Table 5:

FDA Benefit-Risk Analysis

Dimension	Evidence and Uncertainties	Conclusions and Reasons
Analysis of Condition	• ROS1 rearrangement occurs in 1 to 2% of NSCLC.2 • Overall survival (OS) for patients with NSCLC at 5-years has been reported as 22% and between 5.5% to 8% in the metastatic setting.4,5 Patients with or without ROS1-positive NSCLC have similar outcomes.4	Locally advanced or metastatic ROS1-positive NSCLC is a life-threatening condition with poor survival.
Current Treatment Options	• ROS1 TKI therapy is the current standard of care for the treatment of advanced or metastatic ROS1-positive NSCLC.7 • Two products are approved for patients with advanced or metastatic ROS1-positive NSCLC; the response rate included in the product label is 66% (95% CI 51, 79) for crizotinib and is 74% (95 CI 64, 83) for entrectinib. • There are resistance mechanisms to TKIs for ROS1-positive NSCLC; common ROS1-resistance mutations include G2032R, D2033N, and S1986F.8 • Currently, there are no approved targeted therapies in patients previously treated with ROS1 TKI.	Although there are approved therapies for advanced or metastatic ROS1-positive NSCLC, patients may experience drug-related toxicity or their disease may develop resistance mechanisms. Therefore, there is an unmet medical need for adult patients with ROS1-positive NSCLC.
Benefit	• The primary efficacy data supporting this NDA is derived from the TRIDENT-1 Study, an open-label, multi-center, first-in-human study of repotrectinib conducted in adult patients with ROS1-positive NSCLC who were either ROS1 TKI naïve or who had received prior ROS1 therapy. • Among the ROS1 TKI-naïve patients, the ORR was 79% (95% CI 68, 88). The median duration of response was 34.1 months (95% CI 26, NE). In addition, seven out of 8 patients with measurable CNS metastases at baseline had responses in intracranial lesions. • Among the patients who had received 1 prior ROS1 TKI (crizotinib 82%, entrectinib 16%, and other 2%) with no prior platinum-based chemotherapy or immunotherapy, the ORR was 38% (95% CI 25, 52). The median duration of response was 14.8 months (95% CI 7.6, NE). Five of twelve patients with measurable CNS metastases at baseline had responses in intracranial lesions. • Eight of fifty-six patients who had received 1 prior ROS1 TKI had resistance mutations following TKI therapy. Responses were observed in 6 of these 8 patients.	Based on the observed durable ORR, nonclinical, and supportive mechanistic data, the submitted evidence meets the statutory evidentiary standard for traditional approval. A PMR has been issued to obtain the final ORR and DOR in the ROS1 TKI-naive and ROS1 TKI-pretreated patients with ROS1-positive NSCLC enrolled on TRIDENT-1.
Risk and Risk Management	• The pooled safety population for this NDA includes 351 adult patients advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements who received at least one dose of repotrectinib at the RP2D. • The most common (> 20%) adverse reactions were dizziness (64%), dysgeusia (50%), peripheral neuropathy (47%), constipation (37%), dyspnea (30%), ataxia (29%), fatigue (29%), cognitive disorders (23%), and nausea (20%), decreased sodium (3.5%), increased AST (2.9%), increased magnesium (2.9%), increased alkaline phosphatase (2.6%), and increased glucose (2%).	The observed safety profile is acceptable in the context of the treatment of patients with ROS1-positive NSCLC and is overall consistent with the known adverse effects of in-class drug products. There were no significant safety concerns identified during NDA review requiring risk management beyond labeling or warranting consideration for a Risk Evaluation and Mitigation Strategy (REMS). PMRs to address issues related to treatment toxicity with repotrectinib include studies to assess the risk of ocular toxicity, to address the impact of moderate or severe hepatic impairment, and to assess the risk of drug-drug interactions.

Source: Adapted from U.S. Food and Drug Administration, NDA Multi-disciplinary Review and Evaluation and Approval Package: repotrectinib (Augtyro^®).²¹