FDA Grants Fast Track to Repotrectinib in NTRK-Positive Advanced Solid Tumors

The FDA has granted a Fast Track designation to repotrectinib for the treatment of patients with advanced solid tumors that have an NTRK gene fusion and have progressed on at least 1 prior line of chemotherapy and 1 to 2 prior TRK tyrosine kinase inhibitors (TKIs), leaving them with no satisfactory alternative treatment options, announced Turning Point Therapeutics.¹

The designation is supported by findings from the early interim data from the registrational phase 2 TRIDENT-1 study, which has demonstrated an objective response rate of 50% in 3 of 6 patients with NTRK-positive, TKI-pretreated advanced solid tumors. Forty patients are planned for enrollment to this cohort, and the FDA recently provided guidance that 6 months of follow-up from the last response in this cohort may be sufficient enough to support a potential approval, whereas the previous guidance was 12 months.

According to interim data from the TRIDENT-1 study, 39 patients were evaluated for efficacy and safety. Among the 7 patients with ROS1-positive TKI-naïve non–small cell lung cancer (NSCLC), the objective response rate (ORR) was 86% (95% CI, 42%-100%), which included confirmed responses in 6 patients. The duration of response (DOR) ranged from 0.9+ to 2.0+ months, and each patient with a response maintained that response at the time of data cutoff. The remaining patient had an unconfirmed partial response.²

Among the 5 patients in the ROS1-positive NSCLC cohort who had been pretreated with 1 prior TKI and platinum-based chemotherapy, the ORR was 40% (95% CI, 5%-85%), and the DOR ranged from 4.5+ to 5.6+ months. Among the 6 patients with ROS1-positive NSCLC pretreated with 1 prior TKI and no chemotherapy, the ORR was 67% (95% CI, 22%-96%).

The ORR among 6 patients with NTRK-positive NSCLC who were pretreated with a TKI was 50% (95% CI, 12%-88%), and the DOR ranged from 1.7+ to 3.6+ months.

In terms of safety, all 39 patients were evaluable, and the investigators noted that the agent was well-tolerated. The majority of treatment-emergent adverse events were grades 1 or 2, the most common of any grade being dizziness (62%), fatigue (39%), constipation (33%), dysgeusia (33%), and dyspnea (28%). Grade 3 dizziness or dizziness leading to discontinuation was not observed in the study.

Repotrectinib is a next-generation kinase inhibitor that targets the ROS1 and TRK drivers in both NSCLC and solid tumors. This drug is also under evaluation in a phase 1/2 study of pediatric patients (NCT04094610). So far in this study and TRIDENT-1, repotrectinib has shown antitumor activity and durable responses among patients who are either treatment-naïve or pre-treated.¹

To enroll in the phase 1 portion of the TRIDENT-1 study, patients had to have a locally advanced or metastatic solid tumor that harbors an ALK, ROS1, or NTRK gene rearrangement. The ECOG performance status had to be 0 or 1, and patients must be ≥18 years of age to be eligible. Prior cytotoxic chemotherapy and prior immunotherapy were allowed in the study, but patients should have had resolution of all acute toxic effects from any anti-cancer therapy prior to the study. To enroll in the phase 2 portion, patients had to have a ROS1or NTRK gene fusion, an ECOG performance status of 0 or 1, be aged ≥12 years, and have at least 1 measurable target lesion according to RECIST v1.1.

Patients who were concurrently participating in another clinical trial, had symptomatic brain metastases or leptomeningeal involvement, or history of previous cancer, were ineligible to enroll to this study. Patients also may not have undergone a major surgery within 4 weeks of the repotrectinib initiation, nor could they have had a clinically significant cardiovascular disease.

To enroll in the phase 1 portion of the pediatric study, patients must have either an ALK, ROS1, or NTRKalteration and be aged 4 to 12 years old. Patients are allowed to have prior cytotoxic chemotherapy and prior immunotherapy. They must have measurable disease by RECIST v1.1, resolution of all acute toxic effects, a Lansky score of at least 50 (for those <16 years), and a life expectancy of 12 weeks or longer. For the phase 2 portion, patients must be aged 12 to <25 years. For cohort 1, patients must have NTRK fusion-positive advance solid tumor. Cohort 2 will include patients with NTRK fusion-positive advanced solid tumors, and cohort 3 will include patients with tumors or ALCL that is characterized by ALK, ROS1, or NTRK alterations.

The agent previously received 2 Fast Track designations for the treatment of patients with ROS1-positive advanced NSCLC; the first designation included patients with 1 prior line of platinum-based chemotherapy and 1 prior ROS1 TKI, and the second designation included patients without prior ROS1 TKI therapy. At this time, there are no approved targeted therapies for patients who had been previously treated with a ROS1 or TRKTKI.

The Fast Track designation will provide for a faster path to potential approval and is intended to facilitate the development and expedite the review process in order to both treat serious conditions and fulfill an unmet medical need.

<< View more from the interim findings from TRIDENT-1

_Reference

_{1. Turning point therapeutics grants fast track designation for repotrectinib in NTRK-positive TKI-pretreated advanced solid tumors. News Release. Turning Point Therapeutics. August 24, 2020. Accessed August 25, 2020. https://bit.ly/3gvTfBc}

_{2. Turning Point Therapeutics reports early interim data from registrational phase 2 trident-1 study of repotrectinib, provides regulatory update. News release. Turning Point Therapeutics. August 19, 2002. Accessed August 25, 2020. https://bit.ly/3iV1w3h}