Regulatory Decision Summary for Augtyro

The purpose of this New Drug Submission (NDS) was to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Augtyro (repotrectinib) 40 mg and 160 mg capsules orally administered, for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).

Upon review of the submitted data package, Health Canada authorized Augtyro for the indication as proposed by the sponsor.

This submission was reviewed as a Project Orbis Type C submission. Health Canada collaborated with the United States Food and Drug Administration (FDA), the Australian Therapeutic Goods Administration (TGA), Swissmedic (SMC), the Brazilian Health Regulatory Agency (Anvisa), and the Singapore Health Sciences Authority (HSA) for the review.

Evidence supporting the efficacy and safety of Augtyro (repotrectinib) in adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) was provided in TRIDENT-1, a Phase 1/2, multicenter, single-arm, open-label, multi-cohort clinical trial. The efficacy evaluation was based primarily on the prespecified pooled analysis set of 71 ROS1 tyrosine kinase inhibitor (TKI)-naïve patients (8 from Phase 1 and 63 from Phase 2) who had received up to one prior line of platinum-based chemotherapy and/or immunotherapy (EXP-1), and 56 patients (3 from Phase 1 and 53 from Phase 2) who had received one prior ROS1 TKI with no prior platinum-based chemotherapy or immunotherapy (EXP-4). The primary efficacy endpoint was overall response rate (ORR), with key secondary endpoints of duration of response (DOR) and intracranial response, according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as assessed by blinded independent central review (BICR).

Treatment with repotrectinib resulted in a clinically meaningful and durable benefit in both ROS1 TKI-naïve and ROS1 TKI-pretreated patients. In TKI-naïve patients, confirmed ORR by BICR was 78.9% (56 of 71; 95% confidence interval [CI]: 67.6, 87.7), including four complete responses and 52 partial responses. The median DOR was 34.1 months (95% CI: 25.6, not estimable). The efficacy benefit was consistent between patients with or without prior chemotherapy. In TKI-pretreated patients, confirmed ORR by BICR was 37.5% (21 of 56; 95% CI: 24.9, 51.5), including three complete responses and 18 partial responses. The median DOR was 14.75 months (95% CI: 7.56, not estimable). Among patients with measurable central nervous system metastases at baseline, intracranial responses were observed in eight of nine TKI-naïve patients and five of 13 TKI-pretreated patients. The benefit of repotrectinib was generally consistent across prespecified subgroups, including those with resistance mutations.

The overall safety profile of Augtyro was evaluated in 426 patients from TRIDENT-1 (320 patients with ROS1-positive NSCLC and 106 patients with other solid tumors harboring a ROS1, ALK, or NTRK gene alteration) who received Augtyro at the recommended clinical dose of 160 mg twice daily. Most patients experienced at least one treatment-emergent adverse event; 35% experienced a serious adverse event, most commonly pneumonia, dyspnea, pleural effusion, and hypoxia. Clinically significant adverse events identified in the overall population included hepatotoxicity, hyperuricemia, skeletal fractures, myalgia, central nervous system effects (such as dizziness, ataxia, cognitive impairment, mood disorders, and sleep disorders), peripheral neuropathy, vision disorders, and embryofetal toxicity. Other adverse drug reactions experienced in 10% or more of ROS1-positive NSCLC patients included headache, gastrointestinal disorders (constipation, nausea, and diarrhea), dyspnea, cough, pneumonia, fatigue, edema, and increased weight. Overall, there was a low incidence of Grade 3-4 events in TRIDENT-1. Adverse events were mainly managed with Augtyro dose interruption and/or standard medical care; 38% of patients required a dose reduction, and permanent discontinuation occurred in 7% of patients. All significant safety risks are described in the Warnings and Precautions and Adverse Reactions sections of the Augtyro Product Monograph.

A Risk Management Plan for Augtyro was submitted and considered acceptable.

The chemistry and manufacturing information demonstrated that the drug substance and drug product can be consistently manufactured to meet approved specifications.

Comparative bioavailability data showed that a high-fat, high-calorie meal had no significant impact on the rate and extent of exposure of repotrectinib in the commercial formulation of Augtyro.

In summary, the efficacy and safety evidence from TRIDENT-1 was sufficient to establish clinical benefit of repotrectinib in adult patients with advanced ROS1-positive NSCLC. Repotrectinib provides an additional treatment option for TKI-naïve patients and a targeted therapy option for TKI-pretreated patients for whom no approved TKI exists. The safety profile of Augtyro is considered acceptable, with adverse events typically managed through dose modifications and/or standard medical care. Appropriate labelling in the final Product Monograph, including Warnings and Precautions and Recommended Dose and Dosage Adjustment sections, was implemented to adequately manage risks. Clinical pharmacology and non-clinical data also support the intended use of Augtyro in the target population. Key clinical pharmacology and non-clinical findings, relevant risks, and uncertainties were addressed in the final Product Monograph.

Overall, the benefit-harm-uncertainty profile was favourable for Augtyro 40 mg and 160 mg for the approved indication when used under the conditions recommended in the Product Monograph. Therefore, a Notice of Compliance was recommended.

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