In a registrational phase I/II TRIDENT-1 study, repotrectinib showed durable activity and led to a response in a high percentage of patients with ROS1 fusion–positive non-small cell lung cancer (NSCLC), which included patients with tumours that had not been previously treated with a ROS1 tyrosine kinase inhibitor (TKI), tumours that had been previously treated with a ROS1 TKI, ROS1 G2032R resistance mutations, and brain metastases.
Treatment with repotrectinib was mainly associated with low-grade adverse events. Side effects related to decreased TRK activity were as expected, a finding that was similar to that for other TKIs that inhibit TRK. Comparative trials may be needed to define the role of repotrectinib in the treatment sequence according to Dr. Alexander Drilon of the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College in New York, NY, US, Dr. Byoung Chul Cho of the Yonsei University College of Medicine in Seoul, South Korea, and TRIDENT-1 investigators, who published the study findings on the 11th of January 2024 issue of The New England Journal of Medicine.
ROS1 fusions are oncogenic drivers that occur in up to 2% of patients with NSCLC. The early-generation ROS1 TKIs, crizotinib and entrectinib, present two major challenges. First, acquired resistance mutations develop in at least 50% of patients treated with these agents and limit the durability of the response. Neither drug is active against recalcitrant ROS1 mutations, such as the G2032R mutation in the solvent front of the kinase domain, that are commonly acquired during treatment with any of several ROS1 TKIs. Second, intracranial activity can be suboptimal, and brain metastases are common in patients with ROS1 fusion–positive NSCLC.
Repotrectinib is a next-generation ROS1 and TRK TKI. Owing to its compact macrocyclic structure, repotrectinib has a small tyrosine kinase–binding interface. This characteristic allows repotrectinib to circumvent steric hindrance from ROS1 resistance mutations, which, in contrast to other ROS1 TKIs, enables the potent inhibition of both wild-type and G2032R-mutant ROS1 fusions. In addition, repotrectinib was designed to enhance the intracranial activity of the drug.
TRIDENT-1 is an ongoing international, registrational phase I/II study evaluating repotrectinib in patients with advanced, fusion-positive cancers including ROS1 fusion–positive NSCLC. In the latest article, published in The New England Journal of Medicine, the study team reports the efficacy of repotrectinib in patients with ROS1 fusion–positive NSCLC (phase I/II) and the safety of repotrectinib in patients treated at the recommended phase 2 dose.
The primary efficacy endpoint in the phase II study was confirmed objective response; efficacy analyses included patients from phase I and phase II. Duration of response (DoR), progression-free survival (PFS), and safety were secondary endpoints in phase II. Based on the results from the phase I study, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily.
Response occurred in 56 of the 71 patients (79%; 95% confidence interval [CI] 68 to 88) with ROS1 fusion–positive NSCLC who had not previously received a ROS1 TKI; the median DoR was 34.1 months (95% CI 25.6 to could not be estimated), and median PFS was 35.7 months (95% CI 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (38%; 95% CI 25 to 52) with ROS1 fusion–positive NSCLC who had previously received one ROS1 TKI and had never received chemotherapy; the median DoR was 14.8 months (95% CI 7.6 to could not be estimated), and median PFS was 9.0 months (95% CI 6.8 to 19.6). A total, 10 of the 17 patients (59%; 95% CI 33 to 82) with the ROS1 G2032R mutation had a response.
In total, 426 patients received the phase 2 dose. The most common treatment-related adverse events were dizziness occurring in 58% of the patients, dysgeusia in 50%, and paresthesia in 30%, and 3% discontinued repotrectinib owing to treatment-related adverse events. The most common adverse event that led to dose reduction in 11% of patients or to dose interruption in 8% was dizziness. The most common adverse event that led to treatment discontinuation was pneumonitis in 1% of patients. Fatal adverse events occurred in 19 patients (4%); none of the events were considered by the investigator to be related to the study treatment.
In terms of the patient-reported outcomes, in the cohort with no previous receipt of a ROS1 TKI, the mean global health status score at baseline was 61.4, with a stable score defined as less than 10 point increase or decrease from baseline or an improved score defined as at least 10 point increase from baseline in 65% of the patients at cycle 12 and a stable or improved score in 60% at cycle 22. In the pooled group with previous receipt of at least one ROS1 TKI, the mean global health status score at baseline was 58.2, with a stable or improved score in 71% of the patients at cycle 12 and a stable or improved score in 70% of those at cycle 22.
No ROS1 resistance mutations emerged during the treatment period in patients with disease progression who had not received a ROS1 TKI. Although ROS1 mutations emerged during the treatment period in 6 of the 43 patients with disease progression who had previously received at least one ROS1 TKI, these data should be interpreted with caution because of limitations in the sensitivity of the assays used for the detection of mutations. Additional research is needed to understand potential bypass mechanisms, such as up-regulation of bypass signalling pathways (e.g. the MAPK pathway) and phenotypic changes (e.g. histologic transformation).
The authors commented that many responses were deep and occurred quickly, with a median time to response of 1.8 months coinciding with the first follow-up scan. They emphasized that the antitumour activity of repotrectinib was durable, with a median DoR of 34.1 months and a median PFS of 35.7 months. By comparison, entrectinib led to a median DoR of 20.5 months and a median PFS of 15.7 months, and crizotinib led to a median DoR of 24.7 months and a median PFS of 19.3 months.
Time-to-event efficacy endpoints and safety are continuing to be assessed in TRIDENT-1 to characterise long-term outcomes. Although other next-generation ROS1 inhibitors (e.g. taletrectinib and NVL-520) are in development, this registrational study of repotrectinib offers insights into the activity of next-generation, CNS-active ROS1 inhibitors.
The study was supported by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb.
Reference
Drilon A, Camidge R, Lin JJ, et al. for the TRIDENT-1 Investigators. Repotrectinib in ROS1 Fusion–Positive Non–Small-Cell Lung Cancer. N Engl J Med 2024;390:118-131.