Dr Nagasaka on the Efficacy of Repotrectinib in Locally Advanced/Metastatic ROS1+ NSCLC

Misako Nagasaka, MD, associate clinical professor, Division of Hematology/Oncology, University of California, Irvine School of Medicine, discusses key findings from the phase 1/2 TRIDENT-1 trial (NCT03093116) of repotrectinib (Augtyro) in patients with locally advanced or metastatic ROS1-positive non–small cell lung cancer (NSCLC).

On November 15, 2023, the FDA approved repotrectinib for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC. This regulatory decision was based on findings from the open-label, single-arm TRIDENT-1 trial, in which repotrectinib elicited an overall response rate (ORR) of 79% (95% CI, 68%-88%) in patients naive to prior TKIs (n = 71). This included respective complete response (CR) and partial response (PR) rates of 6% and 73%, with a median duration of response (DOR) of 34.1 months (95% CI, 25.6-not evaluable [NE]). In the population of patients who had received 1 prior ROS1 TKI and no prior chemotherapy (n = 56), the ORR was 38% (95% CI, 25%-52%), including respective CR and PR rates of 5% and 32%. In this population, the median DOR was 14.8 months (95% CI, 7.6-NE).

Responses with repotrectinib were also observed in the intracranial lesions of patients with measurable central nervous system metastases at baseline and in patients who displayed resistance mutations following TKI therapy, Nagasaka says. The intracranial ORR was 89% (95% CI, 52%-100%) in TKI-naive patients and 38% (95% CI, 14%-68%) in patients who had received 1 prior TKI and no prior chemotherapy.

Furthermore, no TKI-naive patients who progressed with repotrectinib developed on-target resistance mutations, Nagasaka emphasizes. Among the patients with baseline ROS1 G2032R mutations who had received prior TKIs, the ORR was 59% (95% CI, 33%-82%).

One of the most common adverse effects (AEs) associated with repotrectinib in TRIDENT-1 was dizziness, which was often transient and no longer bothered patients after the first couple weeks of treatment, according to Nagasaka. The recommended starting dose of repotrectinib is 160 mg orally once daily with or without food for 14 days, at which point the recommended dose increases to 160 mg twice daily. Treatment with the agent continued until disease progression or unacceptable toxicity. Most patients in TRIDENT-1 received the increased dose after 2 weeks of treatment, Nagasaka says. Upon consultation, patients were permitted to delay the twice-daily dosing when needed, Nagasaka notes. Repotrectinib dosing should be carefully monitored and titrated appropriately for each patient, Nagasaka emphasizes.

Other common AEs associated with repotrectinib include dysgeusia, peripheral neuropathy, and constipation, Nagasaka concludes.