FDA Grants Priority Review to Repotrectinib for ROS1+ NSCLC

FDA

The FDA has granted priority review to repotrectinib (TPX-0005) for the treatment of patients with ROS1-positive locally advanced or metastatic non–small cell lung cancer (NSCLC).¹

The designation is based on data from the registrational phase 1/2 TRIDENT-1 trial (NCT03093116), which will inform the FDA’s decision regarding the agent’s approval by November 27, 2023, under the Prescription Drug User Fee Act.

“Patients with ROS1-positive NSCLC face a rare disease with a significant unmet medical need given the limited durability of benefit and emergence of resistance to approved therapies,” Jonathan Cheng, MD, senior vice president and head of oncology development at Bristol Myers Squibb, said in a press release.

The global, open-label, multicenter, first-in-human TRIDENT-1 trial is evaluating the safety, tolerability, pharmacokinetics, and efficacy of repotrectinib in patients with advanced solid tumors, including NSCLC. The study consists of two phases, and phase 2 will enroll patients to six expansion cohorts, including TKI-naïve and TKI-pretreated patients with ROS1-positive locally advanced or metastatic NSCLC and NTRK-positive advanced solid tumors.

Phase 1 was designed to identify any dose-limiting toxicity and establish the recommended phase 2 dose of the agent, along with pharmacokinetic end points including repotrectinib’s maximum plasma concentration and area under the plasma concentration time curve. In phase 2, objective response rate (ORR) assessed via blinded independent central review per RECIST v1.1 criteria is serving as the primary end point. Secondary end points include duration of response (DOR), clinical benefit rate, progression-free survival (PFS), overall survival, and intracranial ORR.²

The safety analysis included 380 patients treated in the pooled phase 1 and phase 2 portions of TRIDENT-1, of which 287 patients received the phase 2 dose. The efficacy analyses included patients from phase 1 with an identified ROS1 fusion at baseline and those from phase 2. All patients received at least one dose of repotrectinib and had at least four months of follow-up.

Topline findings from the trial, which were presented with a data cutoff date of February 11, 2022, demonstrated that the confirmed ORR was 79% (n = 56/71; 95% CI, 68%-88%) in patients with ROS1-positive, TKI-naïve advanced NSCLC. Four patients (6%) achieved a complete response, and 52 patients (73%) achieved a partial response.³

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

PFS ranged from 0+ to 40.4+ months. The likelihood of patients remaining progression free at 6, 9, 12, and 18 months was 91% (95% CI, 84%-98%), 85% (95% CI, 75%-94%), 82% (95% CI, 72%-93%), and 72% (95% CI, 58%-86%), respectively.

Among patients who previously received treatment with a TKI (n = 100), the confirmed ORR was 42% (n = 11/26; 95% CI, 23%-63%) in patients pretreated with one TKI and platinum-based chemotherapy, 28% (n = 5/18; 95% CI; 10%-54%) in those pretreated with two prior TKIs without chemotherapy, 36% (n = 20/56; 95% CI; 23%-50%) in those pretreated with 1 TKI without chemotherapy, and 59% (n = 10/17; 95% CI, 33%-82%) in those with a ROS1 G2032R solvent front mutation.

Regarding safety, repotrectinib was generally well tolerated in the pooled phase 1/2 patient population, and no new safety signals were identified. The most frequent treatment-emergent adverse effect was dizziness (any grade, 61%). Similar safety findings were seen in patients treated at the phase 2 dose.

“The FDA’s acceptance of this application marks an exciting milestone on our journey to bring this next-generation tyrosine kinase inhibitor to patients. If approved, this would represent a potential best-in-class option for TKI-naïve patients and a potential first-in-class option for patients with ROS1-positive NSCLC who have been previously treated with TKI, and for whom there are currently no approved targeted therapies available. We are eager to continue working closely with the FDA on the review of this precision medicine, which has shown unprecedented level of durability of responses and robust intracranial responses in patients with ROS1-positive NSCLC,” Cheng added.

References

1. U.S. Food and Drug Administration accepts for priority review Bristol Myers Squibb’s application for repotrectinib for the treatment of patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer. News release. Bristol Myers Squibb. May 30, 2023. Accessed May 30, 2023. https://investors.bms.com/iframes/press-releases/press-release-details/2023
2. A study of repotrectinib (TPX-0005) in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements (TRIDENT-1). ClinicalTrials.gov. Updated May 18, 2023. Accessed May 30, 2023. https://clinicaltrials.gov/ct2/show/NCT03093116
3. Turning Point Therapeutics announces positive topline data by blinded independent central review for repotrectinib across all ROS1-positive NSCLC cohorts of phase 1/2 TRIDENT-1 study. News release. Turning Point Therapeutics. April 12, 2022. Accessed May 30, 2023. https://www.tptherapeutics.com/news-releases/news-release-details/turning-point-therapeutics-announces-positive-topline-data