Regulatory Decision Summary for Tabrecta

The purpose of this New Drug Submission (NDS) was to obtain market authorization for Tabrecta, filed by the sponsor, for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with mesenchymal-epithelial transition (MET) exon 14 skipping mutation, under the Notice of Compliance with Conditions (NOC/c) guidance.

Upon review of the submitted data package, Health Canada authorized Tabrecta for the following indication under the NOC/c guidance: Tabrecta is indicated for the treatment of adult patients with locally advanced unresectable or metastatic non-small cell lung cancer (NSCLC) harbouring mesenchymal-epithelial transition (MET) exon 14 skipping alterations.

This submission was reviewed under Project Orbis Type C. The Canadian regulatory decision was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was used as an added reference.

The efficacy of Tabrecta was evaluated in 160 adult patients with mesenchymal-epithelial transition exon 14 (METex14)-altered locally advanced or metastatic non-small cell lung cancer (NSCLC) in the pivotal study A2201 (GEOMETRY mono-1). Patients received Tabrecta 400 mg twice daily until disease progression or unacceptable toxicities. The primary efficacy endpoint was overall response rate (ORR) determined by a blinded independent review committee according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. The key secondary efficacy endpoint was duration of response (DOR) determined by the blinded independent review committee.

Among the 60 patients who had not received any prior systemic treatments for advanced disease (i.e., treatment-naïve patients), the ORR was 66.7% (95% confidence interval [CI]: 53.3, 78.3) with a median DOR of 12.6 months (95% CI: 8.4, not estimable). Among the 100 patients who had received one or two prior lines of systemic therapy for advanced disease (i.e., previously treated patients), the ORR was 44.0% (95% CI: 34.1, 54.3) with a median DOR of 9.7 months (95% CI: 5.6, 13.0). These efficacy results were considered promising evidence of clinical benefit under the recommended condition of use. There were 13 (8%) patients with METex14-altered advanced squamous cell lung carcinoma, and the ORR was 15.4% (95% CI: 1.9, 45.4) in this subpopulation. This result should be interpreted with caution given the inherent risks with subgroup analyses.

The most common adverse reactions (≥20%) were peripheral edema, nausea, fatigue, vomiting, blood creatinine increased, dyspnea, and decreased appetite. The most common Grade 3 or 4 adverse reactions (≥5%) were peripheral edema, fatigue, dyspnea, alanine aminotransferase increased, and lipase increased. Tabrecta can cause serious, life-threatening adverse reactions including interstitial lung disease/pneumonitis and hepatotoxicity. Based on findings from non-clinical studies, Tabrecta can cause fetal harm when administered to a pregnant woman, and there is a risk of photosensitivity reaction in patients receiving Tabrecta. The safety of Tabrecta has not been evaluated in patients with severe renal or hepatic impairment or with inadequately controlled cardiovascular disease, as these patients were excluded from Tabrecta clinical trials.

Key safety findings were adequately described in the final Product Monograph; recommendations on safety monitoring and management were provided where applicable. A Risk Management Plan for Tabrecta was reviewed by the Marketed Health Products Directorate and modified during the review. The Risk Management Plan was considered acceptable, with revisions required to the Tabrecta Risk Management Plan version 2.0 (dated March 18, 2022) to be submitted within the next six months.

METex14-altered locally advanced unresectable or metastatic NSCLC is a serious, life-threatening disease not adequately managed by available therapies. The ORR and DOR results from the pivotal study A2201 were considered promising evidence supporting clinical benefit of Tabrecta in patients with METex14-altered advanced NSCLC. Based on the data reviewed, Tabrecta presented an acceptable and manageable safety profile in consideration of the intended population. The overall benefit-harm-uncertainty profile of Tabrecta for the recommended indication was favourable, under the Notice of Compliance with Conditions guidance. Additional clinical data are needed to verify Tabrecta’s clinical benefit.

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