Repotrectinib Demonstrates Durable Efficacy in TKI-Naive and -Pretreated ROS1+ NSCLC

Repotrectinib (Augtyro) showcased durable efficacy and intracranial activity in patients with ROS1-positive non–small cell lung cancer (NSCLC) enrolled to the phase 1/2 TRIDENT-1 study (NCT03093116) who were TKI naive or had prior exposure to at least 1 TKI, according to long-term data presented during the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer.1

At a median follow-up of at least 42 months, repotrectinib elicited a confirmed objective response rate (cORR) of 79% in the TKI-naive cohort (n = 71), which comprised a complete response (CR) rate of 14% and a partial response (PR) rate of 65%; the stable disease (SD) rate was 16% and the progressive disease (PD) rate was 3%. At a median follow-up of 44.6 months (range, 34.7-87.1), the median duration of response (DOR) was 36.8 months (95% CI, 27.4-not evaluable [NE]), and the median progression-free survival (PFS) was 31.1 months (95% CI, 21.9-NE). The 12-, 24-, 36-, and 48-month overall survival (OS) rates were 91%, 75%, 69%, and 56%, respectively. In 9 patients with measurable brain metastases at baseline, the intracranial ORR (IC-ORR) was 89% (95% CI, 52%-100%) and the median intracranial DOR (IC-DOR) was 43.2 months (95% CI, 11.1-NE).

In the TKI-pretreated cohort (n = 56), the cORR achieved with the agent was 41%, which included CR and PR rates of 7% and 34%, respectively; SD and PD rates were 38% and 16%. At a median follow-up of 42.0 months (range, 34.7-79.1), the median DOR was 17.8 months (95% CI, 7.5-31.4) and the median PFS was 8.6 months (95% CI, 5.5-14.5). The median OS was 25.1 months (95% CI, 12.8-32.1); the 12-, 24-, 36-, and 48-month OS rates were 68%, 51%, 36%, and 36%, respectively. In 13 patients with measurable brain metastases at baseline, the IC-ORR was 38% (95% CI, 14%-68%) and the median IC-DOR was NE (95% CI, 3.0-NE). Moreover, the cORR was 59% (95% CI, 33%-82%) in those with the ROS1 G2032R mutation spanning 3 TKI-pretreated cohorts (n = 17).

“These results further support repotrectinib as a standard of care for patients with ROS1-positive locally advanced or metastatic NSCLC,” Byoung Chul Cho, MD, PhD, of Yonsei Cancer Center, Yonsei University College of Medicine, in Seoul, South Korea, said in a presentation of the data.

What Is the Significance of the TRIDENT-1 Trial of Repotrectinib in NSCLC, and What Did It Examine?

The trial enrolled patients with locally advanced or metastatic solid tumors harboring ROS1 or NTRK1-3 gene fusions. Notably, those with asymptomatic central nervous system metastases were permitted. Data from the phase 1 dose-escalation portion of the trial led to the identification of the recommended phase 2 dose (RP2D) of the agent, which was 160 mg once daily for 14 days followed by 160 mg twice daily.

The phase 2 dose-expansion cohorts included patients with ROS1-positive locally advanced or metastatic NSCLC. This population was broken into two cohorts: ROS1 TKI naive and ROS TKI pretreated. The primary end point of the phase 2 portion of the research was cORR by blinded independent central review and RECIST 1.1 criteria.

The primary efficacy population of the trial comprised those pooled from both phases of the study who began repotrectinib at any dose before October 15, 2021. Those in the expanded efficacy population involved those pooled from both phases of the trial who began repotrectinib at any dose prior to March 29, 2023. Lastly, those in the safety population were those who received the agent at the RP2D.

Patient characteristics from the study were previously shared. In the TKI-naive cohort, slightly more than half (58%) were from Asia and 42% were from non-Asian regions; in the TKI-pretreated cohort, these respective rates were 41% and 59%, respectively.

In November 2023, the FDA cleared repotrectinib for use in adult patients with locally advanced or metastatic ROS1-positive NSCLC based on earlier data from TRIDENT-1.2,3 In the TKI-naive cohort (n = 71), the cORR was 79% (95% CI, 68%-88%) and the median DOR was 34.1 months (95% CI, 25.6-NE). In the TKI-pretreated cohort, those who received 1 prior ROS1 TKI but not chemotherapy or immunotherapy (n = 56), the cORR was 38% (95% CI, 25%-52%) and the median DOR was 14.8 months (95% CI, 7.6-NE).

The data cutoff date of the current analysis was September 3, 2024.1

What Were the Data Reported in the Expanded Efficacy Population?

At a median follow-up of 37.7 months, in the TKI-naive cohort (n = 121), the median DOR was 33.6 months (95% CI, 25.5-NE), the median PFS was 30.2 months (95% CI, 19.3-38.6), and the median OS was 74.6 months (95% CI, 44.4-NE). At a median follow-up of 34.8 months in the TKI-pretreated cohort (n = 107), the median DOR was 14.9 months (95% CI, 7.7-31.4), the median PFS was 9.2 months (95% CI, 7.4-11.3), and the median OS was 20.5 months (95% CI, 17.8-31.4).

Were Any New Safety Data Reported?

Safety outcomes were consistent with prior reports.

Disclosures: No disclosures were listed for Cho.

References

1. Cho BC, Lin JJ, Camidge DR, et al. Repotrectinib in patients with ROS1 fusion-positive NSCLC: Long-term follow-up from the phase 1/2 TRIDENT-1 trial. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract MA02.03.
2. 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 September 8, 2025. 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
3. Augtyro. Prescribing information. Bristol Myers Squibb; 2023. Accessed September 8, 2025. https://packageinserts.bms.com/pi/pi_augtyro.pdf