC | Cemiplimab + PBC | Difference | |||||
Overall survival | |||||||
Overall survival Median follow-up: 28.42 months | 466 (1 RCT) | Overall survival events (i.e., deaths) at data cut-off (June 14, 2022):
Median overall survival at data cut-off (June 14, 2022):
| Higha | Cemiplimab + PBC results in an increase in overall survival compared to PBC alone. | |||
Progression-free survival | |||||||
Progression-free survival Median follow-up: 28.42 months | 466 (1 RCT) | Progression-free survival events (i.e., disease progression or death) at data cut-off (June 14, 2022):
Median progression-free survival at last data cut-off (June 14, 2022):
| Higha | Cemiplimab + PBC results in an increase in progression-free survival compared to PBC alone. | |||
Response | |||||||
Objective response rate Follow-up: up to 108 weeks | 466 (1 RCT) | 2.82 (1.80 to 4.41) | 22.1 per 100 | 43.6 per 100 (95% CI, 38.0 to 49.3) | 21.51 more per 100 (95% CI, 12.96 to 30.07 more) | Highb | Cemiplimab + PBC results in an increase in the number of people achieving an objective response rate compared to PBC alone. The clinical importance of the increase is uncertain. |
Health-related quality of life | |||||||
EORTC QLQ-C30 – Global Health Status or QoL (100 [best] to 0 [worst])c Follow-up: up to cycle 21 | 466 (1 RCT) | NA | 1.08 more points | 1.69 more points (95% CI, 0.20 to 3.19) | 0.61 more points (95% CI, –2.23 fewer to 3.45 more) | Lowd | Cemiplimab + PBC may result in a little to no clinically important difference in change in EORTC QLQ-C30 when compared to PBC alone. |
Harms | |||||||
Patients with any treatment-emergent adverse events of special interest Follow-up: on-treatment period | 466 (1 RCT) | NR | ||| ||| ||| | ||| ||| ||| | 0.58 (95% CI, −2.96 to 4.11) | Lowe | Cemiplimab + PBC may result in little to no difference in treatment-emergent adverse events of special interest when compared with PBC alone. |
CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30; HR = hazard ratio; MID = minimal important difference; NA = not applicable; NR = not reported; NSCLC = non–small cell lung cancer; PBC = platinum-based chemotherapy; QoL = quality of life; RCT = randomized controlled trial; vs. = versus.
Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the following footnotes.
aIn the absence of available data for the between-group difference in event probabilities at clinically relevant time points, the judgment of imprecision was based on the 95% CI for the HR using the null as the threshold. The clinical expert consulted by CADTH noted that the HR results are clinically meaningful. This observation is consistent with the decision by the trial data and safety monitoring board to terminate the study early due to demonstrated efficacy.
bNo published between-group MID was identified, and the clinical experts consulted by CADTH were unable to estimate a threshold for clinically important effects; therefore, the null was used. This was not rated down for imprecision; a between-group difference of larger than the null and a CI that excludes the null suggest benefit compared to PBC as judged by the CADTH review team.
cThese results are based on data collected for the secondary interim analysis with a data cut-off date of June 14, 2021.
dRated down 2 levels for very serious risk of bias due to missing data. Data were available for |||| |||| ||| of patients ||||| ||||| | in the placebo + PBC group and ||||| ||||| || in the cemiplimab + PBC group. This was not rated down for imprecision. Based on the literature, a 10-point change from baseline in total score was clinically important, the point estimate and entire CI suggest little to no difference.
eRated down 2 levels for very serious concerns about imprecision due to the very small number of events.
Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence. The EMPOWER-Lung 3 part 2 trial Clinical Study Report.
Table 4: Summary of Economic Evaluation
Component | Description |
|---|---|
Type of economic evaluation | Cost-utility analysis PSM |
Target population | First-line treatment of adult patients with NSCLC whose tumours have no EGFR, ALK, or ROS1 aberrations, who have 1 of the following:
|
Treatment | Cemiplimab + PBC |
Dose regimen | 350 mg every 3 weeks, until progression or unacceptable toxicity |
Submitted price | Cemiplimab 350 mg: $8,200 per viala |
Submitted treatment cost | Cemiplimab + PBC = $183,025 per patient annually, if the patient remains on treatment for a full year |
Comparators | Pembrolizumab + PBC
|
Perspective | Canadian publicly funded health care payer |
Outcomes | QALYs, LYs |
Time horizon | Lifetime (30 years) |
Key data sources |
|
Key limitations |
|
CADTH reanalysis results |
|
ICER = incremental cost-effectiveness ratio; LY = life-year; NMA = network meta-analysis; NSCLC = non–small cell lung cancer; PBC = platinum-based chemotherapy; PSM = partitioned survival model; QALY = quality-adjusted life-year; vs. = versus; WTP = wiliness to pay.
aThe sponsor has confirmed that the 250 mg vial is being discontinued in Canada.
CADTH identified the following key limitations with the sponsor’s analysis: the sponsor’s approach to modelling treatment duration was misaligned with the pharmacoeconomic model; the dosing of pembrolizumab and nivolumab did not reflect clinical practice (fixed dosing versus weight-based dosing); and the market share of cemiplimab and pembrolizumab monotherapy was overestimated. The proportion of patients with a driver mutation was also uncertain.
CADTH reanalysis adjusted the market shares for cemiplimab and pembrolizumab monotherapy as well as adopted treatment costs for PBC alone and all immunotherapy arms estimated from the CADTH base case of the cost-utility analysis (which reflected mean treatment duration and weight-based dosing for pembrolizumab and nivolumab, and aligned distribution of PBC components and subsequent therapies across treatment arms with the clinical trial). In the CADTH base case, the 3-year budget impact of reimbursing cemiplimab plus PBC is expected to be $5,279,805 ($1,029,683 in year 1, $2,015,034 in year 2, and $2,235,088 in year 3). The incremental budget impact was sensitive to assumptions on the dosing of pembrolizumab and market shares captured from nivolumab plus ipilimumab plus PBC.
Dr. Maureen Trudeau (Chair), Mr. Daryl Bell, Dr. Phillip Blanchette, Dr. Kelvin Chan, Dr. Matthew Cheung, Dr. Michael Crump, Dr. Jennifer Fishman, Mr. Terry Hawrysh, Dr. Yoo-Joung Ko, Dr. Christian Kollmannsberger, Dr. Catherine Moltzan, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik
Meeting date: March 13, 2024
Regrets: One expert committee member did not attend.
Conflicts of interest: None
ISSN: 2563-6596
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