Repotrectinib NDA Under NMPA Review for Locally Advanced or Metastatic ROS1+ NSCLC

June 28, 2023

Article

The National Medical Products Administration in China has accepted for review a new drug application seeking the approval of repotrectinib for use in adult patients with locally advanced or metastatic ROS1-positive non–small cell lung cancer.

Rafael G. Amado, MD

The National Medical Products Administration (NMPA) in China has accepted for review a new drug application (NDA) seeking the approval of repotrectinib for use in adult patients with locally advanced or metastatic ROS1-positive non–small cell lung cancer (NSCLC).¹

Repotrectinib is under evaluation in the phase 1/2 TRIDENT-1 trial (NCT03093116), and topline data indicated that the agent elicited a confirmed objective response rate (ORR) of 79% (95% CI, 95% CI, 68%-88%) in those with ROS1-positive NSCLC who did not have prior exposure to TKIs (n = 71); this included a complete response rate of 6% and a partial response rate of 73%.²

The duration of response (DOR) ranged from 1.4+ months to 35.1+ months, and at a median follow-up of 10.2 months, the estimated percentage of patients remaining in response for 6 months was 91% (95% CI, 82%-100%). Rates for 9, 12, and 18 months were 88% (95% CI, 78%-98%), 85% (95% CI, 73%-96%), and 76% (95% CI, 61%-91%), respectively.

Moreover, the progression-free survival (PFS) reported with repotrectinib ranged from 0+ months to 40.4+ months, with 91% (95% CI, 84%-98%), 85% (95% CI, 75%-94%), 82% (95% CI, 72%-93%), and 72% (95% CI, 58%-86%) of patients estimated to remain free of disease progression at 6, 9, 12, and 18 months, respectively.

In the patients who previously received treatment with 1 TKI and platinum-based chemotherapy (n = 26), repotrectinib induced an ORR of 42% (95% CI, 23%-63%). In those who previously received 2 prior TKIs and no chemotherapy (n = 18), the ORR with the agent was 28% (95% CI, 10%-54%); this rate was 36% (95% CI, 23%-50%) in those who previously received 1 TKI and no chemotherapy (n = 56). In the 17 patients whose tumors harbored a ROS1 G2032R mutation, the ORR was 59% (95% CI, 33%-82%).

“We are pleased to obtain the NMPA’s acceptance of our NDA for repotrectinib, which further supports repotrectinib as a potential best-in-class treatment for patients with ROS1-positive NSCLC in China,” Rafael G. Amado, MD, president and head of Global Oncology Research and Development at Zai Lab, stated in a press release.¹ “There is a significant unmet need for patients given the limited durability of benefit, the emergence of resistance to approved therapies, and eventual tumor progression. We look forward to collaborating with the NMPA during the review process in a joint effort to bring this important medicine to patients in need as soon as possible.”

TRIDENT-1, a global, open-label, multicenter, first-in-human trial, was comprised of 2 phases that will enroll patients to 6 expansion cohorts, including those with TKI-naïve and -pretreated disease who have ROS1-positive locally advanced or metastatic NSCLC and NTRK-positive advanced solid tumors.³

In the first portion of the research, investigators set out to identify the recommended phase 2 dose of repotrectinib, to assess for dose-limiting toxicities, and to examine the pharmacokinetic profile of the agent, specifically maximum plasma concentration and area under the plasma concentration time curve.

For the second portion, the key objective is ORR as evaluated by blinded independent central review and RECIST v1.1 criteria. Secondary objectives include DOR, clinical benefit rate, PFS, overall survival, and intracranial ORR.

Safety data from the pooled phase 1/2 populations (n = 380) indicated that repotrectinib was well tolerated. No new safety signals were observed. Dizziness represented the most common treatment-emergent toxicity with repotrectinib and occurred in 61% of patients.

In May 2023, the FDA granted priority review to an NDA seeking the approval of repotrectinib in patients with ROS1-positive locally advanced or metastatic NSCLC.⁴ This application is supported by findings from TRIDENT-1. Under the Prescription Drug User Fee Act, the regulatory agency will decide on the NDA by November 27, 2023.