CADTH Reimbursement Review

Atezolizumab (Tecentriq)

Sponsor: Hoffman-La Roche Ltd.

Therapeutic area: Non–small cell lung cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

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

Introduction

Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of cancer deaths in Canada,² with non–small cell lung cancer (NSCLC) accounting for approximately 88% of lung cancer cases.^2,3 Approximately half of all NSCLC cases in Canada are stage I to III at diagnosis,² and 1-third of patients with NSCLC have operable disease.⁴ The 5-year net survival for lung cancer is 22%.⁵ The high mortality rate associated with lung cancer reflects both its high incidence rate and its low survival rate.

The primary goal of treatment for patients with stage IB to IIIA (per the AJCC Cancer Staging Manual, 7th edition¹; the equivalent stages according to the AJCC Cancer Staging Manual, 8th edition⁶ are stages IIA to IIIB) NSCLC is to cure and prolong life. The secondary goal of treatment is to delay disease relapse, thereby allowing patients a longer period of time living disease-free. Attaining these treatment goals primarily involves surgical resection of the tumour,^4,7 followed by adjuvant cisplatin-based doublet chemotherapy.

Atezolizumab is an Fc-engineered humanized IgG1 monoclonal antibody that directly binds to programmed death-ligand 1 (PD-L1) and blocks interactions with the programmed death-1 (PD-1) and B7.1 receptors, releasing PD-L1 and PD-1 pathway–mediated inhibition of the immune response, including reactivating the antitumour immune response. Atezolizumab is administered as an IV infusion at a dosage of 840 mg every 2 weeks, 1,200 mg every 3 weeks, or 1,680 mg every 4 weeks.

Atezolizumab received Notice of Compliance (NOC) from Health Canada on January 14, 2022, as monotherapy for adjuvant treatment following complete resection and no progression after platinum-based adjuvant chemotherapy for adults with stage II to IIIA (according to the AJCC Cancer Staging Manual, 7th edition¹) NSCLC whose tumours have PD-L1 expression on at least 50% of tumour cells (TCs). Although the original indication proposed to Health Canada was for patients with NSCLC whose tumours had PD-L1 expression on at least 1% of TCs, the approved Health Canada indication was limited to patients with stage II to IIIA disease with PD-L1 expression on at least 50% of TCs because of uncertainty about the clinical benefit of atezolizumab in the population with stage II to IIIA NSCLC and PD-L1 expression on 1% to 49% of TCs; Health Canada noted that the improvement in disease-free survival (DFS) was mainly driven by the subgroup of patients with PD-L1 expression on at least 50% of TCs.⁸

Although the reimbursement request for the current review was for atezolizumab as monotherapy for adjuvant treatment after complete resection and no progression after platinum-based adjuvant chemotherapy for adults with stage II to IIIA (according to the AJCC Cancer Staging Manual, 7th edition¹) NSCLC whose tumours have PD-L1 expression on at least 50% of TCs and no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumour aberrations, the review will focus on the Health Canada indication described previously, which is boarder in scope. Therefore, the objective of this report is to perform a systematic review of the beneficial and harmful effects of atezolizumab as monotherapy for adjuvant treatment following complete resection and no progression after platinum-based adjuvant chemotherapy for adults with stage II to IIIA (according to UICC and AJCC [7th edition]¹ staging criteria) NSCLC whose tumours have PD-L1 expression on at least 50% of TCs.

Table 2: Summary of Key Results From IMpower010 Study for Patients With Stage II to IIIA Disease and PD-L1 Expression on at Least 50% of TCs (Clinical Data Cut-Off Date of January 21, 2021)

AE = adverse event; BSC = best supportive care; CI = confidence interval; CNS = central nervous system; DFS = disease-free survival; HR = hazard ratio; NA = not applicable; NE = not estimable; NR = not reported; OS = overall survival; PD-L1 = programmed death-ligand 1; SAE = serious adverse events; TC = tumour cell.

^aSummaries of durations (median and percentiles) are Kaplan-Meier estimates. 95% CIs for the medians are computed using the methods of Brookmeyer and Crowley.⁴²

^bCensored.

^cStratification factors for patients with stage II to IIIA NSCLC and PD-L1 expression on ≥ 50% of TCs: stage from electronic case report form (eCRF) (IB or II vs. IIIA), sex from eCRF (female vs. male), histology from eCRF (squamous vs. nonsquamous).

^dHRs were estimated with Cox regression.

^eStatistical testing for these end points was not adjusted for multiple comparisons, resulting in an increased risk of false-positive conclusions.

^fFor the site of disease recurrence only, there were 50 patients in the BSC group 25 in the atezolizumab group.

^gA patient could have more than 1 distant site.

^hPatients who had CNS distant site only were included. Patients who had any other recurrent site (i.e., locoregional, other distant site, secondary primary lung, or secondary primary non-lung) in addition to CNS distant site were not included in the CNS-only category.

Source: Clinical Study Report for IMpower010.⁹

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups who responded to CADTH’s call for patient input and from clinical experts consulted by CADTH for the purpose of this review.

Patient Input

Patient input was provided by 2 groups: Lung Cancer Canada (LCC) and the Ontario Lung Association (OLA). LCC is a national charity and a member of the Global Lung Cancer Coalition, and serves as a resource for lung cancer education, patient support, research, and advocacy. The OLA, also known as the Lung Health Foundation (LHF), is a charity that provides education, programs, and services for patients and health care providers, and invests in research and policy improvement in lung health. LCC collected the thoughts and experiences from 9 patients with NSCLC or small cell lung cancer and 1 caregiver (from Canada, the US, the UK, and Australia) in December 2021 via phone interviews and environmental scans. LHF conducted phone interviews with 3 patients (Ontario, Manitoba, and Quebec) in September and October 2021 and a registered nurse and certified respiratory educator.

Patients who responded to the 2 surveys reported difficulty coping with their diagnosis and noted that they felt like there was “no hope, no light, and [were] less human” because of the poor prognosis of lung cancer. These feeling were amplified when the cancer was detected late. Patient respondents also reported that cancer-related symptoms were hard to manage. Although the physical symptoms of shortness of breath, cough, and fatigue were reported to be mild, the psychosocial effects (such as anxiety, distress, depression) and some of the harsh side effects of chemotherapy, radiation, and surgery (e.g., nausea, vomiting, neuropathy, lung injury) were harder to manage. Similarly, the psychosocial burden placed on family members and caregivers affected their emotional well-being, ability to travel and socialize, and work life.

Patient respondents deemed the following outcomes as important: delayed disease progression and increased long-term remission that ultimately improved survivorship; minimal side effects from treatments; maintenance of independence and functionality (to minimize burden on caregivers and loved ones); and full and worthwhile quality of life. The survey respondents emphasized a lack of treatment options for patients with PD-L1-positive, driver-mutation-negative lung cancer to reduce a risk of recurrence after post-surgery chemotherapy. Patients emphasized the desire for a choice of therapies that work in the early stages of disease (as opposed to the metastatic stage) with durable efficacy to maintain stable disease and increase chance of cure.

Clinician Input

Input From Clinical Experts Consulted by CADTH

Based on input from the clinical experts consulted by CADTH, despite the current standard of care with adjuvant chemotherapy, many patients who have undergone surgical resection and adjuvant chemotherapy experience disease relapse. In the majority of these cases, the disease is often incurable. The survival benefit that accompanies adjuvant chemotherapy is modest; there is an unmet need for other effective treatments for this patient population. If adopted, atezolizumab would be an additional therapy, not a replacement for pre-existing therapy (i.e., atezolizumab would be given in addition to, not instead of, adjuvant chemotherapy). Also, if adopted, atezolizumab would be offered to patients with resected NSCLC and tumours larger than 5 cm and to patients with node-positive tumours, regardless of the size of the primary tumour, and a PD-L1 tumour score of at least 50%. According to the clinical experts, the only way to know if adjuvant therapy is successful in NSCLC is to follow a patient who has completed all curative-intent therapy to disease relapse. The majority of cases of disease relapse, according to the clinical experts, occur in the 5 years after completion of therapy. The clinical experts recommended that treatment with atezolizumab be discontinued in the event of dangerous or intolerable adverse events (AEs), disease relapse, or patient choice to stop therapy. Atezolizumab may be administered at any outpatient cancer systemic therapy infusion unit where immunotherapy checkpoint inhibitors are already administered.

Clinician Group Input

Input was received from 3 clinicians on behalf of the Cancer Care Ontario (OH-CCO) Drug Advisory Committee (DAC) and 17 physicians who treat lung cancer in Canada on behalf of LCC.

The OH-CCO Lung and Thoracic DAC indicated the need for therapy that increased cure and overall survival (OS) rates. Both clinician input groups stated that patients with stage II to III (according to UICC and AJCC [8th edition]⁶ staging criteria) lung cancer have the greatest unmet need. Both clinician groups also indicated that atezolizumab would supplement and/or be added to the current post-operative management of resected NSCLC after at least 1 dose of adjuvant (platinum-doublet) chemotherapy, and not be a replacement for current therapies. The OH-CCO Lung and Thoracic DAC indicated that patients with PD-L1 tumour scores of at least 50% and all PD-L1-positive patients are suited for atezolizumab. LCC suggested that patients with stage II to IIIA (UICC and AJCC [7th edition]¹ staging criteria) resected lung cancer with a PD-L1–positive tumour (≥ 1%) determined by immunohistochemistry (IHC) after at least 1 cycle of adjuvant therapy, regardless stage or nodal status, are suitable for atezolizumab.

The OH-CCO Lung and Thoracic DAC considered DFS a clinically meaningful outcome measure. LCC emphasized that recurrent disease (DFS) should be considered a critical outcome on its own (besides OS, which is the gold standard), given the high patient, health care, and social-level ramifications associated with recurrence. Both groups indicated that therapy should be discontinued at disease progression or unacceptable toxicity. As for the treatment settings, hospital (outpatient clinic) and any oncology settings where infusions are performed were considered appropriate prescribing settings for atezolizumab by the OH-CCO Lung and Thoracic DAC and LCC, respectively. The OH-CCO Lung and Thoracic DAC agreed that the end points reported in the trial can reasonably be expected to correlate with OS. Also, both clinical groups believed other strategies (e.g., a short course with only 3 doses of neoadjuvant immunotherapy plus chemotherapy) are expected to be less expensive than a full-year course of adjuvant immunotherapy.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CADTH recommendation for atezolizumab:

• consideration for initiation of therapy

• generalizability

• care provision.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

One ongoing phase III, global, multi-centre, open-label, randomized study was included in the review. The IMpower010 trial compared the efficacy and safety of atezolizumab versus best supportive care (BSC) in patients with stage IB to stage IIIA (per UICC and AJCC [7th edition]¹ staging system) NSCLC after complete resection and adjuvant cisplatin-based chemotherapy. A total of 1,005 patients were randomized across 204 sites in 21 countries in North America (including 2 sites in Canada), Europe, Asia, and Australia.

The primary efficacy outcome was DFS, assessed by the investigator. Secondary efficacy outcomes included OS, 3-year and 5-year DFS, and DFS in subpopulations with PD-L1 expression on at least 50% of TCs, assessed with SP263 IHC assay, in patients with stage II to IIIA NSCLC as defined by the UICC and AJCC (7th edition) staging criteria.¹ The IMpower010 study consisted of 2 phases: an enrolment phase and a randomized phase. In the enrolment phase, patients who had undergone completed resection of their NSCLC were screened and, if eligible, received 1 of 4 cisplatin-based chemotherapy regimens (cisplatin plus vinorelbine, docetaxel, gemcitabine, or pemetrexed), based on investigator choice. Patients who were still deemed eligible to continue with the study after up to 4 cycles of cisplatin-based chemotherapy proceeded to the randomization phase, in which patients were randomized in a 1:1 ratio to receive atezolizumab or BSC. The clinical report provided to CADTH presented a protocol-specified interim analysis for DFS of study data collected from the date of the first patient randomized (February 26, 2016) to the clinical data cut-off date of January 21, 2021.

At baseline, there were 229 patients with stage II to IIIA NSCLS and PD-L1 expression on at least 50% of TCs. The indication population had a median age of 62 (range = 36 to 84) years, was predominantly male (72.9%) and White (70.3%), had high functional performance (57.2% with an Eastern Cooperative Oncology Group [ECOG] performance status score of 0), and most reported previous tobacco use (69.9%). At diagnosis, most patients were diagnosed with stage IIIA (48.0%) disease and with nonsquamous histology (59.8%). Of the 137 patients with nonsquamous histology, 94.2% were identified as having adenocarcinoma subtype. EGFR or ALK mutation was detected in 8.7% of patients. Most patients had undergone prior lobectomy (74.2%) and mediastinal lymph node dissection (81.7%)

Efficacy Results

Efficacy results are presented for the subpopulation of patients who had stage II to IIIA NSCLC with PD-L1 expression on at least 50% of TCs (per the indication under review), unless otherwise specified.

Overall Survival

Among the subpopulation of patients with stage II to IIIA disease and PD-L1 expression on at least 50% of TCs, the observed deaths at the time of the interim analysis (median follow-up = 32.2 [range = 0 to 58.8] months) were 22.8% and 9.6% in the BSC and atezolizumab treatment groups, respectively. The stratified hazard ratio (HR) was 0.40 (95% CI, 0.20 to 0.81) in favour of atezolizumab. The median OS could not be estimated in either treatment arm because of the low rate of death events at the time of the planned interim analysis. At year 3, 90.85% of patients in the atezolizumab treatment group were event-free compared with 76.67% of the BSC treatment group, for a difference in proportion of 14.27% (95% CI, 4.19% to 24.35%).

Disease-Free Survival

In the subpopulation of patients with stage II to IIIA disease and PD-L1 expression on at least 50% of TCs, 45.6% in the BSC treatment arm experienced a disease recurrence or death compared with 24.3% in the atezolizumab arm. The stratified HR for DFS was 0.47 (95% CI, 0.29 to 0.75). At year 3, 73.79% of patients in the atezolizumab group were event-free compared with 48.61% in the BSC group, representing a difference in event-free rate of 25.18% (95% CI, 11.01% to 39.36%).

Type of Recurrence

Of patients with stage II to IIIA NSCLC and PD-L1 expression on at least 50% of TCs who experienced a protocol-defined disease recurrence (n = 50 for BSC; n = 25 for atezolizumab), locoregional disease recurrence was experienced by 60% of patients in the atezolizumab treatment arm and by 34% in the BSC arm. Distant-only disease recurrence was experienced by 42% of patients in the BSC arm and 24% in the atezolizumab arm. Central nervous system (CNS)-only disease recurrence was experienced by 14% of patients in the BSC arm and 4% in the atezolizumab arm. Combined locoregional plus distant disease recurrence was similar in the 2 treatment arms (BSC = 18%; atezolizumab = 16%).

Harms Results

Adverse Events

Among patients with stage II to IIIA NSCLC and PD-L1 expression on at least 50% of TCs, 94.7% of patients who received atezolizumab and 69.6% who received BSC reported at least 1 AE. The top 5 reported AEs (BSC versus atezolizumab) were cough (10.7% versus 14.2%), nasopharyngitis (12.5% versus 8.8%), arthralgia (5.4% versus 13.3%), pruritis (2.7% versus 11.5%), and anemia (8.0% versus 7.1%). The following AEs had a difference of at least 5% between the 2 treatment arms, with a greater proportion of affected patients in the atezolizumab arm: arthralgia, asthenia, increased blood creatine, diarrhea, rash, pruritus, and pyrexia.

Adverse Events by Grade

Among patients with stage II to IIIA NSCLC and PD-L1 expression on at least 50% of TCs, at least 1 grade 3 or 4 AE was reported in 11.6% and 20.4% of patients randomized to BSC and atezolizumab, respectively. The most commonly reported grade 3 or 4 AEs in patients who received BSC were decreased neutrophil count (1.8%); in patients who received atezolizumab, the most common AEs were increased alanine aminotransferase (1.8%) and abnormal hepatic function (2.7%). No grade 5 AEs were reported.

Serious Adverse Events

Among patients with stage II to IIIA NSCLC and PD-L1 expression on at least 50% of TCs, 15% of patients who received atezolizumab reported at least 1 serious adverse event (SAE) compared with 5.4% who received BSC. The most commonly reported SAE was pyrexia (1.8%).

Dose Interruptions Due to Adverse Events

Among patients with stage II to IIIA NSCLC and PD-L1 expression on at least 50% of TCs, 29.2% of patients who received atezolizumab had at least 1 dose interruption due to an AE. Reasons for the dose interruptions included hyperthyroidism (3.5%), pneumonia (2.7%), upper respiratory tract infection (1.8%), pyrexia (1.8%), rash (1.8%), and oropharyngeal pain (1.8%).

Discontinuation of Treatment Due to Adverse Events

Among patients with stage II to IIIA NSCLC and PD-L1 expression on at least 50% of TCs, 18.6% of patients who received atezolizumab stopped treatment due to an AE. Reasons for the discontinuation were not available for this subpopulation.

Among the overall safety population, 18.2% of patients who received atezolizumab stopped treatment due to an AE. The most common events leading to treatment discontinuation were pneumonitis (1.4%), hypothyroidism (1.4%), and aspartate aminotransferase increase (1.4%).

Mortality

There were no treatment-related death data in the subpopulation of patients with stage II to IIIA NSCLS and PD-L1 expression on at least 50% of TCs.

Among the overall safety population, the proportion of patients who died was similar in the BSC (18.2%) and atezolizumab (19.2%) treatment groups. Of these deaths, 95.1% occurred more than 30 days after the last study treatment or safety visit. Treatment-related deaths due to AEs occurred in 0.6% and 1.6% of patients in the BSC and atezolizumab arms, respectively. The majority of deaths were due to disease progression.

Notable Harms

Among the subpopulation of patients with stage II to IIIA NSCLC and PD-L1 expression on at least 50% of TCs, reported immune-mediated reactions related to endocrinopathies included hypothyroidism (atezolizumab = 14.2%; BSC = 0%) and hyperthyroidism (atezolizumab = 4.4%; BSC = 1.8%). Overall immune-mediated rashes were reported by 1.8% and 18.6% of patients who received BSC and atezolizumab, respectively. One person who received atezolizumab experienced a grade 3 or 4 rash. Immune-mediated colitis (grade 3 or 4) was reported by 1 person who received atezolizumab. Immune-related pneumonitis was reported by 5.3% of patients who received atezolizumab, 1 case of which was grade 3 or 4. Immune-mediated hepatitis was reported by 4.5% and 13.3% of patients who received BSC and atezolizumab, respectively. Among patients who received atezolizumab, 5.3% experienced grade 3 or 4 immune-mediated hepatitis.

Data related to infusion-related reactions were not reported for the subpopulation of patients with stage II to IIIA NSCLS and PD-L1 expression on at least 50% of TCs.

Critical Appraisal

The critical appraisal of the IMpower010 study by CADTH was limited by a decision made by Health Canada to amend the NOC from the original indication population to only the subset of patients with stage II to IIIA NSCLC whose tumour had PD-L1 expression on at least 50% of TCs. Randomization was stratified by sex (female versus male), tumour histology (squamous versus nonsquamous), extent of disease (stage IB versus stage II versus stage IIIA based on the UICC and AJCC [7th edition] staging criteria) and PD-L1 expression status (TC2/3 and any immune cells [ICs] versus TC0/1 and IC2/3 versus TC0/1 and IC0/1, using the SP142 IHC assay). The choice of stratification factors was considered to be reasonable and, as noted in the Health Canada report, stage of disease is a known prognostic factor for NSCLC and PD-L1 tumour performance status is a predictive factor for immunotherapy efficacy in the setting of incurable NSCLC.⁸ The enrolled subpopulation of patients that met the Health Canada indication only accounted for 22.8% of the total randomized population, and was not a defined subpopulation for the primary end points in the analysis in the IMpower010 trial design. As such, the IMpower010 trial was not powered for the Health Canada indication under review. Of note, Health Canada’s decision to amend the indication to PD-L1 expression on at least 50% of TCs at the time of the interim analysis was due to uncertainty about the clinical benefit of atezolizumab for patients with stage II to IIIA NSCLC and PD-L1 expression on 1% to 49% of TCs; Health Canada noted that the improvement in DFS was mainly driven by the subgroup of patients with PD-L1 expression on at least 50% of TCs.⁸ Likewise, the European Medicines Agency also considered the subgroup with PD-L1 expression on at least 50% of TCs to be the most relevant for labelling at the time of the interim analysis.¹⁰

Although DFS in patients with PD-L1 expression on at least 50% of TCs was a pre-specified secondary end point, it was absent from the statistical testing hierarchy. Thus, the statistical analyses of the efficacy outcomes were conducted with no control for multiplicity, which increases the risk of false-positive conclusions. Several subgroup analyses were performed to examine the consistency of the treatment effect observed for the primary and key secondary efficacy end points. However, proper interpretation of all subgroups was not possible because of the lack of sample size considerations and their absence from the statistical testing hierarchy. Moreover, data for OS were immature, and although clinical experts believe it is plausible that the findings for DFS will translate into OS, there remains uncertainty about this.^11,12

Among the subgroup of patients with PD-L1 expression on at least 50% of TCs and stage II to IIIA disease, there were some minor imbalances across groups but these did not universally favour either group and may be considered reasonable, given the small sample size.⁸ Additionally, minor differences in characteristics between this subgroup and the intention-to-treat (ITT) population were not expected to confound the efficacy analyses.⁸

The demographic characteristics of the study population were considered by the clinical experts to be generally reflective of the relevant population with NSCLC in Canada. The clinical experts considered the results of the IMpower010 multi-national, multi-centre study to be generalizable to the Canadian setting. The clinical experts did highlight a few notable differences in disease characteristics (i.e., the larger proportion of patients with squamous lung cancer) and treatment regimen (i.e., cisplatin doublets containing gemcitabine and docetaxel are not commonly used in Canadian lung cancer practice in the adjuvant setting) between the trial population and the Canadian NSCLC population. Outcomes important to patients, such as health-related quality of life, were not reported.

Indirect Comparisons

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

Other Relevant Evidence

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

Conclusions

Based on the IMpower010 trial, uncertainty remains about the efficacy of adjuvant atezolizumab in increasing DFS in adults with stage II or IIIA (per the UICC and AJCC [7th edition] staging criteria) NSCLC whose tumours have PD-L1 expression on at least 50% of TCs following complete resection and no progression after platinum-based adjuvant chemotherapy at the time of the planned interim analysis, because the analysis was absent from the statistical hierarchy and not controlled for multiplicity. Although based on clinical expert opinion, the findings appeared favourable and are considered clinically important. Conclusions regarding the efficacy of atezolizumab on improved OS cannot be made because of the immature nature of the data at the time of the planned interim analysis. Despite these limitations, the findings from the IMpower010 trial appeared to be generalizable to the real-world setting.

Introduction

Disease Background

Lung cancer is one of the most commonly diagnosed cancers, and the leading cause of cancer deaths in Canada.² Survival after lung cancer across all stages and histologies is poor. Indeed, more Canadians die of lung cancer than colorectal, pancreatic, and breast cancer combined.² Moreover, the 5-year net survival rate for lung cancer is 22%.⁵ The high mortality rate associated with lung cancer reflects both its high incidence rate and its low survival rate. There are 2 types of lung cancer that are classified by the type of cell in which the cancer started: small cell lung cancer and NSCLC.¹³ NSCLC accounts for approximately 80% to 88% of all lung cancer diagnoses in Canada.^2,3 NSCLC is further classified into histologic subtypes, with the most common being adenocarcinoma and squamous cell carcinoma. Squamous cell cancer is a subtype of NSCLC that usually starts in the cells that lie the bronchi in the centre of the lungs. The most common subtype of NSCLC is adenocarcinoma, which usually starts in the glandular cells on the outer part of the lung. Approximately 15% of Canadians with NSCLC also have an EGFR-activating mutation in the region encoding the tyrosine kinase domain.^14-16 A further 2% to 6% have an ALK fusion.¹⁷ The majority of patients with an EGFR or ALK driver mutation are in the adenocarcinoma subset and are less likely to have a history of significant tobacco use.

To determine a patient’s prognosis and treatment, NSCLC is staged using the Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) staging criteria, which involves tumour, node, metastasis (TNM) classification of the disease based on the size and spread of the primary tumour (T), lymph node involvement (N), and the occurrence of metastasis (M).¹⁸ For invasive NSCLC there are 4 stages: I to IV. The International Association for the Study of Lung Cancer Lung Cancer Project, which collected survival data on more than 81,000 patients with lung cancer from 19 countries, including Canada, found that 5-year OS for NSCLC decreased with increasing stage.⁵ Indeed, the 5-year OS of 92% at diagnosis at stage IA1 declined with each stage to less than 40% at stage IIIA and higher.

Approximately half of all lung cancer cases in Canada are stage I to III at diagnosis,² and approximately 1-third of patients with NSCLC have operable disease.⁴ Early-stage (i.e., stages I to IIIA per the AJCC [7th edition]¹ staging criteria) NSCLC is often asymptomic.^18,19 When patients do present with symptoms, these are usually nonspecific and difficult to directly attribute to lung cancer.¹⁹ The most common symptoms include fatigue, cough, chest or shoulder pain, hemoptysis, weight loss, dyspnea, hoarseness, bone pain, and fever.¹⁹ Diagnostic procedures include CT, PET, and/or MRI scans, bronchoscopy with or without endobronchial ultrasound or tissue biopsy.⁴ Pathologic testing of biomarkers on lung biopsy specimens assists in decisions about treatment options and risk stratification.

Standards of Therapy

The primary goal of treatment for patients with stage IB to IIIA (per the UICC and AJCC [7th edition]¹ staging criteria; the equivalent stages using the AJCC [8th edition]⁶ staging criteria are stages IIA to IIIB) NSCLC is to cure and prolong life. The secondary goal of treatment is to delay disease relapse, thereby allowing patients a longer period of time living disease-free. These treatment goals are primarily attained via surgical resection of the tumour and, for some groups, adjuvant therapy is recommended.^4,7

The clinical experts consulted by CADTH noted that although surgery is the gold standard of care for patients with NSCLC that is anatomically amenable to resection, some patients with stage I disease may not be good operative candidates (e.g., those who have significant comorbidities for which general anesthetic is contraindicated), and others may refuse surgery. Those with an appropriate disease location and adequate lung function can be treated with curative intent with stereotactic ablative radiation. Likewise, some patients who are not surgical candidates or who refuse surgery for stage II disease that is too anatomically extensive for stereotactic ablative radiation may receive curative-intent combined chemo-radiation. Patients who undergo curative-intent resection of a NSCLC where the primary tumour is 4 cm or larger, or with involved lymph nodes, are then considered for 4 cycles of adjuvant cisplatin-based doublet chemotherapy, usually with vinorelbine or pemetrexed. This is based on the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis, which showed an absolute benefit of 5% in 5-year OS (HR = 0.89; 95% CI, 0.82 to 0.96; I² = 6%; P = 0.005).²⁰ The LACE meta-analysis also demonstrated an absolute benefit of chemotherapy on DFS of 5.8% and 5.8% at 3 years and 5 years, respectively (HR = 0.84; 95% CI, 0.78 to 0.91; I² = 0.27; P < 0.001).

If a resected tumour is known to harbour 1 of the common EGFR mutations (e.g., exon 19 deletion or L858R), evidence from the ADAURA trial²¹ supports 3 years of osimertinib after adjuvant chemotherapy, if it was given, based on a DFS benefit of 24 months (HR = 0.17, 99% CI, 0.11 to 0.26; P < 0.0001) for those with stage II to IIIA (per the AJCC [7th edition] staging criteria) disease.

Meta-analyses have estimated a 5-year OS benefit of approximately 4% to 5% with adjuvant platinum-based chemotherapy.^20,22,23 Adjuvant chemotherapy is recommended for patients with stage II to IIIA (AJCC [7th edition]¹ staging criteria) disease and stage IB (AJCC [7th edition]¹ staging criteria) patients considered to be at high risk of relapse (e.g., those with tumours > 4 cm in diameter, nodal involvement, perineural or lymphovascular invasion, or spread through airspaces).^4,24 However, not all patients receive post-operative adjuvant chemotherapy. A retrospective cohort study conducted in Europe, which included 831 patients with stage IB to IIIA (AJCC [7th edition] staging criteria)¹ NSCLC, showed that 48% of patients received adjuvant chemotherapy (15.1% with stage IB, 55.1% with stage II, and 71.4% with stage IIIA).²⁵ The most common reasons for not receiving adjuvant chemotherapy were that it was declined by the patient (12.6%), comorbidities (11.9%), complication or delay in surgery recovery (8.4%), and poor performance status (7.0%).²⁵ Additionally, approximately 1-third of patients who received chemotherapy did not finish the planned number of cycles.²⁵

In Canada, cisplatin-based adjuvant chemotherapy is the standard of care. According to the clinical experts consulted by CADTH, the most common chemotherapy combinations are cisplatin plus vinorelbine and cisplatin plus pemetrexed. Carboplatin-based chemotherapy is used by some physicians for patients who are ineligible for cisplatin adjuvant chemotherapy, although its use is controversial.^4,24 Adjuvant radiotherapy is generally only considered in the setting of positive surgical margins; after complete surgical resection, radiation is not routinely recommended.^4,24 After adjuvant chemotherapy is complete, patients receive active surveillance, which most commonly involves CT scans every 3 to 6 months for 2 to 3 years, and annually thereafter until year 5.^7,24

Since January 2021, osimertinib has been approved in Canada as adjuvant therapy after tumour resection and completion of adjuvant chemotherapy for patients with stage IB to IIIA (per the UICC and AJCC [7th edition]¹ staging criteria) NSCLC with EGFR exon 19 deletions or exon 21 (L858R) substitution driver mutations.

Drug

Atezolizumab is an Fc-engineered humanized immunoglobulin G1 monoclonal antibody that directly binds to PD-L1 and blocks interactions with the PD-1 and B7.1 receptors, releasing PD-L1- and PD-1-pathway–mediated inhibition of the immune response, including reactivation of the antitumour immune response. Atezolizumab leaves the PD-L1 and PD-1 interaction intact.

Atezolizumab received an NOC from Health Canada on January 14, 2022 as monotherapy for adjuvant treatment following complete resection and no progression after platinum-based adjuvant chemotherapy for adults with stage II to IIIA (according to the AJCC [7th edition]¹ staging criteria) NSCLC whose tumours have PD-L1 expression on at least 50% of TCs. Although the original indication proposed to Health Canada was for the patients with NSCLC whose tumours had PD-L1 expression on at least 1% of TCs, the approved Health Canada indication was limited to patients with stage II to IIIA disease with PD-L1 expression on at least 50% because of uncertainty about the clinical benefit of atezolizumab in the population with PD-L1 expression on 1% to 49% of TCs; Health Canada noted that the improvement in DFS was mainly driven by improvement in the subgroup with PD-L1 expression on at least 50% of TCs.⁸ Although the reimbursement request from the sponsor was for atezolizumab as monotherapy for adjuvant treatment following complete resection and no progression after platinum-based adjuvant chemotherapy for adults with stage II to IIIA (according to the AJCC [7th edition]¹ staging criteria) NSCLC whose tumours have PD-L1 expression on at least 50% of TCs and no EGFR or ALK genomic tumour aberrations, the current review is focused on Health Canada indication described previously, which is boarder in scope.

Atezolizumab is also indicated:

• in combination with carboplatin and etoposide for the first-line treatment of adults with extensive-stage small cell lung cancer

• as monotherapy for the first-line treatment of patients with metastatic NSCLC whose tumours have high PD-L1 expression (PD-L1 stained ≥ 50% of TCs or PD-L1 stained tumour-infiltrating ICs covering ≥ 10% of the tumour area), determined by a validated test, and with no EGFR or ALK genomic tumour aberrations

• in combination with bevacizumab, paclitaxel, and carboplatin for the first-line treatment of adults with metastatic nonsquamous NSCLC, no EGFR or ALK genomic tumour aberrations, and no prior systemic chemotherapy treatment for metastatic nonsquamous NSCLC

• in combination with nanoparticle albumin-bound paclitaxel and carboplatin for the first-line treatment of adults with metastatic nonsquamous NSCLC and no EGFR or ALK genomic tumour aberrations

• for the treatment of adults with locally advanced or metastatic NSCLC with progression on or after platinum-based chemotherapy

• in combination with bevacizumab for the first-line treatment of adults with unresectable or metastatic hepatocellular carcinoma who require systemic therapy.

Health Canada has also issued a NOC with conditions for the use of atezolizumab in combination with nanoparticle albumin-bound paclitaxel for the treatment of adults with unresectable, locally advanced, or metastatic triple-negative breast cancer whose tumours have PD-L1 expression on at least 1% of TCs and who have not received prior chemotherapy for metastatic disease.

Atezolizumab has received approval as adjuvant treatment following complete resection and no progression after platinum-based adjuvant chemotherapy for adults with stage II to IIIA disease (according to the AJCC [7th edition] staging criteria)¹ whose tumours have PD-L1 expression on at least 50% of TCs in Switzerland (Swissmedic)²⁶ and the UK (Medicine and Healthcare products Regulatory Agency).²⁷ The FDA has approved atezolizumab as adjuvant treatment after resection and platinum-based chemotherapy in patients with PD-L1 expression on at least 1% of TCs in patients with stage II to IIIA (AJCC [7th edition] staging criteria)¹ NSCLC.²⁸ Atezolizumab was approved by Australia’s Therapeutic Goods Administration on September 7, 2022, and by the European Medicines Agency on April 25, 2022.

Atezolizumab was previously reviewed by CADTH in combination with bevacizumab for the first-line treatment of adults with unresectable or metastatic hepatocellular carcinoma who require system therapy.

Atezolizumab is administered as an IV infusion at a dosage of 840 mg every 2 weeks, 1,200 mg every 3 weeks, or 1,680 mg every 4 weeks.

Key characteristics of medical treatments for resected NSCLC are presented in Table 3.

Table 3: Key Characteristics of Medications for the Treatment of Resected NSCLC

AJCC = American Joint Committee on Cancer; EGFR = epidermal growth factor receptor; HSCT = hematopoietic stem cell transplantation; IgG1 = immunoglobulin G1; NSCLC = non–small cell lung cancer; PD-1 = programmed death-1; PD-L1 programmed death-ligand 1; TC = tumour cell; UICC = Union for International Cancer Control.

^aHealth Canada–approved indication

^bAtezolizumab is also indicated for use in adults with small cell lung cancer, NSCLC, and hepatocellular carcinoma in the metastatic setting.

Source: Product monograph for atezolizumab (Tecentriq),²⁹ product monograph for osimertinib (Tagrisso).³⁰

Stakeholder Perspectives

Patient Group Input

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

Patient input was provided by 2 groups: LCC and) LHF. LCC is a national charity and a member of the Global Lung Cancer Coalition and serves as a resource for lung cancer education, patient support, research, and advocacy. LHF is a charity that provides education, programs, and services for patients and health care providers, and invests in research and policy improvement in lung health. LCC collected the thoughts and experiences from 9 patients with NSCLC or small cell lung cancer and from 1 caregiver (from Canada, the US, the UK, and Australia) in December 2021 with phone interviews and environmental scans. LCC conducted phone interviews with 3 patients (from Ontario, Manitoba, and Quebec) in September and October 2021.

Patients who responded to the 2 surveys reported difficulty coping with their diagnosis and noted that they felt like there was “no hope, no light, and [that they were] less human” because of the poor prognosis of lung cancer. These feelings were amplified when the cancer was detected late. Patients also reported that cancer-related symptoms were hard to manage. Although the physical symptoms of shortness of breath, cough, and fatigue were reported to be mild, the psychosocial effects (such as anxiety, distress, depression) and some of the harsh side effects from chemotherapy, radiation, and surgery (e.g., nausea, vomiting, neuropathy, and lung injury) were harder to manage. Similarly, the psychosocial burden placed on family members and caregivers affected their emotional well-being, ability to travel and socialize, and work life.

Patient respondents deemed the following outcomes as important: delayed disease progression and increased long-term remission that ultimately improved survivorship, minimal side effects from treatments, maintenance of independence and functionality (to minimize burden on caregivers and loved ones), and full and worthwhile quality of life. The survey respondents emphasized a lack of treatment options for patients with PD-L1–positive, driver mutation–negative lung cancer to reduce a risk of recurrence after post-surgery chemotherapy. Patients emphasized wanting a choice in therapy that works in the early stages of disease (as opposed to the metastatic stage) with durable efficacy to maintain stable disease and increase chance of cure.

Clinician Input

Input From Clinical Experts Consulted by CADTH

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

Unmet Needs

Based on input from the clinical experts consulted by CADTH, despite the current standard of care with adjuvant chemotherapy, many patients who have undergone surgical resection and adjuvant chemotherapy experience disease relapse. In these cases, the disease is most often incurable. The survival benefit that accompanies adjuvant chemotherapy is modest, so there is an unmet need in this patient population. As noted by the clinical experts, modern population-based survival data from a time when adjuvant chemotherapy was in widespread use mirrors these outcomes.³¹ A 2016 report from the US Surveillance, Epidemiology, and End Results database reported 5-year OS rates ranging from 30% to 55% for patients with stage I to III NSCLC.³¹ The 8th edition of cancer staging from the AJCC,⁶ which is the current staging system being used, reports 5-year survival rates as 60%, 53%, and 36% for stage IIA, stage IIB, and stage IIIA NSCLC, respectively.

Place in Therapy

The clinical experts consulted by CADTH suggested that if adopted, atezolizumab would be an additional therapy, and not a replacement for pre-existing therapy (i.e., atezolizumab would be given in addition to, not instead of, adjuvant chemotherapy). The clinical experts agreed that atezolizumab would be only for use in the curative-intent setting after surgery, with the goal of increasing time before disease recurrence and, presumably, reducing the overall number of patients who experience disease recurrence.

The clinical experts noted that in the IMpower010 study,³² the subset of patients that received cisplatin plus gemcitabine as their adjuvant chemotherapy regimen before atezolizumab did not seem to derive benefit from adjuvant atezolizumab. The clinical experts also noted that there is mounting evidence across multiple tumour types that treatment with gemcitabine chemotherapy may attenuate the efficacy of immunotherapy checkpoint inhibitors.^33,34 Although the use of cisplatin plus gemcitabine is not common in Canada in the adjuvant setting for NSCLC, the clinical experts recommended that the combination not be used at all if there are any other available options if adjuvant atezolizumab is being considered. Specifically, cisplatin plus vinorelbine or cisplatin plus pemetrexed should be recommended, in keeping with the majority of adjuvant chemotherapy currently used in Canada.

According to the clinical experts, there could a potential shift the treatment paradigm for patients who experience disease recurrence while receiving adjuvant atezolizumab, or within 6 months of completion, because standard first-line therapy for this patient population, when diagnosed with incurable disease, is single-agent pembrolizumab or platinum-doublet chemotherapy combined with pembrolizumab; however, that may not be appropriate if their disease is likely to be resistant to PD-L1 inhibition. The clinical experts noted that, currently, there are no data on which to base recommendations for the use of checkpoint inhibitors in the advanced setting if a patient progressed on, or shortly, after adjuvant atezolizumab. The clinical experts did note that 12.2% of patients in the IMpower010 study who experienced disease relapse after receiving adjuvant atezolizumab went on to receive immunotherapy checkpoint inhibitors at the time of relapse^32,35; however, the details of the interval time between completion of atezolizumab and the subsequent immunotherapy is unknown. Also unknown are the specific immunotherapy checkpoint inhibitors used after relapse and the outcomes in this population. Once these data become available, we may be able to clarify this issue.

Patient Population

The clinical experts consulted by CADTH suggested that if adopted, atezolizumab would be offered to patients with resected NSCLC with a PD-L1 tumour proportion score of at least 50% and tumours larger than 5 cm, and to patients with node-positive tumours, regardless of the size of the primary tumour. Accordingly, companion IHC diagnostic testing of PD-L1 would be required. Although the IMpower010 study used the SP263 IHC assay, the clinical experts verified that, according to the Blueprint phase 2 project,³⁶ the SP263 assay has a high concordance with the 22C3 assay, which is currently in use in most pathology laboratories in Canada. Given the high concordance between the 2 IHC procedures, PD-L1 testing with the SP263 assay would not need to be implemented. The clinical experts did acknowledge, however, that there is wide variation in Canadian pathology labs in the current use of PD-L1 testing for patients with stage I to III NSCLC treated for cure. In jurisdictions where PD-L1 testing is currently limited to those with advanced, incurable NSCLC, this indication would expand the need for PD-L1 IHC testing in the broader population.

Eligible patients would be identified by thoracic surgeons, who would then refer patients to a medical oncologist for consideration for systemic adjuvant therapy after resection. Misdiagnosis is not an issue in this setting; however, with lung cancer screening across Canada currently limited to recently launched programs in selected jurisdictions, underdiagnosis of patients with early-stage asymptomatic disease is still an issue. As lung cancer screening programs gain momentum and become more widespread across Canada, more people will be diagnosed at an earlier stage, when still asymptomatic, and may then be eligible for curative-intent surgery and adjuvant therapy; otherwise, they may not be diagnosed until after they develop incurable metastatic disease.

The clinical experts noted that patients who were solid organ transplant recipients, who had severe active autoimmune disease, or who were considered unsuitable for immunotherapy checkpoint therapy, in general, would not be good candidates for adjuvant atezolizumab. In addition, the clinical experts recommended that patients with common EGFR mutations (exon 19 deletion and exon 21 L858R), although included in the IMpower010 trial, not be offered adjuvant atezolizumab instead of adjuvant osimertinib if they were considered to be candidate and had access to both. The clinical experts also noted that the other driver-mutation-defined population in the IMpower010 trial, patients with ALK fusion, is a population in which immunotherapy checkpoint inhibitors do not have significant activity in the advanced setting. Accordingly, it would not be unreasonable to presume limited, if any, benefit from adjuvant immunotherapy for a resected ALK-positive patient.

Assessing Response to Treatment

According to the clinical experts, the only way to know if adjuvant therapy is successful is to follow a patient with NSCLC from completion of all curative-intent therapy to disease relapse. The majority of disease relapse, as noted by the clinical experts, occurs in the 5 years after completion of therapy. Therefore, the clinical experts recommended that 5-year OS and DFS are the gold-standard metrics for success; patients who are alive and disease-free at this key landmark time point are generally considered to be “cured.”

The clinical experts noted that prolongation of DFS, even for patients who ultimately have disease recurrence, is important. When lung cancer recurs, it is usually incurable and generally carries with it significant physical and psychologic impacts that translate into decreased quality of life, decreased functioning and ability to contribute to society, and increased caregiver burden. Further, current standard-of-care therapy in the setting of incurable NSCLC has a significant burden on health care resources. From the point of view of the clinical experts, delaying the time of relapse has value from patient, health care, and societal perspectives.

The clinical experts recommended that patients receiving adjuvant atezolizumab undergo clinical and laboratory monitoring before each treatment (i.e., every 3 weeks). Radiographic reassessments should be done every 3 to 6 months during therapy. The clinical experts did note that follow-up after completion of curative-intent therapy is not standardized, given the lack of definitive literature suggesting the most appropriate timing for serial radiography. However, most commonly, patients are followed for 5 years with CT scans, which are sometimes done more frequently in the first 2 years after surgery, when relapses are most common. Individual practices will vary, however, depending on which guidelines are being followed, but intervals between CT scans of 6 months for the first 2 years and then 12 months out to year 5 are common. This follow-up regimen would not be affected by adjuvant atezolizumab and is already in place for patients who have received adjuvant chemotherapy after surgery. Finally, an initial diagnosis of NSCLC increases a patient’s risk of developing a second primary NSCLC, so lung cancer screening with low-dose, unenhanced chest CT scans may be appropriate after 5 years of surveillance.

Discontinuing Treatment

The clinical experts recommended that treatment with atezolizumab be discontinued in the event of dangerous or intolerable AEs, disease relapse, or a patient's decision to stop therapy.

Prescribing Conditions

The clinical experts recommended that any outpatient cancer systemic therapy infusion unit where immunotherapy checkpoint inhibitors are already administered would be appropriate for the administration of adjuvant atezolizumab. The clinical experts also noted that atezolizumab should be prescribed and supervised by a cancer specialist, generally a medical oncologist, with experience in the treatment of lung cancer and the use of immunotherapy checkpoint inhibitors.

Additional Considerations

The clinical experts noted that data for the subgroup of IMpower010 that includes the stage IB (AJCC [7th edition]¹ staging criteria; primary tumour 4 to 5 cm and node-negative) patient population remain immature; the analysis has yet to be formally completed. If results of the trial are positive for this patient population, the indication may need to be modified. The clinical experts noted that although the Health Canada NOC indication, and hence CADTH, is concerned with patients with PD-L1 expression on at least 50% of TCs, which is the group that derived the most benefit on based on post hoc analysis,^32,35 the entire stage II to III (AJCC [7th edition]¹ staging criteria) population, regardless of PD-L1 status, benefited from atezolizumab. The clinical experts further noted that another positive adjuvant immunotherapy trial, KEYNOTE091 (PEARLS), was presented at the European Society for Medical Oncology virtual plenary in March 2022.³⁷ Using a very similar trial design, the anti-PD-1 inhibitor pembrolizumab was delivered to patients with stage IB to IIIA (UICC and AJCC [7th edition]¹ staging criteria) NSCLC; however, this trial did not mandate adjuvant chemotherapy, but rather stated it should be considered in stage IB and was strongly recommended in stage II to III (AJCC [7th edition]¹ staging criteria). In the KEYNOTE091 trial, the HR for DFS of 0.76 (95% CI, 0.63 to 0.91; P = 0.0014) was similar to that seen in the IMpower010 study (DFS HR = 0.79; 95% CI, 0.64 to 0.96; P = 0.0205 in the stage II to III any PD-L1 analysis).^32,36 Interestingly, although the data from KEYNOTE091 were not mature for the other primary end point of DFS in the group with a PD-L1 tumour proportion score of at least 50%, the HR at the time of reporting was 0.82 (95% CI, 0.57 to 1.18; P = 0.14).

Clinician Group Input

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

Input was received by the following clinician groups: OH-CCO DAC and LCC. OH-CCO DAC provides clinical and health system guidance on drug-related issues in support of CCO’s mandate, including provincial drug-reimbursement programs and the Systemic Treatment Program. Three clinicians provided input on behalf of OH-CCO Lung and Thoracic DAC via email. As described previously, LCC is a national charity and resource for lung cancer education, patient support, research, and advocacy with both regional (Ontario) and pan-Canadian initiatives. LCC gathered expert opinions from 17 physicians who treat lung cancer in Canada and summarized data from published manuscripts and recent presentations.

Unmet Needs

The OH-CCO Lung and Thoracic DAC indicated the need for therapy with better cure and OS rates. According to LCC, currently available therapies provide inadequate 5-year OS (which is far below that of other cancer sites) and DFS (which is associated with OS in early-stage NSCLC). Both groups stated that patients with stage II to III (UICC and AJCC [8th edition]⁶ staging criteria) lung cancer have the greatest unmet need. The OH-CCO Lung and Thoracic DAC added that patients with resected stage II to III (UICC and AJCC [8th edition]⁶ staging criteria) NSCLC and no EGFR mutations who have not received neoadjuvant immunotherapy have the greatest unmet need. LCC emphasized that there has not been a new adjuvant therapy for stage IB to III resected NSCLC in the last 2 decades since adjuvant chemotherapy was introduced. In the meantime, however, there has been significant progress in therapies for metastatic disease.

Place in Therapy

Both clinician groups indicated that atezolizumab would supplement and/or be added to the current post-operative management of resected NSCLC after at least 1 dose of adjuvant (platinum-doublet) chemotherapy, and not be a replacement for current therapies. LCC added that there is currently no alternative PD-L1 inhibitor to atezolizumab. Moreover, LCC suggested that re-treatment with immunotherapy such as atezolizumab after relapse with locoregional disease and/or more than 6 months after completion of prior treatment should be considered.

Patient Population

The OH-CCO Lung and Thoracic DAC indicated that patients with a PD-L1 tumour proportion score of at least 50% and all PD-L1-positive patients are suited for atezolizumab. LCC suggested that patients with stage II to IIIA (UICC and AJCC [7th edition]¹ staging criteria) resected lung cancer with a PD-L1 tumour proportion score of at least 1%, determined with IHC after at least 1 cycle of adjuvant therapy, regardless of stage or nodal status, are suitable for atezolizumab. LCC explained that as long as a test is validated, the results are acceptable, regardless of whether the SP263, 22C3, or 28 to 8 assay is from a commercial vendor or is an institution in-house option. Also, LCC specified the following patient characteristics that are least suitable for atezolizumab: contraindication to immunotherapy (organ transplant), PD-L1–negative disease, and prior gemcitabine treatment (based on results from the POSEIDON trial).³⁸ According to LCC, for patients with a resected lung cancer with a sensitizing EGFR mutation and PD-L1 expression, clinicians should choose the better option (i.e., atezolizumab or osimertinib, based on an assessment of risks and benefits for each individual patient). As for NSCLC with ALK translocation, LCC recommended that atezolizumab not be used unless other treatment options have been exhausted. Last, because active autoimmune disease is considered a relative contraindication, LCC recommended that the risks and benefits of atezolizumab be discussed with patients with prior or active autoimmune disease.

Assessing Response to Treatment

The OH-CCO Lung and Thoracic DAC considered DFS a clinically meaningful outcome measure. LCC suggested that “response to therapy” is not an appropriate outcome in the early-stage resected-cancer setting as it is in the advanced or metastatic setting. LCC added that, based on the standard set by adjuvant chemotherapy in NSCLC, a DFS benefit with a HR of 0.84 or lower may be considered a clinically meaningful response, as demonstrated in the trial by Pignon et al. (2008).²⁰ Both groups agreed that outcome measures (e.g., recurrence rates via DFS) and cure rates (represented by 5-year OS and KM curves for OS) in clinical trials are aligned with clinical practice. LCC emphasized that even though treatment response cannot be determined in the adjuvant setting, radiographic imaging initially performed at 3 to 4 months, and then at intervals of more than 6 months, should be considered. Further, with laboratory and clinical assessments conducted at 3-week intervals (before each cycle of atezolizumab, for toxicity), physical signs or symptoms suggestive of recurrent disease could be identified. However, LCC acknowledged that there is a wide range of follow-up intervals across Canada, and globally, with no consensus. In most settings, LCC indicated that patients with resected stage IB to IIIA (AJCC [7th edition]¹ staging criteria) NSCLC are generally followed for at least 5 years post-operatively by at least 1 (surgical or medical) oncologist. Last, LCC emphasized that recurrent disease (DFS) should be considered a critical outcome on its own (besides OS, which is the gold standard), given the high patient, health care, and social-level ramifications associated with recurrence.

Discontinuing Treatment

Both groups indicated that therapy should be discontinued at disease progression or in the case of unacceptable toxicity.

Prescribing Conditions

As for the treatment settings, hospital (outpatient clinic) and any oncology setting where infusions are performed are considered appropriate prescribing settings for atezolizumab by the OH-CCO Lung and Thoracic DAC and LCC.

Additional Considerations

The OH-CCO Lung and Thoracic DAC agreed that the end points reported in the trial can reasonably be expected to correlate with OS. Also, both clinical groups believed that other strategies (e.g., a short course with only 3 doses of neoadjuvant immunotherapy plus chemotherapy) are expected to be less expensive than a full-year course of adjuvant immunotherapy.

Drug Program Input

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

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

AJCC = American Joint Committee on Cancer; DAC = Drug Advisory Committee; ECOG = Eastern Cooperative Oncology Group; IHC = immunohistochemistry; LCC = Lung Cancer Canada; NSCLC = non–small cell lung cancer; OH-CCC = Ontario Health-Cancer Care Ontario; PAG = Provincial Advisory Group; PD-1 = programmed death-1; PD-L1 = programmed death-ligand 1; TC = tumour cell; UICC = Union for International Cancer Control.

Clinical Evidence

The clinical evidence included in the review of atezolizumab is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as studies that were selected in accordance with an a priori protocol. The second section includes indirect evidence from the sponsor, if submitted, and indirect evidence selected from the literature that met the selection criteria specified in the protocol. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of atezolizumab 840 mg every 2 weeks, 1,200 mg every 3 weeks, or 1,680 mg every 4 weeks delivered by IV infusion as monotherapy for adjuvant treatment following complete resection and no progression after platinum-based adjuvant chemotherapy of adults with stage II to IIIA (according to AJCC [7th edition]¹ staging criteria) NSCLC whose tumours have PD-L1 expression on at least 50% of TCs.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 5: Inclusion Criteria for the Systematic Review

AE = adverse event; AJCC = American Joint Committee on Cancer; ALK = anaplastic lymphoma kinase; ALT = alanine aminotransaminase; AST = aspartate aminotransaminase; BSC = best supportive care; DFS = disease-free survival; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; NSCLC = non–small cell lung cancer; OS = overall survival; PD-1 = programmed death-1; PD-L1 = programmed death-ligand 1; RCT = randomized controlled trial; SAE = serious adverse event; TEAE = treatment-emergent adverse event; WDAE = withdrawal due to adverse event.

^aAn important outcome to patients.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.³⁹

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Tecentriq (atezolizumab) and NSCLC. The following clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

CADTH-developed search filters were applied to limit retrieval to randomized controlled trials or controlled clinical trials. Conference abstracts were excluded from the search results. Refer to Appendix 1 for the detailed search strategies.

The initial search was completed on March 23, 2022. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee (pERC) on July 13, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool for Searching Health-Related Grey Literature checklist.⁴⁰ Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

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

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

Findings From the Literature

A total of 389 studies were identified from the literature for inclusion in the systematic review (Figure 1). One single study (IMpower010) was selected for inclusion.³² The included study is summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of the Impower010 Study

AE = adverse event; AJCC = American Joint Committee on Cancer; ALT = alanine aminotransaminase; AST = aspartate aminotransferase; BSC = best supportive care; DFS = disease-free survival; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; FFPE = formalin-fixed paraffin-embedded; IC = immune cell; IHC = immunohistochemistry; ITT = intention to treat; NGS = next-generation sequencing; NSCLC = non–small cell lung cancer; OS = overall survival; PD-1 = programmed death-1; PD-L1 = programmed death-ligand 1; qRT-PCR = quantitative reverse transcriptase-polymerase chain reaction; RCT = randomized controlled trial; SAE = serious adverse event; TC = tumour cell; UICC = Union for International Cancer Control.

Notes: Two additional reports were included.^8,28

Staging was defined using the AJCC (7th edition) staging criteria.¹

^aPatients who have not experienced recurrence of disease will undergo tumour assessments every 6 months in years 3 to 5 with CT and X-ray after randomization (starting with CT scan, alternating with X-ray), and annually thereafter by X-ray until disease recurrence, death, loss to follow-up, consent withdrawal, or study termination by the sponsor, whichever occurs first.

Source: Clinical Study Report for IMpower010.⁹

Description of the Study

The IMpower010 is an ongoing phase III, global, multi-centre, open-label, randomized study comparing the efficacy and safety of atezolizumab with BSC in patients with stage IB to IIIA (per the UICC and AJCC [7th edition] staging system)¹ NSCLC after complete resection and adjuvant cisplatin-based chemotherapy. A total of 1,280 patients were enrolled across 227 sites in 22 countries within North America (including 2 sites in Canada), Europe, Asia, and Australia. The primary efficacy outcome was DFS, assessed by the investigator. Secondary efficacy outcomes included OS, 3-year and 5-year DFS rates, and DFS in the PD-L1 subpopulations defined as 50% or higher TC expression by detected SP263 immunohistochemistry (IHC) assay in patients with stage II to IIIA NSCLC as defined by the UICC and AJCC (7th edition) staging criteria.¹

To measure PD-L1 expression status, sections from tumour specimens from eligible patients were stained and evaluated by external central laboratories using the VENTANA PD-L1 (SP263) assay. Tumour specimens were scored in accordance with the assay’s instruction for use, and the findings were used to define the primary analysis population.

A schematic of the IMpower010 study is presented in Figure 2. The IMpower010 study consisted of 2 phases: an enrolment phase and a randomized phase. In the enrolment phase, patients who had undergone complete resection of their NSCLC were screened, and if eligible (n = 1,280), were enrolled to receive 1 of 4 cisplatin-based chemotherapy regimens (cisplatin plus vinorelbine, docetaxel, gemcitabine, or pemetrexed) based on investigator choice. The 1,005 patients (from 204 centres in 21 countries, including 2 sites in Canada) deemed eligible to continue with the study after up to 4 cycles of cisplatin-based chemotherapy proceeded to the randomization phase. In the randomization phase, patients were randomized in a 1:1 ratio to receive atezolizumab or BSC. The randomization sequence was generated using a permuted-block randomization method in interactive Voice/Web Response System (IxRS) and was stratified by the following factors: sex (female versus male), tumour histology (squamous versus nonsquamous), extent of disease (stage IB versus stage II versus stage IIIA based on the UICC and AJCC [7th edition]¹ staging criteria), and PD-L1 expression status (TC2 or TC3 and any IC versus TC0 or TC1 and IC2 or IC3 versus TC0 or TC1 and IC0 or IC1, detected with the SP142 IHC assay).

All patients underwent tumour assessment by the investigator every 4 months in the first year, and every 6 months in the second year after randomization through year 5, and annually from year 6 until disease recurrence, death, loss to follow-up, consent withdrawal, or study termination by the sponsor, whichever occurs first. In addition, at the first evidence of radiographic disease recurrence, patients from both treatment arms underwent a mandatory tumour biopsy sample collection.

All patients were monitored for safety and tolerability throughout the study.

The clinical report provided to CADTH presented the analysis of study data collected from the date of the first patient randomized (February 26, 2016) to the clinical data cut-off date of January 21, 2021, for the protocol-specific interim analysis on DFS.

Figure 2: Schematic of the IMpower010 Study

IC = tumour-infiltrating immune cell; NSCLC = non–small cell lung cancer; PD-L1 = programmed death-ligand 1; q3w = every 3 weeks; TC = tumour cell.

Notes: Staging defined using the American Joint Committee on Cancer (7th edition) staging criteria.¹

Patients received up to 4 cycles of cisplatin-based chemotherapy unless unacceptable toxicity or disease relapse occurred, or a patient decided to discontinue therapy.

Source: Clinical Study Report for IMpower010.⁹

Protocol Amendments

Key protocol amendments for the IMpower010 study are detailed in Appendix 3. The first version of the study protocol was issued on April 1, 2015. The protocol was globally amended 7 times. The key protocol amendments are listed in Appendix 3. The 2 most notable amendments were the inclusion of a PD-L1 subpopulation, defined as TC2 or TC3 or IC2 or IC3 with the SP142 IHC assay and stage II to IIIA disease (protocol version 5 and 6), from the initial enrolment population, defined as only TC3 or IC3 with the SP142 IHC assay (protocol versions 1 to 4); and the introduction of the SP263 IHC assay to defined the primary biomarker analysis population in protocol version 8, which replaced the SP142 IHC assay used in previous versions of the protocol.

Populations

Inclusion and Exclusion Criteria

The key inclusion and exclusion criteria applied in the IMpower010 study are summarized in Table 6.

Briefly, patients who had a complete surgical resection of stage IB (tumours ≥ 4 cm) to IIIA (T2 to 2, N0, T1N1 to T3N1, T1N2 to T3N2, T2N0) per the UICC and AJCC (7th edition)¹ staging system NSCLC were eligible for the enrolment phase of the study. A complete resection of NSCLC was required 4 to 12 weeks before enrolment by any of the following procedures: lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy. Patients were required to have adequately recovered from surgery, to be eligible to receive a cisplatin-based chemotherapy regimen, and to have adequate hematologic and end-organ functioning. Patients with malignancies other than NSCLC in the 5 years before enrolment, except those with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated with expected curative outcomes, were excluded from enrolment. Patients who had completed the enrolment phase and up to 4 cycles of cisplatin-based therapy and continued to meet eligibility criteria were eligible for the randomization phase of the study. Patients were required to continue to present with adequate hematologic and end-organ function. Patients who presented with signs or symptoms of infection, who received therapeutic oral or IV antibiotics, or who were treated with systemic corticosteroids or other immunosuppressive medications in the 14 days before randomization were excluded from the randomization phase.

Baseline Characteristics

The baseline characteristics of patients with stage II to IIIA disease and PD-L1 expression on at least 50% of TCs are summarized in Table 7 Baseline characteristics of the overall ITT population are presented in Appendix 5.

The indication population had a median age of 62 (range = 36 to 84) years, was predominantly male (72.9%) and White (70.3%), had high functional performance (57.2% had an ECOG performance status score of 0), and most reported previous tobacco use (69.9%).

At diagnosis, most patients had stage IIIA disease (48.0%) with nonsquamous histology (59.8%). Among the 137 patients with nonsquamous histology, 94.2% were identified as having the adenocarcinoma subtype. EGFR or ALK mutations were detected in 8.7% of patients. The majority of patients had undergone prior lobectomy (74.2%) and mediastinal lymph node dissection (81.7%).

Table 7: Summary of Baseline Characteristics in the Impower010 Study of Patients With Stage II to IIIA Disease With PD-L1 Expression on at Least 50% of TCs

ALK = anaplastic lymphoma kinase; BSC = best supportive care; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EGFR = epidermal growth factor receptor; max = maximum; min = minimum; PD-L1 = programmed death-ligand 1; SD = standard deviation; TCs = tumour cells.

Note: Staging defined using the American Joint Committee on Cancer (7th edition) staging criteria.¹

^aAt randomization is defined as the last assessment value before the start of treatment in the randomization period.

^bFor the histology subtype in nonsquamous disease, there were 69 patients in the BSC group and 68 in the atezolizumab group.

Source: Clinical Study Report for IMpower010.⁹

Interventions

Cisplatin Chemotherapy (Enrolment Phase)

All eligible, surgically resected patients received cisplatin 75 mg/m² on day 1, plus 1 of the following 4 options:

• vinorelbine 30 mg/m² IV push (days 1 and 8)

• docetaxel 75 mg/m² IV (day 1)

• gemcitabine 1,250 mg/m² IV (days 1 and 8)

• pemetrexed 500 mg/m² day 1; nonsquamous NSCLC only).

The investigator selected the chemotherapy regimen (cisplatin plus either vinorelbine, docetaxel, gemcitabine, or pemetrexed) for each patient before enrolment. Each enrolled patient received up to 4 cycles of cisplatin-based chemotherapy, with each cycle being 3 weeks (21 days) in length. The use of antiemetics and hydration modifications were permitted during cisplatin-based chemotherapy.

Atezolizumab (Randomization Phase)

In the randomization phase, patients were assigned to either atezolizumab or BSC. Subsequent cancer therapies were permitted. Patients who were randomized to the atezolizumab arm received 1,200 mg atezolizumab by IV infusion on day 1 of every 21-day cycle for up to 16 cycles. Atezolizumab was infused over 60 (± 15) minutes for the first administration and, if tolerated, subsequent infusions were administered over 30 (± 10) minutes. Dose modifications to atezolizumab were not permitted. However, interruptions or discontinuation due to AEs were allowed.

Best Supportive Care (Randomization Phase)

Patients randomized to the BSC arm received no treatment during the randomized phase of the study other than 16 cycles of BSC. Patients were followed starting on day 1 of each 21-day cycle, for 1 year, and then entered the survival follow-up period. Crossover to the atezolizumab arm was not permitted, but subsequent cancer therapies were permitted.

To maintain a similar frequency of study assessment in the study arms, including assessments of disease recurrence, safety, symptoms, and AEs, patients in the BSC arm had medical contact every 3 weeks during the first year.

Concomitant Medications

The following medications were permitted during the study:

• oral contraceptives

• hormone-replacement therapy

• prophylactic or therapeutic anticoagulation therapy, including low-molecular-weight heparin or warfarin at a stable dose level

• inactive influenza vaccinations (during influenza season only)

• megestrol administered as an appetite stimulant

• corticosteroids (≤ 10 mg oral prednisone or equivalent) for chronic obstructive pulmonary disease

• mineralocorticoid (e.g., fludrocortisone)

• low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical insufficiency.

Pre-medication with antihistamines was permitted for any atezolizumab infusion after cycle 1.

The following medications were prohibited during the study period:

• any live, attenuated vaccine (e.g., FluMist) in the 4 weeks before initiation of study treatment, during atezolizumab treatment, or in the 5 months after the final dose of atezolizumab (for patients randomized to atezolizumab)

• steroids to pre-medicate patients in whom CT scans with contrasts are contraindicated (i.e., patients with contrast allergy or impaired renal clearance); instead, noncontrast CT of the chest and noncontrast CT or MRI of another location (if needed) was recommended.

Although the concomitant use of herbal therapies was not recommended because of unknown pharmacokinetics, safety profiles, and potential drug-drug interactions, their use was allowed at the discretion of the investigator. However, herbal therapies intended for the treatment of cancer were prohibited.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trials included in this review is provided in Table 8. These end points are further summarized below.

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

AE = adverse event; DFS = disease-free survival; ITT = intention to treat; OS = overall survival; PD-L1 = programmed death-ligand 1; SAE = serious adverse event; TC = tumour cell.

Note: Staging defined using the American Joint Committee on Cancer (7th edition) staging criteria.¹

Source: Protocol for IMpower010.⁴¹

Overall Survival

OS was a secondary efficacy end point in the IMpower010 study. OS was defined as the time from the date of randomization to death from any cause. Data for patients who were not reported as having died at the date of analysis were censored at the date they were last known to be alive. If no post-baseline data were available, then OS was censored at the date of randomization.

Survival follow-up information was collected from telephone calls, patient medical records, and/or clinic visits approximately every 3 months until death, loss to follow-up, withdrawal of consent, or termination of study by the sponsor, whichever occurred first. All patients were followed for survival and new anti-cancer therapy information, unless the patient asked to be withdrawn from follow-up, was lost to follow-up, died, or the study was terminated by the sponsor, whichever occurred first. For patients who withdrew from the study, the use of public data (e.g., county records) to obtain information about survival status only was permitted.

Disease-Free Survival

DFS, as assessed by the investigator, was a primary efficacy end point in the IMpower010 study. DFS was defined as the time from the date of randomization to the date of the first documented, investigator-assessed recurrence of disease, new primary NSCLC, or death from any cause, whichever occurred first. Data for patients who were not reported as experiencing disease recurrence, a new primary NSCLC, or death were censored at the date of the last tumour assessment. If no post-baseline data were available, DFS was censored at the time of randomization.

Patients underwent scheduled tumour assessment via CT scan at baseline, every 4 months in the first year, and every 6 months in the second year after randomization. Patients who did not experience disease recurrence underwent tumour assessment every 6 months with CT scan and X-ray at year 3 and year 5 after randomization, and annually thereafter with X-ray. In the absence of disease recurrence, tumour assessments continued, regardless of whether patients started new anti-cancer therapy, until disease recurrence, withdrawal of consent, death, loss to follow-up, or study termination by the sponsor, whichever occurred first. Patients who discontinued treatment before completing the 16 cycles of atezolizumab for reasons other than disease recurrence (e.g., toxicity) continued with their scheduled tumour assessments at the same frequency as they would have if they had remained on the study treatment until disease recurrence, death, withdrawal of consent, loss to follow-up, or study end, whichever occurred first. In addition, patients in either treatment arm who started a new anti-cancer therapy in the absence of disease recurrence were followed according to the protocol schedule, unless they withdrew consent, died, experienced disease recurrence, were lost to follow-up, or the study ended, whichever occurred first.

At the first evidence of radiologic disease recurrence or confirmation of a new primary NSCLC, patients from either treatment arm underwent mandatory tumour biopsy sample collection (within 40 days of disease recurrence or before the start of the next anti-cancer therapy, which was sooner), unless it was not clinically feasible. Acceptable samples included core needle biopsies for deep tumour tissue (at least 3 cores) embedded into a single paraffin block; excisional, incisional, punch, or forceps biopsy specimens for cutaneous, subcutaneous, or mucosal lesions; and tumour tissue resection.

Safety

The following safety outcomes were assessed during the enrolment phase and the randomization phase of the study, and for 90 days after the last dose of the study treatment (last study assessment for patients in the BSC treatment arm) or initiation of a new anti-cancer therapy, which ever occurred first:

• AEs

• SAEs

• Treatment or study discontinuation due to AEs

• Death

• Non-SAEs of special interest, such as:

  • drug-induced liver injury that includes elevated aspartate aminotransferase or alanine aminotransferase levels in combination with either elevated bilirubin or clinical jaundice

  • suspected transmission of an infectious agent by the study drug

  • treatment-emergent autoimmune conditions (including pneumonitis and grade ≥ 3 hypoxia or dyspnea); colitis; endocrinopathies (including diabetes mellitus, pancreatitis, and adrenal insufficiency); vasculitis; hepatitis; transaminitis: grade 2 or higher (AST or ALT > 3 × upper limit of normal [ULN] and bilirubin > 2 ULN or AST/ALT > 10 × ULN); systemic lupus erythematosus; Guillain-Barré syndrome; and skin reactions (including vitiligo and pemphigoid)

  • events suggestive of hypersensitivity, cytokine-release syndrome, influenza-like illness, systemic inflammatory response system, or infusion-reaction syndromes.

The toxicity profile of the study treatments for all patients were classified according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0).

Statistical Analysis

The statistical analysis for efficacy end points conducted in the IMpower010 trial is summarized in Table 9.

Efficacy Analysis

Sample Size Determination

Approximately 1,280 patients were expected to be accrued during the enrolment phase of the study. With an expected dropout rate of 21% during the adjuvant cisplatin-based chemotherapy, approximately 1,005 patients were expected to enter the randomization phase, including approximately 882 patients in the stage II to IIIA population; of these, approximately 474 were in the subpopulation with PD-L1 expression on at least 1% of TCs (detected with the SP263 IHC assay).

Of note, the trial was not powered for the Health Canada–recommended NOC indication. Moreover, the planned sample size did not consider significant efficacy findings for the Health Canada–indicated population.

For the final DFS analysis to occur, approximately |||||||||||||||| in the subpopulation with PD-L1 expression on at least 1% of TCs (detected with the SP263 assay) of the stage II to IIIA population are required. The number of events is expected to correspond to a minimum detectable difference in HR of approximately |||||||||| in the PD-L1 subpopulation with TC expression of at least 1% (detected with the SP263 assay) in the stage II to IIIA population.

For the final OS analysis to occur, given a sample size of 1,005, approximately ||||||||| OS events in all randomized stage IB to IIIA patients are required.

Primary Efficacy Analysis

The HR for duration of DFS was estimated in the ITT population using a stratified Cox regression model, which included a 2-sided 95% CI (Table 10). The KM methodology was used to estimate median DFS for each treatment arm, with KM curves constructed to illustrate potential differences between atezolizumab and BSC. The 2-sided 95% CI for median DFS for each treatment arm was constructed using the methodology of Brookmeyer and Crowley.⁴²

Type and site of disease recurrence were summarized as counts and frequencies.

To control for the overall level of significance at a 1-sided error of 0.025, comparisons between the treatment arms were conducted hierarchically for the PD-L1 subpopulation defined by SP263 TC of at least 1% within the stage II to IIIA population, the entire randomized stage II to IIIA population, and the ITT population (Figure 3)

Of note, the analysis of the indicated population under review was not controlled for multiplicity.

Secondary Efficacy Analysis

The secondary efficacy of OS was assessed in the ITT population using a stratified Cox regression model, which included a 2-sided 95% CI. The KM methodology was used to estimate the median OS for each treatment arm, with KM curves constructed to illustrate the differences between atezolizumab and BSC. The 2-sided 95% CI for median OS for each treatment arm was constructed using the methodology of Brookmeyer and Crowley.⁴² The OS testing schema, as described for the DFS analysis, is illustrated in Figure 3.

The DFS rate at 3 years and at 5 years was analyzed for the subpopulation with PD-L1 expression on at least 50% of TCs (detected with the SP263 assay). These DFS rates were estimated using the KM methodology for each treatment arm, with 2-sided 95% CI using the Greenwood formula.⁴³

DFS in the subpopulation with PD-L1 expression on at least 50% of TCs (detected with the SP263 assay) in all randomized patients with stage II to IIIA NSCLC was assessed using stratified Cox regression model, including a 2-sided 95% CI) (Table 9). The analysis methodology used was the same as described for the primary efficacy analysis. Of note, the analysis of the indicated population under review was not controlled for multiplicity.

Interim Analyses

One interim analysis for DFS was planned for the date when approximately 190 DFS events (approximately |||||||||| of expected observations) occurred in the subpopulation with PD-L1 expression on at least 1% of TCs (detected with the SP263 assay) of the stage II to IIIA population. This was expected to occur approximately |||||||||| after the first patients was randomized. To control for type I error DFS at a 1-sided alpha of 0.025, the stopping boundaries for the DFS interim analysis were computed using the Hwang-Shih-Decani alpha-spending function with gamma parameters of –0.9.⁴⁴

|||||||||||||||||||||||||||||||||||||||| for OS were planned. The first OS interim analysis was planned for the time of the DFS interim analysis if DFS was positive, as shown in Figure 3. The results presented for OS in this report are based on this interim analysis. Further interim analyses are planned at |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Analysis timing and stopping boundaries for DFS and OS are summarized in Appendix 4.

Figure 3: Overview of the Alpha Control

DFS = disease-free survival; ITT = intention to treat; NSCLC = non–small cell lung cancer; OS = overall survival; PD-L1 = programmed death-ligand 1; TC = tumour cell.

Note: Staging defined using the American Joint Committee on Cancer (7th edition) staging criteria.¹

Source: Protocol for IMpower010.⁴¹

Sensitivity Analysis

To evaluate the impact of loss to follow-up, a sensitivity analysis (“worst-case” analysis) was planned if more than 5% of patients were lost to follow-up for DFS in either treatment arm; patients who were lost to follow-up were considered to have recurrent disease at the date of their last tumour assessment.

To evaluate the impact of missed visits, sensitivity analyses with different censoring rules were performed for the primary end point of DFS. Data for patients with a DFS event who missed 2 or more schedule assessments immediately before the event were censored at the most recent date with adequate radiological assessment before the missed visit.

Subgroup Analysis

The following subgroup analyses for duration of DFS and OS were conducted in the ITT population: demographic variables (e.g., age), and baseline prognostic characteristics (e.g., tumour stage, chemotherapy regimen before randomization, histology, smoking history, and ECOG performance status). Results were also presented for the population with PD-L1 expression on at least 50% of TCs and stage II to IIA disease, which is of direct interest as it reflects the indicated population under review. Summaries of DFS and OS were constructed for each level of categorical variable using unstratified HR estimates from Cox proportional hazards models and KM estimates of median survival time.

Exploratory Analysis

DFS and OS rates every year from randomization were estimated using KM methodology for each treatment arm with the Greenwood formulas for exploratory purposes.

DFS rates in other PD-L1 subpopulations were estimated for exploratory purposes, including the stage II to IIA population with PD-L1 expression on at least 50% of TCs, which is of direct interest as it reflects the indicated population under review. Data were analyzed using the same methods used in the primary analysis of DFS.

OS in other subpopulations was estimated for exploratory purposes and analyzed using the same methods as in the secondary analysis of OS. Subpopulations of interest included the stage II to IIIA subpopulation with PD-L1 expression on at least 50% of TCs (detected with the SP263 assay), which reflects the indicated population under review.

Safety Analysis

Safety analyses were performed on all randomized patients who received any amount of study treatment and had at least 1 post-baseline assessment. All AEs that occurred during or after the first study drug dose were summarized using counts and frequencies by treatment arm and NCI CTCAE grade.

Table 9: Statistical Analysis of Efficacy End Points in the IMpower010 Study

CI = confidence interval; DFS = disease-free survival; HR = hazard ratio; IC = immune cell; IHC = immunohistochemistry; ITT = intention to treat; KM = Kaplan-Meier; NA = not applicable; NSCLC = non–small cell lung cancer; OS = overall survival; PD-L1 = programmed death-ligand 1; TC = tumour cell; vs. = versus.

Note: Staging defined using the American Joint Committee on Cancer (7th edition) staging criteria.¹

Source: Protocol for IMpower010.⁴¹

Analysis Populations

ITT Population

The ITT population was defined as all randomized patients with resected stage IB (tumours ≥ 4 cm) to IIIA NSCLC, regardless of whether or not the patient received their assigned treatment. Patients were grouped by their assigned treatment at randomization by IxRS. The population of interest to the CADTH review was a subset of the randomized patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs.

Safety-Evaluable Population

The safety-evaluable population was defined as all randomized patients who received at least 1 dose of atezolizumab and all randomized patients who were randomized to the receive BSC and no atezolizumab, but who had at least 1 post-baseline safety assessment (e.g., AEs, laboratory tests, vital signs), regardless of their assigned treatment at randomization (i.e., patient data were analyzed according to the treatment received). The population of interest to the CADTH review was a subset of safety-evaluable patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs.

Results

Patient Disposition

Details of patient disposition are summarized in Table 10.

A total of 1,600 patients were screened for entry into enter the IMpower010 study. Of those, 1,280 entered the enrolment phase of the study and received adjuvant chemotherapy. From those, 1,070 were screened to enter the randomization phase of the study, in which 498 patients were randomized to treatment with BSC and 507 to treatment with atezolizumab. Treatment is ongoing for 371 (74.5%) and 386 (76.1%) patients randomized to receive BSC and atezolizumab, respectively.

Among patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs, 144 and 155 patients were randomized to receive BSC or atezolizumab, respectively. In this subpopulation, treatment is ongoing for a greater proportion of patients randomized to receive atezolizumab versus BSC (86.1% versus 71.1%), primarily because of a higher number of deaths in the BSC group (22.8%) than in the atezolizumab group (9.6%).

The most common reason for discontinuation from the study was death, followed by withdrawal by the patient.

Duration of Follow-Up

Duration of follow-up to date is summarized in Table 11. Duration of follow-up of the overall ITT population is presented in Appendix 5.

Among all patients randomized into the trial, the median length of follow-up was approximately 32 months (interquartile range = 27.60 to 36.64). Among the subpopulation of patients with stage II to IIIA disease and PD-L1 expression on at least 50% of TCs, the median duration of follow-up was slightly longer in those randomized to atezolizumab (35.98 months; interquartile range [IQR], 29.7 to 40.67) than BSC (33.2 months; IQR, 26.61 to 39.75).

Protocol Deviations

Major protocol deviations related to the inclusion criteria, exclusion criteria, medication, and procedures are summarized in Appendix 5.

Major protocol deviations among the subpopulation of patients with stage II to IIIA and PD-L1 expression on at least 50% of TCs was unavailable.

In the ITT population, at least 1 major protocol deviation was recorded for 24.7% and 29.0% of patients randomized to BSC and atezolizumab, respectively. The most common deviations (BSC versus atezolizumab) were related to study procedures (21.5% versus 22.9%), followed by deviations related to inclusion criteria (4.0% versus 2.6%), exclusion criteria (1.0% versus 1.2%), and medication (0.4% versus 4.1%).

Exposure to Study Treatments

Exposure to atezolizumab is summarized in Table 12. Exposure to atezolizumab in the overall ITT population is presented in Appendix 5.

The median treatment duration with atezolizumab was 10.4 (range = 0 to 16) months, at a median dose intensity of 100% (range = 40% to 100%). The median total cumulative dose of atezolizumab received was 19,200 mg (range = 1,200 mg to 19,200 mg), with most patients receiving 16 doses per cycle.

Concomitant Medications and Nonprotocol Anti-Cancer Therapies

The use of concomitant medications and nonprotocol anti-cancer therapies during the trial is summarized in Table 13. Additional data on the use of concomitant medication and nonprotocol anti-cancer therapies in the overall ITT population are presented in Appendix 5.

Use of concomitant medication among the subpopulation of patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs was unavailable.

Among the subpopulation of patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs, the proportion of patients who reported treatment with at least 1 nonprotocol anti-cancer therapy was 26.3% and 17.4% among those randomized to BSC and atezolizumab, respectively. The most common nonprotocol antineoplastic drug used was carboplatin (7.0% in the BSC group versus 7.8% in the atezolizumab group), followed by pembrolizumab and cisplatin.

Table 10: Patient Disposition in the Impower010 Study (Clinical Data Cut-Off Date of January 21, 2021)

BSC = best supportive care; ITT = intention to treat; NR = not reported; PD-L1 = programmed death-ligand 1; TC = tumour cell.

Note: Staging defined using the American Joint Committee on Cancer (7th edition) staging criteria.¹

Source: Clinical Study Report for IMpower010.⁹

Table 11: Duration of Follow-Up in the Impower010 Study for Patients With Stage II to IIIA Disease With PD-L1 Expression on at Least 50% of TCs (Clinical Data Cut-Off Date of January 21, 2021)

BSC = best supportive care; ITT = intention to treat; PD-L1 = programmed death-ligand 1; TC = tumour cell.

Source: Clinical Study Report for IMpower010.⁹

Table 12: Exposure to Atezolizumab in the Impower010 Study (Safety Population; Clinical Data Cut-Off Date of January 21, 2021)

BSC = best supportive care; PD-L1 = programmed death-ligand 1; TC = tumour cell.

Source: Clinical Study Report for IMpower010.⁹

Table 13: Concomitant Medication and Nonprotocol Anti-Cancer Therapy in the IMpower010 Study for Patients With Stage II to IIIA Disease With PD-L1 Expression on at Least 50% of TCs (Clinical Data Cut-Off Date of January 21, 2021)

BSC = best supportive care; NR = not reported; PD-L1 = programmed death-ligand 1; TC = tumour cell.

^aThe most frequently used (by Anatomical Therapeutic Chemical class level 2, > 40% incidence in any treatment group).

^bOnly treatments reported to be used in at least 2% in any treatment group are listed.

Source: Clinical Study Report for IMpower010.⁹

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported here. Refer to Appendix 5 for additional efficacy data related to the overall ITT population and subgroup analyses of the ITT population.

Overall Survival

OS data are summarized in Table 14. A KM plot of median OS for the subpopulation of patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs is illustrated in ||||||||||. The OS results presented here are descriptive only, given that data were based on subgroup analysis.

Among the subpopulation of patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs, the observed deaths at the time of the interim analysis were 22.8% and 9.6% in the BSC and atezolizumab treatment groups, respectively. The stratified HR was 0.40 (95% CI, 0.20 to 0.81) in favour of atezolizumab. The median OS could not be estimated in either treatment arms because of the low rate of death events at the time of the planned interim analysis. At year 3, a greater proportion of patients in the atezolizumab treatment group (90.85%) were event-free than in the BSC group (76.67%), for a difference in proportion of 14.27% (95% CI, 4.19% to 24.35%). The corresponding year 5 event-free rates were not estimated and require longer follow-up.

Because of the low number of events, the KM estimated median OS could not be calculated.

Disease-Free Survival

DFS data are summarized in Table 15.

A greater proportion of patients in the BSC treatment arm (45.6%) experienced a disease recurrence or death than in the atezolizumab arm (24.3%). The stratified HR of 0.47 (95% CI, 0.29 to 0.75) favoured atezolizumab. At year 3, 73.79% of patients in the atezolizumab group were event-free compared with 48.61% of those in the BSC group, for a difference in the event-free rate of 25.18% (95% CI, 11.01% to 39.36%). Corresponding year 5 event-free rates were not estimated and require longer follow-up.

The findings for DFS with atezolizumab and BSC were consistent across most subgroups in exploratory subgroup analyses (refer to Appendix 3).

Table 14: Overall Survival in the Impower010 Study for Patients With Stage II to IIIA Disease With PD-L1 Expression on at Least 50% of TCs (Clinical Data Cut-Off Date of January 21, 2021)

BSC = best supported care; CI = confidence interval; HR = hazard ratio; NE = not estimable; OS = overall survival; PD-L1 = programmed death-ligand 1; TC = tumour cell.

^aSummaries of durations (median and percentiles) are Kaplan-Meier estimates. 95% CIs for the medians are computed using the methods of Brookmeyer and Crowley.

^bCensored.

^cStratification factors: stage from eCRF (IB or II vs. IIIA), sex from eCRF (female vs. male), histology from eCRF (squamous vs. nonsquamous).

^dHRs were estimated by Cox regression.

^eP values were not adjusted for multiple comparisons; therefore, there is an increased risk of false-positive conclusions.

Source: Clinical Study Report for IMpower010.⁹

Table 15: Disease-Free Survival in the Impower010 Study for Patients With Stage II to IIIA Disease With PD-L1 Expression on at Least 50% of TCs (Clinical Data Cut-Off Date of January 21, 2021)

BSC = best supportive care; CI = confidence interval; DFS = disease-free survival; HR = hazard ratio; NE = not estimable; PD-L1 = programmed death-ligand 1; TC = tumour cell.

^aSummaries of durations (median and percentiles) are Kaplan-Meier estimates. 95% CIs for the medians are computed using the methods of Brookmeyer and Crowley.⁴²

^bCensored.

^cStratification factors: stage from eCRF (IB or II vs. IIIA), sex from eCRF (female vs. male), histology from eCRF (squamous vs. nonsquamous).

^dHRs were estimated by Cox regression.

^eP values were not adjusted for multiple comparisons, resulting in an increased risk of false-positive conclusions.

Source: Clinical Study Report for IMpower010.⁹

KM plots of estimated median DFS among patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs (detected with the SP263 assay), including and excluding EGFR- or ALK-positive mutation, are illustrated in Figure 4. The results presented for the subgroup of patients without EGFR- or ALK-positive mutation are based on a post hoc subgroup analysis provided by the sponsor.

Because of the low number of events in the atezolizumab arm, the KM median DFS for all patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs could not be estimated. The KM median DFS was 35.7 months (lower bound of 95% CI, 29.7 months) in the BSC treatment arm. The KM curve began to separate in favour of atezolizumab approximately 4 to 5 months after randomization, and the separation was maintained.

Because of the low number of events in the atezolizumab arm, the KM estimated median DFS could not be calculated for patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs and without EGFR- or ALK-positive mutation. In the BSC treatment arm, the KM median DFS for patients without an EGFR- or ALK-positive mutation was similar to that for patients with the mutation at 37.5 months and 35.7 months, respectively. The unstratified HR for DFS between the treatment arms was similar for patients with and without an EGFR or ALK mutation (HR = 0.43; 95% CI, 0.26 to 0.71).

The clinical benefit of atezolizumab, compared with BSC, seemed consistent across most subgroups (i.e., age, sex, ECOG performance status score) in exploratory subgroup analyses in the reimbursement indication (Appendix 5).

Figure 4: KM Plot of DFS Among Patients With Stage II to IIIA NSCLC and PD-L1 (SP263) in at Least 50% of TCs by EGFR- or ALK-Positive Mutation Status (Clinical Data Cut-Off Date of January 21, 2021)

ALK = anaplastic lymphoma kinase; BSC = best supportive care; CI = confidence interval; DFS = disease-free survival; EGFR = epidermal growth factor receptor; EGFR/ALK+ = EGFR- or ALK-positive mutations; HR = hazard ratio; KM = Kaplan-Meier; NE = not estimable; PD-L1 = programmed death-ligand 1; TC = tumour cell.

Note: Staging defined using the American Joint Committee on Cancer (7th edition) staging criteria.¹

Source: Clinical Study Report for IMpower010.⁹

Type of Recurrence

The sites of disease recurrence for patients with protocol-defined disease relapse among patients with stage II to IIIA disease and PD-L1 expression on at least 50% of TCs, including and excluding EGFR and ALK mutations, are summarized in Table 16.

At the time of the planned interim analysis, disease recurrence was observed in 50 and 25 patients who had stage II to IIIA disease with PD-L1 at least 50% of TCs randomized to the BSC and atezolizumab treatment groups, respectively. Of those patients, locoregional disease recurrence was experienced by 60% of patients in the atezolizumab treatment arm and 34% in the BSC arm. Distant-only disease recurrence occurred in 42% of patients in the BSC arm and 24% in the atezolizumab arm. CNS-only disease recurrence occurred in 14% of patients in the BSC arm and 4% in the atezolizumab arm. The rate of combined locoregional plus distant disease recurrence was 18% in the BSC arm and 16% in the atezolizumab arm.

In patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs and without an EGFR or ALK mutation, disease recurrence was observed in 43 and 21 patients randomized to the BSC and atezolizumab treatment groups, respectively. Of those patients, locoregional disease recurrence was experienced by 61.9% of patients in the atezolizumab treatment arm and 32.6% in the BSC arm. Distant-only disease recurrence was experienced by 41.9% of patients in the BSC arm and 23.8% in the atezolizumab arm. CNS-only disease recurrence occurred in 16.3% of patients in the BSC arm and 0% in the atezolizumab arm. Locoregional plus distant disease recurrence occurred in 18.6% of patients in the BSC arm and 14.3% in the atezolizumab arm.

Table 16: Site of Disease Recurrence in the Impower010 Study (Clinical Data Cut-Off Date of January 21, 2021)

ALK = anaplastic lymphoma kinase; BSC = best supportive care; CNS = central nervous system; EGFR = epidermal growth factor receptor; PD-L1 = programmed death-ligand 1; TC = tumour cell.

^aA patient could have more than 1 distant site.

^bPatients who had CNS distant site only were included. Patients who had any other recurrent site (i.e., locoregional, other distant site, secondary primary lung, or secondary primary non-lung) in addition to CNS distant site were not included in the CNS-only category.

Source: Clinical Study Report for IMpower010.⁹

Health-Related Quality of Life

Health-related quality of life was not measured in the IMpower010 study.

Harms

Only those harms identified in the review protocol are reported here. Refer to Table 17 for detailed harms data. Harms related to the overall safety population are summarized in Appendix 5.

Table 17: Summary of Harms in the Impower010 Study for Patients With Stage II to IIIA Disease and PD-L1 Expression on at Least 50% of TCs (Safety Population; Clinical Data Cut-Off Date of January 21, 2021)

AE = adverse event; ALT = alanine aminotransaminase; AST = aspartate aminotransferase; BSC = best supported care; NA = not applicable; NR = not reported; PD-L1 = programmed death-ligand 1; SAE = serious adverse event; TCs = tumour cells

Source: Clinical Study Report for IMpower010.⁹

Adverse Events

Among patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs, a greater proportion of patients who received atezolizumab (94.7%) than BSC (69.6%) reported at least 1 AE. The top 5 reported AEs (BSC versus atezolizumab) were cough (10.7% versus 14.2%); nasopharyngitis (12.5% versus 8.8%), arthralgia (5.4% versus 13.3%), pruritis (2.7% versus 11.5%), and anemia (8.0% versus 7.1%). The following AEs had a difference of at least 5% between treatment arms, with a greater proportion in the atezolizumab arm: arthralgia, asthenia, increased blood creatine; diarrhea, rash, pruritus, and pyrexia.

Adverse Events by Grade

Among patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs, at least 1 grade 3 or 4 AE was reported in 11.6% and 20.4% of patients randomized to BSC and atezolizumab, respectively. The most commonly reported grade 3 or 4 AEs were decreased neutrophil count (1.8%) in patients who received BSC, and increased alanine aminotransferase (1.8%) and abnormal hepatic function (2.7%) in patients who received atezolizumab. No grade 5 AEs were reported.

Serious Adverse Events

Among patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs, a greater proportion of patients who received atezolizumab reported at least 1 SAEs compared with BSC (15.0% versus 5.4%). The most commonly reported SAE (BSC versus atezolizumab) for the subpopulation of patients with PD-L1 expression on at least 50% of TCs was pyrexia (0.0% versus 1.8%).

Dose Interruptions Due to Adverse Events

Among patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs, 29.2% of patients who received atezolizumab had at least 1 dose interruption due to an AE. Reasons for the dose interruptions included hyperthyroidism (3.5%), pneumonia (2.7%), upper respiratory tract infection (1.8%), pyrexia (1.8%), rash (1.8%), and oropharyngeal pain (1.8%).

Discontinuation of Treatment Due to Adverse Events

Among patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs, 18.6% of patients who received atezolizumab stopped treatment due to an AE. Data on specific AEs leading to discontinuation were not available for this subpopulation.

In the overall safety population, 18.2% of patients who received atezolizumab stopped treatment due to an AE. The most common events leading to treatment discontinuation were pneumonitis (1.4%), hypothyroidism (1.4%), and aspartate aminotransferase increased (1.4%).

Mortality

There were no data on deaths due to AEs in the subpopulation of patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs.

In the overall safety population, the proportion of patients who died was similar in the BSC (18.2%) and atezolizumab (19.2%) treatment groups. Of these deaths, 95.1% occurred more than 30 days after last study treatment or safety visit. Deaths due to AEs occurred in 0.6% and 1.6% of patients in the BSC and atezolizumab arms, respectively. The majority of deaths were due to disease progression.

Notable Harms

The number of patients who experienced each notable harm event are presented. Among the subpopulation of patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs, reported immune-mediated reactions related to endocrinopathies (BSC versus atezolizumab) included hypothyroidism (0% versus 14.2%) and hyperthyroidism (1.8% versus 4.4%). Overall immune-mediated rash was reported by 1.8% and 18.6% of patients who received BSC and atezolizumab, respectively. One person who received atezolizumab experienced a grade 3 or 4 rash. Immune-mediated colitis (grade 3 or 4) was reported by 1 person who received atezolizumab. Immune-related pneumonitis was reported by 5.3% of patients who received atezolizumab; 1 of these patients experienced graded 3 or 4 pneumonitis. Immune-mediated hepatitis was reported by 4.5% and 13.3% of patients who received BSC and atezolizumab, respectively. Among patients who received atezolizumab, 5.3% had at least 1 grade 3 or 4 immune-mediated hepatitis event.

Infusion-related reactions were not reported for the subpopulation of patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs.

Critical Appraisal

Internal Validity

The IMpower010 trial used appropriate methods for randomization and allocation concealment (i.e., central randomization by a computerized system). Randomization was stratified by sex (female versus male), tumour histology (squamous versus nonsquamous), extent of disease (stage IB versus stage II versus stage IIIA based on the UICC and AJCC [7th edition]¹ staging criteria) and PD-L1 expression status (TC2/3 and any IC versus TC0/1 and IC2/3 versus TC0/1 and IC0/1, detected with the SP142 IHC assay). The choice of stratification factors was considered to be reasonable and, as noted in the Health Canada report, disease stage is a known prognostic factor for NSCLC and PD-L1 tumour performance status is a predictive factor for immunotherapy efficacy in the setting of incurable NSCLC.⁸ Baseline characteristics of the ITT population appeared to be relatively similar across groups, indicating that randomization was likely successful. However, the Health Canada–indicated population was a subgroup of the main ITT population, so cannot truly be considered randomized. Among the subgroup of patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs, there were some minor imbalances across groups, but these did not universally favour either group and may be considered reasonable, given the small sample size.⁸ Additionally, minor differences in characteristics between this subgroup and the ITT population are not expected to confound the efficacy analyses.⁸

Despite being an open-label study, the investigators remained blinded to treatment assignment information — including treatment assignment at randomization and patient-level PD-L1 status with a link to patient indication — until the boundary for statistical significance of the planned DFS interim analysis was crossed, as reviewed by the Independent Data Monitoring Committee. The interim analysis that the clinical report was based on was conducted, as specified, by the statistical analysis plan (i.e., when approximately 190 DFS events occurred in the subpopulation with PD-L1 expression on at least 1% of TCs, detected with the SP263 assay, in the stage II to IIIA population). However, at the time of the data cut-off, the pre-specified interim analysis alpha boundary (2-sided alpha = 0.0368) for DFS was not crossed in the ITT population, and OS data were immature. As such, OS was presented as descriptive only, precluding definitive conclusions.

The IMpower010 efficacy end points were well described and employed appropriate censoring criteria. Although OS is the gold standard for demonstrating clinical benefit in cancer treatment trials, the time required to observe a clinically meaningful effect can be long. Accordingly, DFS was the primary outcome and OS was the key secondary outcome in the IMpower010 trial. The European Medicines Agency recommends that when DFS is the primary end point, OS should be the secondary end point, which was done in the IMpower010 trial.⁴⁵ The use of DFS as an surrogate end point for OS is accepted by the FDA for both accelerated and regular approval.⁴⁶ To minimize any bias of the open-label study design on investigator-determined tumour assessment for treatment response, American Society of Clinical Oncology, National Comprehensive Cancer Network, and European Society for Medical Oncology guidelines were adhered to by ensuring standard of care in both treatment arms. In response to the Health Canada review report,⁸ it was noted that recurrence events in the ITT population were confirmed by radiologic evidence in 99.4% and 98% of patients in the atezolizumab and BSC arms, respectively. The remaining recurrence events were determined with biopsy. Furthermore, a retrospective audit demonstrated a concordance rate of 92% between the blinded independent central review and investigator assessment of DFS in a subset of the ITT population. Therefore, the risk of bias related to the open-label investigator-determined tumour assessments is low.

As described earlier, the study protocol underwent several amendments in response to emerging evidence from the POPLAR study,⁴⁷ which demonstrated increasing improvement in OS with increasing PD-L1 expression, and from the KEYNOTE-024 and KEYNOTE-042 studies and the PACIFIC study that supported the use of the SP263 IHC assay to define the primary biomarker analysis population.^48-51 The protocol amendments were well addressed and unlikely to affect the end results or introduce bias related to end point evaluation or patient selection.

A greater proportion of patients in the BSC arm than in the atezolizumab arm discontinued the study (29% versus 14%). The primary reason for study discontinuation was death (23% versus 9.6%). Patients for whom the outcome was not known would have been censored in the efficacy analyses. Although the direction of any bias is unclear, it did not appear to favour atezolizumab.⁸

The analysis of the IMpower010 study presented here was limited by design issues that were affected by the decision of Health Canada to amend the indicated population to include only a subset of the enrolled population at the time of the interim analysis, which had an impact on the ability to draw definitive conclusions about efficacy in the subgroup of patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs. The IMpower010 study population included patients who had a complete surgical resection of stage IB (tumours > 4 cm) to IIIA (T2 to 2, N0, T1 to 3 N1, T1 to 3 N2, T2 N0) NSCLC per the UICC and AJCC (7th edition)¹ staging system. The Health Canada–indicated population, however, was a more narrow population, consisting of patients with stage II or IIIA (per the UICC and AJCC [7th edition]¹ staging system) NSCLC whose tumours have PD-L1 expression on at least 50% of TCs following complete resection and no progression after platinum-based adjuvant chemotherapy. The enrolled subpopulation of patients with PD-L1 expression on at least 50% of TCs only accounted for 22.8% of the total randomized population. As such, the IMpower010 trial was not powered for the Health Canada indication under review. Moreover, according to the statistical analysis plan, alpha control was achieved with hierarchical testing of DFS in the population with PD-L1 expression on at least 1% of TCs (detected with the SP263 assay) and stage II to IIIA disease; DFS in the stage II to IIIA population; DFS in the ITT population; and OS in the ITT population. Although DFS in the stage II to IIIA population with PD-L1 expression on at least 50% of TCs was a pre-specified secondary end point, it was absent from the statistical testing hierarchy. Thus, the statistical analyses of the efficacy outcomes were conducted with no control for multiplicity, which resulted in the inability to draw definitive conclusions because of the increased risk of false-positive findings. Moreover, as the reported results were based on an interim analysis, there is some risk that the efficacy findings are overestimated.⁵² Analyses related to the reimbursement request population (i.e., stage II to IIIA population with PD-L1 expression on at least 50% of TCs and no EGFR or ALK mutations) included a small number of patients and were available only as post hoc analyses provided by the sponsor; these are therefore affected by uncertainty related to the underpowered sample and potential bias because the analysis was not pre-specified nor adjusted for multiple testing, which increases the risk of false-positive conclusions.⁵³

Several subgroup analyses were performed to examine the consistency of the treatment effect observed for the primary and key secondary efficacy end points. However, drawing conclusions about these subgroups was not possible because of a lack of sample size considerations for these subgroups and their absence from the statistical testing hierarchy.

External Validity

Table 18 summarizes the generalizability of the evidence.

The demographic characteristics of the study population were considered by the clinical experts to be generally reflective of the relevant population with NSCLC in Canada. The clinical experts considered the results of the IMpower010 multi-national, multi-centre study to be generalizable to the Canadian setting. The clinical experts did highlight a few notable differences in disease characteristics and treatment regimens between the trial population and the Canadian NSCLC population, as follows.

Disease Characteristics

Approximately 50% of patients in the study population were diagnosed with stage IIIA NSCLC. According to the clinical experts consulted, it is not typical to have such a high proportion of resected patients with stage IIIA disease in the adjuvant setting. Moreover, the clinical experts noted that the trial population had a higher proportion of patients with squamous lung cancer compared with the Canadian lung cancer population. The clinical experts noted that squamous lung cancer is associated with smoking history, and that the proportion of patients with squamous lung cancer in the trial is reflective of patients enrolled from countries with higher rates of tobacco use.

EGFR and/or ALK Mutations

Patients with an EGFR and/or ALK mutation account for less than 10% of the randomized patient population. As the proportion of patients with EGFR or ALK mutations was small, the results were likely not affected by their inclusion, so the results can be generalized to those without the mutations. The clinical experts highlighted that although the study results are generalizable to patients with EGFR or ALK mutations, given that these patients were included in the IMpower010 study, they would not use atezolizumab for patients with an EGFR or ALK mutation. The clinical experts explained that there are better treatment options for these patients (i.e., adjuvant osimertinib), as immunotherapy tends to be ineffective in metastatic ALK-mutated NSCLC. The clinical experts noted that it would be less complicated to analyze the benefits of adjuvant atezolizumab in patients who are EGFR- or ALK-negative, as that obviates the need to make a comparison with adjuvant osimertinib in the population with a classic exon 19 deletion or exon 21 L858R EGFR mutation.

PD-L1 Expression Assessment

In the IMpower010 study, the VENTANA PD-L1 SP142 assay was used to recruit and stratify patients, whereas the VENTANA PD-L1 SP263 assay was used to determine PD-L1 expression for the evaluation of efficacy outcomes. Although the VENTANA PD-L1 SP263 assay is authorized for use in Canada, it is the 22C3 assay that is currently in use in most Canadian pathology laboratories. Based on the Blueprint study,³⁶ the SP263 IHC assay is comparable to the 22C3 assay in its analytical performance of assessing PD-L1 expression on TCs. Thus, the current IHC assay used in Canada is adequate, and the IMpower010 efficacy results may be applied to the Canadian system of PD-L1 expression testing. As described in the Health Canada product monograph, patients who should be selected for treatment have PD-L1 expression on at least 50% of TCs, determined by an experienced laboratory using a validated test equivalent to that used in the IMpower010 trial.²⁹

AJCC/UICC Staging

Disease staging in the IMpower010 study was based on the UICC and AJCC (7th edition) staging system.¹ Currently, the 8th edition of the AJCC staging system⁶ is used in clinical practice. The clinical experts consulted by CADTH stressed that the 7th edition staging system¹ should be used to interpret and apply to the trial results in clinical practice. This is because under the current 8th edition staging system,⁶ eligibility criteria would change because of shifts between editions. For example, some patients diagnosed as stage IB according to the 7th edition¹ would be stage II according to the 8th edition.⁶ Given that even more changes in stage definition are expected in the future, with the advent of the 9th edition and beyond, eligibility criteria for adjuvant atezolizumab in this setting should be defined by the specific disease characteristics used to define stage II and III disease in the 7th edition,¹ as opposed to disease stage determined using the 8th edition definition.⁶ Doing so would mean that for the current Health Canada indication, any patient with completely resected NSCLC with a PD-L1 score of at least 50% and either a primary tumour 5 cm or larger or a primary tumour of any size completely resected with associated lymph node involvement would be eligible for adjuvant atezolizumab.

Table 18: Assessment of Generalizability of Evidence for Atezolizumab

AJCC = American Joint Committee on Cancer; ALK = anaplastic lymphoma kinase; DFS = disease-free survival; EGFR = epidermal growth factor receptor; IHC = immunohistochemistry; NSCLC = non–small cell lung cancer; OS = overall survival; PD-L1 = programmed death-ligand 1; TC = tumour cell; UICC = Union for International Cancer Control.

Cisplatin Therapy

In the IMpower010 trial, all patients received cisplatin 75 mg/m² on day 1 plus 1 the following 4 options: vinorelbine 30 mg/m² IV push (days 1 and 8), docetaxel 75 mg/m² IV (day 1), gemcitabine 1,250 mg/m² (days 1 and 8), or pemetrexed 500 mg/m² (day 1; nonsquamous cell NSCLC only). Although all the 4 options used in the IMpower010 trial are available in Canada, gemcitabine and docetaxel are not commonly used in practice. Further, on subset analysis, the patients in IMpower010 who received the cisplatin and gemcitabine adjuvant chemotherapy regimen did not derive benefit from adjuvant atezolizumab. Thus, of the 4 options, the clinical experts consulted by CADTH encourage maintaining current practice, which favours the use of cisplatin plus vinorelbine or cisplatin plus pemetrexed, and only using cisplatin plus gemcitabine when there are no other available options (e.g., a chemotherapy shortage).

Requirement of Adjuvant Chemotherapy

The IMpower010 study required patients to undergo at least 1 cycle of adjuvant chemotherapy before the initiation of anti-PD-L1 therapy. The clinical experts noted that atezolizumab would be considered off-label in practice without any prior adjuvant chemotherapy. However, it should be made available to patients who have received any adjuvant chemotherapy. Specifically, there is a relatively large group of patients who cannot tolerate all recommended cycles of a cisplatin doublet because of toxicity, but even having received 1 cycle should be enough to be considered for adjuvant atezolizumab.

Outcome

The primary efficacy end point in the IMpower010 trial was DFS. According to the clinical experts, it is plausible that improved DFS will translate into OS benefit. Moreover, the clinical experts noted that DFS is a clinically meaningful outcome on its own, as the impact of recurrence is felt at the individual, personal, and health care system levels. From the perspective of patients with lung cancer, DFS is also considered a meaningful end point.⁵⁴ Of note, outcomes important to patients, such as health-related quality of life, were not measured in the IMpower010 trial. Although the clinical experts acknowledged that it is biologically plausible that improvement in DFS will translate into OS benefit, uncertainty remains given that there is not yet empirical evidence to support this.^11,12

Indirect Evidence

A focused literature search for network meta-analyses dealing with NSCLC was run in MEDLINE All (1946–) on March 23, 2022. No limits were applied to the search.

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

Other Relevant Evidence

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

Discussion

Summary of Available Evidence

The current CADTH systematic review included 1 phase III, global, multi-centre, open-label, randomized study: the IMpower010 trial. The IMpower010 trial evaluated the efficacy and safety of atezolizumab, compared with BSC, in patients with stage IB to IIIA (per the UICC and AJCC [7th edition]¹ staging system) NSCLC after complete resection and adjuvant cisplatin-based chemotherapy. The IMpower010 study consisted of 2 phases: an enrolment phase, and a randomized phase. In the enrolment phase, patients who had undergone complete resection of their NSCLC were screened and, if eligible, received 1 of 4 cisplatin-based chemotherapy regimens (cisplatin plus vinorelbine, docetaxel, gemcitabine, or pemetrexed), based on investigator choice. Patients who were deemed eligible to continue the study after up to 4 cycles of cisplatin-based chemotherapy proceeded to the randomization phase of the study and were randomized to receive atezolizumab or BSC. The primary efficacy outcome was DFS assessed by the investigator. Secondary efficacy outcomes included OS, 3-year and 5-year DFS rates, and DFS in the subpopulation with PD-L1 expression on at least 50% of TCs (detected with SP263 IHC assay) and with stage II to IIIA (per UICC and AJCC [7th edition]¹ staging criteria) NSCLC (i.e., the Health Canada–indicated population). The clinical report provided to CADTH presented the analysis of study data collected from the date of the first patient randomized (February 26, 2016) to the clinical data cut-off date of January 21, 2021, for the protocol-specific interim analysis on DFS.

Although the reimbursement request for the current review was for atezolizumab as monotherapy for adjuvant treatment following complete resection and no progression after platinum-based adjuvant chemotherapy for adults with stage II to IIIA (according to the AJCC [7th edition]¹ staging criteria) NSCLC whose tumours have PD-L1 expression on at least 50% of TCs and who do not have EGFR or ALK genomic tumour aberrations, the systematic review was focused on the Health Canada indication. Therefore, the objective of this review was to perform a systematic review of the beneficial and harmful effects of atezolizumab as monotherapy for adjuvant treatment following complete resection and no progression after platinum-based adjuvant chemotherapy for adults with stage II to IIIA (according to UICC and AJCC [7th edition]¹ staging criteria) NSCLC whose tumours have PD-L1 expression on at least 50% of TCs. Of note, the number of patients with EGFR or ALK mutations made up a small proportion of population (< 10%). Moreover, the Clinical Study Report did not include data specific to the reimbursement population, but was received post hoc from the sponsor.

Among patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs, 144 and 155 patients were randomized to receive BSC or atezolizumab, respectively. In this subpopulation, follow-up is ongoing for a greater proportion of patients who were randomized to receive atezolizumab versus BSC (86.1% versus 71.1%). The indication population had a median age of 62 (range = 36 to 84) years, was predominantly male (72.9%) and White (70.3%), had high functional performance (57.2% had an ECOG performance status score of 0), and most reported previous tobacco use (69.9%). At diagnosis, 48.0% of patients were diagnosed with stage IIIA (per AJCC [7th edition] staging criteria¹) disease and 59.8% had nonsquamous histology. Among the 137 patients with nonsquamous histology, 94.2% were identified as having adenocarcinoma subtype. EGFR or ALK mutations were detected in 8.7% of patients.

No indirect treatment comparisons or other evidence were included in the sponsor’s submission to CADTH or identified in the literature search. However, indirect treatment comparisons were not expected, as there are no relevant comparators to atezolizumab, except for a subset of EGFR- or ALK-positive patients for whom osimertinib may be comparator.

The IMpower010 study was limited by design issues that were affected by the Health Canada decision to amend the indication population to include only a subset of the enrolment population. The enrolled subpopulation of patients who made up the indication population (stage II to IIIA disease with PD-L1 expression on at least 50% of TCs) only accounted for 22.8% of the total randomized population. As such, the IMpower010 trial was not powered for the indication under review. In addition, all relevant outcomes in the subpopulation of patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs were absent from the statistical testing hierarchy. This precluded definitive conclusions about efficacy in this population, given the increased risk of false-positive results. Despite these limitations, the study results were found to be generalizable to the clinical setting.

Interpretation of Results

Efficacy

The results from the IMpower010 trial were from a planned interim analysis, in which the median length of follow-up was 32.2 (range = 0 to 58.8) months in the ITT population and similar between groups. In the IMpower010 trial, the proportion of deaths observed in patients who were randomized to receive BSC was 23%, compared with 10% in patients who received atezolizumab in the subpopulation of patients who had stage II to IIIA disease with PD-L1 expression on at least 50% of TCs. At year 3, the difference in the proportion of patients in the atezolizumab group who were event-free compared with the BSC group, was 14.27% (95% CI, 4.19% to 24.35%). Similarly, 46% of patients in the BSC treatment arm experienced a disease recurrence or death compared with 24% in the atezolizumab arm at the time of the planned interim analysis. At year 3, the difference in the proportion of patients in the atezolizumab group who were event-free compared with the BSC arm was 25.18% (95% CI, 11.01% to 39.36%).

DFS was considered an important outcome by the clinical experts consulted by CADTH, clinician groups, and the patient-advocacy groups that provided input for this review. The clinical experts consulted by CADTH remarked that the protective effects of atezolizumab against death and/or disease recurrence (DFS) (HR = 0.47; 95% CI, 0.29 to 0.75) was impressive. It should be noted, however, that the relative importance of DFS compared with OS is controversial among clinicians who treat NSCLC,^11,12 and it is unclear whether benefits in DFS translate into benefits in OS or just delay the time to recurrence in this particular trial. Regardless, the clinical experts consulted by CADTH for this review found the protective effects of atezolizumab against death at the time of the interim analysis to be equally notable (OS) (HR = 0.40; 95% CI, 0.20 to 0.81). Although the available data for OS were immature at the time of analysis, the clinical experts agreed that improved DFS is likely to translate to improved OS and a higher proportion of patients who are cured. The clinical experts specifically cited the example of the PACIFIC trial, in which 1 year of anti-PD-L1 Immunotherapy checkpoint inhibition delivered in the curative-intent setting in NSCLC with durvalumab was approved for funding in Canada before mature OS results were available, a decision that was confirmed to have been the correct choice, as the 5-year updated data from PACIFIC showed significant OS benefit (HR = 0.72; 95% CI, 0.59 to 0.89; median = 47.5 versus 29.1 months), and an ongoing approximate 10% difference in OS rates at the 5-year mark, illustrating that consolidation durvalumab has led to improved OS by achieving more cures, not just by delaying relapse. The durability of immunotherapy’s survival benefit has also been demonstrated in patients with metastatic NSCLC⁵⁵ and advanced melanoma.⁵⁶ Additionally, the clinical experts noted that DFS is a clinically meaningful outcome on its own because the impact of recurrence is felt at the individual, personal, and health care system level.

According to the clinical experts consulted by CADTH, patients with 1 of the 2 common EGFR mutations (exon 19 deletion or L858R) should be considered for adjuvant osimertinib or adjuvant atezolizumab, and the superior efficacy of osimertinib in this setting will mean that osimertinib is the best choice for most patients eligible for both. Patients in this group should not receive both adjuvant osimertinib and adjuvant atezolizumab.

Interpretability of the efficacy end points may be limited because the subpopulation of patients who have stage II to IIIA disease with PD-L1 expression on at least 50% of TCs only accounted for 23% of the total randomized population. Any minor differences in characteristics between this subgroup and the ITT population, however, were not expected to confound the efficacy analyses. The decision by Health Canada to amend the indication population to only include patients who had stage II to IIIA disease with a PD-L1 expression on at least 50% of TCs underpowered the trial to detect a meaningful statistical difference. The Health Canada indication limited to patients with stage II to IIIA disease with PD-L1 expression on at least 50% of TCs because of uncertainty about the clinical benefit of atezolizumab in patients with stage II to IIIA disease with PD-L1 expression on 1% to 49% of TCs; Health Canada noted that the improvement in DFS was mainly driven by the subgroup with PD-L1 expression on at least 50% of TCs.⁸ Likewise, the European Medicines Agency considered the subgroup with PD-L1 expression on at least 50% of TCs the most relevant for labelling at the time of the interim analysis.¹⁰ It should be noted that findings for DFS in patients who had stage II to IIIA with PD-L1 expression on at least 1% of TCs (stratified HR = 0.66; 95% CI, 0.50 to 0.88; P = 0.0039) and in all patients with stage II to IIIA disease (stratified HR = 0.79; 95% CI, 0.64 to 0.96; P = 0.0205) also favoured atezolizumab, although the CIs in those groups (especially the all-stage II to IIIA group) included the potential that the benefit was small. Findings in the ITT population did not cross the pre-specified interim analysis alpha boundary. However, given that the statistical analyses of the efficacy outcomes were conducted with no control for multiplicity, which increases the risk of false-positive findings, precludes the ability to draw definitive conclusions. Moreover, there is some risk that the effect has been overestimated because it is derived from an interim analysis.

Regarding type of recurrence site, it appeared that distant relapse was lower and locoregional relapse was higher in the atezolizumab arm. According to the clinical experts, locoregional relapse increases the likelihood of definitive management with surgery, radiation, or combined chemotherapy-radiation on relapse. Moreover, fewer patients had CNS relapses and rates of new primary lung cancers seemed lower in patients treated with atezolizumab. Based on clinical expert opinion, atezolizumab may be protective against future NSCLC or more widespread, incurable relapse, both of which would derive significant ancillary benefits from adjuvant atezolizumab. However, such statements must be tempered with caution, as there are limited data to support the hypothesis.

Finally, the patient-advocacy groups that provided input for this review emphasized the importance of treatments maintaining health-related quality of life. In the IMpower010 study, health-related quality of life was not assessed. As such, the impact of adjuvant atezolizumab on health-related quality of life in patients with NSCLC is unknown. In other tumour sites, however, PD-1 and PD-L1 have not been shown to negatively affect patients’ quality of life or symptom scores.^57-60

Harms

Atezolizumab appeared to be well tolerated, with no concerning safety signals identified. According to the clinical experts consulted by CADTH, the overall safety profile of atezolizumab in IMpower010 appeared consistent with its well-established safety profile in the monotherapy setting across other indications. Of note, there were no AEs with fatal outcomes reported in the atezolizumab treatment arm.

The product monographs for atezolizumab contains warnings and precautions for immune-mediated adverse reactions, including immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune-mediated nephritis and renal dysfunction, and solid organ transplant rejection. The most common adverse reactions (≥ 20%) as a single agent were fatigue and asthenia, decreased appetite, nausea, cough, and dyspnea. The most common adverse reactions (≥ 20%) related to atezolizumab used in combination with other antineoplastic drugs in patients with NSCLC were fatigue and asthenia, nausea, alopecia, constipation, diarrhea, and decreased appetite.

Conclusions

Based on the IMpower010 trial, uncertainty remains about the efficacy of adjuvant atezolizumab in increasing DFS in adults with stage II or IIIA (per the UICC and AJCC [7th edition]¹ staging criteria) NSCLC whose tumours have PD-L1 expression on at least 50% of TCs following completed resection and no progression after platinum-based adjuvant chemotherapy at the time of the planned interim analysis, because the analysis was absent from the statistical hierarchy and not controlled for multiplicity. Based on clinical expert opinion, the findings appeared favourable and are considered clinically important. Conclusions regarding the efficacy of atezolizumab on improved OS cannot be made because of the immature nature of the data at the time of the planned interim analysis. Despite these limitations, the findings from the IMpower010 trial appeared to be generalizable to the real-world setting.

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Appendix 1: Literature Search Strategy

Note that this appendix is not copy-edited.

Clinical Literature Search

Overview

Interface: Ovid

Databases:

• MEDLINE All (1946-present)

• Embase (1974-present)

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

Date of search: March 23, 2022

Alerts: Bi-weekly search updates until project completion

Search filters applied: randomized controlled trials; controlled clinical trials

Limits:

• No date or language limits were used

• Conference abstracts: excluded

Table 19: Syntax Guide

Multi-Database Strategy

1. (atezolizumab* or Tecentriq* or tecntriq or MPDL3280A or MPDL-3280A or RG7446 or RG-7446 or L01FF05 or 52CMI0WC3Y).ti,ab,kf,ot,hw,rn,nm.

2. ((Carcinoma, Non-Small-Cell Lung/ or exp LUNG/) and Carcinoma, Large Cell/) or exp Adenocarcinoma of Lung/

3. (exp Lung/ or exp Lung neoplasms/) and (Carcinoma, Large Cell/ or Adenocarcinoma/)

4. (NSCLC* or LCLC* or mNSCLC* or mLCLC*).ti,ab,kf.

5. ((non small cell* or nonsmall cell* or large cell or undifferentiated) adj5 (lung* or bronch* or pulmonar*) adj5 (cancer* or tumor* or tumour* or carcinoma* or neoplas*)).ti,ab,kf.

6. ((bronchial or pulmonary or lung) adj3 (adenocarcinoma* or adeno-carcinoma*)).ti,ab,kf.

7. ((bronchioloalveolar or bronchiolo alveolar) adj3 (carcinoma* or cancer* or neoplas* or tumor* or tumour*)).ti,ab,kf.

8. or/2-7

9. 1 and 8

10. 9 use medall

11. *atezolizumab/

12. (atezolizumab* or Tecentriq* or tecntriq or MPDL3280A or MPDL-3280A or RG7446 or RG-7446 or L01FF05).ti,ab,kf,dq.

13. 11 or 12

14. non small cell lung cancer/ or large cell lung carcinoma/ or lung adenocarcinoma/

15. (NSCLC* or LCLC* or mNSCLC* or mLCLC*).ti,ab,kf,dq.

16. ((non small* cell or nonsmall cell* or large cell or undifferentiated) adj5 (lung* or bronch* or pulmonary*) adj5 (cancer* or tumor* or tumour* or carcinoma* or neoplas*)).ti,ab,kf,dq.

17. ((bronchial or pulmonary or lung) adj3 (adenocarcinoma* or adeno-carcinoma*)).ti,ab,kf,dq

18. ((bronchioloalveolar or bronchiolo alveolar) adj3 (carcinoma* or cancer* or neoplas* or tumor* or tumour*)).ti,ab,kf,dq.

19. or/14-18

20. 13 and 19

21. 20 use oemezd

22. 21 not (conference review or conference abstract).pt.

23. 23.10 or 22

24. remove duplicates from 23

25. (Randomized Controlled Trial or Controlled Clinical Trial or Pragmatic Clinical Trial or Equivalence Trial or Clinical Trial, Phase III).pt.

26. Randomized Controlled Trial/

27. exp Randomized Controlled Trials as Topic/

28. "Randomized Controlled Trial (topic)"/

29. Controlled Clinical Trial/

30. exp Controlled Clinical Trials as Topic/

31. "Controlled Clinical Trial (topic)"/

32. Randomization/

33. Random Allocation/

34. Double-Blind Method/

35. Double Blind Procedure/

36. Double-Blind Studies/

37. Single-Blind Method/

38. Single Blind Procedure/

39. Single-Blind Studies/

40. Placebos/

41. Placebo/

42. Control Groups/

43. Control Group/

44. (random* or sham or placebo*).ti,ab,hw,kf.

45. ((singl* or doubl*) adj (blind* or dumm* or mask*)).ti,ab,hw,kf.

46. ((tripl* or trebl*) adj (blind* or dumm* or mask*)).ti,ab,hw,kf.

47. (control* adj3 (study or studies or trial* or group*)).ti,ab,kf.

48. (Nonrandom* or non random* or non-random* or quasi-random* or quasirandom*).ti,ab,hw,kf.

49. allocated.ti,ab,hw.

50. ((open label or open-label) adj5 (study or studies or trial*)).ti,ab,hw,kf.

51. ((equivalence or superiority or non-inferiority or noninferiority) adj3 (study or studies or trial*)).ti,ab,hw,kf.

52. pragmatic study or pragmatic studies).ti,ab,hw,kf

53. ((pragmatic or practical) adj3 trial*).ti,ab,hw,kf.

54. ((quasiexperimental or quasi-experimental) adj3 (study or studies or trial*)).ti,ab,hw,kf

55. (phase adj3 (III or "3") adj3 (study or studies or trial*)).ti,hw,kf.

56. or/25-55

57. 23 and 56

58. remove duplicates from 57

Clinical Trials Registries

ClinicalTrials.gov

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

[Search -- Studies with results | atezolizumab or Tecentriq and non-small cell lung cancer]

WHO ICTRP

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

[Search terms -- atezolizumab or Tecentriq and non-small cell lung cancer]

Health Canada’s Clinical Trials Database

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

[Search terms -- atezolizumab or Tecentriq and non-small cell lung cancer]

EU Clinical Trials Register

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

[Search terms -- atezolizumab or Tecentriq and non-small cell lung cancer]

Grey Literature

Search dates: March 11 to March 23, 2022

Keywords: atezolizumab or Tecentriq, non-small cell lung cancer

Limits: None

Updated: Search updated prior to the completion of stakeholder feedback period

Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool for Searching Health-Related Grey Literature were searched:

• Health Technology Assessment Agencies

• Health Economics

• Clinical Practice Guidelines

• Drug and Device Regulatory Approvals

• Advisories and Warnings

• Drug Class Reviews

• Clinical Trials Registries

• Databases (free)

• Health Statistics

• Internet Search

Appendix 2: Excluded Studies

Note that this appendix is not copy-edited.

Table 20: Excluded Studies

RCT = randomized controlled trial

Appendix 3: Protocol Amendments

Note that this appendix is not copy-edited.

Table 21: Key Protocol Amendments for the IMpower010 Study

DFS = disease-free survival; IC = tumour-infiltrating immune cell; INV = investigator; ITT = intention to treat; OS = overall survival; PD-L1 = programmed death-ligand 1; TC = tumour cell

Note: Staging defined using the American Joint Committee on Cancer (7th edition) staging criteria.¹

Source: Clinical Study Report for IMpower010⁹

Appendix 4: Statistical Analysis

Note that this appendix has not been copy-edited.

Table 22: Redacted

||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||

Note: This table has been redacted as per the sponsor’s request.

Appendix 5: Detailed Outcome Data

Note that this appendix has not been copy-edited.

Table 23: Summary of Baseline Characteristics of Patients in the IMpower010 Study