Regulatory Decision Summary for Tagrisso

The purpose of this Supplement to a New Drug Submission (SNDS) was to obtain marketing authorization for the use of Tagrisso for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

To support the proposed indication, the FLAURA study, a randomised, double-blind, Phase III study conducted in 556 patients with locally-advanced (not amenable to curative surgery or radiotherapy) or metastatic EGFRm NSCLC was submitted. Patients were randomised in a 1:1 ratio to receive once daily either osimertinib 80 mg or standard of care (SoC) EGFR-TKI therapy (either gefitinib, 250 mg; or erlotinib, 150 mg). The primary endpoint Progression Free Survival (PFS) was shown to be superior in patients treated with osimertinib as a first line treatment over standard of care (SoC) in the pivotal FLAURA trial. The analysis of PFS by blinded independent central review (BICR) was consistent with the Investigator-based primary analysis: the HR was 0.45 (95% CI: 0.36, 0.57; p-value <0.0001) indicating a 55% reduction in the risk of disease progression or death in the osimertinib arm compared to the SoC arm

The additional post-progression endpoints such as time from randomisation to second progression on subsequent anti-cancer treatment or death (PFS2), time from randomisation to first subsequent therapy or death (TFST) and time from randomisation to second subsequent therapy or death (TSST), demonstrated that PFS benefit was preserved through subsequent lines of therapy in patients treated with osimertinib.

A high number of objective response rates (ORR)s was demonstrated, even though a similar number of responses was observed in the comparator arm as well.

A clinical improvement in the central nervous system (CNS) efficacy outcomes in the Tagrisso patients was an important contributor to osimertinib efficacy as it provided responses for patients with CNS metastases at baseline and reduced new CNS lesions in those patients without CNS metastases at baseline. The advantage of CNS efficacy is an important feature of osimertinib in comparison with other EGFR-TKIs in first-line setting.

The Overall Survival (OS) data were immature during the interim analysis, and no formal statistical significance was reached at the time of the analysis.

Safety of osimertinib in the first-line setting was consistent with the known safety profile of osimertinib from the previous studies. There was a lower incidence of adverse events (AEs) leading to treatment discontinuation in the osimertinib arm and a lower incidence of AEs grade 3 or higher when compared to the SoC arm. The most commonly reported AEs in the first-line setting with osimertinib therapy were AEs associated with EGFR-TKIs (diarrhea, skin effects, upper GI inflammatory events, nail effects, ocular effects). Patients treated with osimertinib had a lower incidence of AEs leading to treatment discontinuation and a lower incidence of AEs of CTCAE grade 3 or higher compared to SoC. Interstitial lung disease (ILD), QTc interval prolongation, changes in cardiac contractility and keratitis were the key safety events which have been adequately described in the Tagrisso Product Monograph.

Benefit-risk ratio of Tagrisso used 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), is considered positive.