FDA Approves Repotrectinib for Locally Advanced or Metastatic ROS1+ NSCLC


The FDA has approved repotrectinib (Augtyro) for the treatment of adult patients with locally advanced or metastatic ROS1-positive non–small cell lung cancer.



The FDA has approved repotrectinib (Augtyro) for the treatment of adult patients with locally advanced or metastatic ROS1-positive non–small cell lung cancer.1,2

The regulatory decision is based on findings from the phase 1/2 TRIDENT-1 study (NCT03093116). In TKI-naive patients (n = 71), repotrectinib elicited a confirmed objective response rate (ORR) of 79% (95% CI, 68%-88%), which included a complete response (CR) rate of 6% and a partial response (PR) rate of 73%. The median duration of response (DOR) was 34.1 months (95% CI, 25.6-not evaluable [NE]). Seventy percent of patients experienced a response that lasted for at least 12 months.

In those who were pretreated with 1 prior ROS1 TKI and who did not receive prior chemotherapy or immunotherapy (n = 56), the confirmed ORR was 38% (95% CI, 25%-52%), which was comprised of a 5% CR rate and a 32% PR rate. In this group, the median DOR was 14.8 months (95% CI, 7.6-NE) with 48% of patients experiencing a response that persisted for 12 months or longer.

Moreover, in patients who had measurable central nervous system (CNS) metastases at baseline, responses in intracranial lesions were observed in 7 of 8 TKI-naive patients and 5 of 12 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,” Jessica J. Lin, MD, TRIDENT-1 primary investigator and attending physician at the Center for Thoracic Cancers at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, stated 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.”

The global, multicenter, single-arm, open-label, multicohort TRIDENT-1 trial enrolled patients with locally advanced or metastatic NSCLC harboring ROS1 fusions who have measurable disease by RECIST v1.1 criteria and an ECOG performance status of 0 or 1. Those with symptomatic brain metastases were excluded.

Those in the TKI-naive population received up to 1 prior line of platinum-based chemotherapy and/or immunotherapy; those in the TKI-pretreated population received 1 previous ROS1 TKI without prior platinum-based chemotherapy or immunotherapy.

Study participants received 160 mg of repotrectinib once daily for 14 days; the dose was then increased to 160 mg twice daily until progressive disease or unacceptable toxicity. Tumor assessments were conducted at least every 8 weeks.

The trial's primary end points were ORR and DOR per blinded independent central review (BICR) assessment and by RECIST v1.1 criteria. Investigators also evaluated intracranial response by BICR and modified RECIST v1.1 criteria.

In the TKI-naive population, the median age was 57 years (range, 28-80). Most patients were female (60.6%), Asian (67.6%), never-smokers (63.4%), had a baseline ECOG performance status of 1 (66.2%), had metastatic disease (94.4%), and adenocarcinoma (97.2%). CNS metastases were present in 25.4% of patients. Moreover, 28.2% of patients previously received chemotherapy comprised of platinum-based chemotherapy and/or immunotherapy for locally advanced disease.

In the TKI-pretreated population, the median age was 57 years (range, 33-78). Patients previously received crizotinib (Xalkori; 82%) and entrectinib (Rozlytrek; 16%). More than half of patients were female (67.9%) and Asian (48.2%). Additionally, 64.3% of patients were never-smokers and 67.9% had an ECOG performance status of 1 at baseline. Most patients had metastatic disease (98.2%) and adenocarcinoma (94.6%). Just under half of patients (42.9%) had CNS metastases.

Additional data revealed that in the 56 ROS1 inhibitor–pretreated patients, 8 harbored resistance mutations after TKI therapy. Responses were reported in 6 of these 8 patients; responders included those with solvent front (G2032R), gatekeeper (L2026M), and other mutations (S1986F/Y).

The safety of repotrectinib was examined in 264 patients with ROS1-positive NSCLC enrolled in the trial. Fifty-two percent of patients were exposed for 6 months or longer and 27% were exposed for longer than 12 months.

Serious toxicities were experienced by 33% of patients, and 4.2% experienced adverse effects (AEs) that proved fatal. Dose interruptions and reductions due to AEs were required by 48% and 35% of patients, respectively; 8% experienced AEs that resulted in treatment discontinuation.

The most common AEs to occur in at least 10% of patients included dizziness (all grade, 63%; grade 3 or 4, 1.9%), dysgeusia (48%; 0%), peripheral neuropathy (47%; 1.9%), ataxia (28%; 0.4%), cognitive disorders (23%; 0.8%), headache (19%; 0%), constipation (36%; 0%), nausea (19%; 0.4%), diarrhea (13%; 0.4%), vomiting (10%; 0.8%), dyspnea (30%; 7%), cough (14%; 0%), fatigue (24%; 1.1%), edema (12%; 0.8%), muscular weakness (21%; 1.5%), myalgia (12%; 0.4%), increased weight (14%; 1.9%), and vision disorders (11%; 0%).


  1. US Food and Drug Administration approves Augtyro™ (repotrectinib), a next-generation Tyrosine Kinase Inhibitor (TKI), for the treatment of Locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). News release. Bristol Myers Squibb. November 15, 2023. Accessed November 15, 2023. https://news.bms.com/news/corporate-financial/2023/U.S.-Food-and-Drug-Administration-Approves-Augtyro-repotrectinib-a-Next-Generation-Tyrosine-Kinase-Inhibitor-TKI-for-the-Treatment-of-Locally-Advanced-or-Metastatic-ROS1-Positive-Non-Small-Cell-Lung-Cancer-NSCLC/default.aspx
  2. Repotrectinib (Augtyro). Prescribing information; November 2023; Bristol Myers Squibb. Accessed November 15, 2023.
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