Drugs, Health Technologies, Health Systems
Indication: Durvalumab in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by durvalumab as monotherapy after surgery, is indicated for the treatment of resectable stage II, IIIA, or IIIB (T3‑4 N2) non–small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements
Sponsor: AstraZeneca Canada Inc.
Recommendation: Do not reimburse
Summary
What Is the Reimbursement Recommendation for Imfinzi?
Canada’s Drug Agency (CDA-AMC) recommends that Imfinzi in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by Imfinzi as a monotherapy after surgery, should not be reimbursed by public drug plans for the treatment of resectable stage II, IIIA, or IIIB (T3-4N2) non–small cell lung cancer (NSCLC) and no known EGFR mutations or ALK rearrangements.
Why Did CDA-AMC Make This Recommendation?
Evidence from 1 clinical trial showed that perioperative Imfinzi with neoadjuvant chemotherapy resulted in little to no difference in overall survival (OS) — an important outcome for curative intent therapy — and health-related quality of life (HRQoL) compared to placebo with neoadjuvant chemotherapy among patients with resectable stage II, IIIA, or IIIB (T3-4N2) NSCLC and no known EGFR mutations or ALK rearrangements. Treatment with perioperative Imfinzi with neoadjuvant chemotherapy may result in added clinical benefit in event-free survival and pathological complete response.
The sponsor-submitted indirect treatment comparisons (ITCs) assessing the comparative effects of perioperative Imfinzi with neoadjuvant chemotherapy to relevant comparators in the setting in Canada were inconclusive due to methodological limitations. Additionally, the absence of comparative OS evidence was considered a notable gap in assessing the clinical benefit of Imfinzi relative to relevant comparators.
There was insufficient evidence to suggest that perioperative Imfinzi with neoadjuvant chemotherapy addresses any unmet needs not currently being met by perioperative pembrolizumab for resectable NSCLC.
Additional Information
What Is NSCLC?
In 2024, an estimated 32,100 Canadians were expected to be diagnosed with lung cancer and an estimated 20,700 deaths were expected to be attributed to the disease. Approximately 22% of patients with lung cancer survive for 5 or more years. NSCLC is the most common type of lung cancer, accounting for about 88% of all cases.
Unmet Needs in NSCLC
There remains an unmet need for treatment options that improve survival, delay tumour growth, and reduce disease symptoms and treatment-related side effects.
How Much Does Imfinzi Cost?
Treatment with Imfinzi in combination with chemotherapy before surgery is expected to cost between $12,638 and $14,783 per 21‑day treatment cycle (depending on the chemotherapy), and treatment with Imfinzi monotherapy postsurgery is expected to cost $8,700 per 21-day treatment cycle.
The pCODR Expert Review Committee (pERC) recommends that durvalumab in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by durvalumab as monotherapy after surgery, not be reimbursed for the treatment of patients with resectable stage II, IIIA, or IIIB (T3-4N2) NSCLC and no known EGFR mutations or ALK rearrangements.
One ongoing phase III, double-blind, placebo-controlled, randomized trial, AEGEAN, demonstrated that perioperative durvalumab with neoadjuvant chemotherapy resulted in little to no difference in OS (Grading of Recommendations Assessment, Development and Evaluation [GRADE] certainty of evidence) — an important outcome for curative intent therapy — compared to placebo with neoadjuvant chemotherapy among patients with resectable stage II, IIIA, or IIIB (T3-4N2) NSCLC and no known EGFR mutations or ALK rearrangements. This result was demonstrated at both 12 and 48 months of follow-up. Added clinical benefit with perioperative durvalumab with neoadjuvant chemotherapy was observed for event-free survival (EFS) and pathological complete response (pCR), the coprimary end points in the AEGEAN trial. Perioperative durvalumab with neoadjuvant chemotherapy likely results in a clinically important increase in the probability of being event-free and alive at 12 months and at 36 months, and in a clinically important increase in the probability of achieving pCR compared to placebo with neoadjuvant chemotherapy. Perioperative durvalumab with neoadjuvant chemotherapy may result in little to no difference in HRQoL compared to placebo with neoadjuvant chemotherapy during the neoadjuvant period; however, the effects on HRQoL during the adjuvant period of treatment were uncertain. pERC considered the safety profile of perioperative durvalumab in combination with neoadjuvant chemotherapy to be manageable and consistent with the known safety profile of its individual treatment components.
pERC discussed that the results of the sponsor-submitted ITCs comparing perioperative durvalumab in combination with neoadjuvant chemotherapy against perioperative pembrolizumab in combination with neoadjuvant chemotherapy, neoadjuvant nivolumab in combination with neoadjuvant chemotherapy, adjuvant chemotherapy, and surgery alone were inconclusive, due to methodological limitations. The ITC analyses were insufficient to determine whether perioperative durvalumab or the comparator therapies were favoured for EFS. pERC also noted that the ITCs did not include a comparison of OS. Given that OS is an important outcome in this setting, the absence of comparative OS evidence was considered a notable gap in assessing the clinical benefit of durvalumab relative to relevant comparators, particularly perioperative pembrolizumab, which is the only other perioperative regimen funded in this setting. pERC concluded that there was insufficient evidence to suggest that perioperative durvalumab addresses any unmet needs currently not met by perioperative pembrolizumab for resectable NSCLC.
Efficacy and safety: pERC discussed evidence from the pivotal AEGEAN trial, which demonstrated moderate certainty (based on the GRADE assessment) that perioperative durvalumab in combination with neoadjuvant chemotherapy improved EFS and increased pCR compared to neoadjuvant chemotherapy alone. Perioperative durvalumab plus neoadjuvant chemotherapy resulted in a statistically significant improvement in EFS compared to placebo with neoadjuvant chemotherapy (hazard ratio [HR]: 0.69; 95% CI, 0.55 to 0.88, █████). At the final pCR analysis, 17.21% (95% confidence interval [CI], 13.49 to 21.48) of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm and 4.28% (95% CI, 2.46 to 6.85) of patients in the placebo with neoadjuvant chemotherapy arm had achieved pCR; the between-group difference was 12.96% (95% CI, 8.67 to 17.57). However, perioperative durvalumab in combination with neoadjuvant chemotherapy resulted in little to no difference in OS compared to neoadjuvant chemotherapy alone. Although perioperative durvalumab showed little to no effect on HRQoL and serious adverse events (AEs), immune-mediated AEs occurred more frequently in patients receiving perioperative durvalumab with neoadjuvant chemotherapy than in those receiving neoadjuvant chemotherapy alone. pERC considered the clinical expert input, noting that the adverse effects of durvalumab are generally manageable and consistent with its mechanism of action, and they concluded that the associated risks may be acceptable given the potential benefits.
Comparators: pERC discussed the results from the sponsor-submitted ITCs comparing EFS between perioperative durvalumab in combination with neoadjuvant chemotherapy and perioperative pembrolizumab in combination with chemotherapy, neoadjuvant nivolumab in combination with neoadjuvant chemotherapy, adjuvant chemotherapy, and surgery alone. The results of these indirect comparisons were inconclusive due to methodological limitations such as heterogeneity across the included studies with respect to the study designs and patient characteristics, and imprecision of the ITC estimates (i.e., ████ ████████ █████████ █████ ███ ███ ██████ █████████). The point estimates for the difference in EFS from the ITCs (matching-adjusted indirect comparison [MAIC] and network meta-analysis [NMA] ████████ █████████████ ██████████ ████ ███████████ ████████████ ████ ███████████ ██████████ █████████████ ██████████████ ████████ █████████████ ███ ███████ █████ ████████ ███ ███ ███ ███ █████ ███ ███ █████████ ████ ███ ████ ██ ████ ███ ██████████ ██ ██ ███████ █████████████ ██████████ ████ ███████████ ████████████ ███████ ██ ██████ ██ █████ ██████████████████████████████. The ITCs did not include comparisons of other outcomes important to patients, notably OS as well as HRQoL, and harms.
OS: Improved survival was identified as a key treatment priority for patients when considering their options. pERC noted that OS is particularly relevant given that the intent of the therapy in this setting is long-term remission or cure. The clinical experts consulted for this review also considered OS to be 1 of the most important outcomes to assess. They indicated that a between-group difference of 5% to 10% in OS would be considered clinically meaningful. Based on this threshold, at 48 months, perioperative durvalumab in combination with neoadjuvant chemotherapy may result in little to no difference in the probability of being alive compared to placebo with neoadjuvant chemotherapy. At a median OS follow-up time of 29.80 months, median OS was not reached in the perioperative durvalumab with neoadjuvant chemotherapy arm. Given the median length of follow-up and number of patients at risk, OS results at 12 months were considered to have high certainty of evidence. However, at 48 months, there were relatively few patients at risk, resulting in substantial uncertainty in results at later time points, and the confidence intervals crossed the clinically meaningful threshold, resulting in low certainty of evidence. The OS data in the AEGEAN trial were immature and not formally tested for statistical significance due to failure of disease-free survival (DFS) in reaching statistical significance; as such, the OS results are considered only as supportive evidence. Moreover, the comparative efficacy of perioperative durvalumab in combination with neoadjuvant chemotherapy to funded comparators remains unknown, given that OS was not assessed in the ITCs with relevant comparators.
Unmet need: pERC considered the needs expressed by patients and clinicians for treatment options that delay tumour growth, improve survival, and reduce disease symptoms and treatment-related side effects. pERC noted that the use of perioperative immune checkpoint inhibitor (ICI) therapy in combination with chemotherapy is a relatively new treatment option in Canada at this time and noted that although perioperative durvalumab may meet some treatment needs expressed by patients, including reducing tumour growth and disease symptoms, it is uncertain whether perioperative durvalumab addresses any unmet need that is currently not met by perioperative pembrolizumab for resectable NSCLC.
In 2024 alone, an estimated 32,100 Canadians were expected to be diagnosed with lung cancer and around 20,700 deaths were expected to be attributed to the disease — making lung cancer the most commonly diagnosed cancer and leading cause of cancer-related death in Canada. Lung cancer predominantly affects older adults, with 98% of cases occurring in individuals aged 50 years and older. NSCLC accounts for approximately 88% of all lung cancer cases in Canada (excluding Quebec), and approximately 25% to 30% of patients with NSCLC present with resectable early-stage disease (stage II to III). The standard of care for early-stage NSCLC has historically been surgical resection with curative intent followed by adjuvant chemotherapy. However, given that an estimated 30% to 55% of patients develop postoperative recurrence, there remains an unmet need for treatments that reduce recurrence and improve OS. Further, patients with NSCLC experience a variety of symptoms, including dyspnea, malaise, depression, anxiety, worsening cough, hemoptysis, pain, weight loss, and hoarseness. These symptoms, coupled with poor disease outlook, intensive treatment modalities and side effects, and other comorbidities common in patients with NSCLC, significantly impact patients’ quality of life (QoL). Patients with NSCLC also face significant productivity losses and stigma, with patients who do not smoke, in particular, experiencing negative perceptions associated with lung cancer. The adjusted 5-year and 10-year net survival rates for all forms and stages of lung cancer are estimated to be 22% and 15%, respectively. Recently, ICIs, such as neoadjuvant nivolumab with chemotherapy, have shown promising results, including improved survival and tumour response.
Durvalumab in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by durvalumab as monotherapy after surgery, has been approved by Health Canada (Notice of Compliance: February 20, 2026) for the treatment of resectable stage II, IIIA, or IIIB (T3-4N2) NSCLC and no known EGFR mutations or ALK rearrangements. Durvalumab is a monoclonal antibody. It is available as an IV infusion, and the dosage recommended in the product monograph is 1,500 mg in combination with chemotherapy every 3 weeks for up to 4 cycles before surgery (neoadjuvant period), followed by 1,500 mg monotherapy every 4 weeks for up to 12 cycles after surgery (adjuvant period).
To make its recommendation, the committee considered the following information:
a review of 1 phase III, double-blind, placebo-controlled, randomized, multicentre, international study in patients with resectable NSCLC, and 4 ITCs
patients’ perspectives gathered by 1 joint patient group, Canadian Cancer Survivor Network (CCSN), Lung Cancer Canada, and the Lung Health Foundation
input from public drug plans that participate in the reimbursement review process
2 clinical specialists with expertise in diagnosing and treating patients with NSCLC
input from 2 clinician groups, Lung Cancer Canada Drug Advisory Committee and Ontario Health (Cancer Care Ontario) (OH [CCO])
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 who responded to our call for input and from clinical experts consulted for the purpose of this review.
A joint submission was received from CCSN, LCC, and the Lung Health Foundation in response to the CDA-AMC call for patient input on the current review of durvalumab.
Information for this submission was collected via an online survey conducted by CCSN from June 11, 2024, to July 17, 2024, with input from Lung Cancer Canada and the Lung Health Foundation. A total of 5 respondents completed the survey, all of whom were patients with lung cancer living in Canada; 4 patients were female and 1 was male. Three of the 5 survey respondents had prior experience with durvalumab.
Respondents included patients with various stages of lung cancer, primarily stage IV. Common symptoms affecting their QoL were fatigue, pain, and shortness of breath. Chemotherapy was the most common treatment received by survey respondents, followed by immunotherapy, targeted therapy, radiation, and surgery.
According to the survey respondents, key aspects of their disease to control included tumour growth, shortness of breath, pain, and chemotherapy-related side effects; a lack of mental health support and difficulties accessing counselling and managing travel costs to access treatment were identified as unmet needs.
Respondents experienced a range of side effects, such as joint or muscle pain, fatigue, nausea, and diarrhea, with 3 out of 5 respondents considering these side effects intolerable. In terms of treatment goals, maintaining QoL, finding a cure, and prolonging life were prioritized, followed by delaying symptoms and improving ease of use.
Durvalumab was reported as beneficial by the 3 respondents with prior experience using it. They rated durvalumab significantly better for symptom management and disease progression compared to other therapies, with side effects being similar. All 3 respondents recommended making durvalumab available to eligible patients.
The clinical experts consulted for this review felt the overarching goal of NSCLC treatment is to cure the disease and, in doing so, improve OS, reduce recurrence rates, improve QoL, and reduce the symptom burden. Although recent treatment advancements have improved disease outlook, survival rates and disease burden remain suboptimal. According to the clinical experts, ICIs have achieved better results compared to chemotherapy alone; however, atezolizumab remains the only reimbursed ICI regimen in the adjuvant setting for NSCLC in Canada, and more than half of patients are ineligible due to low PD-L1 expression status. In the neoadjuvant setting, neoadjuvant nivolumab in combination with chemotherapy is currently funded. At the time of submission of this review in 2024, no perioperative ICI regimens were approved for resectable NSCLC in Canada. Note that since April 2025, CDA-AMC has issued a positive reimbursement recommendation for perioperative pembrolizumab for resectable NSCLC. The clinical experts noted that patient selection (e.g., based on histology, PD-L1 expression, disease stage, patient preference) is key when determining which patients will best respond to treatment regimens including the use of neoadjuvant, adjuvant, and perioperative approaches; currently, there are no robust head-to-head data to compare these treatment regimens.
The clinical experts noted that perioperative durvalumab with neoadjuvant chemotherapy would add an alternative first-line treatment option for patients with resectable NSCLC. The experts felt that patients with resectable NSCLC who are fit for systemic chemotherapy and ICIs without any EGFR mutations or ALK rearrangements would be best suited for perioperative durvalumab with neoadjuvant chemotherapy. Clinical experts highlighted the importance of patient preferences when selecting treatment and that those with questionable resectable disease or who are not fit for platinum-based chemotherapy may be less suited for this approach. Experts emphasized that a short time to treatment initiation is crucial to achieve the best treatment results and the proposed requirement for EGFR and ALK testing is one potential area associated with treatment delay.
Outcome metrics for resectable NSCLC used in clinical practice are typically aligned with those used in clinical trials. The clinical experts stated that in clinical trials, patient response to treatment is assessed at the time of surgery using pCR and major pathological response (MPR), using survival measures such as OS and DFS (recurrence-free) according to the Response Evaluation in Solid Tumours (RECIST) criteria, and by disease symptoms. In clinical practice, response at the time of surgery using pCR is the first step to assess benefit from therapy, followed by survival, QoL outcomes (such as patient-reported outcomes), and AEs. In clinical practice, as in trials, clinical assessments are performed before each cycle of therapy. However, assessments of disease response and recurrence usually occur every 3 to 6 months during treatment, every 6 months in the first 2 years following the last treatment cycle, and then annually thereafter, which is generally less frequent than in clinical trials.
Clinical experts consulted for this review indicated that perioperative durvalumab with neoadjuvant chemotherapy should be discontinued in the event of disease progression (including the tumour no longer being resectable, metastasis, and/or tumour growth) or recurrence, significant side effects (such as immune‑related side effects that can be life-threatening or permanent), or on a patient’s request.
Clinical experts consulted for this review indicated that treatment with perioperative durvalumab with neoadjuvant chemotherapy should be prescribed and managed in outpatient clinics or specialty clinics by a multidisciplinary thoracic team of thoracic surgeons, medical oncologists, and supportive staff, such as nursing and allied health staff.
Two clinician groups provided input for this review: Lung Cancer Canada Drug Advisory Committee (18 clinicians contributed to the input) and OH (CCO); 5 clinicians contributed to the input). Overall, the input was aligned with the clinical experts consulted by CDA-AMC.
Both clinician groups and the clinical experts consulted agreed that the treatment paradigm for patients with resectable NSCLC who do not have EGFR mutations or ALK rearrangements consists of 2 main phases: neoadjuvant and adjuvant. Neoadjuvant therapy, administered before surgery, includes chemotherapy and ICIs. OH (CCO) and Lung Cancer Canada recommend neoadjuvant platinum-based chemotherapy combined with ICIs (nivolumab) for 3 cycles. Additionally, Lung Cancer Canada noted an alternative involving chemotherapy with ICIs (durvalumab) for 4 cycles. Following surgery, adjuvant therapy involves chemotherapy and/or ICIs, whereas radiation therapy is reserved for specific cases, such as positive margins, as noted by the clinical experts consulted for this review.
The common treatment goals identified across clinician groups included achieving a cure, as measured by OS, and improving DFS. Lung Cancer Canada and the clinical experts emphasized reducing recurrence rates and enhancing QoL.
The most significant treatment gap identified by the 2 clinician groups and the clinical experts is the lack of data comparing the efficacy and role of adjuvant ICIs following neoadjuvant therapy, including which patients might benefit from it. This uncertainty makes it challenging to determine the optimal strategy for improving survival outcomes, especially given that not all patients respond to current treatments. Currently, ICIs in the adjuvant setting is only available to those with high PD-L1 expression.
Both the clinician groups and the clinical experts stated that perioperative durvalumab combined with neoadjuvant chemotherapy would offer an alternative treatment approach to neoadjuvant nivolumab in combination with chemotherapy for resectable NSCLC. The clinical experts emphasized its importance, especially for patients who do not achieve a complete pathological response to neoadjuvant therapy, highlighting the potential value of adjuvant ICIs in such cases.
According to the clinician groups, the patients who are best suited for perioperative durvalumab in combination with neoadjuvant chemotherapy are those with resectable NSCLC, no EGFR mutations or ALK rearrangements, and no contraindications to ICIs. They emphasized the role of CT scans for monitoring, with imaging recommended before and after surgery and at regular intervals during and after treatment to check for recurrence. In clinical practice, treatment response is assessed through clinical symptoms, survival outcomes (OS and DFS), and pathological response at surgery (pCR and MPR), as highlighted by the clinical expert.
Both clinician groups indicated that factors for discontinuing treatment primarily include disease progression and significant side effects, with patient preferences also playing a key role. For treatment with perioperative durvalumab with neoadjuvant chemotherapy, patients should be treated in an outpatient setting under the supervision of a medical oncologist or a pulmonologist experienced in the management of thoracic malignancies.
Input was obtained from the drug programs that participate in the reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a recommendation for durvalumab in combination with chemotherapy as neoadjuvant treatment, followed by durvalumab as monotherapy after surgery:
relevant comparators,
considerations for initiation of therapy,
considerations for prescribing of therapy,
generalizability of trial populations to the broader populations in the jurisdictions, and
potential need for a provisional funding algorithm.
The clinical experts consulted for the review provided advice on the potential implementation issues raised by the drug programs.
One ongoing trial, a phase III, double-blind, placebo-controlled, randomized, multicentre, international study (including 5 sites in Canada), AEGEAN, met the inclusion criteria for the systematic review conducted by the sponsor. The AEGEAN trial was aimed at comparing the efficacy and activity of perioperative durvalumab with neoadjuvant chemotherapy to placebo with neoadjuvant chemotherapy. Following confirmation of eligibility, a total of 802 patients (including 8 patients in Canada) were randomized in a 1:1 ratio (intention-to-treat population) using stratified randomization (by disease stage II versus III [eighth edition for tumour-nodes-metastasis] and PD-L1 expression tumour cells < 1% versus tumour cells ≥ 1%) into the 2 treatment arms. Following a protocol amendment, 62 patients with known EGFR mutations or ALK rearrangements were excluded, leaving 740 patients in the modified intention-to-treat (mITT) population: 366 patients included in the perioperative durvalumab with neoadjuvant chemotherapy arm and 374 patients included in the placebo with neoadjuvant chemotherapy arm. The outcomes relevant to this review included the final pCR and MPR analyses performed at the November 10, 2022, data cut-off date (DCO), and EFS, DFS, OS, patient-reported outcomes, and harm data collected at the May 10, 2024, DCO.
In the AEGEAN trial, patients were primarily white (397/740 [53.6%]) or Asian (307/740 [41.5%]) (all other races accounted for 36/740 [4.9%]), aged 50 years or older (703/740 [95.0%]) with a median age of 65.0 years (range: 39 to 85 years), male (530/740 [71.6%]) (210/740 [28.4%] were female), and either currently or formerly smoked (633/740 [85.5%]). Overall, at baseline, patients tended to have an Eastern Cooperative Oncology Group performance status of 0 (506/740 [68.4%]), present with stage III disease (525/740 [70.9%]), and have a baseline PD-L1 expression status greater than or equal to 1% (493/740 [66.6%]). In total, 5 patients had unknown EGFR mutation status and 12 patients had unknown ALK translocation status; these patients were balanced across both treatment arms.
Efficacy outcomes presented in this section are from the most recent DCOs (November 10, 2022, for pCR, MPR, and neoadjuvant QoL outcomes, and May 10, 2024, for all other outcomes).
pCR was tested at the pCR interim analysis (IA) (DCO on January 14, 2022) when it was deemed statistically significant, and thus statistical significance was not retested at the final analysis.
At the November 10, 2022, DCO, the final pCR analysis was completed. The percentage of patients achieving pCR was 17.21% (95% CI, 13.49 to 21.48) in the perioperative durvalumab with neoadjuvant chemotherapy arm and 4.28% (95% CI, 2.46 to 6.85) in the placebo with neoadjuvant chemotherapy arm. The between-group difference in the percentage of patients achieving pCR was 12.96% (95% CI, 8.67 to 17.57). Results of the sensitivity and subgroup analysis were consistent with the primary analysis.
MPR statistical significance was tested at the pCR IA (DCO on January 14, 2022) when it was deemed statistically significant, and thus, statistical significance was not retested at the final analysis.
At the November 10, 2022, DCO, the percentage of patients achieving MPR was 33.33% (95% CI, 28.52 to 38.42) in the perioperative durvalumab with neoadjuvant chemotherapy arm and 12.30% (95% CI, 9.15 to 16.06) in the placebo with neoadjuvant chemotherapy arm. The between-group difference in the percentage of patients achieving MPR was 21.03% (95% CI, 15.14 to 26.93).
At the May 10, 2024, DCO, the median duration of EFS follow-up was █████ ██████ ███████ ███ ██ █████ at which point 124 (44.1%) EFS events had occurred in the perioperative durvalumab with neoadjuvant chemotherapy arm and 165 (33.9%) in the placebo with neoadjuvant chemotherapy arm. The Kaplan-Meier (KM) estimate for median EFS was not reached (NR) (95% CI, 42.3 to NR) in the perioperative durvalumab with neoadjuvant chemotherapy arm and 30.0 months (95% CI, 20.6 to NR) in the placebo with neoadjuvant chemotherapy arm, with an HR of 0.69 (95% CI, 0.55 to 0.88, █████). The between-group difference in the probability of EFS at 12 and 36 months was 9.2% ████ ███ ███ ██ █████ and 12.2% ████ ███ ███ ██ ██████ respectively. Results of the sensitivity and subgroup analysis were consistent with the primary analysis.
At the May 10, 2024, DCO, DFS was tested and did not meet the prespecified boundary for declaring statistical significance. The median of DFS follow-up was █████ ██████ ███████ ███ ██ █████ at which point 60 (24.8%) DFS events had occurred in the perioperative durvalumab with neoadjuvant chemotherapy arm versus 81 (35.1%) in the placebo with neoadjuvant chemotherapy arm. The KM estimate for median DFS was NR (95% CI, NR to NR) in the perioperative durvalumab with neoadjuvant chemotherapy arm and NR (95% CI, 41.5 to NR) in the placebo with neoadjuvant chemotherapy arm, with a stratified HR of 0.66 (95% CI, 0.47 to 0.92). The between-group difference in the probability of DFS at 12 and 36 months was 6.9% (███ ███ ████ ██ █████ and 9.8% (███ ███ ████ ██ ████), respectively.
At the EFS IA2 DCOs, OS was not eligible for statistical testing (as DFS was not statistically significant and therefore OS was not formally tested based on the multiple testing procedure).
At the May 10, 2024 DCO, the median duration of OS follow-up was █████ ██████ ███████ ███ ██ █████ at which point 121 (33.1%) deaths had occurred in the perioperative durvalumab with neoadjuvant chemotherapy arm and 140 (37.4%) deaths in the placebo with neoadjuvant chemotherapy arm. The KM estimate for median OS was NR (95% CI, NR to NR) in the perioperative durvalumab with neoadjuvant chemotherapy arm and 53.2 months (95% CI, 44.3 to NR) in the placebo with neoadjuvant chemotherapy arm, with a stratified HR of 0.89 (95% CI, 0.70 to 1.14). The between-group difference in the probability of survival at 12 and 48 months was −1.0% (███ ███ ████ ██ ███) and 4.7% (███ ███ ████ ██ ████), respectively.
European Organization for Research and Treatment of Cancer (EORTC) QoL Questionnaire Core 30 (QLQ-C30) questionnaire-based outcomes were secondary end points and not adjusted for multiplicity in the AEGEAN trial.
The change from baseline to week 12 in the EORTC QLQ-C30 Global Health Status and QoL score was evaluated in the mITT population (n = 740), whereas the change from adjuvant baseline to week 44 was evaluated in the modified resected set (n = 473). The between-group difference for EORTC QLQ-C30 at week 12 of the neoadjuvant period was −0.50 (95% CI, −3.74 to 2.74). The between-group difference for EORTC QLQ-C30 at week 44 of the adjuvant period was −5.60 (95% CI, −9.38 to −1.82).
Safety outcomes presented in the following paragraph are from the May 10, 2024, DCO.
An overview of safety data is initially presented for the modified safety analysis set (consisting of all patients in the AEGEAN trial who received at least 1 dose of the study treatment and excluding those whose tumours had EGFR mutations or ALK gene rearrangements; N = 367 for the perioperative durvalumab with neoadjuvant chemotherapy arm and N = 370 for the placebo with neoadjuvant chemotherapy arm). As granular safety data were not available for the modified safety analysis set, additional data are presented for the safety analysis set, which consists of all randomized patients who received at least 1 dose of study treatment, with treatment arm allocation in accordance with the treatment actually received. The safety analysis set consisted of 799 patients (N = 401 in the perioperative durvalumab with neoadjuvant chemotherapy arm and N = 398 in the placebo with neoadjuvant chemotherapy arm).
In the modified safety analysis set, a similar percentage of patients in both treatment arms experienced any AE over the course of treatment (█████ █████████ in the perioperative durvalumab with neoadjuvant chemotherapy arm versus █████ █████████ in the placebo with neoadjuvant chemotherapy arm). The 3 most frequently reported AEs in both treatment arms of the safety analysis set were anemia (█████ in the perioperative durvalumab with neoadjuvant chemotherapy arm and █████ in the placebo with neoadjuvant chemotherapy arm), nausea (█████ in the perioperative durvalumab with neoadjuvant chemotherapy arm and █████ in the placebo with neoadjuvant chemotherapy arm), and constipation (█████ in the perioperative durvalumab with neoadjuvant chemotherapy arm and █████ in the placebo with neoadjuvant chemotherapy arm).
Slightly more patients in the perioperative durvalumab with neoadjuvant chemotherapy arm of the modified safety analysis set experienced a serious AE (█████ ████████]) than in the placebo with neoadjuvant chemotherapy arm (█████ ███████████ In the safety analysis set, the 4 most frequently reported serious AEs in the perioperative durvalumab with neoadjuvant chemotherapy arm were pneumonia (████), anemia (████), COVID-19 (████), and pneumonitis (████), whereas in the placebo with neoadjuvant chemotherapy arm, it was pneumonia (████), pneumothorax (████), anemia (████), and COVID-19 (████).
More patients in the perioperative durvalumab with neoadjuvant chemotherapy arm of the modified safety analysis set prematurely stopped study treatment (i.e., durvalumab, placebo, or neoadjuvant chemotherapy) due to AEs than in the placebo with neoadjuvant chemotherapy arm (█████ ████████ versus █████ ███████], respectively). In the safety analysis set, the 3 most common AEs leading to treatment discontinuation were blood and lymphatic system disorders ███████ respiratory, thoracic, and mediastinal disorders (██████ and nervous system disorder (█████ in the perioperative durvalumab with neoadjuvant chemotherapy arm compared to respiratory, thoracic, and mediastinal disorders ██████, investigations ██████, and blood and lymphatic system disorders ██████ and nervous system disorder ██████ in the placebo with neoadjuvant chemotherapy arm.
As of May 10, 2024, in the modified resected set ████ ███████) of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm and ████ ████████ of patients in the placebo with neoadjuvant chemotherapy arm experienced an AE resulting in death. In this analysis set, the 2 most common AEs resulting in death in the perioperative durvalumab with neoadjuvant chemotherapy arm were infections and infestations ██████ and respiratory, thoracic, and mediastinal disorders ██████ compared to infections and infestations ██████ and cardiac disorders ██████ in the placebo with neoadjuvant chemotherapy arm.
Immune-mediated AEs occurred in █████ █████████ of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm and in █████ ████████ of patients in the placebo with neoadjuvant chemotherapy arm.
The AEGEAN study is a double-blind, placebo-controlled, phase III randomized controlled trial (RCT). Randomization and allocation concealment methods were adequate. The postrandomization exclusion of those with known EGFR mutations or ALK rearrangements was judged not to be related to treatment group assignment, and therefore is not expected to introduce bias.
To mitigate the potential bias arising from the subjective interpretation of disease progression and tumour response, a blinded independent review committee reviewed all available radiographic tumour assessments to determine tumour response based on RECIST 1.1 criteria. As such, the risk of bias resulting from unblinding due to unbalanced harms across treatment arms is lower for pCR, MPR, and survival outcomes; however, there are some concerns for HRQoL outcomes. Although pCR and MPR are based on final analyses, EFS, DFS, OS, and HRQoL results should be interpreted in light of the fact that these are based on interim analyses, which may overestimate treatment effects. At the most recent AEGEAN trial DCO, results of the coprimary end points, pCR and EFS, were adjusted using the Lan-DeMets alpha spending function with O’Brien-Fleming boundaries that accounted for the actual number of patients at the time of analyses at an overall alpha of 0.5% and 4.5%, respectively. DFS and OS were included in the AEGEAN trial’s multiple testing procedure; OS was not eligible for statistical testing because DFS was not statistically significant. Although there was an adequate number of patients at risk in the AEGEAN trial for earlier DFS and OS time points, only approximately 11% of patients in both treatment arms remain at risk for OS at 48 months, and 13% to 19% remain at risk for DFS at 36 months, resulting in substantial uncertainty in results at later time points.
Biases resulting from the self-reporting nature of HRQoL outcomes were deemed to be minimal, given that participants were blinded to the intervention received. In the EORTC QLQ-C30 analyses, aimed at estimating the impact on patients’ HRQoL, 55.5% of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm and 58.5% of patients in the placebo with neoadjuvant chemotherapy arm were available to provide assessments at week 12 of the neoadjuvant period. In the modified resected set, by week 44 of the adjuvant period, 58.7% of patients in the perioperative durvalumab with neoadjuvant chemotherapy arm and 55.4% of patients in the placebo with neoadjuvant chemotherapy arm were available to provide EORTC QLQ-C30 assessments. No data imputations were involved in these analyses, so there is a risk of bias due to missing outcomes data. Further, given that analyses of the HRQoL end points were not adjusted for multiple testing, there is a higher risk of type I error for statistically significant results.
Because the analysis of EORTC QLQ-C30 in the adjuvant period, as well as the DFS analyses, are limited to the modified resected set (n = 473), and given that this is a subgroup of the mITT population (n = 740), randomization is not maintained and results are not measuring the effect of assignment to the intervention.
The outcomes measured in the AEGEAN trial evaluated the key treatment goals identified by patient input collected for this review and were deemed to be relevant by clinical experts consulted for this review. The generalizability of outcomes in the AEGEAN trial to the Canadian context is limited by the fact that only 8 patients included in the intention-to-treat population were from Canada. However, this limitation was deemed minimal by the clinical experts consulted for this review, who noted the baseline characteristics of patients enrolled in the AEGEAN trial were aligned with those seen in clinical practice in Canada. The clinical experts consulted for this review noted that currently, the 2 most commonly used regimens in clinical practice in Canada are neoadjuvant nivolumab with chemotherapy and adjuvant chemotherapy. According to the clinical experts consulted for this review, adjuvant atezolizumab after surgery and adjuvant chemotherapy for patients with PD-L1 of 50% or greater was the least relevant comparator, given that the treatment decision for perioperative durvalumab has to be made before surgery, whereas the approach for adjuvant atezolizumab would be considered after surgery and adjuvant chemotherapy. In addition to the standard-of-care chemotherapy regimens used in the AEGEAN trial, clinical experts indicated that in Canada, carboplatin and gemcitabine could also be used for squamous cell NSCLC, and cisplatin and vinorelbine may also sometimes be used for both squamous and nonsquamous cell NSCLC. The lack of these regimens used for standard chemotherapy in the AEGEAN trial further limits the generalizability to the setting in Canada; however, clinical experts consulted for this review noted they would feel comfortable combining perioperative durvalumab with these regimens.
For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform CDA-AMC 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.
The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:
OS (probabilities at 12 and 48 months), EFS (probabilities at 12 and 36 months), and pCR
HRQoL (change in EORTC QLQ-C30 Global Health Status and QoL score from adjuvant baseline to week 12 and neoadjuvant baseline to week 44)
harms (immune-mediated AEs, serious AEs).
Table 1 presents the GRADE summary of findings for perioperative durvalumab with neoadjuvant chemotherapy versus placebo with neoadjuvant chemotherapy for adults with resectable NSCLC without any EGFR mutations or ALK rearrangements.
Table 1: Summary of Findings for Perioperative Durvalumab With Neoadjuvant Chemotherapy vs. Placebo With Neoadjuvant Chemotherapy
Outcome and follow‑up | Patients (studies), N | Relative effect (95% CI) | Absolute effects (95% CI) | Certainty | What happens | ||
|---|---|---|---|---|---|---|---|
Placebo + neoadjuvant chemotherapy | Perioperative durvalumab + neoadjuvant chemotherapy | Difference | |||||
EFS | |||||||
Probability of EFS at 12 months Median (range) follow-up: █████ ██████ ██ | 740 (1 RCT) | NR | 641 per 1,000 | 733 per 1,000 (681 to 777 per 1,000) | 92 more per 1,000 (██ ██ per 1,000) | Moderatea | Perioperative durvalumab with neoadjuvant chemotherapy likely results in a clinically important increase in the probability of being event-free and alive at 12 months compared to placebo with neoadjuvant chemotherapy. |
Probability of EFS at 36 months Median (range) follow-up: █████ ██████ ██ | 740 (1 RCT) | NR | 479 per 1,000 | 601 per 1,000 (539 to 658 per 1,000) | 122 more per 1,000 (██ ██ per 1,000) | Moderateb | Perioperative durvalumab with neoadjuvant chemotherapy likely results in a clinically important increase in the probability of being event-free and alive at 36 months compared to placebo with neoadjuvant chemotherapy. |
OS | |||||||
Probability of OS at 12 months Median (range) follow-up: █████ ██████ ██ | 740 (1 RCT) | NR | 853 per 1,000 | 843 per 1,000 (801 to 877 per 1,000) | 10 less per 1,000 (██ ███ per 1,000) | Highc | Perioperative durvalumab with neoadjuvant chemotherapy results in little to no difference in the probability of being alive at 12 months compared to placebo with neoadjuvant chemotherapy. |
Probability of OS at 48 months Median (range) follow-up: █████ ██████ ██ | 740 (1 RCT) | NR | ███ per 1,000 | ███ per 1,000 (███ ██ █ per 1,000) | 47 more per 1,000 (██ ██ per 1,000) | Lowd | Perioperative durvalumab with neoadjuvant chemotherapy may result in little to no difference in the probability of being alive at 48 months compared to placebo with neoadjuvant chemotherapy. |
EORTC QLQ-C30 global health status and QoL | |||||||
Change from baseline to end of neoadjuvant period (week 12) | 383 (1 RCT) | NA | −2.86 | −3.36 (−5.69 to −1.04) | −0.50 (−3.74 to 2.74) | Lowe | Perioperative durvalumab with neoadjuvant chemotherapy may result in little to no difference in quality of life during the neoadjuvant period compared to placebo with neoadjuvant chemotherapy. |
Change from adjuvant baseline to end of adjuvant period (week 44) | 245 (1 RCT) | NA | 5.08 | −0.52 (−3.14 to 2.10) | −5.60 (−9.38 to −1.82) | Very lowf | The evidence is very uncertain about the effect of perioperative durvalumab with neoadjuvant chemotherapy on quality of life during the adjuvant period compared to placebo with neoadjuvant chemotherapy. |
pCR | |||||||
pCR | 740 (1 RCT) | NR | 43 per 1,000 | 172 per 1,000 (135 to 215 per 1,000) | 130 more per 100 (87 to 176 more per 1,000) | Moderateg | Perioperative durvalumab with neoadjuvant chemotherapy likely results in a clinically important increase in the probability of achieving pCR compared to placebo with neoadjuvant chemotherapy. |
Harms | |||||||
Immune-mediated AE Median (range) follow-up: █████ ██████ ██ | 737 (1 RCT) | NR | ███ per 1,000 | ███ per 1,000 (NR) | ███ more per 1,000 (███ ████ per 1,000) | Highh | Perioperative durvalumab with neoadjuvant chemotherapy results in a clinically important increase in the proportion of patients who experience ≥ 1 immune-mediated AEs compared to placebo with neoadjuvant chemotherapy. |
Serious AE Median (range) follow-up: █████ ██████ ██ | 737 (1 RCT) | NR | ███ per 1,000 | ███ per 1,000 (NR) | ██ more per 1,000 (█ ██ more per 1,000) | Moderatei | Perioperative durvalumab with neoadjuvant chemotherapy likely results in little to no clinically important difference in the proportion of patients who experience ≥ 1 serious AEs compared to placebo with neoadjuvant chemotherapy. |
AE = adverse event; CI = confidence interval; EFS = event-free survival; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; HRQoL = health-related quality of life; IA1 = interim analysis 1; IA2 = interim analysis 2; KM = Kaplan-Meier; NA = not applicable; NR = not reported; OS = overall survival; pCR = pathological complete response; 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 table footnotes.
aCertainty was not rated down for study limitations or indirectness. Rated down 1 level for imprecision. The point estimate suggests a clinically important difference in EFS at 12 months based on a clinically important between-group difference threshold of 5% to 10% suggested by clinical experts; however, ███ █████ █████ ██ ███ ███ ██ ███████ ████ ██████████ The between-group difference in the probability of EFS was requested from the sponsor to aid in the interpretation of the results for this end point.
bCertainty was not rated down for study limitations or indirectness. Rated down 1 level for imprecision. The point estimate suggests a clinically important difference in EFS at 36 months based on a clinically important between-group difference threshold of 5% to 10% suggested by clinical experts; however, ███ █████ █████ ██ ███ ███ ██ ███████ ████ ██████████ The between-group difference in the probability of EFS was requested from the sponsor to aid in the interpretation of the results for this end point.
cCertainty was not rated down for study limitations, indirectness, or imprecision. The clinical expert consulted for this review suggested that a 5% to 10% between-group difference could be considered clinically meaningful. OS was not eligible for statistical testing at EFS IA2. The results are considered as supportive evidence. The between-group difference in survival probability was requested from the sponsor to aid in the interpretation of the results for this end point.
dCertainty was not rated down for indirectness. Rated down 1 level due to serious study limitations. Visual inspection of the KM curves suggests substantial censoring after 24 months in both groups and few patients at risk at 48 months, contributing to uncertainty in the OS results. Rated down 1 level for imprecision. The point estimate suggests little to no difference █████ ███ █████ █████ ██ ███ ███ ██ █████████ ████████ based on a clinical importance between-group difference threshold of 5% to 10% suggested by clinical experts. OS was not eligible for statistical testing at EFS IA2. The results are considered as supportive evidence. The between-group difference in survival probability was requested from the sponsor to aid in the interpretation of the results for this end point.
eCertainty was not rated down for indirectness or imprecision. Rated down 2 levels due to missing data in both arms at week 12 (44.5% missing in the perioperative durvalumab with neoadjuvant chemotherapy arm and 41.5% in the placebo with neoadjuvant chemotherapy). EORTC QLQ-C30 was not adjusted for multiplicity in the trial and should be considered as supportive evidence.
fCertainty was not rated down for indirectness. Rated down 2 levels due to missing data in both arms at week 44 (41.3% missing in the perioperative durvalumab with neoadjuvant chemotherapy arm and 44.6% in the placebo with neoadjuvant chemotherapy), and given that the modified resected set was analyzed, there may not be prognostic balance between the treatment groups. Rated down a third level for imprecision. The point estimate suggests a detrimental effect on HRQoL, whereas the upper bound of the 95% CI crosses the minimally important difference threshold of −4 identified in the literature. EORTC QLQ-C30 was not adjusted for multiplicity in the trial and should be considered as supportive evidence.
gCertainty was not rated down for study limitations or indirectness. Rated down 1 level for imprecision. The point estimate suggests a clinically important difference in pCR based on a clinically important between-group difference threshold of 10% suggested by clinical experts; however, the lower bound of the 95% CI crosses this threshold.
hCertainty was not rated down for study limitations, indirectness, or imprecision. The clinical expert consulted for this review suggested that a 10% between-group difference could be considered clinically meaningful. The between-group difference was requested from the sponsor to aid in the interpretation of the results.
iCertainty was not rated down for study limitations or indirectness. Rated down 1 level for imprecision. The point estimate suggests little to no difference █████ ███ █████ █████ ██ ███ ███ ██ █████████ ██████████ █████████ ████████ ██ ███████ ███ based on a clinically important between-group difference threshold of 10% suggested by clinical experts. The between-group difference was requested from the sponsor to aid in the interpretation of the results.
Source: AEGEAN study EFS IA1 Clinical Study Report and AEGEAN study EFS IA2 Clinical Study Report Appendix 14 data tables and figures. Details included in the table are from the sponsor’s Summary of Clinical Evidence.
No long-term extension studies were submitted by the sponsor.
Due to the lack of direct evidence comparing perioperative durvalumab (durvalumab in combination with chemotherapy as neoadjuvant treatment, followed by durvalumab as monotherapy after surgery) compared with relevant comparator regimens including neoadjuvant nivolumab, perioperative pembrolizumab, adjuvant chemotherapy, and surgery only in the treatment of patients with resectable (tumours ≥ 4 cm and/or node positive) NSCLC and no known EGFR mutations or ALK rearrangements, the sponsor conducted ITCs, including an MAIC and an NMA.
The MAIC analyses were insufficient to inform whether perioperative durvalumab or the comparator therapies were favoured for EFS. ███ ███ ██ ███ █████ ███ ███ ██████ ███████ ████ ████ ████ ███ ████████ ███ █████████ ████ ██████ ██ ███ ██████████ █████ ████████ █████ ██ █████████. No other efficacy outcomes were assessed in the ITCs.
No ITCs were done for harms outcomes.
Overall, the ITCs (MAIC and NMA) were conducted according to accepted methodological guidance. The potential key limitations of the MAIC analyses included that not all important effect modifiers could be adjusted in the analysis. Furthermore, the MAIC methods reduced the effective sample size in both comparisons (> 65% reduction in the base-case analysis for the comparison versus neoadjuvant nivolumab, whereas a smaller [15% to 17%] reduction occurred in the pembrolizumab comparison). Such reductions in effective sample size may indicate limited overlap in baseline characteristics between the trial populations and increase uncertainty in the weighted estimates. ███████████ █████ ███ ████ ██ ███ ██████ █████████ █████████ ███████████ ██ ██ ███████ █████████████ ██████████ ██ ███ ██████████ █████████ ████ ████████ ███ ████.
The potential key limitation of the NMA was the heterogeneity (in effect modifiers) across the included studies in terms of the study designs and patient characteristics; notably, some included studies were conducted starting before 1990 and the standard of care has changed since that time. Given differences across studies in staging and tumour assessment criteria, the use of second-generation chemotherapy agents, and other unmeasured characteristics potentially impacting outcomes (e.g., smoking status was infrequently reported), the plausibility of the transitivity assumption is uncertain. In addition, several studies met the inclusion criteria for the ITC, but were excluded due to the absence of EFS KM curves and HRs. The impact of the exclusion of these studies on the NMA results was unknown; however, there is a risk of bias due to missing evidence in the synthesis. Finally, all evidence networks were sparse, with no closed loops formed by multiple studies. ███ ████ ███ ███ ██████ █████████ ████ ███ ██████ ██████ ██████ ████ █████ ██████████ ███████████ ██ ██ ███████ █████████████ ██████████ ██ ███ ██████████ █████████ ████ ████████ ███ ████.
No studies addressing gaps in the systematic review evidence were submitted by the sponsor.
Table 2: Summary of the Economic Evaluation
Component | Description |
|---|---|
Type of economic evaluation | Cost-utility analysis Semi-Markov Model |
Target population | Adult patients with resectable NSCLC (stages IIA to IIIB [N2 only], according to AJCC staging eighth edition) whose tumours have no EGFR mutations or ALK aberrations. |
Treatment | Perioperative durvalumab plus neoadjuvant chemotherapy (referred to as perioperative durvalumab) consists of neoadjuvant durvalumab plus chemotherapy before surgery and adjuvant durvalumab monotherapy following surgery. |
Dose regimen |
|
Submitted price | Durvalumab: $938.67 per 120 mg/2.4 mL single-use vial for IV infusion Durvalumab: $3,911.11 per 500 mg/10 mL single-use vial for IV infusion |
Submitted treatment cost | The average 21-day cycle cost of durvalumab is $11,733 before surgery and $8,700 after surgery. The total cost of perioperative durvalumab (including the cost of neoadjuvant chemotherapy) is $198,250 ($207,642 including the cost of surgery)b |
Comparators |
|
Perspective | Canadian publicly funded health care payer |
Outcomes | QALYs, LYs |
Time horizon | Lifetime (36 years) |
Key data sources | Sponsor-submitted MAIC and ITC in which efficacy inputs for perioperative durvalumab were informed by the AEGEAN trial (data cut-off date: May 10, 2024) |
Key limitations |
|
CDA-AMC reanalysis results |
|
AJCC = American Joint Committee on Cancer; CDA-AMC = Canada’s Drug Agency; EF = event-free; EFS = event-free survival; GPM = general population mortality; HR = hazard ratio; HRQoL = health-related quality of life; ICER = incremental cost-effectiveness ratio; ITC = indirect treatment comparison; LRR = locoregional recurrence; LY = life-year; MAIC = matching-adjusted indirect comparison; NSCLC = non–small cell lung cancer; QALY = quality-adjusted life-year; rNSCLC = resectable non–small cell lung cancer; SMR = standardized mortality ratio; vs. = versus; WTP = willingness-to-pay.
Note: Platinum-based chemotherapy in the neoadjuvant setting includes cisplatin plus pemetrexed, cisplatin plus gemcitabine, cisplatin plus paclitaxel, carboplatin plus paclitaxel, carboplatin plus pemetrexed, or carboplatin plus gemcitabine. In the adjuvant setting, cisplatin plus vinorelbine and carboplatin plus vinorelbine are assumed to be used in addition to the aforementioned neoadjuvant chemotherapy regimens.
aPatients with a body weight of 30 kg or less must receive weight-based dosing of durvalumab, in combination with chemotherapy, at 20 mg/kg 21 days before surgery and durvalumab monotherapy at 20 mg/kg every 28 days after surgery until their weight increases to greater than 30 kg.
bAssumes durvalumab is administered for the maximum number of cycles (i.e., four 21-day cycles in the neoadjuvant period and twelve 28-day cycles in the adjuvant period).
cNeoadjuvant nivolumab consists of neoadjuvant nivolumab plus chemotherapy.
CDA-AMC identified the following key limitations with the sponsor’s analysis: EFS is highly uncertain, impacting estimated treatment duration; drug costs are uncertain owing to the assumption that durvalumab and pembrolizumab are administered based on a fixed dosage, as well as discrepancies in drug acquisition costs between the unit costs calculated by CDA-AMC and those calculated by the sponsor; market shares are uncertain; and market uptake of perioperative durvalumab is uncertain.
The limitations identified by CDA-AMC had minimal impact on the results of the budget impact analysis. Furthermore, in the absence of more reliable estimates to inform the key parameters of the budget impact analysis (i.e., market shares and market uptake), the sponsor’s submitted base case was maintained.
The 3-year budget impact of reimbursing perioperative durvalumab for adult patients with resectable NSCLC (stages IIA to IIIB [N2 only] per AJCC eighth edition) without EGFR mutations or ALK aberrations is projected to be $65,193,469, distributed as follows: $18,566,320 in year 1; $22,298,502 in year 2; and $24,328,646 in year 3.
Dr. Catherine Moltzan (Chair), Dr. Kelvin Chan (Vice-Chair), Paul Agbulu, Dr. Phillip Blanchette, Dr. Matthew Cheung, Dr. Michael Crump, Annette Cyr, Dr. Jennifer Fishman, Dr. Jason Hart, Terry Hawrysh, Dr. Yoo-Joung Ko, Dr. Aly-Khan Lalani, Amy Peasgood, Dr. Anca Prica, Dr. Michael Raphael, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Pierre Villeneuve, and Danica Wasney.
Meeting date: April 8, 2026
Regrets: Two expert committee members did not attend.
Conflicts of interest: None
ISSN: 2563-6596
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