Regulatory Decision Summary for Tagrisso

This Supplement to a New Drug Submission (SNDS) was filed under the Priority Review Policy by AstraZeneca Canada Inc. to obtain market authorization pursuant to section C.08.004 of the Food and Drugs Regulations for Tagrisso. The submission supported updates to the Product Monograph for a proposed new indication at the recommended dose of 80 mg orally once daily.

The proposed indication was for the treatment of patients with locally advanced, unresectable stage III non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, either alone or in combination with other EGFR mutations, and whose disease had not progressed during or following platinum-based chemoradiation therapy. A validated test was required to confirm EGFR mutation-positive status prior to treatment.

Health Canada issued a Notice of Compliance with Conditions (NOC/c) Qualifying Notice on April 1, 2025. On April 11, 2025, AstraZeneca submitted the final version of the Response to the NOC/c Qualifying Notice. Upon review of the response, Health Canada recommended granting approval for the indication under the NOC/c pathway.

The approved indication under the NOC/c pathway is for Tagrisso 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 chemoradiation therapy. A validated test is required to confirm EGFR mutation-positive status prior to treatment. Marketing authorization with conditions was based on the primary efficacy endpoint of progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in subsequent analyses.

The pivotal LAURA study (D5160C00048) was a Phase III randomized, double-blind, placebo-controlled, multicentre global trial that enrolled 216 patients. Participants were randomized in a 2:1 ratio to receive Tagrisso 80 mg once daily or placebo until disease progression or treatment discontinuation. Eligible patients had locally advanced, unresectable Stage III non-small cell lung cancer (NSCLC) with an EGFR exon 19 deletion or L858R point mutation and had not progressed following chemoradiation therapy. Randomization was stratified by sequence of chemoradiation therapy, disease stage prior to chemoradiation therapy (IIIA versus IIIB/IIIC), and inclusion in the China cohort. Upon progression, all patients were permitted to receive open-label Tagrisso.

At the primary analysis (data cutoff January 5, 2024), Tagrisso demonstrated a statistically significant and clinically meaningful improvement in the primary efficacy endpoint of progression-free survival (PFS), assessed by blinded independent central review per RECIST v1.1, compared with placebo. Median PFS was 39.1 months for Tagrisso versus 5.6 months for placebo, with a hazard ratio of 0.16 (95% confidence interval [CI]: 0.10, 0.24) and a two-sided p-value of less than 0.001. This improvement was supported by a nominal improvement in a key secondary endpoint, central nervous system progression-free survival, with a descriptive hazard ratio of 0.17 (95% CI: 0.09, 0.32).

At the planned interim analysis for overall survival (OS), a key secondary endpoint, the median OS was 54 months (95% CI: 46.5, not calculable) for Tagrisso and not calculable (95% CI: 42.1, not calculable) for placebo, with a hazard ratio of 0.81 (95% CI: 0.42, 1.56) and a two-sided p-value of 0.530. The confidence interval crossed 1. The Kaplan-Meier plot suggested that an early OS detriment for Tagrisso could not be ruled out, likely explained by the high rate of crossover to open-label Tagrisso in the placebo arm.

The safety profile of Tagrisso was based on data from 143 patients with EGFR mutation-positive NSCLC who received Tagrisso in the LAURA trial. The median duration of treatment was 24 months in the Tagrisso arm compared with 8.3 months in the placebo arm. The most commonly reported adverse drug reactions were radiation pneumonitis, diarrhea, rash, paronychia, dry skin, stomatitis, and pruritus. Adverse drug reactions of Grade 3 or higher included diarrhea, interstitial lung disease (ILD), and radiation pneumonitis. The most common serious adverse reactions were ILD and pneumonitis, mostly Grade 1 and 2. Fatal adverse drug reactions occurred in 1.4% of Tagrisso-treated patients due to pneumonia and ILD/pneumonitis (0.7% each). The known risk of ILD/pneumonitis was observed at a higher incidence in the Tagrisso arm compared with placebo (56% versus 38%). While radiation pneumonitis is related to prior chemoradiation therapy, the higher rate observed in the Tagrisso arm suggests that a potential contribution of Tagrisso cannot be ruled out. Labelling was revised to include specific recommendations regarding ILD and radiation pneumonitis based on prior chemoradiation therapy.

The Marketed Health Products Directorate determined that no changes to the Canadian Risk Management Plan or post-market safety monitoring activities were warranted.

Unresectable Stage III NSCLC is a life-threatening condition associated with poor survival. In Canada, there are no approved therapies for patients with unresectable Stage III EGFR-mutated NSCLC whose disease has not progressed during or following chemoradiation therapy. Data from the primary PFS analysis of the LAURA trial constitute promising evidence of clinical benefit for Tagrisso. However, it remains uncertain whether initiating Tagrisso upfront translates into long-term OS benefit, as there are no published data correlating PFS and OS in this population. The observed safety profile of Tagrisso is considered manageable through revised labelling. The sponsor agreed to provide confirmatory data from the final OS analysis of the LAURA study to verify clinical benefit.

The benefit-risk-uncertainty profile remains favourable for Tagrisso 80 mg oral tablets for the conditionally approved indication. A Notice of Compliance with Conditions-Qualifying Notice (NOC/c-QN) was recommended and issued.

In response to the Qualifying Notice, a Letter of Undertaking dated April 2, 2025, and a revised version dated April 11, 2025, were submitted in Sequence 0280 to provide details on annual progress report submissions. AstraZeneca agreed to the NOC/c for Tagrisso for the new indication: 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 chemoradiation therapy. AstraZeneca agreed to all commitments outlined in the NOC/c-QN. The conditions associated with market authorization will be removed upon determination that the final OS analysis, expected in the second half of 2027, verifies clinical benefit and supports a favourable benefit-risk-uncertainty profile in the target population.

For further details about Tagrisso, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.