On November 15, 2023, the FDA approved repotrectinib (Augtyro; Bristol Myers Squibb), a ROS1 tyrosine kinase inhibitor (TKI), for the treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) associated with ROS1 fusion.
The FDA granted repotrectinib priority review, breakthrough therapy, and fast track designations for this indication.
Repotrectinib is a next-generation TKI and the first ROS1 inhibitor that is approved by the FDA for the treatment ROS1-positive locally advanced or metastatic NSCLC in patients who have previously received another ROS1 TKI, as well as for those who have not previously received a TKI treatment.
The FDA approval of repotrectinib was based on the results of the TRIDENT-1 study, an international, multicenter, single-arm, open-label, multicohort, phase 1/2 clinical trial. TRIDENT-1 evaluated the efficacy of repotrectinib in patients with locally advanced or metastatic NSCLC and ROS1 fusion who were either TKI naïve (n=71) or had received 1 previous line of platinum-based chemotherapy and/or immunotherapy, or in patients who previously had received a TKI (n=56) but not chemotherapy or immunotherapy. The main efficacy measures were overall response rate (ORR) to repotrectinib therapy and the duration of response (DOR), based on RECIST V1.1, as assessed by blinded independent central review.
The ORR was 79% (95% confidence interval [CI], 68-88), including 6% complete responses and 73% partial responses, in the ROS1 TKI-naïve group, and 38% (95% CI, 25-52), which included 5% complete responses and 34.1% partial responses, in the patients who had previously received treatment with a ROS1 inhibitor. The median DOR was 34.1 months (95% CI, 25.6-not evaluable) in the TKI-naïve group and 14.8 months (95% CI, 7.6-not evaluable) in the TKI-pretreatment group.
In addition, among the patients who had measurable central nervous system metastases at baseline (ie, 8 TKI-naïve and 12 TKI-experienced patients), responses in intracranial lesions were observed in 7 of the 8 TKI-naïve patients and in 5 of the 12 TKI-experienced patients. Patients with symptomatic brain metastases were excluded from the study.
“ROS1-positive NSCLC patients and their families face a stressful journey because our cancer can be difficult to treat, especially when it spreads to the brain,” said Janet Freeman-Daily, Cofounder and President of the patient advocacy organization, The ROS1ders, in a press release. “Today’s approval [of repotrectinib] brings a new treatment option for the ROS1-positive patient community, which gives us hope for more time with loved ones,” she added.
The study results showed the benefits of repotrectinib therapy for patients with locally advanced or metastatic ROS1 fusion–positive NSCLC who were TKI naïve, as well as for those who received previous TKI treatment, which may suggest the role of repotrectinib as a new standard of care for this patient population, as indicated by Jessica J. Lin, MD, primary investigator of TRIDENT-1, Attending Physician, Center for Thoracic Cancers, Massachusetts General Hospital, and Assistant Professor of Medicine, Harvard Medical School, Boston.
“New treatment options continue to be needed for patients with ROS1 fusion-positive NSCLC that support important clinical goals, including achieving durable therapeutic responses,” Dr Lin said in a press release. “Based on the data we have seen in the TRIDENT-1 trial, repotrectinib has the potential to become a new standard of care option for patients with locally advanced or metastatic ROS1 fusion–positive lung cancer,” she noted.
The most common (≥20%) adverse events with repotrectinib in the TRIDENT-1 study were dizziness (63%, including 1.9% grade 3), dysgeusia (48%), peripheral neuropathy (47%), constipation (36%), dyspnea (30%), ataxia (28%), fatigue (24%), cognitive disorders (23%), and muscular weakness (21%).
Serious adverse events (≥2%) with repotrectinib included pneumonia (5.7%), dyspnea (3.8%), pleural effusion (3.4%), and hypoxia (3%).
A total of 8% of patients discontinued repotrectinib treatment, 48% had dose interruptions, and 35% had dose reductions because of adverse events; fatal adverse events occurred in 4.2% of the patients.
The recommended dose of repotrectinib is 160 mg orally once daily for 14 days, followed by 160 mg twice daily until disease progression or unacceptable adverse events.