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The FDA approved repotrectinib (Augtyro) -- an oral tyrosine kinase inhibitor (TKI) targeting ROS1 oncogenic fusions -- for the treatment of locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC), on Wednesday.

Approval was based on the study, in which the drug was shown to achieve high objective response rates (ORRs) in TKI-naive and TKI-pretreated patients.

"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, of Massachusetts General Hospital and Harvard Medical School in Boston, who was the primary investigator of TRIDENT-1, in the company's 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."

TRIDENT-1 is a global, multicenter, single-arm, open-label, multi-cohort, phase I/II clinical trial evaluating the safety, tolerability, pharmacokinetics, and anti-tumor activity of repotrectinib in patients with advanced solid tumors, including NSCLC.

In a cohort of 71 patients who were TKI-naive, the ORR was 79% (95% CI 68-88), with 6% experiencing complete responses and 73% having partial responses. The median duration of response (mDOR) was 34.1 months.

Among 56 patients who had been pretreated with one prior ROS1 TKI and no prior chemotherapy, the ORR was 38% (95% CI 25-52), with 5% achieving complete responses and 32% experiencing partial responses. The mDOR was 14.8 months.

In patients who had measurable central nervous system metastases at baseline, responses in intracranial lesions were observed in seven of eight TKI-naive patients, and five of 12 of those who were TKI-pretreated.

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.

Regarding safety, among a total of 264 patients who received repotrectinib for ROS1-positive NSCLC, the most common adverse reactions were dizziness (63%), dysgeusia (48%), peripheral neuropathy (47%), constipation (36%), dyspnea (30%), ataxia (28%), fatigue (24%), cognitive disorders (23%), and muscular weakness (21%).

Serious adverse reactions occurred in 33% of patients, and included pneumonia (5.7%), dyspnea (3.8%), pleural effusion (3.4%), and hypoxia (3%).

Fatal adverse reactions occurred in 4.2% of patients who received repotrectinib, including death, pneumonia, pneumonia aspiration, cardiac arrest, sudden cardiac death, cardiac failure, sudden death, hypoxia, dyspnea, respiratory failure, tremor, and disseminated intravascular coagulation.

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