Reimbursement Review

Osimertinib (Tagrisso)

Sponsor: AstraZeneca Canada Inc.

Therapeutic area: Unresectable (stage III) non–small cell lung cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

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

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance; NOC/c = Notice of Compliance with Conditions; NSCLC = non–small cell lung cancer.

Introduction

Lung cancer is the most commonly diagnosed cancer in Canada and the leading cause of cancer-related deaths.^1,2 In 2024 alone, approximately 32,100 people living in Canada were expected to be diagnosed with lung cancer, and 20,700 annual deaths were expected to be attributable to lung cancer.³ Survival from lung cancer of all stages and histologies are poor, with an overall 5-year net survival of 22%.² Lung cancer is classified into non–small cell lung cancer (NSCLC) or small cell lung cancer, with NSCLC accounting for approximately 88% of cases in Canada, excluding Quebec.¹ One of the most prominent NSCLC molecular alterations are EGFR mutations which cause abnormal signalling pathways that drive tumour growth.⁴ EGFR mutations are more frequently observed in never smokers, people of Asian ethnicity, patients with adenocarcinoma, and females.^5,6 The most common EGFR mutations are exon 19 deletions and the exon 21 codon 858 point mutation (L858R), accounting for 70% to 90% of EGFR mutations.^7,8 NSCLC is often asymptomatic and due to its insidious nature patients may live for several years before presentation.⁹ The most common symptoms include unspecific cough, chest and shoulder pain, hemoptysis, weight loss, dyspnea, hoarseness, bone pain, fever, and recurring infections with bronchitis and pneumonia.^9,10 Diagnostic procedures include imaging of the lungs, sputum cytology, and tissue biopsy.¹¹

The treatment goals for locally advanced, unresectable stage III NSCLC are to cure the disease; prevent local recurrence, distant metastases, and disease progression; and improve quality of life (QoL).^12-15 Before establishing a treatment plan, tumours should undergo testing for oncogenic drivers, including EGFR mutations. Testing for EGFR mutations, including EGFR exon 19 deletions and exon 21 (L858R) substitution mutations, is currently performed at the time of diagnosis as part of the standard of care for all nonsquamous NSCLC including locally advanced, unresectable NSCLC in Canada.

The current conventional treatment for patients presenting with unresectable stage III NSCLC, irrespective of EGFR mutation status, in the first-line setting is definitive concurrent chemoradiation therapy (cCRT).^12,16-18 In patients who cannot tolerate cCRT, such as those with poor performance status or comorbid conditions, sequential chemoradiation therapy (sCRT) is recommended.^12,19,20 In Canada, durvalumab, a PD-L1 inhibitor, is currently reimbursed for the treatment of patients with unresectable, stage III NSCLC whose disease has not progressed following concurrent platinum-based chemoradiation therapy (CRT). However, post hoc subgroup analysis of the PACIFIC trial suggested that durvalumab consolidation therapy has similar efficacy and more frequent adverse effects than placebo in patients with EGFR-mutated disease.²¹ As a result, in clinical practice, and based on a recent European Society for Medical Oncology consensus statement, durvalumab consolidation post-CRT is not used nor recommended for patients with unresectable NSCLC and EGFR mutations,²² leaving these patients with no effective reimbursed consolidation treatment. In the absence of an effective and available consolidation therapy (also referred to as maintenance therapy) for unresectable EGFR-mutated NSCLC in Canada, clinical experts consulted for this review with experience in the diagnosis and management of NSCLC indicated that active surveillance is the current standard of care for these patients. Active surveillance consists of regular imaging (e.g., CT scan) and clinical monitoring to detect early disease progression every 6 months for the first 2 years following completion of CRT and yearly thereafter for the next 3 years.²³ Most patients with locally advanced, unresectable (stage III) EGFR-mutated NSCLC who remain progression-free during or post CRT are at risk of recurrence during the first year of the surveillance phase.²⁴

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of osimertinib 80 mg taken orally once daily for the treatment of locally advanced, unresectable (stage III) NSCLC in patients whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations (either alone or in combination with other EGFR mutations) and whose disease has not progressed during or following platinum-based CRT.

Osimertinib has been previously reviewed by Canada’s Drug Agency (CDA-AMC) for the treatment of locally advanced or metastatic NSCLC in patients whose tumours have EGFR exon 19 deletions or exon 21 (L858R) mutations and used as a monotherapy or in combination with pemetrexed and platinum-based chemotherapy; in patients with stage IB to stage IIIA NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations; and locally advanced or metastatic EGFR T790M mutation–positive NSCLC in patients who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy. All final CDA-AMC recommendations were to reimburse with clinical criteria and/or conditions.

Perspectives of Patient, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups who responded to our call for input and from clinical expert(s) consulted for the purpose of this review.

Patient Input

CDA-AMC received 1 joint patient input submission from the Lung Health Foundation (LHF), Lung Cancer Canada (LCC), and the Canadian Cancer Survivor Network (CCSN). LHF is a registered charity that assists and empowers people living with or caring for others with lung disease. LCC is a registered national charitable organization that supports patients through providing education, research, and advocacy. CCSN is a national network that promotes the standard of care and provides support for patients with cancer, and issues related to survivorship or quality of end-of-life care.

The information was gathered through an online survey conducted from July 2024 to December 2024 with 23 respondents from Canada identifying as living with lung cancer, including 20 patients and 3 caregivers, all of whom had experience with osimertinib. Additionally, LFH conducted interviews with 6 patients (5 females and 1 male) who completed the online survey in January 2025. Interviewees ranged in age from 49 years to 72 years. Four interviewees were diagnosed with stage IV NSCLC with an EGFR exon 19 mutation. One interviewee was diagnosed with stage IV lung cancer (not specific as to which type) with the same mutation, and another was diagnosed with stage IIIC adenocarcinoma.

Based on the patient group input, fatigue was the most detrimental physical symptom of lung cancer, reported by 81% of survey respondents, followed by reduced appetite or weight loss (47.6%), cough (33.3%), pain (28.6%), and shortness of breath (23.8%). Additionally, 39.1% of survey respondents specifically cited fatigue and 26.1% cited shortness of breath as the primary reasons they were unable to perform daily activities. Fatigue as the most detrimental physical symptom was also echoed by interviewees, with 3 out of 6 interviewees noting fatigue and weakness as the reason they had to stop working.

As noted in the input, lung cancer impacted multiple aspects of patients’ daily life. The most impacted daily activity was the ability to work (57.1% of survey respondents and 67% of interviewees), followed by participation in sports (38.1% of respondents), travel (33.3% of respondents), leisure or hobbies (28.6% of respondents), and housework (23.8% of respondents). Survey respondents felt their experiences with lung cancer led to negative impacts on their emotional well-being (43.5%), feeling cold (43.5%), feeling isolated (34.8%), and impacted their family relationships (26.1%). The interviewees noted that the negative impacts of having lung cancer included emotional distress, mental health challenges, concerns regarding insurance coverage (e.g., travel and car insurance), changing medications and managing side effects, and job limitations due to infection risks (e.g., exposure to viruses).

The patient groups noted that concerns surrounding personal health, financial burdens, and concern for family members were some of the reasons for experiencing anxiety. These experiences highlight the profound and intertwined physical, emotional, and social toll of lung cancer on patients, their families, and their caregivers. Many respondents noted that both their symptoms and the time it took to manage their treatments negatively impacted their ability to continue working.

Survey respondents tried a range of treatments, included targeted therapy (47.6%), chemotherapies (33.3%; such as pemetrexed and carboplatin, double platinum-based chemotherapy, and others), surgery (4.8%; such as lobectomy), radiation (4.8%), immunotherapy (4.8%), and clinical trials (4.8%). Side effects were frequently associated with current treatment options, with 81.0% of survey respondents mentioning fatigue as a side effect associated with lung cancer treatments. Two interviewees who shared their experiences with lung cancer medications reported adverse effects including fatigue, anemia, bothersome mouth feel or altered taste, joint pain, edema in extremities, nausea, and constipation. Additionally, both interviewees noted that while additional medications could be taken to manage side effects, such medications were costly. The patient groups highlighted that while current lung cancer treatments extend patients’ lives, there are still concerns around health-related quality of life (HRQoL), with patients continuing to experience residual symptoms and debilitating side effects.

When considering new medication to treat lung cancer, survey respondents identified the most important outcomes as improved HRQoL (78.3%), reduced symptoms (60.9%), improved energy (43.5%), improved symptom management (39.1%), improved and/or prolonged efficacy (26.0%), reduced cost (21.7%), reduced travel time to obtain medication or treatment (8.7%), and zero cost (4.3%). The most important outcomes reported by 2 interviewees included treatment effectiveness (i.e., extending life), improved QoL, ability to effectively manage lung cancer without destroying healthy cells, ease of administration (daily oral pill is preferred over an IV infusion), manageable side effects, and affordability.

The patient groups stated that most respondents had positive experiences with osimertinib, with 90.8% preferring or strongly preferring it to other treatments or medications they had tried. Two interviewees reported a substantial change in QoL with osimertinib, stating that it gave them the ability to have a normal life and to return to work. The 3 most common side effects of osimertinib reported by survey respondents were negative changes in appearance (e.g., hair and nail issues) (73.9%), fatigue (69.6%), and diarrhea (69.6%); however, 95.7% of respondents felt their side effects were manageable. The top 10 benefits of osimertinib reported by survey respondents included reduced or eliminated pain (36.4%), stabilization of cancer or prolonged life (27.3%), ability to exercise (27.3%), increased energy (22.7%), reduced fatigue (18.2%), increased participation in daily activities (18.2%), reduced shortness of breath (18.2%), improved appetite or weight gain (18.2%), reduced cough (13.6%), and improved mood (13.6%).

Overall, the patient groups highlighted that there is an unmet need for lung cancer therapies that prolong progression-free survival (PFS) and improve HRQoL for patients. Patients also raised consideration about accessibility and needs for equity across all provinces in diagnoses and treatments. In addition, respondents expressed concerns about their continued ability to access medications due to costs, lack of availability, and the development of resistance to those medications that work for them.

Clinician Input

Input From Clinical Experts Consulted for This Review

Two clinical experts with expertise in the diagnosis and management of NSCLC provided input for this review.

Both experts felt the overarching goal of treatment for unresectable NSCLC in patients whose tumours have EGFR mutations is to reduce the risk of recurrence, increase the proportion of patients who remain cancer-free in the long term, improve survival, and in doing so, enhance HRQoL. The clinical experts noted that conventional treatments (e.g., CRT) often lead to high rates of disease recurrence, and relapsed stage III NSCLC is generally considered incurable. Additionally, the experts flagged that patients with EGFR mutations are more likely to develop central nervous system (CNS) metastases compared to those without driver mutations, increasing the risk of symptoms at recurrence. Therefore, reducing relapse risk in patients with unresectable NSCLC and EGFR mutations was identified as a critical unmet need by the clinical experts consulted for this review.

While patients with unresectable NSCLC are eligible for consolidation treatment with durvalumab after CRT, the clinical experts consulted for this review indicated that most oncologists in Canada would not administer durvalumab after CRT in patients with EGFR mutation due to its limited efficacy and increased toxicity.

The experts believe that using osimertinib after successful completion of platinum-based CRT would provide a new therapeutic option for patients with unresectable NSCLC with EGFR mutations. Because osimertinib is currently reimbursed for relapsing cases, the clinical experts noted that using it in the current setting would cause a shift in the current treatment paradigm. Currently, patients with locally advanced or metastatic disease are eligible for osimertinib as first-line treatment with palliative intent. If recurrence occurs on maintenance osimertinib or within 6 months of stopping therapy, these patients would no longer be eligible for palliative osimertinib.

The clinical experts noted that patients with unresectable stage III NSCLC whose tumours contain a common EGFR mutation (i.e., exon 19 deletion or exon 21 [L858R] substitution) and who have not progressed following platinum-based CRT would be best suited for maintenance treatment with osimertinib. The clinical experts felt that any patient who received nonplatinum-based CRT should not be routinely eligible for osimertinib treatment, but felt there should be mechanisms for individual patient requests. The experts noted that EGFR mutations are identified with molecular testing, either using polymerase chain reaction (PCR) or next-generation sequencing (NGS), and this testing should be performed at diagnosis or during CRT treatment. Following platinum-based CRT, a CT scan should be performed to evaluate disease response or progression before initiating treatment with osimertinib.

Outcome metrics used in clinical practice are generally aligned with those used in clinical trials. The clinical experts consulted for this review noted that the metrics most often used in clinical practice include progression, overall survival (OS), QoL (e.g., symptoms and the patients’ overall impression), and prevention of brain metastases. The experts noted that in current clinical practice, imaging is performed every 3 months to 6 months for the first 2 years following CRT and then annually thereafter. If osimertinib is reimbursed for patients with unresectable EGFR-mutated NSCLC who have not progressed during or following platinum-based CRT, the experts anticipated more frequent visits would be required when starting treatment (e.g., assessments approximately every 4 weeks for the first 3 months) and then every 3 months thereafter for the duration of treatment.

Clinical experts consulted for this review indicated that osimertinib should be discontinued in the event of disease progression or significant toxicities that cannot be safely managed with dose reductions or modifications. The clinical experts consulted for this review felt that in the event of disease progression that is not amenable to any other local therapies, patients should be able to continue treatment with osimertinib if there is evidence of ongoing clinical benefit. The clinical experts noted that if a patient discontinued maintenance osimertinib treatment in the absence of recurrence, they should be eligible for first-line palliative intent osimertinib treatment if at least 6 months have passed since discontinuation and recurrence.

The experts indicated that treatment with osimertinib should be prescribed and managed by a physician familiar with managing systemic lung cancers (i.e., medical oncologist or pulmonologist). In some regions, care may be supervised by another physician (e.g., a general practitioner) under the direction from a physician trained in managing systemic anticancer therapies.

Clinician Group Input

CDA-AMC received 2 clinician group input submissions from the LCC Medical Advisory Committee (LCC MAC) and Ontario Health–Cancer Care Ontario (OH-CCO) Lung Cancer Drug Advisory Committee. LCC is a national charity with the purpose of increasing awareness about lung cancer, providing support to patients with lung cancer, research, and advocacy. LCC MAC consists of clinicians in the field of lung cancer across the country. OH-CCO’s Cancer Drug Advisory Committees provide timely evidence-based clinical and health system guidance on drug-related issues in support of Cancer Care Ontario’s mandate. In total, 27 clinicians contributed to this submission, 23 from LCC MAC and 4 from the OH-CCO Lung Cancer Drug Advisory Committee.

Both clinician groups and the clinical experts consulted for this review agreed that the current standard treatment for patients with unresectable, locally advanced NSCLC with EGFR mutations is cCRT. Clinician groups agreed that while consolidation immunotherapy with durvalumab is currently Health Canada approved and provincially funded for unresectable NSCLC agnostic of PD-L1 expression or EGFR mutation, it is not used in practice or recommended as conventional treatment for patients with EGFR mutations. Post hoc subgroup analyses of the PACIFIC trial revealed that patients with EGFR mutations receiving durvalumab had similar efficacy and increased toxicity compared to those receiving placebo. As such, both clinician groups agreed that currently there are no targetable treatments approved for patients with unresectable stage III NSCLC with EGFR mutations. Clinician groups noted that the goal of treatment is to cure the disease, as measured by OS, PFS, and disease-free survival, and LCC MAC added delaying disease progression in extrathoracic sites as a critical secondary goal.

The OH-CCO Lung Cancer Drug Advisory Committee explained patients with stage III (per standard Canadian staging techniques) unresectable NSCLC with EGFR exon 19 deletion or exon 21 (L858R) substation mutation who do not have disease progression by standard restaging techniques within 6 weeks of completion of platinum-based CRT (either concurrently or sequentially), with no contraindication to EGFR TKIs, no history of interstitial lung disease before CRT, and no evidence of symptomatic pneumonitis following definitive CRT, are best suited for treatment with osimertinib. The OH-CCO flagged that while one of the criteria is restaging within 6 weeks of completion of CRT, there should be some flexibility in this criterion as some centres have issues with CT scan wait times. While the OH-CCO Lung Cancer Drug Advisory Committee indicated that the reimbursement of molecular EGFR testing may not be universal across the country and additional funding may be needed for those provinces that do not currently have provincial reimbursement, LCC MAC indicated that they anticipated no increase in cost for testing for EGFR rearrangements to accommodate maintenance use of osimertinib.

LCC MAC stated that the outcomes to determine whether a patient is responding to treatment in clinical practice included PFS. LCC MAC suggested including the use of scans (CT of the body with or without brain imaging) and symptoms to monitor recurrence or progression with a frequency of every 3 months to 4 months while the OH-CCO Lung Cancer Drug Advisory Committee suggested restaging investigations every 3 months to 6 months.

Both clinician groups agreed that treatment should be discontinued if there is disease recurrence or progression, intolerance, or clinically important toxicity, and the OH-CCO Lung Cancer Drug Advisory Committee further added that treatment should be discontinued upon a patient’s request.

Clinician groups agreed that osimertinib can be delivered in a medical oncology outpatient setting. The OH-COO Lung Cancer Drug Advisory Committee further specified that osimertinib should be managed under the supervision of a specialist or medical oncologist with training in systemic therapy for thoracic malignancies.

Drug Program Input

Input was obtained from the drug programs that participate in the CDA-AMC reimbursement review process. Key factors identified that could potentially impact the implementation of the CDA-AMC recommendation for using osimertinib following successful completion of platinum-based CRT in the first-line setting were the use in patients with a WHO performance status greater than 1 (i.e., beyond the pivotal trial’s inclusion criteria), initiation of treatment beyond 6 weeks following the completion of platinum-based CRT, and continuation of treatment following disease progression.

Clinical Evidence

Systematic Review

Description of Studies

The LAURA trial is an ongoing, multinational, phase III, double-blinded, placebo-controlled, randomized study that met the inclusion criteria for the systematic review conducted by the sponsor. This trial has no sites in Canada. The LAURA trial was aimed at evaluating the efficacy and safety of osimertinib as maintenance therapy in patients with locally advanced, unresectable (stage III) NSCLC with centrally confirmed EGFR mutations (exon 19 deletions or exon 21 [L858R] substitution) whose disease had not progressed during or following definitive platinum-based CRT. Following confirmation of eligibility, patients were randomized in a 2:1 ratio to receive either osimertinib 80 mg orally once daily or placebo until objective radiological disease progression (defined by Response Evaluation Criteria in Solid Tumours [RECIST] Version 1.1 and confirmed by blinded independent central review [BICR]) or another discontinuation criterion was met (e.g., patient decision or unacceptable toxicity). Randomization was stratified by prior chemoradiation strategy (cCRT versus sCRT), tumour stage before chemoradiation (stage IIIA versus stage IIIB or stage IIIC) and China cohort (enrolled at a Chinese site and patient declaring themselves of Chinese ethnicity versus enrolled at non-Chinese site or patient declaring themselves of non-Chinese ethnicity). Overall, 216 patients were randomized to either the osimertinib group (n = 143 patients) or the placebo group (n = 73 patients) and included in the full analysis set (FAS). The outcomes relevant to this review include OS, PFS, CNS PFS, response outcomes, time to death or distant metastases (TTDM), time to treatment discontinuation or death (TTD), patient-reported outcomes, and harms data. These were all collected at the planned January 5, 2024, data cut-off (DCO) date and OS was additionally collected at an unplanned, updated analysis using the November 29, 2024, DCO date.

In the FAS of the LAURA trial, slightly more patients were female (132 of 216 [61.1%]) than male (38.9%), the mean age of patients was 61.4 years (standard deviation [SD] = 10.95), and patients were primarily Asian (82.4%), followed by white (13.9%), American Indian or Alaska Native (1.4%), or another race (2.3%). At baseline, patients primarily had stage IIIA (35.2%) or stage IIIB (48.6%) NSCLC with just 16.2% of patients classified as having stage IIIC NSCLC. At screening, fewer patients in the osimertinib group were positive for exon 19 deletions (74 of 143 [51.7%]) and more were positive for exon 21 (L858R) substitutions (47.6%) compared to the placebo group (43 of 73 [58.9%] and 41.1%, respectively). Notable differences in baseline characteristics across treatment groups included fewer former smokers in the osimertinib group (25.9%) than in the placebo group (31.5%), more patients in the osimertinib group (55.9%) with a WHO performance status of 0 than in the placebo group (42.5%), and more patients in the osimertinib group receiving cCRT (91.6%) than in the placebo group (84.9%).

Efficacy Results

Efficacy outcomes presented in the following are from the most recent DCOs (November 29, 2024, for OS and January 5, 2024, for PFS, CNS PFS, TTDM, TTD, and HRQoL).

Overall Survival

At the January 5, 2024, DCO date, OS was tested and did not meet the prespecified boundary for declaring statistical significance.

At the November 29, 2024, DCO date, the median OS follow-up time for all patients was 39.36 months ███████ ████ ██ ██████ in the osimertinib group and 35.15 months ███████ ████ ██ ██████ in the placebo group at which point 40 deaths had occurred in the osimertinib group (of a total of 143 patients [28.0%]) and 26 deaths had occurred in the placebo group (of a total of 73 patients [35.6%]). The Kaplan-Meier (KM) estimate for median OS was 58.81 months (95% confidence interval [CI], 54.08 months to not calculable [NC]) in the osimertinib group and 53.98 months (95% CI, 42.05 months to NC) in the placebo group with a stratified hazard ratio (HR) of 0.67 (95% CI, 0.40 to 1.14). The between-group difference in the probability of survival for the osimertinib group versus the placebo group was ████ ████ ███ ████ ██ ████) at 36 months and █████ ████ ███ ███ ██ █████ at 48 months.

Progression-Free Survival

The median PFS follow-up time for all patients was 21.98 months (range, 0.03 months to 60.55 months) in the osimertinib group and 5.55 months (range, 0.03 months to 49.71 months) in the placebo group at which point 57 of 143 patients (39.9%) experienced progression events in the osimertinib group and 63 of 73 patients (86.3%) experienced progression events in the placebo group. The KM estimate for median PFS was 39.13 months (95% CI, 31.51 months to NC) in the osimertinib group and 5.55 months (95% CI, 3.71 months to 7.43 months) in the placebo group with a stratified HR of 0.16 (95% CI, 0.10 to 0.24) favouring the osimertinib group. The between-group difference in the probability of PFS for the osimertinib group versus the placebo group was █████ ████ ███ ████ ██ █████ at 12 months and █████ ████ ███ ████ ██ █████ at 36 months.

CNS Progression-Free Survival

At the January 5, 2024, DCO date, CNS PFS was not eligible for statistical testing (as OS was not statistically significant and therefore CNS PFS was not formally tested based on the multiple testing procedure [MTP]).

The median CNS PFS follow-up time for all patients was 24.64 months (██████ ████ ██ █████) in the osimertinib group and 5.72 months (██████ ████ ██ █████) in the placebo group at which point 29 CNS progression events had occurred in the osimertinib group (of a total of 143 patients [20.3%]) and 30 CNS progression events had occurred in the placebo group (of a total of 73 patients [41.1%]). The KM estimate for median CNS PFS was NC in the osimertinib group and 14.88 months (95% CI, 7.36 months to NC) in the placebo group with a stratified HR of 0.17 (95% CI, 0.09 to 0.32). The between-group difference in the probability of CNS PFS for the osimertinib group versus the placebo group was █████ ████ ███ ████ ██ █████ at 12 months and █████ ████ ███ ████ ██ █████ at 24 months.

Time to Death or Distant Metastases

TTDM was a secondary end point and not adjusted for multiplicity in the LAURA trial.

By the January 5, 2024, DCO date, 33 death or distant metastases events had occurred in the osimertinib group (of a total of 143 patients [23.1%]) and 31 death or distant metastases events had occurred in the placebo group (of a total of 73 patients [42.5%]) . The median TTDM was not reached (95% CI, 39.29 months to NC) in the osimertinib group and was 13.04 months (95% CI, 9.03 months to NC) in the placebo group with a stratified HR of 0.21 (95% CI, 0.11 to 0.38) favouring the osimertinib group.

Time to Treatment Discontinuation or Death

TTD was a secondary end point and not adjusted for multiplicity in the LAURA trial.

By the January 5, 2024, DCO date, 63 patients had a death or treatment discontinuation event in the osimertinib group (of a total of 143 patients [44.1%]) compared to 66 patients in the placebo group (of a total of 73 patients [90.4%]). The median TTD was 40.28 months (95% CI, 32.72 months to NC) in the osimertinib group compared to 8.31 months (95% CI, 6.14 months to 11.10 months) in the placebo group with a stratified HR of 0.21 (95% CI, 0.14 to 0.32) favouring the osimertinib group.

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Global Health Status/Quality of Life

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) questionnaire-based outcomes were secondary end points and not adjusted for multiplicity in the LAURA trial.

The between-group difference for the mean change from baseline across all visits to week 40 in the EORTC QLQ-C30 global health status/QoL did not meet the minimal important difference (MID) threshold of 4 points; however, the CI crosses the MID threshold of −4 points for deterioration (−1.9 points; 95% CI, −5.89 to 2.00 points).²⁵

Harms Results

Safety outcomes presented in the following are from the January 5, 2024, DCO date and reported among the safety analysis set (i.e., all randomized patients who received at least 1 dose of study treatment).

Any Adverse Event

More patients in the osimertinib group experienced an adverse event (AE) (140 of 143 [97.9%]) than in the placebo group (64 of 73 [87.7%]). In both groups, the 3 most frequently reported AEs were radiation pneumonitis (47.6% in the osimertinib group and 38.4% in the placebo group), diarrhea (35.7% and 13.7%, respectively), and rash (23.8% and 13.7%, respectively).

Serious AEs

More patients in the osimertinib group experienced a serious AE (SAE) (55 of 143 [38.5%]) than in the placebo group (11 of 73 [15.1%]). In the osimertinib group, the most frequently reported SAEs were radiation pneumonitis (10.5%), pneumonia (4.9%), and gastroenteritis (1.4%) and pneumonitis (1.4%). In comparison, the most frequently reported SAEs in the placebo group were pneumonia (4.1%) and radiation pneumonitis (2.7%) with all other SAEs reported by only 1 patient.

Withdrawals Due to AEs

More patients in the osimertinib group prematurely stopped treatment due to an AE (██████ ████████ than in the placebo group (████ ██████). In the osimertinib group, the 3 most common AEs leading to treatment discontinuation were radiation pneumonitis (4.9%), █████████ ███████ ███ ███████████ ███████ ██ ███ ███████ █████ █ ████████ ██████ ███████████ █████████ ███████████ ████ ███ ██ █████████ ███████████████ █████ ███ █████ ███ ███████ ██ █████████ ███████████████ ████ ███████████ ██ ████ █ ████████

Death Due to AEs

A similar percentage of patients in both the osimertinib and placebo group experienced an AE with an outcome of death (█████ ██████ in the osimertinib group and ████ ██████ in the placebo group). In the osimertinib group, the fatal AEs were due to pneumonia (████), pneumonitis (████), and a road traffic accident (████). In the placebo group, the fatal AEs were due to myocardial infarction (████) and aortic aneurysm rupture (████).

Notable Harms

Generally, a higher percentage of patients in the osimertinib group tended to experience AEs of special interest identified in the product monograph and highlighted as important by clinical experts consulted for this review. In both treatment groups, radiation pneumonitis was the most common AE of special interest (experienced by 68 of 143 patients [47.6%] in the osimertinib group and 28 of 73 patients [38.5%] in the placebo group), followed by ███████ █████████ ██████ ███ █████ ████████████), and interstitial lung disease or pneumonitis (7.7% and 1.4%, respectively). Pneumonitis occurred in slightly more patients in the osimertinib group (████) than in the placebo group (████). Similarly, grade 3 or greater diarrhea occurred in ████ of patients in the osimertinib group and ████ in the placebo group.

Critical Appraisal

Despite the use of stratified randomization, differences in baseline characteristics across treatment groups poses questions about the comparability of the 2 groups. Notably, there was a higher percentage of patients with WHO performance status 0 at baseline in the osimertinib group (55.3%) versus the placebo group (42.5%) and fewer former smokers in the osimertinib group (25.9%) than the placebo group (31.5%).These differences may indicate that patients in the osimertinib group had a more favourable prognosis, which could introduce confounding and bias the results in favour of osimertinib. It is acknowledged that between-group differences in baseline characteristics may occur in trials with smaller sample sizes (e.g., < 100 patients per group) and multiple strata per covariates, which may apply to the LAURA trial.^26,27 Subgroup analyses among current or former smokers were similar to the overall population. The sponsor conducted a post hoc subgroup analysis on baseline WHO performance status that was consistent with the PFS benefit for osimertinib in the primary analysis and the clinical experts consulted for this review did not anticipate the differences in WHO performance status to substantially impact the results. Nonetheless, the potential for residual confounding due to baseline imbalances remains a limitation in the internal validity of the trial.

Date of death, start and end dates for concomitant medication, radiotherapy, AEs, and subsequent anticancer treatment dates were imputed if missing. Instances where only partial information was available relied on assumptions of noninformative missingness (i.e., data missing completely at random or missing at random) which may introduce bias if missing not at random mechanisms are present. Additionally, this approach may not capture uncertainty in the imputed values resulting in an underestimation in the variability and narrowing the resulting CIs. A sensitivity analysis was conducted to assess the potential for evaluation time bias by imputing progression dates as the midpoint between the last progression-free and progression-confirming BICR assessments. Although the HR for the sensitivity analysis (████; 95% CI ████ ██ ████; refer to Table 19) ███ █████ to that for the primary PFS analysis (HR = 0.16; 95% CI, 0.10 to 0.24; refer to Table 15) it does not fully mitigate the risk of bias. It assumes progression occurs uniformly and does not account for differences in assessment schedules or missing data patterns between treatment groups. Importantly, the extent of missing data leading to imputation for these critical time-dependent variables was not reported, making it difficult to assess the overall impact of this approach on potential bias in the results.

BICR-assessed PFS, followed by OS, and BICR-assessed CNS PFS were addressed using a hierarchical MTP which controlled for type I error at the January 5, 2024, DCO date. At this time, PFS met the prespecified threshold for statistical significance. Per the testing procedure, the interim analysis of OS was also conducted at this DCO; however, OS failed to reach statistical significance. Consequently, the CNS PFS end point, which was next in the hierarchy, could not be formally tested. In this case, the reporting of a nominal P value for CNS PFS can be misleading and does not follow the statistical analysis plan; however, there is a substantial between-group difference that is unlikely attributable to chance or inflated type I error.

The OS analysis was based on the intention-to-treat approach, which assumes postprogression therapies are nondifferentially distributed between groups — a condition that may not hold given the observed disparities in postrelapse therapy used. A higher percentage of patients in the placebo group used subsequent anticancer treatments (█████) than in the osimertinib group (█████) by the November 29, 2024, DCO date. The largest discrepancy in postprogression therapies was for osimertinib (█████ in the placebo group versus █████ in the osimertinib group received subsequent osimertinib treatment at the November 29, 2024, DCO date). This imbalance challenges the intention-to-treat assumption and introduces potential bias in the OS analysis. The trial did not implement methods to adjust for treatment switching (e.g., rank-preserving structural failure time models). The crossover for patients on placebo who had progression potentially leads to an underestimation of the between-group difference in OS; however, the findings align with clinical practice, as osimertinib is the standard of care for disease that has progressed.

OS results from the LAURA trial are based on interim analyses, which may overestimate treatment effects.²⁸ At the November 29, 2024, DCO date, the OS analysis included 66 events (in 40 of 143 patients [28.0%] in the osimertinib group and 26 of 73 patients [35.6%] in the placebo group), corresponding to approximately 30.6% of the total number of events required for the final analysis (120 events). This DCO date was not part of the prespecified analysis plan. Results from this time point may therefore be more susceptible to bias due to early data truncation and post hoc decision-making. This DCO date was conducted as part of regulatory marketing requirements.

Stratified Cox proportional hazards models were used to estimate the HRs and CIs for OS, PFS, and CNS PFS. The proportional hazards assumption is likely not met for OS based on the KM curves that cross several times over the duration of follow-up. While this suggests that the HRs may not reflect the treatment effect over time for OS, it may be partially explained by the frequent use of osimertinib in patients in the placebo group whose disease progressed. Clinical experts consulted for this review felt that the OS KM curves accurately reflected the natural history of EGFR-mutated NSCLC, with a typical median survival of 3 years to 4 years after recurrence. Alternative methods of analysis that do not rely on the proportional hazards assumption were not conducted for any of the time-to-event analyses, which makes it more difficult to assess the robustness of the results.

Visual inspection of KM plots indicated that fewer than 20% of patients in the placebo group remained at risk beyond 45 months for OS and beyond 12 months for PFS and CNS PFS. In the osimertinib group, fewer than 20% of patients were at risk beyond 51 months for OS and beyond 33 months for PFS and CNS PFS. Under such conditions, standard assumptions used in survival analysis (e.g., noninformative censoring) may be violated, which limits the reliability of survival estimates at later time points.^29-31

The FDA and the EMA (European Medicines Agency) consider OS the gold standard primary outcome in trials, including NSCLC trials.^32,33 However, PFS is considered to be an important cancer end point by the FDA in situations where survival may be prolonged, making an OS end point impractical.^33,34 When observed differences in PFS are substantial in magnitude (viewed in the context of toxicities, the relatively short survival of patients with NSCLC, availability of alternative therapies, histologic or genetic subtype of NSCLC, and extent of prior treatment), the FDA and EMA consider PFS to provide clinical evidence to support approvals.^32,33 While a correlation between PFS and OS in patients with locally advanced NSCLC has been shown,^35,36 no correlation has been established for the current setting (i.e., unresectable EGFR-mutated NSCLC) and thus the validity of PFS as a surrogate for OS is unclear in the current context.

The completion rates for the EORTC QLQ-C30 and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module (EORTC QLQ-LC13) scales declined over time — particularly in the placebo group — reducing the certainty of the treatment effects at the later time points.

The clinical experts with expertise in the diagnosis and management of patients with NSCLC felt the inclusion and exclusion criteria used in the LAURA trial were generally aligned with those typically used in NSCLC trials and the sponsor’s reimbursement request. The clinical experts felt the reimbursement of osimertinib should include those with a WHO performance status of 0 to 2 (rather than only those with a WHO performance status of 0 and 1 as included in the trial).

The clinical experts consulted for this review indicated the baseline characteristics of the study population were representative of patients seen in clinical practice in Canada. Notably, a high percentage of patients enrolled in the LAURA trial identified as Asian (82.4%); however, this was partially expected as EGFR mutations are more common in patients of Asian ethnicity.⁵ The clinical experts consulted for this review did not expect racial differences to significantly impact treatment effects.

The clinical experts consulted for this review noted that the prior platinum-based CRT regimens used for treatment in the definitive setting for stage III disease in the LAURA trial were representative of those used to treat unresectable EGFR-mutated NSCLC in Canada. The same clinical experts also felt that watchful waiting was the most relevant comparator.

GRADE Summary of Findings and Certainty of the Evidence

For pivotal studies and randomized controlled trials (RCTs) identified in the sponsor’s systematic review, Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^37,38 Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• OS (probabilities at 36 months and 48 months), PFS (probabilities at 12 months and 36 months), CNS PFS (probabilities at 12 months and 24 months)

• HRQoL (average change in EORTC QLQ-C30 global health status/QoL score from baseline across all visits)

• harms (pneumonitis, ≥ grade 3 diarrhea, withdrawal due to AEs, and fatal AEs).

Table 2 presents the GRADE summary of findings for osimertinib versus placebo for patients with locally advanced, unresectable (stage III) NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations and who have not progressed during or following platinum-based CRT.

Table 2: Summary of Findings for Osimertinib Versus Placebo for Patients With Locally Advanced, Unresectable (Stage III) NSCLC Whose Tumours Have EGFR Exon 19 Deletions or Exon 21 (L858R) Substitution Mutations and Have Not Progressed During or Following Platinum-Based CRT

AE = adverse event; CI = confidence interval; CNS = central nervous system; CRT = chemoradiation therapy; DCO = data cut-off; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; MID = minimally important difference; NR = not reported; NSCLC = non–small cell lung cancer; OS = overall survival; PFS = progression-free survival; RCT = randomized controlled trial.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aThe between-group differences were requested from the sponsor to aid in the interpretation of the results for these end points.

^bCertainty was rated down 1 level for risk of bias. While a planned interim analysis of OS was conducted at the January 5, 2024, DCO date and could have been used to avoid concerns related to post hoc decision-making, this analysis was based on a shorter duration of follow-up and fewer events (43 OS events), reducing its reliability for drawing robust conclusions. The later OS results, using the November 29, 2024, DCO date provide longer follow-up and more events (OS analysis included 66 events; 40 of 143 [28.0%] in the osimertinib group and 26 of 73 [35.6%] in the placebo group), but were from an unplanned, interim analysis, increasing the risk of post hoc decisions and the potential for inflated treatment effects. In both analyses, the presence of time-varying treatment effects, including a delayed separation and crossing of KM curves, limit the validity and reliability of the estimate of absolute difference between groups. Differences in postprogression anticancer therapies, including 74% of placebo group patients receiving osimertinib, also likely influence the between-group OS difference. No empirically derived and validated MID was identified for the between-group difference in the probability of OS. The clinical experts consulted for this review suggested that a 5% to 10% between-group difference would be clinically meaningful and this value was used as the threshold. Certainty was rated down 1 level for imprecision. Using the 5% between-group difference threshold, the point estimate suggests a clinically meaningful effect on OS at 36 months, while the lower bound of the 95% CI crossed the between-group difference threshold of 5%.

^cCertainty was rated down 1 level for risk of bias. While a planned interim analysis of OS was conducted at the January 5, 2024, DCO date, and could have been used to avoid concerns related to post hoc decision-making, this analysis was based on a shorter duration of follow-up and fewer events (43 OS events), reducing its reliability for drawing robust conclusions. The later OS results, using the November 29, 2024, DCO date, provide longer follow-up and more events, but were from an unplanned analysis, increasing the risk of post hoc decisions and the potential for inflated treatment effects. In both analyses, the presence of time-varying treatment effects, including a higher probability of OS with placebo during the first 18 months and delayed separation and crossing of KM curves, limit the validity and reliability of the estimate of absolute difference between groups. Differences in postprogression anticancer therapies, including 74% of placebo group patients receiving osimertinib, also likely influence the between-group OS difference. In addition, at 48 months there was high attrition in the placebo group (n = 11), which may result in informative censoring and bias the between-group difference in OS at this time point. No empirically derived and validated MID was identified for the between-group difference in the probability of survival. The clinical experts consulted for this review suggested that a 5% to 10% between-group difference would be clinically meaningful and this value was used as the threshold. Certainty was rated down 1 level for imprecision. While the point estimate suggests a clinically meaningful effect on OS at 48 months, the lower bound of the 95% CI did not cross the threshold, suggesting little to no difference.

^dCertainty was not rated down for indirectness for PFS as a surrogate outcome for OS. While direct validation of PFS as a surrogate for OS in the setting of unresectable EGFR-mutated NSCLC treated with maintenance therapy is lacking, the clinical experts considered PFS to be of clinical relevance for patients in delaying progression to metastatic disease and administration of more toxic treatment. Certainty was not rated down for imprecision. No empirically derived and validated MID was identified for the between-group difference in the probability of PFS. The clinical experts consulted for this review suggested that a 10% to 15% between-group difference would be clinically meaningful. The effect estimate as well as both lower and upper boundaries of the 95% CI of the between-group difference exceeded the threshold and suggested a benefit.

^eCertainty was not rated down for indirectness for PFS as a surrogate outcome for OS. While direct validation of PFS as a surrogate for OS in the setting of unresectable EGFR-mutated NSCLC treated with maintenance therapy is lacking, PFS is a clinically relevant end point in oncology trials, including NSCLC, especially because patient input signalled value in therapies that prevent disease progression. Certainty was rated down 1 level for risk of bias due to high attrition at 36 months (n = 28 in the osimertinib group and n = 3 in the placebo group), which may result in informative censoring and bias the between-group difference in OS at this time point. No empirically derived and validated MID was identified for the between-group difference in the probability of PFS. The clinical experts consulted for this review suggested that a 10% to 15% between-group difference would be clinically meaningful and this value was used as the threshold. The effect estimate as well as both lower and upper boundaries of the 95% CI of the between-group difference exceeded the threshold and suggested a benefit.

^fCNS PFS is not a validated surrogate for OS and does not capture extracranial progression. However, it is a clinically important outcome in the context of EGFR-mutated NSCLC, given the incidence and burden of CNS metastases in this population. The end point provides direct information on intracranial disease control that is relevant to patients and clinicians. No empirically derived and validated MID was identified for the between-group difference in the probability of CNS PFS. The clinical experts consulted for this review suggested that a 10% between-group difference would be clinically meaningful and this value was used as the threshold. The effect estimate as well as both lower and upper boundaries of the 95%CI of the between-group difference exceeded the threshold and suggested a benefit.

^gCNS PFS is not a validated surrogate for OS and does not capture extracranial progression. However, it is a clinically important outcome in the context of EGFR-mutated NSCLC, given the incidence and burden of CNS metastases in this population. The end point provides direct information on intracranial disease control that is relevant to patients and clinicians. Certainty was rated down 1 level for risk of bias due to high attrition in the placebo group at 24 months (n = 8), which may result in informative censoring and bias the between-group difference in CNS PFS at this time point. No empirically derived and validated MID was identified for the between-group difference in the probability of CNS PFS. The clinical experts consulted for this review suggested that a 10% between-group difference would be clinically meaningful and this value was used as the threshold. The effect estimate as well as both lower and upper boundaries of the 95% CI of the between-group difference exceeded the threshold and suggested a benefit.

^hCertainty was rated down 1 level for risk of bias. Beyond week 16 █████ ████ ███ of patients in the placebo group were available to contribute to the analysis. Certainty was rated down 1 level for imprecision. A MID for the EORTC QLQ-C30 global health status scale has not been definitively established, although a difference of 10 points is often cited. One recent review estimated the MID for the scale may be 4 points in patients with lung cancer, and 4 points was adopted as the MID for this assessment.²⁵ Although the point estimate suggests little to no difference in HRQoL, the lower CI crosses the MID for deterioration and the possibility of a negative effect cannot be ruled out. EORTC QLQ-C30 was not adjusted for multiplicity in the trial and should be considered as supportive evidence.

ⁱNo empirically derived and validated MID was identified for the between-group difference in the frequency of withdrawal due to AEs. The clinical experts consulted for this review suggested that a 10% between-group difference would be clinically meaningful and this value was used as the threshold. Certainty was rated down 1 level for imprecision. The between-group difference suggests no clinically meaningful effect on the frequency of withdrawal due to AEs at the January 5, 2024, DCO date while the upper bound of the 95% CI crosses the between-group difference threshold of 10%.

^jNo empirically derived and validated MID was identified for the between-group difference in the frequency in fatal AEs. The clinical experts consulted for this review suggested that a 5% between-group difference would be clinically meaningful and this value was used as the threshold. Certainty was rated down 2 levels for imprecision. The between-group difference suggests no clinically meaningful effect on the frequency of fatal AEs at the January 5, 2024, DCO date while the lower bound of the 95% CI crosses the between-group difference threshold of 5%. Additionally, the absolute number of events was low in both groups, contributing to uncertainty.

^kNo empirically derived and validated MID was identified for the between-group difference in the frequency of pneumonitis. The clinical experts consulted for this review suggested that a 5% between-group difference would be clinically meaningful and this value was used as the threshold. Certainty was rated down 2 levels for imprecision. The between-group difference suggests no clinically meaningful effect on the frequency of pneumonitis at the January 5, 2024, DCO date while the upper bound of the 95% CI crosses the between-group difference threshold of 5%. Additionally, the absolute number of events was low in both groups, contributing to uncertainty.

^lNo empirically derived and validated MID was identified for the between-group difference in the frequency of grade ≥ 3 diarrhea. The clinical experts consulted for this review suggested that a 10% between-group difference would be clinically meaningful and this value was used as the threshold. Certainty was rated down 1 level for imprecision. The absolute number of events was low in both groups, contributing to uncertainty.

Source: The LAURA Clinical Study Report³⁹ and LAURA Overall Survival Analysis Update.⁴⁰ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Long-Term Extension Studies

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

Indirect Comparisons

No indirect comparisons were submitted by the sponsor.

Studies Addressing Gaps in the Evidence From the Systematic Review

No studies addressing gaps in the evidence from the systematic review evidence were submitted by the sponsor.

Conclusions

The LAURA trial was a phase III, double-blinded, placebo-controlled, randomized, multinational trial comparing the efficacy and safety of maintenance osimertinib for patients with locally advanced, unresectable (stage III) NSCLC whose tumours harboured either EGFR exon 19 deletions or exon 21 (L858R) substitution mutations and whose disease has not progressed during or following platinum-based CRT. Compared to placebo, osimertinib results in a clinically important improvement in PFS and CNS PFS at 12 months (high-certainty evidence) and likely results in clinically important increases in PFS at 36 months and CNS PFS at 24 months (moderate certainty evidence). At the planned PFS interim analysis, relatively few OS events (43 events across both groups) had occurred and OS failed to achieve statistical significance. Results from a subsequent unplanned OS analysis showed osimertinib may result in a clinically important increase in OS at 36 months and 48 months compared to the placebo group (low certainty evidence at both time points). Results from the LAURA trial showed that osimertinib may result in little to no difference in HRQoL compared to placebo (low certainty of evidence). Clinical experts consulted for this review deemed the harms profile of osimertinib to be consistent with their expectations based on osimertinib’s known toxicity profile.

Clinical experts noted that conventional treatments (e.g., CRT) often lead to high rates of disease recurrence, and relapsing stage III NSCLC is generally considered incurable. Additionally, the experts flagged that patients with EGFR mutations are more likely to develop CNS metastasis compared to those with driver mutation–negative NSCLC, increasing the risk of symptoms at recurrence. Therefore, reducing relapse risk in patients with unresectable NSCLC and EGFR mutations was identified as a critical unmet need by the clinical experts consulted for this review.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of osimertinib, 80 mg oral tablets taken once daily in the treatment of locally advanced, unresectable (stage III) NSCLC in patients whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations (either alone or in combination with other EGFR mutations) and whose disease has not progressed during or following platinum-based CRT.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the review team.

Lung cancer is the most commonly diagnosed cancer in Canada and the leading cause of cancer-related deaths.^1,2 In 2024 alone, approximately 32,100 people living in Canada were expected to be diagnosed with lung cancer, and 20,700 annual deaths were expected to be attributable to lung cancer.³ Lung cancer predominantly affects males (53% of new lung cancer cases) and adults aged 50 years and older (98% of new lung cancer cases).^2,3 Survival from lung cancer of all stages and histologies is poor, with an overall 5-year net survival of 22%.² First Nations, Inuit, and Métis Peoples in Canada face significant lung cancer disparities. Adults of First Nations ancestry have a 35% lower 5-year survival rate despite similar incidence rates; adults of Métis ancestry are more likely to be diagnosed and have a 30% lower 5-year survival rate, and Inuit living in Inuit Nunangat are more than twice as likely to be diagnosed.⁴¹

Lung cancer is classified into NSCLC or small cell lung cancer, with NSCLC accounting for approximately 88% of cases in Canada, excluding Quebec.¹ NSCLC is further classified into 3 main histologic subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.¹ To date, several molecular alterations, defined as “driver mutations” have been identified in NSCLC, with the 2 prominent drivers being ALK rearrangements and EGFR mutations. ALK rearrangements occur through gene fusions, leading to abnormal cell proliferation.⁴² EGFR mutations are particularly common in adenocarcinomas, resulting in abnormal signalling pathways that drive tumour growth.⁴ Approximately 15% of Canadians with NSCLC have an EGFR-activating mutation in the region encoding the tyrosine kinase domain.^6-8 EGFR mutations are more frequently observed in never smokers, people of Asian ethnicity, patients with adenocarcinoma, and females.^5,6 The most common EGFR mutations are exon 19 deletions and the exon 21 codon 858 point mutation (L858R), accounting for 70% to 90% of EGFR mutations.^43-47 A common feature of EGFR-mutated NSCLC is the development of CNS metastases, which are detected in approximately 25% of patients at diagnosis and can affect approximately 50% of all patients within 3 years from diagnosis.⁴⁸ Brain metastases are associated with decreased QoL and poor prognosis and are a significant cause of cancer-related mortality.^49,50

NSCLC diagnosis typically begins with a comprehensive medical history, smoking assessment, and standard tests, including evaluations of lung, renal, and liver function, along with blood and biochemistry tests.⁹ Imaging techniques such as X-rays, CT scans, PET scans of the chest and abdomen, and MRI of the CNS are then used before tissue biopsy is performed to confirm the diagnosis.^11,51 To determine a patient’s prognosis and best course of treatment, NSCLC is staged using the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control TMN Staging System, which involves tumour, node, metastasis classification of the disease based on the size and spread of the primary tumour, lymph node involvement, and occurrence of metastasis.⁵² Once a confirmed diagnosis of NSCLC has taken place, patients undergo testing for oncogenic drivers, including EGFR mutations. Such testing is performed by molecular tissue testing on a sample obtained via biopsy.⁵³

While resectability in stage III disease is not clearly defined and is dependent on a variety of factors including the size and location of the tumour, any lymph node metastases, and a surgical assessment, typically patients with stage III NSCLC without mediastinal nodal involvement (T3N1, T4N0 or T4N1) are considered resectable.¹⁴ An estimated 21% of patients diagnosed with NSCLC have stage III disease and among these patients, 87% are considered to have unresectable (nonoperable) disease.⁵⁴

NSCLC is often asymptomatic and due to its insidious nature, patients may live for several years before presentation.⁹ The most common symptoms include unspecific cough, chest and shoulder pain, hemoptysis, weight loss, dyspnea, hoarseness, bone pain, fever, and recurring infections with bronchitis and pneumonia.^9,10 Diagnostic procedures include imaging of the lungs, sputum cytology, and tissue biopsy.¹¹

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the review team.

The treatment goals for locally advanced, unresectable stage III NSCLC are to prevent local recurrence, distant metastases, and progression as well as improve QoL.^12-15

Before establishing a treatment plan, tumours should undergo testing for oncogenic drivers, including EGFR mutations. Such testing is performed by molecular tissue testing on a sample obtained via biopsy.⁵³ The Canadian consensus for optimizing biomarker testing highlights the following recommendations for EGFR mutation testing.⁵⁵

• EGFR mutation testing should be performed as part of a comprehensive panel that includes the current standard of care biomarkers.

• Comprehensive reflex biomarker testing, including EGFR, is recommended for all patients diagnosed with nonsquamous NSCLC regardless of disease stage and should be initiated by the pathologist at the time of initial diagnosis with targeted NGS.

• When tissue biopsy harbours scarce tumour cells, when time for a tissue biopsy is too lengthy, or when invasive procedures for tissue procurement are contraindicated, liquid biopsy for the detection of activating EGFR mutations and other biomarkers is recommended at baseline, if available and publicly funded.

The current conventional treatment for patients presenting with unresectable stage III NSCLC, irrespective of EGFR mutation status, is definitive cCRT.^12,16-18 The chemotherapy component typically consists of 2 to 4 cycles of preferred platinum-doublet options including cisplatin plus pemetrexed (nonsquamous only) or carboplatin plus pemetrexed, cisplatin plus etoposide, carboplatin plus paclitaxel, or cisplatin plus vinorelbine.^12,19 For the radiotherapy portion, the current conventional radiation dose to be delivered with concurrent chemotherapy is 60 Gy given in 2 Gy fraction sizes delivered over 6 to 7 weeks; doses higher than 60 Gy and up to 70 Gy may be considered for select patients, with careful attention to doses to the heart, lungs, and esophagus.^12,19 In patients with unresectable stage III NSCLC who cannot tolerate cCRT, sCRT is recommended^12,19; typically sCRT is the preferred treatment in patients with poor performance status or comorbid conditions.²⁰

While immunotherapy consolidation treatment after CRT has shown improved outcomes in patients with unresectable stage III NSCLC without EGFR mutations (e.g., durvalumab), subgroup analyses suggest it does not provide similar benefits in patients with EGFR mutations. In Canada, durvalumab, a PD-L1 inhibitor, is currently reimbursed for the treatment of patients with unresectable, stage III NSCLC whose disease has not progressed following concurrent platinum-based CRT. However, post hoc subgroup analysis of the PACIFIC trial suggested that durvalumab consolidation therapy has similar efficacy and more frequent adverse effects than placebo in patients with EGFR-mutated disease.²¹ As a result, in clinical practice, and based on a recent European Society for Medical Oncology consensus statement, the use of durvalumab consolidation post CRT is not recommended for patients with unresectable NSCLC and EGFR mutations,²² leaving these patients with no effective reimbursed immunotherapy consolidation treatment. In the absence of an effective and available consolidation therapy (also called maintenance therapy) for unresectable EGFR-mutated NSCLC in Canada, clinical experts consulted for this review with experience in the diagnosis and management of NSCLC indicated that active surveillance is the current standard of care for these patients. Active surveillance consists of regular imaging (e.g., CT scans) and clinical monitoring to detect early disease progression every 6 months for the first 2 years following completion of CRT and yearly thereafter for the next 3 years.²³ Most patients with locally advanced, unresectable (stage III) EGFR-mutated NSCLC who remain progression-free during or post CRT are at risk of recurrence during the first year of the surveillance phase.²⁴

Drug Under Review

Osimertinib, a TKI, is an oral, potent, and selective irreversible inhibitor of both EGFR-sensitizing mutations and the T790M resistance mutation that has limited activity against wild-type EGFR. Key characteristics of osimertinib are summarized in Table 3.

Osimertinib received conditional Health Canada authorization for the treatment of patients with locally advanced, unresectable (stage III) NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations (either alone or in combination with other EGFR mutations) and whose disease has not progressed during or following platinum-based CRT. Health Canada’s authorization is conditional on the final OS results from the LAURA trial (at approximately 60% maturity) which will be used to confirm clinical benefit of osimertinib observed in the primary end point, PFS for the intention-to-treat target population. The final OS analysis is event driven and anticipated to occur in the first half of 2027.

The recommended dose of osimertinib is 80 mg tablet taken orally once a day.

The sponsor’s reimbursement request is the same as the Health Canada–approved indication. Osimertinib for the treatment of locally advanced, unresectable (stage III) NSCLC with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations following completion of CRT without progression has been approved by FDA and EMA for this indication.^56,57

In Canada, osimertinib is also Health Canada authorized for the following indications.

• As adjuvant therapy after tumour resection in patients with stage IB to stage IIIA1 NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

• For the first-line treatment of patients with locally advanced (not amenable to curative therapies), or metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations (either alone or in combination with other EGFR mutations).

• In combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of patients with locally advanced (not amenable to curative therapies) or metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations.

• For the treatment of patients with locally advanced or metastatic EGFR T790M mutation–positive NSCLC whose disease has progressed on or after EGFR TKI therapy.

Osimertinib has been previously reviewed by CDA-AMC and received recommendations for reimbursement with conditions:

• in October 2024, in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 L858R mutations

• in January 2022, as adjuvant therapy after tumour resection in patients with stage IB to stage IIIA NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations

• in January 2019, for the first-line treatment of patients with locally advanced or metastatic NSCLC whose tumours have EGFR mutations

• in May 2017, for the treatment of patients with locally advanced or metastatic EGFR T790M mutation–positive NSCLC who have progressed on or after EGFR TKI therapy.

Table 3: Key Characteristics of Osimertinib

NSCLC = non–small cell lung cancer; QTcF = QT interval corrected using the Fridericia formula.

^aHealth Canada–approved indication.

Source: Osimertinib product monograph.⁵⁸

Testing Procedure Considerations

With a growing landscape of targeted therapies available for the treatment of NSCLC, biomarker testing for oncogenic driver mutations is increasingly becoming part of a routine diagnostic work-up.^55,59,60 Canadian consensus guidelines recommend testing for the presence of actionable biomarkers — at minimum EGFR, ALK, and ROS1 — to guide treatment.^55,59,60 The clinical experts consulted for this review confirmed that EGFR testing, including testing for exon 19 deletions and exon 21 (L858R) substitution mutations, is currently conducted as part of routine care in patients with locally advanced, unresectable NSCLC, with testing performed at the time of initial diagnosis. It is estimated that 10% to 20% of patients with NSCLC have EGFR-sensitizing mutations, of which 70% to 90% are exon 19 deletions and exon 21 (L858R) substitution mutations^55,59 EGFR mutations are more prevalent in people who are nonsmokers, females, and of Asian descent.^55,59,60

EGFR mutations can be identified by either PCR or NGS testing methods, using biopsied tissue samples obtained as part of diagnostic work-up.^18,55,60 NGS is preferred over single-gene PCR testing as parallel testing of multiple genes is more efficient overall in terms of turnaround times and tissue use.^55,60,61 Liquid biopsy using circulating tumour DNA (ctDNA) from peripheral blood samples is also possible when insufficient tumour cells are available from tissue biopsy, patients are unable to undergo invasive tissue sampling procedures, or rapid biomarker testing results are required.^18,55,60,62 However, according to the clinical experts, access to funded liquid biopsy testing in Canada is very limited and presents an ongoing challenge. Due to high false-negative rates, negative ctDNA results must be confirmed with tissue testing, but positive ctDNA results can be used to identify actionable biomarker targets.^18,55,60,62

We considered the potential impacts of testing for EGFR mutations to ascertain eligibility for treatment with osimertinib in patients with locally advanced, unresectable (stage III) NSCLC, including those to health systems, patients (including families and caregivers), and costs. No new impacts are anticipated because EGFR testing is currently performed as the standard of care for patients with locally advanced, unresectable NSCLC across jurisdictions in Canada. Key considerations and relevant information available from materials submitted by the sponsor, input from the clinical experts consulted for this review, and sources from the literature were validated by the review team when possible and are summarized in Table 4.

Table 4: Considerations for Testing for EGFR Exon 19 Deletions or Exon 21 (L858R) Substitution Mutations to Establish Treatment Eligibility With Osimertinib

NGS = next-generation sequencing; NSCLC = non–small cell lung cancer; PCR = polymerase chain reaction.

^aCanada’s Drug Agency has not evaluated or critically appraised this evidence to determine its validity or reliability.

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

CDA-AMC received 1 joint patient input submission from the LHF, LCC, and the CCSN. The LHF is a registered charity that assists and empowers people living with or caring for others with lung disease. LCC is a registered national charitable organization that supports patients through providing education, research, and advocacy. CCSN is a national network that promotes the standard of care and provides support for patients with cancer, and issues related to survivorship or quality of end-of-life care.

The information was gathered through an online survey conducted from July 2024 to December 2024 with 23 respondents identifying as living with lung cancer in Canada, including 20 patients and 3 caregivers, all of whom had experience with osimertinib. Additionally, LFH conducted interviews with 6 patients (5 females and 1 male) who completed the online survey in January 2025. Interviewees ranged in age from 49 years to 72 years. Four interviewees were diagnosed with stage IV NSCLC with an EGFR exon 19 mutation. One interviewee was diagnosed with stage IV lung cancer (not specific as to which type) with the same mutation, and another was diagnosed with stage IIIC adenocarcinoma.

Based on the patient group input, fatigue was the most detrimental physical symptom of lung cancer reported by 81% of survey respondents followed by reduced appetite or weight loss (47.6%), cough (33.3%), pain (28.6%), and shortness of breath (23.8%). Additionally, 39.1% of survey respondents specifically cited fatigue and 26.1% cited shortness of breath as the primary reasons they were unable to perform daily activities. Fatigue as the most detrimental physical symptom was also echoed by interviewees, with 3 out of 6 interviewees noting fatigue and weakness as the reason they had to stop working.

As noted in the input, lung cancer impacted multiple aspects of patients’ daily life. The most impacted daily activity was the ability to work (57.1% of survey respondents and 67% of interviewees), followed by participation in sports (38.1% of respondents), travel (33.3% of respondents), leisure or hobbies (28.6% of respondents), and housework (23.8% of respondents). Survey respondents felt their experiences with lung cancer led to negative impacts on their emotional well-being (43.5%), feeling cold (43.5%), feeling isolated (34.8%), and impacted their family relationships (26.1%). The interviewees noted that the negative impacts of having lung cancer included emotional distress, mental health challenges, concerns regarding insurance coverage (e.g., travel and car insurance), changing medications and managing side effects, and job limitations due to infection risks (e.g., exposure to viruses).

The patient groups noted that concerns surrounding personal health, financial burdens, and concern for family members were some of the reasons for experiencing anxiety. These experiences highlight the profound and intertwined physical, emotional, and social toll of lung cancer on patients, their families, and their caregivers. Many respondents noted that both their symptoms and the time it took to manage their treatments negatively impacted their ability to continue working.

Survey respondents tried a range of treatments, included targeted therapy (47.6%), chemotherapies (33.3%; such as pemetrexed and carboplatin, double platinum-based chemotherapy, and others), surgery (4.8%; such as lobectomy), radiation (4.8%), immunotherapy (4.8%), and clinical trials (4.8%). Side effects were frequently associated with current treatment options, with 81.0% of survey respondents mentioning fatigue as a side effect associated with lung cancer treatments. Two interviewees who shared their experiences with lung cancer medications reported adverse effects including fatigue, anemia, bothersome mouth feel or altered taste, joint pain, edema in extremities, nausea, and constipation. Additionally, both interviewees noted that while additional medications could be taken to manage side effects, such medications were costly. The patient groups highlighted that while current lung cancer treatments extend patients’ lives, there are still concerns around HRQoL, with patients continuing to experience residual symptoms and debilitating side effects.

When considering new medication to treat lung cancer, survey respondents identified the most important outcomes as improved HRQoL (78.3%), reduced symptoms (60.9%), improved energy (43.5%), improved symptom management (39.1%), improved and/or prolonged efficacy (26.0%), reduced cost (21.7%), reduced travel time to obtain medication or treatment (8.7%), and zero cost (4.3%). The most important outcomes reported by 2 interviewees included treatment effectiveness (i.e., extending life), improved QoL, ability to effectively manage lung cancer without destroying healthy cells, ease of administration (daily oral pill is preferred over an IV infusion), manageable side effects, and affordability.

The patient groups stated that most respondents had positive experiences with osimertinib, with 90.8% preferring or strongly preferring it to other treatments or medications they had tried. Two interviewees reported a substantial change in QoL with osimertinib, stating that it gave them the ability to have a normal life and to return to work. The 3 most common side effects of osimertinib reported by survey respondents were negative changes in appearance (e.g., hair and nail issues) (73.9%), fatigue (69.6%), and diarrhea (69.6%); however, 95.7% of respondents felt their side effects were manageable. The top 10 benefits of osimertinib reported by survey respondents included reduced or eliminated pain (36.4%), stabilization of cancer or prolonged life (27.3%), ability to exercise (27.3%), increased energy (22.7%), reduced fatigue (18.2%), increased participation in daily activities (18.2%), reduced shortness of breath (18.2%), improved appetite or weight gain (18.2%), reduced cough (13.6%), and improved mood (13.6%).

Overall, the patient groups highlighted that there is an unmet need for lung cancer therapies that prolong PFS and improve HRQoL for patients. Patients also raised consideration about accessibility and needs for equity across all provinces in diagnoses and treatments. In addition, respondents expressed concerns about their continued ability to access medications due to costs, lack of availability, and the development of resistance to those medications that work for them.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC review teams include at least 1 clinical specialist with expertise regarding 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 lung cancer.

Unmet Needs

The clinical experts consulted for this review believed the overarching goal of treatment for unresectable NSCLC in patients whose tumours have EGFR mutations is to increase the proportion of patients who remain cancer-free in the long term, improve survival, reduce the risk of recurrence, and in doing so, enhance HRQoL. Clinical experts noted that conventional treatments (e.g., CRT) often lead to high rates of disease recurrence, and relapsing stage III NSCLC is generally considered incurable. Additionally, the experts flagged that patients with EGFR mutations are more likely to develop CNS metastasis compared to those with driver mutation–negative NSCLC, increasing the risk of symptoms at recurrence. Therefore, reducing relapse risk in patients with unresectable NSCLC and EGFR mutations was identified as a critical unmet need by the clinical experts consulted for this review.

Although consolidation treatment with durvalumab after CRT is currently reimbursed for patients in Canada with unresectable NSCLC, the clinical experts consulted for this review indicated that most oncologists in Canada would not administer durvalumab after CRT in patients who have an EGFR mutation as the current best evidence suggested a lack of efficacy and increased toxicity compared with placebo.

Place in Therapy

The experts felt maintenance treatment with osimertinib following the successful completion of platinum-based CRT would offer a new therapy for patients with unresectable NSCLC with EGFR mutations. Because osimertinib is currently reimbursed for relapsing cases, the clinical experts noted that using it in this setting would cause a shift in the current treatment paradigm. Currently, patients with locally advanced or metastatic disease are eligible for osimertinib as first-line treatment with palliative intent. If recurrence occurs on maintenance osimertinib or within 6 months of stopping therapy, these patients would no longer be eligible for palliative osimertinib.

Patient Population

The clinical experts noted that patients with unresectable stage III NSCLC whose tumours contain a common EGFR mutation (i.e., exon 19 deletion or exon 21 [L858R] point mutation) and who have not progressed following platinum-based CRT would be best suited for maintenance treatment with osimertinib. The clinical experts felt that any patient who received nonplatinum-based CRT should not be eligible for osimertinib treatment. The experts noted that EGFR mutations are identified with molecular testing, either using PCR or NGS, and this testing should be performed at diagnosis or during CRT treatment. Following platinum-based CRT, a CT scan must be performed to evaluate disease response or progression before initiating treatment with osimertinib. Patients who progress during or following platinum-based CRT would be eligible for osimertinib treatment as the initial therapy for recurrent disease (i.e., they would not be eligible for osimertinib under this reimbursement request).

Assessing the Response to Treatment

Outcome metrics used in clinical practice are generally aligned with those used in clinical trials. The clinical experts consulted for this review noted that the metrics most often used in clinical practice include response to treatment assessed by progression, OS, QoL (e.g., symptoms and the patients’ overall impression), and prevention of brain metastases. The experts noted that in current clinical practice, imaging is performed every 3 months to 6 months for the first 2 years following CRT and then annually thereafter. If osimertinib is reimbursed for patients with unresectable EGFR-mutated NSCLC who have not progressed during or following platinum-based CRT, the experts anticipated more frequent visits would be required when starting treatment (e.g., assessments approximately every 2 weeks for the first 3 months) and then every 3 months thereafter for the duration of treatment.

Discontinuing Treatment

Clinical experts consulted for this review indicated that osimertinib should be discontinued in the event of disease progression or significant toxicities that cannot be safely managed with dose reductions or modifications. The clinical experts consulted for this review felt that in the event of disease progression that is not amenable to any other local therapies, patients should be able to continue treatment with osimertinib if there is evidence of ongoing clinical benefit. The clinical experts noted that if a patient discontinued maintenance osimertinib treatment in the absence of recurrence, they should be eligible for first-line osimertinib treatment in the relapsed setting if at least 6 months have passed since discontinuation and recurrence.

Prescribing Considerations

Clinical experts indicated that treatment with osimertinib should be prescribed and managed by a physician familiar with managing systemic lung cancers (i.e., medical oncologist or pulmonologist). In some regions, care may be supervised by another physician (e.g., a general practitioner) under direction from a physician trained in managing systemic anticancer therapies.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

CDA-AMC received 2 clinician group input submissions, from LCC MAC and OH-CCO Lung Cancer Drug Advisory Committee. LCC is a national charity with the purpose of increasing awareness about lung cancer, providing support to patients with lung cancer, research, and advocacy. The LCC MAC consists of clinicians in the field of lung cancer across the country. The OH-CCO Cancer Drug Advisory Committees provide timely evidence-based clinical and health system guidance on drug-related issues in support of CCO’s mandate. In total 27 clinicians contributed to this submission, 23 from LCC MAC and 4 from the OH-CCO Lung Cancer Drug Advisory Committee.

Both clinician groups and the clinical experts consulted for this review agreed that the current standard treatment for patients with unresectable, locally advanced NSCLC with EGFR mutations is cCRT. Clinician groups agreed that while consolidation immunotherapy with durvalumab is currently Health Canada approved and provincially funded for unresectable NSCLC agnostic of PD-L1 expression or EGFR mutation, it is not used in practice or recommended as conventional treatment for patients with EGFR mutations. Post hoc subgroup analyses of the PACIFIC trial revealed that patients with EGFR mutations receiving durvalumab had similar efficacy and increased toxicity compared to those receiving placebo. As such, both clinician groups agreed that currently there are no targetable treatments approved for patients with unresectable stage III NSCLC with EGFR mutations. Clinician groups noted that the goal of treatment is to cure the disease, as measured by OS, PFS, and disease-free survival, and LCC MAC added delaying disease progression in extrathoracic sites as a critical secondary goal.

The OH-CCO Lung Cancer Drug Advisory Committee explained patients with stage III (per standard Canadian staging techniques) unresectable NSCLC with EGFR exon 19 deletion or exon 21 (L858R) substation mutation who do not have disease progression by standard restaging techniques within 6 weeks of completion of platinum-based CRT (either concurrently or sequentially), with no contraindication to EGFR TKIs, no history of interstitial lung disease before CRT, and no evidence of symptomatic pneumonitis following definitive CRT are best suited for treatment with osimertinib. The OH-CCO flagged that while one of the criteria is restaging within 6 weeks of completion of CRT, there should be some flexibility in this criterion as some centres have issues with CT scan wait times. While the OH-CCO Lung Cancer Drug Advisory Committee indicated that the reimbursement of molecular EGFR testing may not be universal across the country and additional funding may be needed for those provinces that do not currently have provincial reimbursement, LCC MAC indicated that they anticipated no increase in cost for testing for EGFR rearrangements to accommodate maintenance use of osimertinib.

LCC MAC stated that the outcomes to determine whether a patient is responding to treatment in clinical practice included PFS. LCC MAC suggested including the use of scans (CT of the body with or without brain imaging) and symptoms to monitor recurrence or progression with a frequency of every 3 months to 4 months while the OH-CCO Lung Cancer Drug Advisory Committee suggested restaging investigations every 3 months to 6 months.

Both clinician groups agreed that treatment should be discontinued if there is disease recurrence or progression, intolerance, or clinically important toxicity, and the OH-CCO Lung Cancer Drug Advisory Committee further added that treatment should be discontinued upon a patient’s request.

Clinician groups agreed that osimertinib can be delivered in the medical oncology outpatient setting. The OH-COO Lung Cancer Drug Advisory Committee further specified that osimertinib should be managed under the supervision of a specialist or medical oncologist with training in systemic therapy for thoracic malignancies.

Drug Program Input

The drug programs provide input on each drug being reviewed through the reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted for this review are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

cCRT = concurrent chemoradiation therapy; CRT = chemoradiation therapy; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; NSCLC = non–small cell lung cancer; PAG = Provincial Advisory Group; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; sCRT = sequential chemoradiation therapy; TKI = tyrosine kinase inhibitor.

Clinical Evidence

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of osimertinib 80 mg oral tablets taken once daily in the treatment of locally advanced, unresectable (stage III) NSCLC in patients whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations (either alone or in combination with other EGFR mutations) and whose disease has not progressed during or following platinum-based CRT. The focus will be placed on comparing osimertinib to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of osimertinib is presented in one section with our critical appraisal of the evidence included at the end of the section. The systematic review section includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. Our assessment of the certainty of the evidence in this section using the GRADE approach follows the critical appraisal of the evidence.

Included Studies

Clinical evidence from the following is included in the review and appraised in this document:

• 1 pivotal study identified in a systematic review.

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the review team.

Description of Studies

Characteristics of the included study are summarized in Table 6.

Table 6: Details of Studies Included in the Systematic Review

AE = adverse event; BICR = blinded independent central review; cCRT = concurrent chemoradiotherapy; CNS = central nervous system; CRT = chemoradiation therapy; CTCAE = Common Terminology Criteria for Adverse Events; CYP = cytochrome P450; DCR = disease control rate; DoR = duration of response; ECG = electrocardiogram; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-LC13 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module; HRU = health resource use; IASLC = International Association for the Study of Lung Cancer; ILD = interstitial lung disease; NSCLC = non–small cell lung cancer; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PFS2 = time to second progression; PGI-S = Patient Global Impressions Scale–Severity; PRO = patient-reported outcomes; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; sCRT = sequential chemoradiation therapy; TFST = time to first subsequent therapy; TKI = tyrosine kinase inhibitor; TSST = time to subsequent treatment; TTD = time to treatment discontinuation; TTDM = time to death or distant metastases.

^aPatients with a stage III tumour of squamous histology who had a pre-existing local positive test result (exon 19 deletion or L858R), irrespective of EGFR test used or lab accreditation, and confirmed by central testing during part I screening, were eligible for part II screening.

Source: LAURA Clinical Study Report.³⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

The LAURA trial is an ongoing, multinational, phase III, double-blinded, placebo-controlled, randomized study aimed at evaluating the efficacy and safety of osimertinib as maintenance therapy in patients with locally advanced, unresectable stage III NSCLC with centrally confirmed EGFR mutations (exon 19 deletions or exon 21 [L858R] substitutions) whose disease has not progressed during or following definitive platinum-based CRT. Patients were recruited from 74 international sites with none coming from Canada. Patients without a pre-existing approved local EGFR test result were required to undergo part I screening in which they provided a recent tumour tissue sample for central prospective EGFR mutation testing. All patients underwent part II screening to confirm eligibility, stage the disease, and confirm progression during or following platinum-based CRT. All patients who met the criteria for inclusion were randomized within 6 weeks of completion of CRT. Patients were randomized in a 2:1 ratio using an interactive voice or web response system to receive either osimertinib or placebo; no rationale for randomizing patients 2:1 was provided. Randomization was stratified by prior chemoradiation strategy (cCRT versus sCRT), tumour stage before chemoradiation (stage IIIA versus stage IIIB or stage IIIC) and China cohort (enrolled at a Chinese site and patient declaring themselves of Chinese ethnicity versus enrolled at non-Chinese site or patient declaring themselves of non-Chinese ethnicity) to allow separate randomization for China.

The primary objectives were to assess the PFS benefit of osimertinib compared to placebo. Key secondary objectives were to assess the OS and CNS PFS benefit of osimertinib treatment compared to placebo. All results presented here are from the January 5, 2024, DCO date, except for the OS outcome, for which data are based on the January 5, 2024, DCO date and an unplanned, updated analysis using the November 29, 2024, DCO date; the latter DCO date was requested as part of the regulatory marketing application.

Figure 1: Schematic of LAURA Trial Study Design

BICR = blinded independent central review; CRT = chemoradiation therapy; CCRT = concurrent chemoradiation therapy; ctDNA = circulating tumour DNA; EGFRm = epidermal growth factor receptor mutation; NSCLC = non–small cell lung cancer; PD = progressive disease; PS = performance status; QD = every day; RECIST = Response Evaluation Criteria in Solid Tumours; SCRT = sequential chemoradiation therapy; vs = versus.

Source: LAURA Clinical Study Report.³⁹

Populations

Inclusion and Exclusion Criteria

Detailed inclusion and exclusion criteria are provided in Table 6. Briefly, the trial enrolled patients aged 18 years or older (aged ≥ 20 years in Japan) with histologically documented NSCLC of predominantly nonsquamous pathology who present with locally advanced, unresectable (stage III) disease (according to Version 8 of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology). Only patients with local or central laboratory confirmation that the tumour harboured 1 of the 2 common EGFR mutations known to be associated with EGFR TKI sensitivity (exon 19 deletion and/or exon 21 [L858R] substitutions), either alone or in combination with other EGFR mutations, and without disease progression during or following platinum-based cCRT or sCRT were eligible for randomization. Patients with mixed small cell and NSCLC histology, history of interstitial lung disease before CRT, symptomatic pneumonitis following chemoradiation, unresolved toxicity with a grade greater than 2, cardiac irregularities, inadequate bone marrow reserve or organ function, history of other malignancies, severe or uncontrolled systemic diseases, or any resection that would preclude adequate absorption of osimertinib were excluded from the study. In addition, patients with prior treatment for NSCLC outside of that received in the definitive setting for stage III disease, prior treatment with EGFR TKI therapy, major surgery within 4 weeks of the first dose of the study drug, and patients currently receiving and unable to stop medications or herbal supplements known to be strong inducers of cytochrome P450 3A4 were ineligible for randomization.

Interventions

In the LAURA trial, patients were randomized to 1 of 2 treatment groups to receive:

• osimertinib 80 mg oral tablets, once daily, or

• placebo oral tablets, once daily.

Placebo tablets were identical and presented in the same packaging as osimertinib to ensure blinding of the medication. Osimertinib or placebo was administered orally, once daily, commencing on day 1. Doses were to be taken approximately 24 hours apart at the same time each day without interruption. If a patient missed taking a scheduled dose, within a window of 12 hours, it was acceptable to take the dose. If it was more than 12 hours after the scheduled dose time, the missed dose was not to be taken, and patients were instructed to take the next dose at the next scheduled time. The initial dose of osimertinib and placebo was 80 mg every day. In the event of grade 3 or higher toxicity and/or unacceptable toxicity (any grade) not attributable to the disease or disease-related processes under investigation and deemed by the investigator to possibly be related to the study drug, the study drug could be interrupted and supportive therapy administered according to local practice or guidelines. If a toxicity resolved or reverted to less than grade 2 within 3 weeks of interruption, treatment with the study drug could be restarted at the same dose (i.e., 80 mg) or a lower dose (osimertinib 40 mg or matching placebo) with discussion and agreement with the AstraZeneca Study Team Physician, as needed. Once the dose of osimertinib or placebo was reduced to 40 mg every day, the patient was to remain on the reduced dose until termination from study treatment. If the toxicity did not resolve to grade 2 or less after 3 weeks, then the patient was withdrawn from the study drug and observed until resolution of the toxicity. In the event of any of the following, the patient was discontinued from the study treatment:

• patient decision

• patient experiencing any of the following AEs:

  • grade 3 or higher pneumonitis

  • grade 2 pneumonitis where symptoms did not resolve within 4 weeks after interrupting study treatment

  • recurrent symptomatic pneumonitis following prior dose interruption and study treatment rechallenge

  • QTc interval prolongation with signs or symptoms of serious arrhythmia

  • grade 3 or higher adverse reaction that did not improve to grade 0, 1, or 2, and treatment was not restarted within 3 weeks of interrupting study treatment

  • any AE that, in the opinion of the investigator or AstraZeneca, contraindicates further dosing

• severe noncompliance with the Clinical Study Protocol as judged by the investigator and/or AstraZeneca representative

• pregnancy

• initiation of alternative anticancer therapy including another investigational agent

• before primary PFS analysis: objective disease progression as per RECIST Version 1.1 assessed by BICR

• postprimary PFS analysis: disease progression as assessed by investigator

• patients who were incorrectly initiated on study treatment.

Patients who discontinued from the study treatment were to continue attending subsequent study visits and data collection continued according to protocol. If the patient did not agree to continue in-person study visits, a modified follow-up was arranged to ensure the collection of end points and safety information including new AEs and follow-up on any ongoing AEs and concomitant medications. Patients who agreed to modified follow-up were not considered to have withdrawn consent or to have withdrawn from the study. Before the primary PFS analysis, patients who discontinued the study drug for reasons other than RECIST Version 1.1–defined progression as assessed by BICR, continued assessments in accordance with the protocol. After the primary PFS analysis, patients who were in progression at follow-up continued to provide survival follow-up (every 12 weeks until death, withdrawal of consent, or the end of the study defined as at the time of final OS analysis), but had progression assessed in accordance with local clinical practice. Formal RECIST Version 1.1 measurements, electronic patient-reported outcomes, health resource use, WHO performance status, ctDNA, and blood borne biomarkers were no longer collected.

Following BICR-confirmed progression per RECIST Version 1.1, patients could receive open-label osimertinib if:

• progression was confirmed by BICR, or, if progression occurred after the primary PFS analysis, investigator-assessed progression had been diagnosed

• in the opinion of the treating physician, they were continuing to derive clinical benefit (for patients assigned to the osimertinib treatment group), or treatment was in accordance with local clinical practice at the judgment of their treating physician (for patients assigned to the placebo group)

• they had not received any other anticancer therapy following the discontinuation of study treatment; palliative radiotherapy was allowed

• disease extent had been characterized by CT or MRI scan at the time of progression.

All patients receiving open-label osimertinib postprogression entered survival follow-up data. Treatment with open-label osimertinib continued until the patient stopped deriving clinical benefit (as judged by the investigator).

Medication which is considered necessary for the patient’s safety and well-being could be given at the discretion of the investigator and recorded in the source document and appropriate sections of electronic case report form (eCRF). Once enrolled, all patients had to try to avoid concomitant use of medications, herbal supplements, and/or ingestion of foods that are strong inducers of cytochrome P450 3A4. Other anticancer therapies, investigational agents, and radiotherapy were not to be given while the patient initiated the study drug. Premedications were allowed after, but not before, the first dose of study drug. These included medications for the management of diarrhea, nausea, and vomiting, which were to be administered as directed by the investigator. Drugs that prolong the QT interval and have a known risk of torsades de pointes, even when taken as recommended, must have been discontinued before the start of administration of study treatment and were not to be coadministered with osimertinib or placebo for 2 weeks after discontinuing the study treatment.

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 7, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as any outcomes identified as important to this review according to the clinical experts consulted for this review and input from patient and clinician groups and public drug plans. Using the same considerations, we selected end points that were considered most relevant to inform expert committee deliberations and finalized this list of end points in consultation with members of the expert committee.

The following efficacy and HRQoL outcomes were included in the GRADE assessment: OS, PFS, CNS PFS, and the EORTC QLQ-C30. Select harms outcomes considered important for expert committee deliberations were also assessed using GRADE: pneumonitis, grade 3 or greater diarrhea, withdrawal due to AEs, and fatal AEs. These outcomes were deemed the most important for determining the comparative efficacy and safety of osimertinib compared to the current standard of care (i.e., watchful waiting).

Other outcomes were summarized in the review report to aid clinical decision-making but not appraised using GRADE, including: TTDM, TTD, response, and EORTC QLQ-LC13. While TTDM and TTD are informative for understanding the length of time to distant metastases, death, and treatment discontinuation, the CDA-AMC review team in consultation with the clinical experts consulted for this review, felt survival outcomes (i.e., OS, PFS, and CNS PFS) were more informative for clinical decision-making and captured outcomes most important to patients. The EORTC QLQ-C30 was appraised using GRADE as it is a generic measure that provides a comprehensive picture of patients’ HRQoL. The EORTC QLQ-LC13 focuses on lung cancer–specific symptoms and results were reported in this report.

Objective response rate (ORR) and duration of response (DoR) results from the LAURA trial are included in the appendix of this report as supportive evidence. The clinical experts cautioned that response outcomes may be confounded by prior chemoradiation and felt that for treatment selection PFS provides more relevant informative.

Time to second progression was deemed less clinically meaningful for decision-making and was not included in this report. Time to second progression was not identified as most important to guide treatment selection by the clinical experts consulted for this review and the relationship between this outcome and those deemed important by clinical experts is poor. Further, time to second progression may bias the intervention group due to the higher likelihood of remaining on study treatment.

While the Patient Global Impressions Scale–Severity and the EQ-5D-5L were assessed as exploratory objectives in the LAURA trial, the clinical experts consulted for this review felt the EORTC QLQ-C30 and EORTC QLQ-LC13 were the most informative HRQoL outcomes for decision-making and thus data on the Patient Global Impressions Scale–Severity and EQ-5D-5L are not reported in this Clinical Study Report. This is because the EORTC QLQ-C30 and EORTC QLQ-LC13 capture a comprehensive range of disease-specific symptoms, functioning impairments, and treatment-related effects that are particularly important for patients with locally advanced unresectable stage III NSCLC. In comparison, the Patient Global Impressions Scale–Severity and the EQ-5D-5L do not offer the same detailed, condition-specific insights into the HRQoL impacts of treatment and disease progression.

Table 7: Outcomes Summarized From the Studies Included in the Systematic Review

AE = adverse event; CDA-AMC = Canada's Drug Agency; CNS = central nervous system; DCO = data cut-off; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-LC13 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module; GRADE = Grading of Recommendations, Assessment, Development and Evaluations; IA = interim analysis; OS = overall survival; PFS = progression-free survival; QoL = quality of life; TTD = time to treatment discontinuation or death; TTDM = time to death or distant metastases.

Source: LAURA Clinical Study Report.³⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Tumour assessments included CT scan (preferred) or MRI with IV contrast of the chest and abdomen (including the entire liver and both adrenal glands). Tumour assessments were performed at screening (within 28 days before randomization), then after 8 weeks (± 1 week) relative to randomization for the first 48 weeks, and then every 12 weeks (± 1 week) until objective radiological disease progression per RECIST Version 1.1 as confirmed by BICR. Assessments occurred irrespective of whether the patient was receiving study treatment or had previously discontinued treatment for another discontinuation criterion and may have started alternative anticancer treatment. Additional scans were performed if clinically indicated (i.e., if disease progression was suspected).

EORTC QLQ-C30 was assessed at randomization, at week 4 and 8 (relative to randomization), thereafter every 8 weeks (± 3 days) until treatment discontinuation, and then at week 8 (± 3 days), week 16 (± 3 days), and week 32 (± 3 days) relative to the treatment discontinuation visit. EORTC QLQ-LC13 was assessed at randomization, weekly up to week 8 (relative to randomization), and thereafter every 4 weeks (± 3 days) until treatment discontinuation. For patients who discontinued study treatment before BICR-confirmed progression, patient-reported outcomes were collected at the study treatment discontinuation visit and continued to be collected at the same frequency as the treatment period during progression follow-up until BICR-confirmed disease progression, then at the disease progression visit and at week 8 (± 3 days), week 16 (± 3 days), and week 32 (± 3 days; relative to the disease progression visit).

AEs were assessed during the screening period, at randomization, and then at every visit including postprogression visits.

Overall Survival

OS was one of the key secondary outcomes of the LAURA trial and was defined as the time from randomization to death due to any cause.

Clinical experts consulted for this review advised an OS between-group difference of 5% to 10% is considered clinically meaningful.

Progression-Free Survival

PFS was the primary outcome of the LAURA trial based on BICR assessment according to RECIST Version 1.1 and was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdrew from study treatment or received another anticancer therapy before progression.

Clinical experts consulted for this review advised a PFS between-group difference of 10% to15% is considered clinically meaningful.

CNS Progression-Free Survival

CNS PFS based on BICR assessment according to RECIST Version 1.1 was the second key secondary outcome in the LAURA trial and was defined as the time from randomization until the date of CNS objective disease progression or death (by any cause in the absence of CNS progression), regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy before CNS progression.

Clinical experts consulted for this review advised a CNS PFS between-group difference of 10% is considered clinically meaningful.

Time to Death or Distant Metastases

TTDM was one of the secondary outcomes of the LAURA trial and was defined as the time from randomization until the first date of distant metastasis or date of death in the absence of distant metastasis. Distant metastasis was defined as any new lesion that was detected on a scan that was anywhere other than the lung or regional lymph node according to RECIST Version 1.1 or proven by biopsy.

Clinical experts consulted for this review advised a TTDM between-group difference of 3 months to 6 months is considered clinically meaningful.

Time to Treatment Discontinuation or Death

TTD was one of the secondary outcomes of the LAURA trial and was defined as the time from randomization to the earlier of the date of study treatment discontinuation (regardless of the reason for study treatment discontinuation) or death.

Clinical experts consulted for this review advised a TTD between-group difference of 3 months to 6 months is considered clinically meaningful.

HRQoL End Points

To compare disease-related symptoms and HRQoL, the EORTC QLQ-C30 and EORTC QLQ-LC13 were collected as other secondary outcomes in the LAURA trial.^67,68 Descriptions of each measure are as follows (further details in Table 8).

• The EORTC QLQ-C30 is a multidimensional, cancer-specific, self-administered, measure of HRQoL consisting of 30 questions across 5 multi-item functional scales (physical, role, emotional, cognitive, and social); 3 multi-item symptom scales (fatigue, pain, and nausea and vomiting); 5 single items assessing additional symptoms commonly reported by patients with cancer (dyspnea, loss of appetite, insomnia, constipation, and diarrhea); a 2-item global measure of health status/QoL; and a single item on the financial impact of the disease. Each item is evaluated using 4-point and 7-point Likert scales, raw scores for each scale are computed as the average of the items that contribute to a particular scale, and each raw scale score is converted to a standardized score that ranges from 0 to 100 using a linear transformation. Higher scores in symptom scales reflect more symptoms or problems, while higher scores in functional scales reflect healthier functioning.⁶⁹ A higher score on the global scale reflects better HRQoL. The EORTC QLQ-C30 was scored according to the EORTC QLQ-C30 scoring manual.⁶⁹

• The EORTC QLQ-LC13 is a 13-item lung cancer–specific module used to assess lung cancer symptoms, treatment-related side effects, and pain medication. Except for a multi-item scale for dyspnea, all are single items. The dyspnea scale was only to be used if all 3 items were scored; otherwise, the items were treated as single-item measures.

The average change in scores from baseline across all visits were evaluated for the scales or items from EORTC QLQ-C30 and EORTC QLQ-LC13 and results are included in this Clinical Study Report.

A between-group MID in the EORTC QLQ-C30 global health status/QoL score has previously been estimated for patients with lung cancer as an increase or decrease of 4 points for improvement and deterioration, respectively.⁷⁰ No MIDs for the EORTC QLQ-LC13 in patients with NSCLC were identified.

Harm End Points

To assess the safety and tolerability profile of osimertinib compared with placebo, AEs were collected throughout the study, from the date of informed consent until 28 days after the last dose of study treatment. The Medical Dictionary for Regulatory Activities Version 26.1 was used to code the AEs. AEs were also graded for severity according to the Common Terminology Criteria for Adverse Events Version 5.0. AE data were evaluated according to the following categories and results are included in this Clinical Study Report: all AEs, SAEs, withdrawals due to AEs, AEs with an outcome of death, and AEs of special interest. An AE of special interest is one of scientific and medical interest specific to understanding of the investigational product and may be serious or nonserious. The AEs of special interest in the LAURA trial included those listed in the product monograph and highlighted as important by clinical experts consulted for this review: lung disease including pneumonitis and radiation pneumonitis, cardiac effects (e.g., QT interval corrected using the Fridericia formula interval prolongation, left ventricular dysfunction, and cardiomyopathy), and grade 3 or greater diarrhea.

Clinical experts consulted for this review advised that a 5% between-group difference in the occurrence of pneumonitis and fatal AEs and a 10% between-group difference in grade 3 or greater diarrhea and withdrawal due to AEs is considered clinically meaningful.

Table 8: Summary of Outcome Measures and Their Measurement Properties

BPI = Brief Pain Inventory; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-LC13 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module; FACT-G = Functional Assessment of Cancer Therapy–General; GHS = global health status; HADS = Hospital Anxiety and Depression Scale; HRQoL = health-related quality of life; MID = minimal important difference; NA = not applicable; NSCLC = non–small cell lung cancer; QoL = quality of life.

Statistical Analysis

The statistical analyses for all study end points included in this review are presented in Table 9.

Sample Size and Power Calculation

The LAURA trial planned to enrol approximately 1,333 patients to randomize approximately 200 eligible patients. Of those it was planned that approximately 30 to 40 patients would be recruited in China to satisfy the China Regulatory Authority requirements. The primary analysis was to occur when approximately 120 PFS BICR events (approximately 60% maturity) had been observed in the global cohort. With 120 PFS BICR events, the study had 90% power to show a statistically significant difference in PFS at the 2-sided 5% level if the assumed true treatment effect HR was 0.53; this would translate to an approximate 7-month improvement from a median 8-month PFS on placebo. The smallest treatment difference that would be statistically significant is a PFS HR of 0.68 (translating to an approximate 4-month improvement).

Statistical Testing

The primary end point (PFS), key secondary end points (OS and CNS PFS), TTDM, and TTD were analyzed using a stratified log-rank test stratified by prior chemoradiation strategy (cCRT versus sCRT), disease stage before chemoradiation strategy (stage IIIA versus stage IIIB or stage IIIC), and China cohort (enrolled at a Chinese site and patient declaring themselves of Chinese ethnicity versus enrolled at non-Chinese site or patient declaring themselves as non-Chinese ethnicity) for generating the P value. The effect of treatment was estimated using a HR and 2-sided 95% CI. OS and CNS PFS were only analyzed if there were a sufficient number of events defined as more than 20 OS events (with at least 5 events per group) and at least 20 CNS PFS events across both treatment groups.

The assumption of proportionality in the primary analysis was assessed by examining the plots of complementary log–log (event times) versus log (time) and, if necessary, a time-dependent covariate was to be fitted to assess the extent to which random variation occurred. If a lack of proportionality was evident, the variation in treatment effect was described by presenting a piecewise HR calculated over distinct time periods. If lack of proportionality was found, which may be a result of a treatment-by-covariate interaction, it was investigated. If the resulting strata were too small (i.e., < 10 events) the strata were to be collapsed in the following predefined order to allow analysis: the China cohort strata were collapsed first, followed by prior chemoradiation strategy, and finally stage before chemoradiation. In the event of nonproportionality, the HR was to be interpreted as an average HR over the observed extent of follow-up.

Additionally, KM plots of OS, PFS, and CNS PFS were presented by treatment group. Summaries of the number and percentage of patients experiencing an event and the type of event were provided along with median time to event and associated 95% CIs for each treatment group. PFS rates at 6-month intervals, OS rates at set time intervals (e.g., 12 months and 24 months), and CNS PFS at 12 months and 24 months along with 95% CIs were estimated for each treatment group using the KM method.

Multiple Testing Procedure

To control for type I error rate at the 5% two-sided level, a sequential MTP was used for the primary end point (PFS) and key secondary end points (OS and CNS PFS). If any previous analysis in the sequence was not statistically significant, the alpha could not be transferred to subsequent analyses. Hypotheses were tested using a MTP with an alpha recycling strategy.⁷⁴ With this approach, hypotheses were tested in the predefined order of PFS, OS, and CNS PFS.

The primary end point of BICR-assessed PFS and the key secondary efficacy end point of CNS PFS were planned to be analyzed only once, at the time of the primary analysis, when approximately 120 BICR-assessed PFS events had been observed in 200 patients (approximately 60% data maturity). Two analyses of the key secondary end point of OS were planned: 1 interim analysis at the time of the primary PFS analysis, and 1 final OS analysis when approximately 120 death events have been reported in 200 patients (approximately 60% data maturity). The alpha (2-sided 5%) level allocated to OS is controlled at the interim and final analyses by using the Lan-DeMets spending function that approximates an O’Brien-Fleming approach, where the alpha level applied at the interim and final analyses depends on the number of death events observed. This approach maintains an overall 2-sided 5% type I error across the 2 planned analyses of OS.

At the primary PFS analysis (January 5, 2024, DCO date), PFS was tested and declared statistically significant with a data maturity of 55.6% (120 PFS events in 216 patients). As per the MTP, OS was tested at this same DCO date and failed to meet the prespecified boundary for declaring statistical significance (P < 0.00036 was required to declare statistical significance at the interim analysis). As OS failed to reach statistical significance, CNS PFS statistical significance was not tested for drawing inferences.

All other clinical outcomes (e.g., TTDM and TTD), HRQoL outcomes, and harms data were not included in the MTP.

Data Imputation Methods

If a patient was known to have died where only a partial death date was available, then the date of death was imputed as the latest of the last date known to be alive plus 1 from the database and the death date using the available information provided as follows:

• for missing day only, the first of the month was used

• for missing day and month, January 1 was used.

If there is evidence of death but the date is entirely missing, it was treated as missing (i.e., censored at the last known alive date).

Missing safety data were generally not imputed; however, if the value was above or below the limit of quantification, the value was imputed to equal the limit. Missing start dates for concomitant medication, radiotherapy, and AE start dates were imputed as follows.

• If the year was missing, the first dose date was imputed unless the end date suggested it could have started before this in which case January 1 of the same year was imputed as the end date .

• If the year was present and the month and day were missing, then January 1 was imputed unless the year is the same as first dose date; in this situation, the first dose date was imputed .

• If the year and month were present and the day was missing, the first of the month was imputed unless the month is the same month of the first dose of the study drug; in this situation, the first dose date was imputed.

For missing end concomitant medication, radiotherapy, and AE dates, the following was to be applied.

• Missing day: the last day of the month was imputed unless the month is the same month of the last dose of the study drug; in this situation, the last dose date was imputed. For prior anticancer medications, the date of informed consent was imputed if the month is the same as the month informed consent was provided.

• Missing day and month: December 31 was imputed unless the year is the same as the last dose date; in this situation, the last dose date was imputed. For prior anticancer medications, the date of informed consent was imputed if the month is the same as the month informed consent was provided.

• Completely missing: consider when it started in relation to study drug. If the AE or medication was stopped and the start date is before the first dose date, then the first dose date was imputed. If it started on or after the first dose date, then a date that is after the last dose date (i.e., last dose + 1) was imputed, unless this is for a prior anticancer medication; in this situation, the date of informed consent was imputed.

For partial subsequent anticancer therapy dates, the following rules were applied for missing start dates:

• Missing day: if the month is the same as the treatment end date, then the day after treatment was imputed, otherwise the first day of the month was used.

• Missing day and month: if the year is the same as the treatment end date, then the day after treatment was imputed, otherwise January 1 of the same year as the anticancer therapy date was imputed.

Subgroup Analyses

Prespecified subgroup analyses were performed to assess the consistency of the treatment effect in the primary end point (PFS) across expected prognostic and/or predictive factors in the following subgroups:

• age (aged < 65 years versus ≥ 65 years)

• sex (female versus male)

• smoking status (current or former smoker versus never smoker)

• chemoradiotherapy (cCRT versus sCRT)

• disease stage before chemoradiotherapy (stage IIIA versus stage IIIB or stage IIIC)

• China cohort (Chinese patients enrolled at Chinese sites versus non-Chinese patients or patients enrolled at non-Chinese sites)

• central plasma ctDNA EGFR mutation (exon 19 deletions or exon 21 [L858R] substitutions) status at screening (positive versus negative versus unknown)

• tissue EGFR mutation at screening (exon 19 deletions versus exon 21 [L858R] substitutions)

• race (Asian versus non-Asian)

• response to prior chemoradiotherapy (complete response versus partial response [PR] versus stable disease versus nonevaluable response).

For each subgroup level of a factor, the HR and 95% CI was calculated from a Cox proportional hazards model that only contains a term for treatment, the factor, and treatment-by-factor interaction term. The Cox models were fitted using PROC PHREG with the Efron method to control for ties. If there were too few events available for a meaningful analysis of a particular subgroup comparison (i.e., < 20 events across both treatment groups), the relationship between that subgroup and the primary end point (PFS) was not formally analyzed. In this case, only descriptive summaries were provided. The clinical experts consulted for this review felt examining PFS by type of EGFR mutation at screening (exon 19 deletions or exon 21 [L858R] substitution mutations) would be relevant to investigate any differences in treatment effect. Differences in treatment effect across other subgroups were not expected based on clinical rationale.

Sensitivity Analyses

Sensitivity analyses on the primary efficacy analyses (PFS by BICR) were repeated to assess the following.

• Ascertainment bias: This was determined with PFS based on the site investigator assessments according to RECIST Version 1.1. The stratified log-rank test was repeated, and a KM plot was presented with 95% CIs for PFS rated at 6-month intervals.

• Stratification according to the eCRF: Stratified log-rank test was repeated where the stratification factors were recorded according to the eCRF.

• Evaluation time bias: The stratified log-rank test was repeated using the midpoint between the time of progression and the previous nonmissing RECIST assessments. For patients who die in the absence of progression, the date of death was used to derive the PFS time used in the analysis. For those patients who did not experience disease progression during the study, the PFS time was right-censored at the date of the last nonmissing RECIST assessment. If the patient had no evaluable visits or did not have baseline data, they were to be censored at day 1. Note that midpoint values resulting in noninteger values were rounded down. To support this analysis, the means of patient-level average interassessment times were tabulated for each treatment. This approach used the BICR RECIST assessments.

• Attrition bias: A stratified log-rank test and a reversed KM plot at the time of censoring, where the censoring indicator of the primary PFS analysis was reversed, were drafted where the actual PFS event times, rather than the censored times, of patients who progressed or died in the absence of progression immediately following 2 or more nonmissing tumour assessments, were included. In addition, and within the same sensitivity analysis, patients who took subsequent therapy before progression or death were censored at their last nonmissing assessment before taking the subsequent therapy.

• The effect of COVID-19 deaths: If there were a sufficient number of patients with a confirmed or suspected COVID-19 death event (either ≥ 5 patients and/or ≥ 2% of the patient population), a sensitivity analysis was conducted to assess the potential impact of COVID-19 deaths on PFS. This was assessed by repeating the primary PFS analysis, but with patients whose disease did not progress before death and whose primary or secondary cause of death was due to COVID-19 infection, who had a COVID-19 infection reported as a fatal AE, or were censored at their last nonmissing assessment before their COVID-19 infection death date.

• The primary analysis of PFS by BICR in the FAS was repeated using the evaluable for response analysis set as a sensitivity analyses. The evaluable for response analysis set includes all patients in the FAS who had measurable disease at baseline according to the BICR of baseline imaging data.

In the case that there was a sufficient number of patients with a confirmed or suspected COVID-19 death event (either at ≥ 5 patients and/or ≥ 2% of the patient population), a sensitivity analysis was planned to be conducted to assess the potential impact of COVID-19 deaths on OS. This was assessed by repeating the primary OS analysis, but for patients whose primary or secondary cause of death was due to COVID-19 infection, or who had a COVID-19 infection reported as a fatal AE, or who were censored at their last nonmissing assessment before their COVID-19 infection death date.

A sensitivity analysis of the primary CNS PFS analysis was conducted using the investigator-assessed CNS PFS using RECIST Version 1.1 assessments.

Table 9: Statistical Analysis of Efficacy End Points in the LAURA Trial

BICR = blinded independent central review; CI = confidence interval; CNS = central nervous system; CRT = chemoradiotherapy; eCRF = electronic case report form; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-LC13 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module; HR = hazard ratio; KM = Kaplan-Meier; MMRM = mixed effect model for repeated measures; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PRO = patient-reported outcome; RECIST = Response Evaluation Criteria in Solid Tumours; TTD = time to treatment discontinuation or death; TTDM = time to death or distant metastases; vs. = versus.

Source: LAURA Clinical Study Protocol,⁷⁵ LAURA Statistical Analysis Plan,⁷⁶ and LAURA Clinical Study Report.³⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Analysis Populations

The analysis population are defined in Table 10.

Table 10: Analysis Populations of the LAURA Trial

BICR = blinded independent central review; ECG = electrocardiogram; FAS = full analysis set; ITT = intention to treat; LVEF = left ventricular ejection fraction; ORR = objective response rate; PFS = progression-free survival.

Source: LAURA Clinical Study Report.³⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Results

Patient Disposition

Patient disposition is summarized in Table 11. Of the 746 patients screened in the LAURA trial, 216 were ultimately randomized to either the osimertinib group (n = 143 patients) or the placebo group (n = 73 patients) and included in the FAS. All patients randomized received at least 1 dose of study treatment and were included in the safety analysis set. At the January 5, 2024, DCO date, 87 patients were ongoing on their randomized treatment (55.9% of patients in the osimertinib group and 9.6% of patients in the placebo group). In both groups, the primary reason for treatment discontinuation was due to progression (25.2% in the osimertinib group and 74.0% in the placebo group), followed by AEs (13.3% in the osimertinib group and 6.8% in the placebo group), and patient decision (2.8% in the osimertinib group and 4.1% in the placebo group). Following a treatment discontinuation event, a higher percentage of patients in the placebo group received open-label osimertinib (69.9%) compared to the osimertinib group (10.5%).

Table 11: Summary of Patient Disposition From Studies Included in the Systematic Review

AE = adverse event; BICR = blinded independent central review; DCO = data cut-off; eCRF = electronic case report form; FAS = full analysis set; PD = progressive disease; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumours.

Note: DCO date was January 5, 2024.

^aBefore primary PFS analysis, assessed by BICR.

^bIt is noted that the number of patients who discontinued study treatment due to AEs in this disposition summary differs from the number of patients with AEs leading to discontinuation of study treatment in the safety summaries. This discrepancy is due to AEs in 2 patients (1 patient in each treatment group) occurring outside of the safety data collection window.

^cAny reason not specifically captured in earlier categories. Per the eCRF, other reasons for treatment discontinuation were captured as: “Other–Death” (2 patients) and “Other–PD by Investigator” (1 patient) in the osimertinib group; and “Other–Death” (1 patient) and “Other–PD by Investigator” (1 patient) in the placebo group (data on file).

^dOne patient (1.4%) in the placebo group discontinued study treatment due to the reason of “incorrect study treatment initiation.” This patient was identified after the start of study treatment as having pre-existing brain metastases and was discontinued at the decision of the investigator.

Source: LAURA Clinical Study Report.³⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Baseline Characteristics

The baseline characteristics outlined in Table 12 are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results. The mean age in the osimertinib group (n = 143) was 60.9 years (SD = 10.38) compared to 62.4 years (SD = 12.01) in the placebo group (n = 73) and patients were primarily Asian (81.1% and 84.9%, respectively), had AJCC/Union for International Cancer Control disease stage IIIB (46.9% and 52.1%, respectively) or stage IIIC (16.8% and 15.1%, respectively), and had adenocarcinoma histology (97.2% and 94.5%, respectively). Notable differences were observed across the 2 treatment groups including proportionally more females than males in the osimertinib group (62.9% females and 37.1% males) than in the placebo group (57.5% females and 42.5% males), fewer former smokers in the osimertinib group (25.9%) than in the placebo group (31.5%), more patients in the osimertinib group (55.9%) with a WHO performance status of 0 at baseline than in the placebo group (42.5%), and more patients in the osimertinib group receiving cCRT (91.6%) than in the placebo group (84.9%). At screening, fewer patients in the osimertinib group were positive for exon 19 deletions (51.7%) and more were positive for exon 21 (L858R) substitutions (47.6%) compared to the placebo group (58.9% and 41.1%, respectively). Additionally, patients in the osimertinib group had a shorter mean time from unresectable stage III diagnosis to randomization than patients in the placebo group (117.6 days [SD = 37.71] versus 129.2 days [SD = 47.67], respectively) and more patients in the osimertinib group achieved a PR than in the placebo group (46.9% versus 37.0%, respectively).

Table 12: Summary of Baseline Characteristics From Studies Included in the Systematic Review

AJCC = American Joint Committee on Cancer; BICR = blinded independent central review; cCRT = concurrent chemoradiotherapy; CRT = chemoradiotherapy; ctDNA = circulating tumour DNA; eCRF = electronic case report form; EGFRm = EGFR mutation; sCRT = sequential chemoradiation therapy; SD = standard deviation; UICC = Union for International Cancer Control.

Note: Data cut-off date was January 5, 2024.

^aData reported in this table are based on values entered into the eCRF.

^bDisease stage summarized based on values entered into the eCRF and categorized before CRT according to the TMN Classification of Malignant Tumours, 8th Edition.

^cPer the eCRF, these patients had adenosquamous histology and were eligible for inclusion (data on file).

^dPatient has any metastatic site of disease.

^ePatient has only locally advanced sites of disease.

^fThese patients had a complete response to prior CRT and therefore their disease was not detectable at randomization for classification (data on file).

^gSummarized based on central cobas EGFR plasma testing results.

^hStatus was unknown due to the unavailability or inadequacy of plasma samples for central testing.

ⁱPatients randomized without an approved local positive EGFR test result or central EGFR test result.

Source: LAURA Clinical Study Report.³⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Exposure to Treatments

Study Treatments

At the January 5, 2024, DCO date, the mean total study treatment duration was longer in the osimertinib group (23.71 months [SD = 14.46]) than in the placebo group (11.77 months [SD = 10.88]) (refer to Table 13). Similar results were observed when excluding time related to dose interruptions indicating that the frequency of dose interruptions for any reason and their duration did not have a meaningful impact on the exposure to study treatments. More patients in the osimertinib group experienced a dose interruption (55.2%) or reduction (8.4%) than in the placebo group (28.8% and 1.4%, respectively).

Table 13: Summary of Patient Exposure to Study Treatment From Studies Included in the Systematic Review

eCRF = electronic case report form; SD = standard deviation.

Note: Data cut-off date was January 5, 2024.

^aExposure is calculated for on-study treatment only. Open-label osimertinib exposure is not included in this summary table. Total treatment-years = sum of treatment duration (months) for all patients per treatment.

^bTotal treatment duration = (last dose date – first dose date + 1)/(365.25/12).

^cActual treatment duration = total treatment duration, excluding dose interruptions.

^dReasons for interruption are not mutually exclusive for patients with multiple interruptions although they were counted only once per category. Missed or forgotten doses have not been summarized as dose interruptions.

^eNo specific pattern in the reasons for treatment interruption captured in the “Other” category was noted from a review of information captured in the eCRF.

Source: LAURA Clinical Study Report.³⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Concomitant Medications and Cointerventions

In both groups of the LAURA trial, the majority of patients received at least 1 concomitant medication (██████ of patients in the osimertinib group and █████ in the placebo group; Table 14). The most frequently used concomitant medication in the osimertinib group was ███████████████ (█████), followed by ██████ ████ ██████████ (█████) and ██████████ (█████). In the placebo group, the most commonly used concomitant medications were ██████ ████ ██████████ (█████), followed by ███████████████ (█████) and ██████████ (█████).

Table 14: Summary of Allowed Concomitant Medication in at Least 20% of Patients in Either Study Group of Studies Included in the Systematic Review

ATC = anatomic therapeutic chemical; FAS = full analysis set; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A.

Note: Data cut-off date was January 5, 2024.

^aA patient can have ≥ 1 generic terms reported under a given ATC code. Concomitant medications are those with a stop date on or after the first dose date of study treatment (and could have started before or during study treatment).

Source: LAURA Clinical Study Report.³⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Subsequent Treatments

By the January 5, 2024, DCO date, 63 of 143 patients (44.1%) in the osimertinib group had discontinued the study treatment and 42 patients (29.4%) went on to receive a subsequent anticancer treatment compared to 66 of 73 patients (90.4%) in the placebo group discontinuing the study treatment with 57 patients (78.1%) receiving a subsequent anticancer treatment (Table 15). In both treatment groups, patients tended to receive 1 or 2 subsequent lines of treatment (1 subsequent line: 19.6% of patients in the osimertinib group and 58.9% in the placebo group; 2 subsequent lines: 6.3% of patients in the osimertinib group and 15.1% in the placebo group), with relatively few patients receiving 3 or more lines of therapy. The most frequently reported category of subsequent anticancer treatment in both groups were EGFR TKIs (used by 19.6% of patients in the osimertinib group and 78.1% in the placebo group). Notably, 10.5% of patients in the osimertinib group and 69.9% of patients in the placebo group received osimertinib as subsequent anticancer treatment. The mean length of open-label osimertinib treatment was ████ ███ █ █████ months in the placebo group and ████ ███ █ █████ months in the osimertinib group.

Following a treatment discontinuation event, patients in the osimertinib group had a longer median time to first subsequent treatment (median = 43.83 months; 95% CI, 38.87 months to NC) compared to those in the placebo group (median = 9.46 months; 95% CI, 6.60 months to 11.53 months), favouring the osimertinib group (Table 15).

Similarly, at the unplanned November 29, 2024, OS analysis, more patients in the placebo group discontinued treatment (69 of 73 [94.5%]) and received a subsequent anticancer treatment (█████) than in the osimertinib group (74 of 143 [51.7%] and ██████ respectively; Table 15). Most patients in the placebo group received osimertinib as a subsequent anticancer treatment (█████) compared to █████ of patients in the osimertinib group. A higher percentage of patients in the osimertinib group received subsequent radiotherapy (19.6%) than in the placebo group (9.6%).

Table 15: Summary of Subsequent Treatments From Studies Included in the Systematic Review

DCO = data cut-off; FAS = full analysis set; NC = not calculable; NR = not reported; SD = standard deviation; TKI = tyrosine kinase inhibitor.

^aThe number of patients is shown with percentages calculated as the proportion of patients in the FAS.

^bA patient may be counted in multiple rows if they receive > 1 posttreatment anticancer therapy; includes anticancer therapies with a start date after the last dose date of study treatment.

^cWHO Drug Dictionary version September 2022 format B3. A subsequent medical review has taken place to assign treatment classifications.

^dNot available in Canada.

^eIncludes pyrimidine analogues, vinca alkaloids and analogues, podophyllotoxin derivatives, and topoisomerase 1 inhibitors.

^fCalculated using Kaplan-Meier techniques.

Source: LAURA Clinical Study Report³⁹ and LAURA Overall Survival Analysis Update.⁴⁰ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Efficacy

Efficacy outcomes presented in the following are from the most recent DCO dates (January 5, 2024, for all outcomes with the addition of the November 29, 2024, DCO date for OS).

Overall Survival

At the January 5, 2024, DCO date, OS was tested but did not meet the prespecified boundary for declaring statistical significance (P = 0. 530; P < 0.00036 was required to declare statistical significance at this interim analysis) (refer to Table 16 and Figure 5).

OS results at the January 5, 2024, DCO date and the November 29, 2024, DCO date are summarized in Table 16.

At the November 29, 2024, DCO date, the median OS follow-up time for patients was 39.36 months (range, ████ ██ █████) in the osimertinib group and 35.15 months (range, ████ ██ █████) in the placebo group. The OS stratified HR was 0.67 (95% CI, 0.40 to 1.14) favouring the osimertinib group. The between-group difference in survival probabilities for osimertinib versus placebo was ████ at 36 months and █████ at 48 months. The KM plot for OS in the FAS is presented in Figure 2.

Figure 2: Kaplan-Meier Plot of OS — FAS

CI = confidence interval; FAS = full analysis set; HR = hazard ratio; NC = not calculable; OS = overall survival.

Notes: Circles indicate censored observations.

Data cut-off date was November 29, 2024.

Source: LAURA Overall Survival Analysis Update.⁴⁰

Progression-Free Survival

PFS (based on BICR assessment according to RECIST Version 1.1) results at the January 5, 2024, DCO date are summarized in Table 16. The median PFS follow-up time for all patients was 21.98 months (range, 0.03 months to 60.55 months) in the osimertinib group and 5.55 months (range, 0.03 months to 49.71 months) in the placebo group. The PFS stratified HR was 0.16 (95% CI, 0.10 to 0.24), favouring the osimertinib group. The difference in PFS probabilities for osimertinib versus placebo was █████ at 12 months and █████ at 36 months. The KM plot for PFS in the FAS is presented in Figure 3.

With the exception of the sensitivity analysis to assess possible attrition bias which did not show a clear separation of the osimertinib and placebo curves (Figure 7), sensitivity analyses were generally consistent with those of the main analysis (Table 19, Figure 6, and Figure 8). Subgroup analyses are shown in Figure 9 and Table 21 and were generally consistent with the main analyses; however, some subgroups had relatively small sample sizes increasing the risk for imprecision.

Figure 3: Kaplan-Meier Plot of PFS by BICR Assessment — FAS

BICR = blinded independent central review; CI = confidence interval; FAS = full analysis set; HR = hazard ratio; NC = not calculable; PFS = progression-free survival.

Notes: Circles indicate censored observations.

Data cut-off date was January 5, 2024.

Source: LAURA Clinical Study Report.³⁹

CNS Progression-Free Survival

CNS PFS (based on neuroradiologist BICR assessment according to RECIST Version 1.1) results at the January 5, 2024, DCO date are summarized in Table 16. The median CNS PFS follow-up time for all patients was 24.64 months (range, ████ ██ █████) in the osimertinib group and 5.72 months (range, ████ ██ █████) in the placebo group. The CNS PFS stratified HR was 0.17 (95% CI, 0.09 to 0.32) favouring the osimertinib group. The difference in CNS PFS probabilities for osimertinib versus placebo was █████ at 12 months and █████ at 24 months. The KM plot for CNS PFS in the FAS is presented in Figure 4.

The sensitivity analysis using investigator-assessed CNS PFS was consistent with the results of the main analysis (Table 20).

Figure 4: Kaplan-Meier Plot of CNS PFS by Neuroradiologist BICR Assessment — FAS

BICR = blinded independent central review; CI = confidence interval; CNS = central nervous system; FAS = full analysis set; HR = hazard ratio; NC = not calculable; PFS = progression-free survival.

Notes: Circles indicate censored observations.

Data cut-off date was January 5, 2024.

Source: LAURA Clinical Study Report.³⁹

Time to Death or Distant Metastases

TTDM results at the January 5, 2024, DCO date are summarized in Table 16. A higher percentage of patients in the placebo group experienced a death or distant metastatic event than in the osimertinib group (42.5% versus 23.1%, respectively). The median TTDM was not reached (95% CI, 39.29 months to NC) in the osimertinib group and 13.04 months (95% CI, 9.03 months to NC) in the placebo group. The stratified HR was 0.21 (95% CI, 0.11 to 0.38), favouring the osimertinib group.

Time to Treatment Discontinuation or Death

TTD results at the January 5, 2024, DCO date are summarized in Table 16. A higher percentage of patients in the placebo group had a death or treatment discontinuation event than in the osimertinib group (90.4% versus 44.1%, respectively). The median TTD in the osimertinib group was 40.28 months (95% CI, 32.72 months to NC) compared to 8.31 months (95% CI, 6.14 months to 11.10 months) in the placebo group. The stratified HR was 0.21 (95% CI, 0.14 to 0.32), favouring the osimertinib group.

Table 16: Summary of Key Efficacy Results From Studies Included in the Systematic Review

BICR = blinded independent central review; CI = confidence interval; CNS = central nervous system; DCO = data cut-off; HR = hazard ratio; IxRS = interactive voice and web response system; KM = Kaplan-Meier; NC = not calculable; NR = not reported; OS = overall survival; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumours; SAP = statistical analysis plan; TTD = time to treatment discontinuation or death; TTDM = time to death or distant metastases.

^aIncludes patients known to be alive at DCO.

^bIncludes patients with unknown survival status or patients who were lost to follow-up.

^cThe analysis was performed using a log-rank test stratified by disease stage before chemoradiation (stage IIIA versus stage IIIB or stage IIIC) based on values entered into the IxRS, after applying the SAP rule to collapse strata if there were < 10 events per stratum. A HR < 1 favours osimertinib to be associated with a longer PFS than placebo.

^dHierarchical testing procedure to adjust for multiplicity stopped here as the P value was greater than the specified threshold of 0.00036.

^eCalculated using the KM technique.

^fNo threshold for significance was assigned to this analysis.

^gPFS events that did not occur within 2 scheduled visits (plus visit window) of the last evaluable assessment (or randomization) were censored.

^hTarget lesions, nontarget lesions, and new lesions are not necessarily mutually exclusive categories.

ⁱOccurred after ≥ 2 consecutive missed visits following last nonmissing RECIST assessment (or randomization).

^jCNS PFS events that did not occur within 2 scheduled visits (plus visit window) of the last nonmissing assessment (or randomization) are censored.

^kIt is noted that while patients were free of CNS disease at baseline according to the investigator, the neuroradiologist BICR reader could independently assign target and nontarget lesions during CNS BICR assessment.

^lP value should not be interpreted for rejecting the null hypothesis as a higher order comparison in the hierarchical procedure (OS at the DCO date of January 5, 2024) failed to reach statistical significance thereby preventing interpretation of the P value for CNS PFS comparisons.

^mTested outside of the hierarchical testing procedure and not adjusted for multiplicity.

Source: LAURA Clinical Study Report³⁹ and LAURA Overall Survival Analysis Update.⁴⁰ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Health-Related Quality of Life

The percentage of patients who completed the EORTC QLQ-C30 at baseline was 92.9% in the osimertinib group and 93.2% in the placebo group. From baseline to week 40, more than 50% of patients in the osimertinib group completed the EORTC QLQ-C30 and the EORTC QLQ-LC13; however, in the placebo group by week 24 █████ ████ ███ of patients completed the assessments.

Baseline EORTC QLQ-C30 and EORTC QLQ-LC13 scores were similar across both treatment groups (Table 22).

While the MID of the EORTC QLQ-C30 varies by cancer type and subscale, global and subscale-specific changes did not exceed the MID in all instances.²⁵ The point estimate for the between-group difference for the mean change in EORTC QLQ-C30 global health status/QoL score from baseline across all visits did not meet the MID threshold of 4 points; however, the CI crosses the MID threshold of −4 points for deterioration (−1.9 points; 95% CI, −5.89 to 2.00 points; Table 17). The only scores for which the CIs for the between-group difference for the mean change in scores from baseline across all visits did not include a value of 0 were for EORTC QLQ-C30 appetite loss (estimated difference = 8.1; 95% CI, 2.77 to 13.37; MID = 10) and for EORTC QLQ-C30 diarrhea (estimated difference = 7.9; 95% CI, 3.63 to 12.12; MID = not estimated).

Table 17: Mean Change From Baseline to Week 40 (Over All Visits) in EORTC QLQ-C30 and EORTC QLQ-LC13 Scores by Mixed Model for Repeated Measures Analysis — FAS

CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-LC13 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module; FAS = full analysis set; MMRM = mixed model for repeated measures.

Note: Data cut-off date was January 5, 2024.

^aThe analysis was performed using an MMRM analysis of change from baseline score for all postbaseline assessments, with patient, treatment, visit, and treatment-by-visit interaction as explanatory variables and the baseline score as a covariable along with the baseline score-by-visit interaction. Treatment, visit, and treatment-by-visit interaction are fixed effects in the model and the patient is included as a random effect. Restricted maximum likelihood estimation is used. An overall adjusted mean estimate to estimate the average treatment effect over visits is derived giving each visit equal weight. The treatment-by-visit interaction is kept in the model regardless of significance. Data are summarized up to the earlier of the date of progression or 10 months of follow-up, excluding any visits with missing data from 75% of patients or more.

^bNot adjusted for multiple testing.

Source: LAURA Clinical Study Report.³⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Harms

Refer to Table 18 for harms data.

Adverse Events

More patients in the osimertinib group experienced an AE (140 of 143 [97.9%]) than in the placebo group (64 of 73 [87.7%]). In both groups, the 3 most frequently reported AEs were radiation pneumonitis (47.6% in the osimertinib group and 38.4% in the placebo group), diarrhea (35.7% and 13.7%, respectively), and rash (23.8% and 13.7%, respectively).

Serious Adverse Events

More patients in the osimertinib group experienced a SAE (55 of 143 [38.5%]) than in the placebo group (11 of 73 [15.1%]). In the osimertinib group, the most frequently reported SAEs were radiation pneumonitis (10.5%), pneumonia (4.9%), and gastroenteritis (1.4%) and pneumonitis (1.4%). In comparison, the most frequently reported SAEs in the placebo group were pneumonia (2.1%) and radiation pneumonitis (2.7%) with all other SAEs reported by only 1 patient.

Withdrawals Due to AEs

More patients in the osimertinib group prematurely stopped treatment due to an AE ███████ ████████ than in the placebo group █████ ███████. In the osimertinib group, the 3 most common AEs leading to treatment discontinuation were radiation pneumonitis (4.9%), █████████ ███████ ███ ███████████ ███████ ██ ███ ███████ █████ █ ████████ ██████ ██████████ █████████ ███████████ ████ ███ ██ █████████ ███████████████ █████ ███ █████ ███ ███████ ██ █████████ ███████████████ ████ ███████████ ██ ████ █ ████████

Mortality

A similar percentage of patients in both the osimertinib and placebo group experienced an AE with an outcome of death ██████ ██████ in the osimertinib group and ████ ██████ in the placebo group). In the osimertinib group, the fatal AEs were due to pneumonia ██████, pneumonitis (████), and a road traffic accident (████). In the placebo group, the fatal AEs were due to myocardial infarction (████) and aortic aneurysm rupture (████).

Notable Harms

Generally, a higher percentage of patients in the osimertinib group tended to experience AEs of special interest identified in the product monograph and highlighted as important by clinical experts consulted for this review. In both treatment groups, radiation pneumonitis was the most common AE of special interest (68 of 143 patients [47.6%] in the osimertinib group and 28 of 73 patients [38.5%] in the placebo group), followed by ███████ █████████ ██████ ███ █████ █████████████, and interstitial lung disease or pneumonitis (7.7% and 1.4%, respectively). Pneumonitis occurred in slightly more patients in the osimertinib group ██████ than in the placebo group ██████. Similarly, grade 3 or greater diarrhea occurred in ████ of patients in the osimertinib group and ████ in placebo group.

Table 18: Summary of Harms Results From Studies Included in the Systematic Review

AE = adverse event; ILD = interstitial lung disease; PT = preferred term; SAE = serious adverse event.

Note: Data cut-off date was January 5, 2024.

^aPatients with multiple events in the same PT are counted only once in that PT. Patients with events in > 1 PT are counted once in each of those PTs.

^bIncludes AEs with an onset date on or after the date of first dose and up to and including the earlier of 28 days following the date of last dose of study medication and the day before the start of subsequent anticancer therapy.

^cIncluded the following preferred terms: ILD, pneumonitis, acute interstitial pneumonitis, alveolitis, diffuse alveolar damage, idiopathic pulmonary fibrosis, lung disorder, organizing pneumonia, pulmonary toxicity, and pulmonary fibrosis.

Source: LAURA Clinical Study Report.³⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Critical Appraisal

Internal Validity

While the LAURA trial planned to screen an estimated 1,333 patients to randomize approximately 200, only 746 were screened to enrol the 216 patients randomized. One possible explanation for the discrepancy between the planned and actual number of patients screened could be more patients than anticipated had EGFR testing performed before screening. However, as neither these data nor a rationale are provided, the exact reason for the difference remains unknown.

Allocation concealment methods used in the LAURA trial were deemed adequate by the CDA-AMC team. The LAURA trial randomized patients in a 2:1 ratio; however, no rationale for this ratio was provided. While such an approach is often used in oncology trials based on an established role of the investigational treatment and to improve data collection on the investigational treatment’s efficacy and harms, unequal allocation may reduce the precision of comparisons for the smaller control group and increase the potential for baseline imbalances, which could introduce bias or limit the interpretability of subgroup analyses. As will be described, there were notable differences in distribution of certain baseline characteristics between treatment groups, and the relatively smaller sample size in the placebo group potentially impacts the stability of the PFS estimates given the smaller number of patients at risk after 9 months (Figure 3).

Randomization in the LAURA trial was performed using an interactive voice or web response system and was stratified by prior platinum-based CRT strategy (cCRT versus sCRT), tumour stage before chemoradiation (stage IIIA versus stage IIIB or stage IIIC), and China cohort (enrolled at a Chinese site and patient declaring themselves of Chinese ethnicity versus enrolled at non-Chinese site or patient declaring themselves of non-Chinese ethnicity). These stratification factors were considered appropriate by the clinical experts consulted for this review and intended to balance known prognostic variables between treatment groups.

Despite randomization, differences in baseline characteristics between treatment groups were observed. Notable differences included a higher percentage of patients in the osimertinib group who had a WHO performance status of 0 (55.9%) at baseline than in the placebo group (42.5%), fewer former smokers in the osimertinib group (25.9%) than in the placebo group (31.5%), and a higher percentage of patients with PR in the osimertinib group (46.9%) than in the placebo group (37.0%) These differences may indicate that patients in the osimertinib group had a more favourable prognosis, which could introduce confounding and bias the results in favour of osimertinib. Another difference was observed in EGFR mutation types with 47.6% of patients in the osimertinib group and 41.1% in the placebo group having L858R-positive disease, while 51.7% and 58.9%, respectively, had exon 19 deletion–positive disease. It is acknowledged that between-group differences in baseline characteristics may occur in trials with smaller sample sizes (e.g., < 100 patients per group) and multiple strata per covariates, which may apply to the LAURA trial.^26,27 Subgroup analyses among current or former smokers, by PR to prior CRT, and type of EGFR mutation were similar to the overall population findings. The sponsor conducted a post hoc subgroup analysis on baseline WHO performance status that was consistent overall with the PFS benefit for osimertinib in the primary analysis (refer to Table 21). While the results show some differences in the HRs between groups (HR = 0.17 for the WHO performance status of 0 subgroup and HR = 0.34 for the WHO performance status of 1 subgroup), these are inconclusive, due to the post hoc nature of the analyses and lack of test for interaction. Overall results were consistent with the PFS benefit for osimertinib in the primary analysis and the clinical experts consulted for this review did not anticipate the observed differences in WHO performance status at baseline to be clinically meaningful as to substantially impact the overall treatment effect. Nonetheless, the potential for residual confounding due to baseline imbalances remains a limitation in the internal validity of the trial.

While the LAURA trial was double-blinded, treatment unblinding was permitted for medical emergencies requiring knowledge of the treatment for appropriate management, and following BICR-confirmed progression of disease if the investigator deemed unblinding essential for the ongoing management of the patient. To mitigate potential bias related to subjective interpretation of disease progression and tumour response, a BICR committee reviewed all radiographic tumour assessments to determine response based on RECIST Version 1.1 criteria. As such, the risk of detection bias in tumour-related outcomes (e.g., PFS) due to selective unblinding is considered low. However, because unblinding was allowed for management decisions and may have occurred more frequently in one group (e.g., the placebo group upon progression), there remains a risk of bias for outcomes more susceptible to subjective influence or reporting bias, especially HRQoL and AEs. These domains rely more heavily on patient and investigator perception and were not centrally adjudicated, making them more vulnerable to differential reporting following unblinding.

While all patients in each treatment group received at least 1 dose of study treatment, the mean duration of treatment was longer for the osimertinib group (24 months [SD = 14]) than the placebo group (12 months [SD = 11]), reflecting longer PFS in the osimertinib group. Despite a higher percentage of patients in the osimertinib group experiencing dose interruptions (55.2%) than in the placebo group (28.8%), the mean treatment duration excluding time related to dose interruptions remained similar, indicating that the frequency and duration of interruptions for any reason did not have a meaningful impact on the cumulative exposure to study treatments.

Date of death, start and end dates for concomitant medication, radiotherapy, AEs, and subsequent anticancer treatment dates were imputed if missing. Instances where only partial information was available — dates with year only, or imputation based on first dose date — relied on assumptions of noninformative missingness (i.e., data missing completely at random or missing at random) which may introduce bias. If data were missing not at random, such as unrecorded events following specific treatments, these assumptions would be violated, potentially introducing bias in the estimation of treatment effects. Further, this imputation approach may not capture the uncertainty associated with the missing values, which could have led to underestimation in the variability and narrowing the resulting CIs. This undermines confidence in the precision of the effect estimates. A sensitivity analysis was conducted to assess the potential for evaluation time bias by imputing progression dates as the midpoint between the last progression-free and progression-confirming BICR assessments. This approach provides a standardized estimate of progression timing. Although the HR for the sensitivity (████; 95% CI ████ ██ ████; Table 19) was close to that for the primary PFS analysis (HR = 0.16; 95% CI, 0.10 to 0.24; Table 16) it does not fully mitigate the risk of bias. It assumes progression occurs uniformly and does not account for differences in assessment schedules or missing data patterns between treatment groups. Critically, the extent of missing data leading to imputation was not reported, making it difficult to assess the overall impact of this approach on potential bias in the results.

The LAURA trial used a hierarchical MTP to control the overall type I error rate across key efficacy end points, BICR-assessed PFS, followed by interim OS, and BICR-assessed CNS PFS. At the January 5, 2024, DCO date, PFS met the prespecified threshold for statistical significance. Per the testing procedure, the interim analysis of OS was also conducted at this DCO date, requiring a P value less than 0.00036 to declare statistical significance. The observed log-rank P value for OS was 0.530, which did not meet the statistical significance threshold. Consequently, the CNS PFS end point, which was next in the hierarchy, could not be formally tested. In this case, the reporting of a nominal P value for CNS PFS can be misleading and does not follow the statistical analysis plan; however, there is a substantial between-group difference that is unlikely attributable to chance or inflated type I error.

The OS analysis was based on the intention-to-treat approach, which assumes postprogression therapies are nondifferentially distributed between groups — a condition that may not hold given the observed disparities in postrelapse therapy used (Table 15). A higher percentage of patients in the placebo group had used subsequent anticancer treatments (█████) than in the osimertinib group (█████) by the November 29, 2024, DCO date. The largest discrepancy in postprogression therapies was for osimertinib (█████ in the placebo group versus █████ in the osimertinib group received subsequent osimertinib treatment at the November 29, 2024, DCO date). This imbalance challenges the intention-to-treat assumption and introduces potential bias in the OS analysis. The trial did not implement methods to adjust for treatment switching (e.g., rank-preserving structural failure time models). The crossover for patients on placebo who had progression potentially leads to an underestimation of the between-group difference in OS; however, the findings align with clinical practice, as osimertinib is the standard of care for disease that has progressed.

OS results from the LAURA trial are based on interim analyses, which may overestimate treatment effects.²⁸ At the November 29, 2024, DCO date, the OS analysis included 66 events (40 of 143 patients [28.0%] in the osimertinib group and 26 of 73 patients [35.6%] in the placebo group), corresponding to approximately 30.6% of the total number of events required for the final analysis (120 events). This DCO date was not part of the prespecified analysis plan, nor was the number of events specified to trigger a second interim analysis. Results from this time point may therefore be more susceptible to bias due to early data truncation and post hoc decision-making. This DCO date was conducted as part of regulatory marketing requirements.

Cox proportional hazards models were used to estimate the HRs and CIs for OS, PFS, and CNS PFS. The proportional hazards assumption appeared to hold for PFS and CNS PFS based on visual inspection of KM plots. However, the early and rapid separation of the curves followed by the placebo curve plateauing could indicate either the hazard rates changed in this group leading to the hazards no longer being proportional, or the small (< 20%) proportion of patients remaining in the analysis led to less sensitive estimates, or both. Nevertheless, the visually apparent and sustained separation of the PFS and CNS PFS curves indicates there is likely little concern regarding the proportional hazards assumption. In contrast, the proportional hazards assumption is likely not met for OS. The placebo curve lies close to and slightly above that of osimertinib for the first 17 to 18 months. Following this, the curves overlap and remain close until around 30 months. From that point onward, the osimertinib curve shows higher survival compared to placebo, with a separation maintained through to approximately 58 months. While this suggests that the HRs may not reflect the treatment effect over time for OS, it may be partially explained by the frequent use of osimertinib in patients in the placebo group whose disease progressed. The clinical experts consulted for this review felt the OS curves were sufficiently close with no meaningful difference in the first 30 months. Clinical experts consulted for this review felt that the OS KM curves accurately reflected the natural history of EGFR-mutated NSCLC, with a typical median survival of 3 years to 4 years after recurrence. Alternative methods of analysis that do not rely on the proportional hazards assumption were not conducted for any of the time-to-event analyses, which makes it more difficult to assess the robustness of the results.

Visual inspection of KM plots indicated that fewer than 20% of patients in the placebo group remained at risk beyond 45 months for OS at the November 29, 2024, DCO date and beyond 12 months for PFS and CNS PFS at the January 5, 2024, DCO date. In the osimertinib group, fewer than 20% of patients were at risk beyond 51 months for OS at the November 29, 2024, DCO date and beyond 33 months for PFS and CNS PFS at the January 5, 2024, DCO date. Under such conditions, standard assumptions used in survival analysis (e.g., noninformative censoring) may be violated, which limits the reliability of survival estimates at later time points.^29-31 Based on the available data, the clinical experts consulted for the review suggested 36 months and 48 months as clinically important time points for OS, 12 months and 36 months for PFS, and 12 months and 24 months for CNS PFS. Therefore, the certainty (potential risk of bias and imprecision) of the treatment effects of osimertinib versus placebo at the later time points for each of the end points may be reduced.

Due to too few events (i.e., < 10 events per strata), the stratified log-rank tests for PFS, OS, CNS PFS, TTDM, and TTD did not stratify by the China cohort or prior CRT strategy. This collapsing of stratification factors may introduce bias as it overlooks important differences such as geographic variations in clinical practice and variation in the efficacy of cCRT versus sCRT. It is acknowledged that to run the analysis, collapsing strata would be needed when the sample size is small. While the pooled analysis increases precision of PFS and OS estimates by combining strata, it sacrifices the accuracy of stratified analyses, which is most feasible when there are sufficient events per strata. Second, the proportional hazards assumption may no longer hold, potentially affecting the validity of the outcomes.

The FDA and the EMA consider OS the gold standard primary outcome in trials, including NSCLC trials.^32,33 However, PFS is considered by the FDA to be an important cancer end point in situations where survival may be prolonged, making an OS end point impractical.^33,34 When observed differences in PFS are substantial in magnitude (viewed in the context of toxicities, the relatively short survival of patients with NSCLC, availability of alternative therapies, histologic or genetic subtype of NSCLC, and extent of prior treatment), the FDA and EMA considered PFS to provide clinical evidence to support approvals.^32,33 While a correlation between PFS and OS in patients with locally advanced NSCLC has been suggested,^35,36 no correlation has been established for the current setting (i.e., unresectable EGFR-mutated NSCLC) and thus the validity of PFS as a surrogate for OS is unclear in the current context.

The primary PFS analysis and CNS PFS analysis censored patients who progressed or died after 2 or more consecutive missed visits. For both PFS and CNS PFS, censoring due to 2 or more consecutive missed visits was well balanced across both treatment groups. While results of the sensitivity analysis assessing attrition bias in PFS did not show a clear separation of the osimertinib and placebo curves which suggests possible attrition bias, the majority of PFS events in the placebo group occurred before 6 months (median PFS = ████ months in the placebo group) resulting in few patients censored beyond 6 months. Therefore, PFS attrition bias was deemed to be minimal.

Results from the EORTC QLQ-C30 and EORTC QLQ-LC13 showed that osimertinib did not meaningfully impact HRQoL compared to placebo. Across all items assessed, appetite loss and diarrhea (both assessed using the EORTC QLQ-C30) were the only items for which the CIs for the between-group difference in mean change in scores from baseline across all visits did not include the null value of 0. However, the completion rates for both scales declined over time reducing the certainty of the treatment effects at the later time points. By week 16 only ███ and ███ of patients in the placebo and osimertinib groups, respectively, were available to provide EORTC QLQ-C30 assessments; at week 32 these numbers had dropped to ███ and ████ respectively. For the EORTC QLQ-LC13, by week 16 only ███ and ███ of patients in the placebo and osimertinib groups, respectively, were available to provide assessments; at week 32 these numbers had dropped to ███ and ████ respectively.

External Validity

The clinical experts with expertise in the diagnosis and management of patients with NSCLC felt the inclusion and exclusion criteria used in the LAURA trial were generally aligned with those typically used in NSCLC trials and the sponsor’s reimbursement request. Additionally, the clinical experts felt the reimbursement of osimertinib should include patients with poorer performance status, that is, with a WHO performance status of 0 to 2 (rather than only those with a WHO performance status of 0 and 1 as included in the trial). The same clinical experts felt that the percentage of patients completing and discontinuing treatment throughout the trial aligned with clinical practice in Canada.

While none of the patients enrolled and randomized in the LAURA trial were from Canada, which may lower the generalizability of the results to the Canadian setting, the clinical experts consulted for this review indicated the baseline characteristics of the study population were generally representative of patients seen in Canadian clinical practice. Notably, a high percentage of patients enrolled in the LAURA trial identified as Asian (82.4%); however, this was partially expected as EGFR mutations are more common in patients of Asian ethnicity.⁵ The clinical experts consulted for this review did not anticipate the safety and efficacy of osimertinib to differ by race.

The outcomes measured in the LAURA trial addressed the key treatment goals identified by patient and clinician group inputs submitted to CDA-AMC and were deemed to be relevant by the consulted clinical experts.

The clinical experts consulted for this review noted that the prior platinum-based CRT regimens used for treatment in the definitive setting for stage III disease in the LAURA trial were representative of those used to treat unresectable EGFR-mutated NSCLC in Canada. The same clinical experts also felt that watchful waiting was the most relevant comparator. Additionally, osimertinib is currently reimbursed as first-line therapy in patients who progressed to metastatic disease (unresectable setting) and thus the clinical experts consulted for this review felt the high percentage of patients using postprogression osimertinib in the placebo group was representative of standard Canadian practice.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^37,38

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate — the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited — the true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate — the true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for osimertinib versus placebo.

Long-Term Extension Studies

No long-term extension studies were submitted.

Indirect Evidence

No indirect evidence was submitted.

Studies Addressing Gaps in the Systematic Review Evidence

No additional studies to address gaps within the systematic review evidence were submitted.

Discussion

Summary of Available Evidence

One ongoing phase III, double-blinded, placebo-controlled, randomized, multinational study, the LAURA trial (N = 216), met the inclusion criteria for the systematic review conducted by the sponsor. The LAURA trial enrolled adults with locally advanced, unresectable (stage III) NSCLC whose tumours harboured either EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. None of the study sites were in Canada. Before randomization, patients received either concurrent or sequential platinum-based CRT. Only those whose disease did not progress during or following definitive platinum-based CRT, who had a WHO performance status of 0 or 1, and who did not have any unresolved toxicity greater than grade 2 were eligible for randomization. Patients were randomized 2:1 to receive either osimertinib 80 mg orally once daily or placebo until objective radiological disease progression (defined by RECIST Version 1.1 and confirmed by BICR) or another discontinuation criterion was met (e.g., patient decision or unacceptable toxicity). Patients assigned to osimertinib could continue receiving osimertinib (open label) after BICR-confirmed progression if, in the opinion of their treating physician, they were continuing to derive clinical benefit. The outcomes relevant to this review include the trial’s primary end point of PFS and select secondary end points of OS, CNS PFS, TTDM, TTD, response outcomes, and HRQoL assessed via EORTC QLC-C3 and EORTC QLC-LC13, and harms data. The trial population had a mean age of 61.4 years (SD = 10.95) and was primarily female (132 of 216 [61.1%]), never smokers (69.9%), and Asian (82.4%). Most patients were classified as having stage IIIA (35.2%) or stage IIIB (48.6%) NSCLC, received cCRT (89.4%), and were positive for exon 19 deletions (54.2%).

Interpretation of Results

The patient group input collected for this review highlighted the key treatment goals for patients are to prolong life, prolong PFS, reduce symptoms, and improve HRQoL. The effect of osimertinib following the successful completion of platinum-based CRT on achieving these goals was evaluated in the LAURA trial through the assessment of OS, PFS, CNS PFS, response outcomes, EORCT QLQ-C30 global health score/QoL, and AEs.

Efficacy

OS was determined to be the most clinically important outcome for this review. The clinical experts consulted for the review agreed with the importance of OS as an outcome and suggested a 5% to 10% between-group difference in the probability of OS to be clinically meaningful. Osimertinib compared to placebo may result in a clinically important increase in OS at 36 months and 48 months, based on the 5% threshold. However, the certainty of evidence for both time points was rated as low (per GRADE assessment; Table 2) due to risk of bias and imprecision. At a median OS follow-up of 39.36 months (range, ████ ██ █████) in the osimertinib group and 35.15 months (range, ████ ██ █████) in the placebo group, 66 deaths had occurred in the FAS and the KM estimate for median OS was 58.81 months (95% CI, 54.08 months to NC) in the osimertinib group and 53.98 months (95% CI, 42.05 months to NC) in the placebo group. Thus, a key limitation of the OS data is the insufficient sample size and duration of follow-up to adequately assess OS in the studied population. Further, a late divergence of the KM curves was observed (i.e., did not separate until approximately 30 months post randomization). The clinical experts consulted on this file agreed that this observation was expected. According to the experts, even in cases where patients experience disease progression, the median survival after recurrence is typically 3 years to 4 years. Additionally, they confirmed that the placebo curve followed the expected trajectory considering that the frequent use of osimertinib post progression in the placebo group is anticipated to reduce the observed treatment effect. Health Canada’s authorization of osimertinib is conditional on the final OS analysis. The final OS analyses is planned for when approximately 60% of OS events have occurred. However, uncertainties related to OS will likely remain due to the high level of cross over to the osimertinib group.

PFS was the primary outcome in the LAURA trial and considered to be a clinically important outcome for this review. The consulted clinical experts considered a 10% to 15% between-group difference to be clinically meaningful. At a median PFS follow-up of 21.98 months (range, 0.03 months to 60.55 months) in the osimertinib group and 5.55 months (range, 0.03 months to 49.71 months) in the placebo group, 120 progression events had occurred in the FAS and the median PFS was 39.13 months (95% CI, 31.51 months to NC) in the osimertinib group and 5.55 months (95% CI, 3.71 months to 7.43 months) in the placebo group. The between-group difference in PFS probabilities for osimertinib versus placebo were █████ ████ ███ ████ ██ █████ at 12 months and █████ ████ ███ ████ ██ █████ at 36 months. Using the thresholds suggested by the clinical experts, these point estimates suggest clinically meaningful increases in the probability of being progression-free at 12 months and 36 months. Certainty of evidence was rated as high at 12 months, but rated down at 36 months due to fewer than 20% of patients remaining at risk in both groups.^29,31 While differences in baseline characteristics were observed across the treatment groups, including WHO performance status and smoking status, prespecified and post hoc PFS subgroup analyses were generally consistent with the primary result.

Given the uncertainty in the currently available OS results from the LAURA trial, the extent to which benefits observed in PFS translate into improvements in OS is a key consideration. While a correlation between PFS and OS in patients with locally advanced NSCLC treated with CRT has been suggested,^35,36 no such correlation has been established for patients with locally advanced, unresectable EGFR-mutated NSCLC; thus, the validity of PFS as a surrogate for OS is unclear in the current context.

The between-group differences in CNS PFS rates at 12 months and 24 months were above the 10% to 15% threshold suggested by the clinical experts consulted for this review, indicating a clinically meaningful improvement in favour of osimertinib. However, the certainty of evidence was rated down at 24 months due to high attrition in the placebo group.

The antitumour effects of osimertinib compared with placebo were supported by the TTDM and TTD results. By the January 5, 2024, DCO date, the median TTDM was not reached in the osimertinib group and was 13.04 months in the placebo group. The HR and associated 95% CI favour the osimertinib group compared to placebo. The median TTD was approximately 5 times longer for the osimertinib group compared to the placebo group (40.28 months for the osimertinib group versus 8.31 months for the placebo group). The between-group difference in TTD was above the 6-month threshold suggested by clinical experts, demonstrating that osimertinib led to a clinically meaningful improvement in TTD compared to placebo. ORR and DoR results from the LAURA trial were also supportive of the observed PFS benefit (Table 23). However, these end points were outside of the MTP and were considered as supportive evidence.

Patient and clinician input highlighted that maintaining or improving HRQoL is an important treatment goal. HRQoL was measured in the LAURA trial using the well-established EORTC QLQ-C30, a cancer-specific HRQoL questionnaire. Published estimates for a between-group MID in the EORTC QLQ-C30 global health status/QoL score among patients with lung cancer are a 4-point increase or decrease, for improvement and deterioration, respectively.⁷⁰ At the January 5, 2024, DCO date, the between-group difference in mean change across all visits until week 40 in EORTC QLQ-C30 global health status/QoL was −1.9 points (95% CI, −5.89 points to 2.00 points), indicating than osimertinib may result in little to no difference in HRQoL compared to placebo (low certainty per GRADE assessment).

Locally advanced, unresectable (stage III) EGFR-mutated NSCLC is a debilitating and life-threatening disease.^2,77 While durvalumab, and alternative immunotherapy, is reimbursed in Canada after successful completion of platinum-based cCRT in patients with unresectable stage III NSCLC, post hoc subgroup analyses suggest it has similar efficacy and more frequent AEs compared to placebo in patients with EGFR-mutated NSCLC.²¹ Therefore, following the successful completion of CRT, there is currently no established treatment option for EGFR-mutated NSCLC, according to the clinical experts consulted for this review. Clinical experts noted that conventional treatments (e.g., CRT) followed by watchful waiting often lead to high rates of disease recurrence, as seen in the PFS data from the placebo group of the LAURA trial. The experts noted that relapsing stage III NSCLC is generally considered incurable. Additionally, the experts flagged that patients with EGFR mutations are more likely to develop CNS metastasis compared to those with driver mutation–negative NSCLC, increasing the risk of symptoms at recurrence. Therefore, reducing relapse risk in patients with unresectable NSCLC and EGFR mutations was identified as a critical unmet need by the clinical experts consulted for this review.

Harms

More patients in the osimertinib group experienced an AE (98%) and a SAE (39%) than in the placebo group (88% and 15%, respectively). Osimertinib likely results in little to no difference in withdrawals due to AEs (█████) compared to placebo (████) (moderate certainty of evidence per the GRADE assessment). A total of || patients in the safety analysis set experienced an AE with an outcome of death with ██████ occurring in the osimertinib group and ██████ occurring in the placebo group; based on the GRADE assessment, osimertinib may result in little to no difference in the incidence of fatal AEs compared to placebo. Pneumonitis and grade 3 or greater diarrhea were identified in the product monograph and highlighted as important by clinical experts consulted for this review. While a similar percentage of patients in the osimertinib group and placebo group experience pneumonitis (low certainty of evidence per GRADE assessment) and grade 3 or greater diarrhea (moderate certainty of evidence per GRADE assessment), the absolute number of events was low for both AEs.

The proposed product monograph further indicates that once osimertinib treatment has been initiated, patients should be monitored for interstitial lung disease (including pneumonitis), QT interval corrected using the Fridericia formula interval prolongation, left ventricular dysfunction, and cardiomyopathy.

For the LAURA trial, the clinical experts consulted for this review felt the data presented did not raise any new concerns about the safety profile of osimertinib, and the observed events were consistent with what is expected with the drug.

Conclusion

The LAURA trial was a phase III, double-blinded, placebo-controlled, randomized, multinational trial comparing the efficacy and safety of maintenance osimertinib for patients with locally advanced, unresectable (stage III) NSCLC whose tumours harboured either EGFR exon 19 deletions or exon 21 (L858R) substitution mutations and whose disease has not progressed during or following platinum-based CRT. Compared to placebo, osimertinib results in a clinically important improvement in PFS and CNS PFS at 12 months (high-certainty evidence) and likely results in clinically important increases in PFS at 36 months and CNS PFS at 24 months (moderate-certainty evidence). At the planned PFS interim analysis, relatively few OS events (43 events across both groups) had occurred and OS failed to achieve statistical significance. Results from a subsequent unplanned OS analysis showed osimertinib may result in a clinically important increase in OS at 36 months and 48 months compared to the placebo group (low-certainty evidence at both time points). Results from the LAURA trial showed that osimertinib may result in little to no difference in HRQoL compared to placebo (low certainty of evidence). Clinical experts consulted for this review deemed the harms profile of osimertinib to be consistent with their expectations based on osimertinib’s known toxicity profile.

Clinical experts noted that conventional treatments (e.g., CRT) often lead to high rates of disease recurrence, and relapsing stage III NSCLC is generally considered incurable. Additionally, the experts flagged that patients with EGFR mutations are more likely to develop CNS metastasis compared to those with driver mutation–negative NSCLC, increasing the risk of symptoms at recurrence. Therefore, reducing relapse risk in patients with unresectable NSCLC and EGFR mutations was identified as a critical unmet need by the clinical experts consulted for this review.

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Appendix 1: Overall Survival at the January 5, 2024, DCO

Please note that this appendix has not been copy-edited.

Figure 5: Kaplan-Meier Plot of Overall Survival at the January 5, 2024, DCO, FAS

CI = confidence interval; DCO = data cut-off; FAS = full analysis set; HR = hazard ratio; NC = not calculable; OS = overall survival.

Note: Circles indicate censored observations.

Data cut-off: January 5, 2024

Source: LAURA Clinical Study Report.³⁹

Appendix 2: The LAURA Trial Sensitivity Analyses

Please note that this appendix has not been copy-edited.

Table 19: Sensitivity Analysis: Progression-Free Survival

BICR = blinded independent central review; CI = confidence interval; FAS = full analysis set; HR = hazard ratio; IxRS = interactive voice/web response system; NC = not calculable; NR = not reported; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumours; SAP = statistical analysis plan.

^aPFS events that do not occur within 2 scheduled visits (plus visit window) of the last assessment (or randomization) are censored.

^bTarget Lesions, Nontarget Lesions, and New Lesions are not necessarily mutually exclusive categories.

^cOccurred after 2 or more consecutive missed visits following last nonmissing RECIST assessment (or randomization).

^dThe analysis was performed using a log-rank test stratified by disease stage before chemoradiation (IIIA vs IIIB/IIIC) based on values entered into the IxRS, after applying the SAP rule to collapse strata if there are < 10 events per stratum. A HR < 1 favours osimertinib to be associated with a longer PFS than placebo.

^eCalculated using the Kaplan-Meier technique.

Data cut-off: January 5, 2024

Source: LAURA Clinical Study Report.³⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Figure 6: Sensitivity Analysis — Kaplan-Meier Plot of Progression-Free Survival According to Investigator Assessment, FAS

CI = confidence interval; FAS = full analysis set; HR = hazard ratio; NC = not calculable.

Note: Circles indicate censored observations.

Data cut-off: January 5, 2024

Source: LAURA Clinical Study Report.³⁹

Figure 7: Sensitivity Analysis — Kaplan-Meier Plot of Progression-Free Survival According to BICR With Censoring Flag Reversed to Assess Possible Attrition Bias, FAS

CI = confidence interval; FAS = full analysis set; HR = hazard ratio; NC = not calculable.

Note: Circles indicate censored observations.

Data cut-off: January 5, 2024

Source: LAURA Clinical Study Report.³⁹

Figure 8: Sensitivity Analysis — Kaplan-Meier Plot of Progression-Free Survival According to BICR, Evaluable for Response Set

CI = confidence interval; FAS = full analysis set; HR = hazard ratio; NC = not calculable.

Note: Circles indicate censored observations.

Data cut-off: January 5, 2024

Source: LAURA Clinical Study Report.³⁹

Table 20: Sensitivity Analysis: Central Nervous System Progression-Free Survival by Investigator Assessment, FAS

CI = confidence interval; FAS = full analysis set; HR = hazard ratio; IxRS = interactive voice and web response system; NC = not calculable; PFS = progression-free survival.

^aProgression determined by RECIST v1.1 assessments.

^bThe analysis was performed using a log-rank test stratified by disease stage before chemoradiation (IIIA vs IIIB/IIIC) based on values entered into the IxRS, after applying the SAP rule to collapse strata if there are < 10 events per stratum. A HR < 1 favours osimertinib to be associated with a longer PFS than placebo.

^cCalculated using the Kaplan-Meier technique.

Data cut-off: January 5, 2024

Source: LAURA Clinical Study Report.³⁹ Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Appendix 3: The LAURA Trial Subgroup Analyses

Please note that this appendix has not been copy-edited.

Figure 9: Subgroup Analysis — Kaplan-Meier Plot of Progression-Free Survival According to BICR, Evaluable for Response Set

AJCC = American Joint Committee on Cancer; CI = confidence interval; CRT = chemoradiation; cCRT = concurrent chemoradiation; CRF = case report form; ctDNA = circulating tumour DNA; EGFR = epidermal growth factor receptor; FAS = full analysis set; HR = hazard ratio; NC = not calculable; sCRT = sequential chemoradiation therapy.

^aSubgroup analyses for the stratification factors are based on the values entered into the CRF.

^bTMN Classification of Malignant Tumours, 8th Edition.

^cSummarized based on tissue-based central EGFR testing OR local pre-existing EGFR results.

Notes: Circles indicate censored observations.

Grey band represents the 95% CI for the overall HR (stratified log-rank test).

An HR < 1 implies a lower risk of progression on osimertinib than placebo. HRs and 95% CIs are presented where there are > = 20 events across both treatment groups only.

Data cut-off: January 5, 2024.

Source: LAURA Clinical Study Report.³⁹

Table 21: Post Hoc Subgroup Analysis by WHO Performance Status

CI = confidence interval.

Data cut-off: January 5, 2024

Source: LAURA Clinical Study Report.³⁹

Appendix 4: The LAURA Trial Baseline EORTC QLQ-C30 and EORTC QLQ-LC13 Scores

Please note that this appendix has not been copy-edited.

Table 22: Baseline EORTC QLQ-C30 and EORTC QLQ-LC13 Scores in the LAURA Trial