Regulatory Decision Summary for Tagrisso

The purpose of this Supplement to a New Drug Submission (SNDS) was to obtain market authorization for Tagrisso (osimertinib), filed by the sponsor, for use in combination with pemetrexed and platinum-based chemotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. The submission also aimed to ensure that appropriate risk minimization measures had been implemented in the proposed Product Monograph.

This submission was reviewed as part of Project Orbis Type A (PO#108) and was filed under the Priority Review Policy.

A Notice of Deficiency was issued in January 2024. The present submission included the sponsor’s response to the Notice of Deficiency.

This submission was based on the results of the FLAURA2 study randomized period. The FLAURA2 study randomized period was a Phase 3 open-label randomized study designed to assess the safety and efficacy of osimertinib, with or without pemetrexed and platinum-based chemotherapy, in patients with locally advanced (not amenable to curative surgery or radiotherapy) or metastatic epidermal growth factor receptor mutation-positive (EGFRm; Ex19del and/or L858R) non-small cell lung cancer (NSCLC), who had not received any prior therapy for advanced disease.

The study met its primary objective of progression-free survival (PFS) at the first interim analysis (data cut-off 1 [DCO-1], April 3, 2023). There was a statistically significant 38% reduction in the risk of progression in the osimertinib plus chemotherapy arm compared to the osimertinib monotherapy arm (hazard ratio [HR] = 0.62; 95% confidence interval [CI]: 0.49, 0.79; p < 0.0001). An improvement in median PFS of 8.8 months was observed for the osimertinib plus chemotherapy arm (25.5 months) compared with the osimertinib arm (16.7 months). At DCO-1, overall survival (OS) data was immature, with 71 patients (25.4%) having died in the osimertinib plus chemotherapy arm and 78 patients (28.1%) having died in the osimertinib arm (26.8% maturity of data). The HR at the time of the interim OS analysis was 0.90 (adjusted 99.84% CI: 0.54, 1.51) and not statistically significant (p = 0.5238). All other secondary endpoints such as objective response rate (ORR), duration of response (DOR), depth of response, and disease control rate (DCR) favoured the osimertinib plus chemotherapy arm.

At DCO-1, the most common adverse events (AEs) reported in the osimertinib plus chemotherapy arm were mostly associated with chemotherapy toxicity. Causally related AEs with a fatal outcome were reported for five patients (1.8%) in the osimertinib plus chemotherapy arm and one patient (0.4%) in the osimertinib arm. Grade 3 or greater AEs were reported at a rate of 63.8% in the osimertinib plus chemotherapy arm compared to 27.3% in the osimertinib arm and were mainly due to toxicity associated with chemotherapy. Dose modifications (dose reduction and/or interruption) of any study drug were more frequently encountered in the osimertinib plus chemotherapy arm compared to the osimertinib arm.

A Notice of Deficiency was issued on January 31, 2024, based on two major objections: (1) the positive results observed at the first interim analysis for the primary endpoint, PFS (HR = 0.62; 95% CI: 0.49, 0.79; p < 0.0001), did not correlate with a gain in OS. The analysis of more mature OS data was needed to allow the documentation of an OS benefit with the osimertinib plus chemotherapy arm; and (2) the absence of a correlation between PFS and OS was accompanied by an increase in toxicity due to the use of chemotherapy. As a result, the sponsor was asked to provide the updated descriptive OS analysis requested by the United States Food and Drug Administration (FDA) (DCO January 8, 2024) for further review.

As discussed with the FDA, the sponsor updated the FLAURA2 statistical plan to allow for an additional interim analysis for OS data. At this second interim analysis (DCO January 8, 2024), the OS maturity increased from 26.8% to 40.6%. An improvement in OS was observed favouring the osimertinib plus chemotherapy arm with a HR of 0.75 (95% CI: 0.57, 0.97; p = 0.028). The CI derived for the OS HR result did not cross 1, as observed during the first interim OS analysis.

Overall, the safety and tolerability of the combination were considered manageable. However, considering the potential additive effect of cardiotoxicity associated with osimertinib and chemotherapy treatments, a recommendation to conduct cardiac monitoring, including assessment of left ventricular ejection fraction at baseline and during treatment, in all patients treated with osimertinib in combination with pemetrexed and platinum-based chemotherapy was added to the Tagrisso Product Monograph.

Considering the gain in PFS observed in the first interim analysis and the results observed for OS at the second interim analysis, the benefit-risk profile of the combination was deemed favourable. Therefore, a Notice of Compliance was recommended for Tagrisso 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 further details about Tagrisso, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.