Repotrectinib shows high response rates, durable activity in ROS1 fusion–positive NSCLC

The next-generation ROS1 and TRK tyrosine kinase inhibitor (TKI) repotrectinib has demonstrated high response rates and durable activity in patients with ROS1 fusion–positive non-small-cell lung cancer (NSCLC), regardless of whether they have previously received ROS1 TKI therapy, according to phase II results of the ongoing registrational TRIDENT-1 trial.

The international phase I–II trial evaluated the efficacy and safety of repotrectinib in patients with advanced solid tumours harbouring ROS1, NTRK1–3 or ALK gene fusions. Results of the phase I trial, in which 103 patients with fusion-positive tumours were treated, established 160 mg daily for 14 days followed by 160 mg twice daily as the recommended phase II dose. [N Engl J Med 2024;390:118-131]

The phase II trial, conducted at 152 sites across 19 countries, included six cohorts of patients, four of which were patients with ROS1 fusion–positive NSCLC included in the efficacy population, while the other two were patients with NTRK fusion–positive solid tumours included in the safety analysis population. All patients enrolled in the phase II trial received repotrectinib until disease progression, onset of unacceptable toxicity, or withdrawal of consent.

The phase II primary efficacy endpoint of confirmed objective response rate was 79 percent among 71 patients with ROS1 fusion–positive NSCLC not previously treated with a ROS1 TKI, and 38 percent among 56 patients with ROS1 fusion–positive NSCLC previously treated with one ROS1 TKI but not chemotherapy. Complete response rates were 10 percent and 5 percent, respectively.

The median duration of response (DoR) was 34.1 months in patients with ROS1 fusion–positive NSCLC not previously treated with a ROS1 TKI, and 14.8 months in patients with ROS1 fusion–positive NSCLC previously treated with one ROS1 TKI but not chemotherapy. Median time to response was 1.8 months in both cohorts.

In the two respective cohorts, median progression-free survival (PFS) was 35.7 months and 9.0 months. Estimated PFS rate was 70 percent at 18 months in patients with ROS1 fusion–positive NSCLC not previously treated with a ROS1 TKI, and 41 percent at 12 months in patients with ROS1 fusion–positive NSCLC previously treated with one ROS1 TKI but not chemotherapy.

Among patients previously treated with a ROS1 TKI but not chemotherapy, crizotinib had been used in 82 percent of the patients, while entrectinib had been used in 16 percent of the patients. The phase II dose of repotrectinib led to a response in 38 percent of the 53 treated patients, with a median DoR of 14.8 months, while median PFS was 9.0 months and estimated 12-month PFS rate was 42 percent.

In 17 patients with the ROS1 G2032R mutation, 59 percent had a response to repotrectinib.

Among 426 patients who received the phase II dose, the most common treatment-related adverse events (TRAEs) were dizziness (58 percent), dysgeusia (50 percent), and parethesia (30 percent). Treatment discontinuation due to TRAEs occurred in 3 percent of patients.

“[However], adverse events were mainly of low grade,” the investigators noted. “Side effects related to decreased TRK activity were as expected – a finding similar to that for other TKIs that inhibit TRK.”

“Comparative trials may be needed to define the role of repotrectinib in the treatment sequence,” they suggested.