On November 15, 2023, the U.S. Food and Drug Administration (FDA) approved the next-generation tyrosine kinase inhibitor repotrectinib (Augtyro) for the treatment of locally advanced or metastatic ROS1-positive non–small cell lung cancer (NSCLC). According to the American Lung Association, the ROS1 gene alteration occurs in about 1% to 2% of lung cancers and is more common in patients with little to no smoking history.
Pivotal Study
The approval is based on results from the TRIDENT-1 trial, an open-label, single-arm, phase I/II that evaluated repotrectinib in both patients who had received a prior tyrosine kinase inhibitor (n = 56) and those who had not (n = 71). The primary endpoint was objective response rate. Key secondary endpoints included duration of response according to Response Evaluation Criteria in Solid Tumors, version 1.1, as assessed by blinded independent central review; progression-free survival; and intracranial response.
In tyrosine kinase inhibitor–naive patients, the objective response rate was 79% (95% confidence interval [CI] = 68%–88%). The median duration of response was 34.1 months. Among patients pretreated with one prior ROS1 tyrosine kinase inhibitor and no prior chemotherapy, the overall response rate was 38% (95% CI = 25%–52%), and the median duration of response was 14.8 months. Among those who had measurable central nervous system metastases at baseline, responses in intracranial lesions were observed in 7 of 8 tyrosine kinase inhibitor–naive patients and 5 of 12 of those who had been pretreated with a tyrosine kinase inhibitor.
In TRIDENT-1, the most common adverse reactions to repotrectinib were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. Serious adverse reactions—including pneumonia, dyspnea, pleural effusion, and hypoxia—occurred in 33% of patients who received the drug. Fatal adverse reactions were reported in 4.2% of repotrectinib recipients.
The FDA-approved dosing for repotrectinib is 160 mg orally once daily for 14 days, then increased to 160 mg twice daily until disease progression or unacceptable toxicity.
Investigator Comments
“New treatment options continue to be needed for patients with ROS1 fusion–positive NSCLC that support important clinical goals, including achieving durable therapeutic responses,” said Jessica J. Lin, MD, TRIDENT-1 primary investigator, Attending Physician at the Center for Thoracic Cancers at Massachusetts General Hospital, and Assistant Professor of Medicine at Harvard Medical School. “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.”
