Repotrectinib Yields Enduring Activity in NTRK+ Solid Tumor Trial

Treatment with repotrectinib (Augtyro) produced enduring clinical activity among adults with NTRK fusion-positive solid tumors, according to updated findings from the phase 1/2 TRIDENT-1 trial (NCT03093116) published in Nature Medicine.¹

With a median follow-up of 25.7 months (range, 8.7-74.5) among 51 patients with no prior tyrosine kinase inhibitor (TKI) therapy, repotrectinib yielded a confirmed response in 59% (95% CI, 44%-72%), including complete responses (CRs) in 16% and partial responses (PRs) in 43%. The median duration of response (DOR) was not evaluable (NE), and approximately 85% (95% CI, 70%-99%) of patients with a response sustained their response for a minimum of 24 months. The median progression-free survival (PFS) in this cohort was 30.3 months (95% CI, 9.0-NE), and the estimated 24-month PFS rate was 60% (95% CI, 46%-74%); the estimated overall survival (OS) rate at 24 months was 68% (95% CI, 54%-83%).

After a median follow-up of 21.3 months (range, 8.4-79.2), among 69 patients previously treated with TKIs, data showed confirmed responses in 48% (95% CI, 36%-60%) of patients, CRs in 3%, and PRs in 45%. The median time to first response was 1.9 months, and the median DOR was 9.8 months (95% CI, 7.4-13.0), with 42% (95% CI, 24%-59%) of responders estimated to sustain their responses for 12 months or longer. Additionally, the median PFS was 7.4 months (95% CI, 3.9-9.7), with an estimated 12-month PFS rate of 26% (95% CI, 14%-37%). Data showed a median OS of 18.6 months (95% CI, 11.6-25.3) and an estimated 12-month OS rate of 62% (95% CI, 50%-75%).

Investigators noted intracranial activity with repotrectinib in 2 of 3 patients in the TKI-naive cohort as well as 4 of 6 in the TKI-pretreated group; intracranial DOR ranged from 17.5 to 24.0 months and 5.5 to 10.6 months in each respective cohort. Regarding patients without intracranial disease at baseline, the intracranial PFS rates were 87% at 24 months for patients without prior TKI therapy and 67% at 12 months for those with prior TKI therapy.

“[R]epotrectinib, a next-generation TKI, showed durable clinical activity in adult patients with [NTRK fusion-positive] solid tumors, including in patients with previous TKI treatment, with or without NTRK solvent front mutations, across multiple NTRK genes and fusion partners and in patients with or without intracranial disease. Repotrectinib was mainly associated with low-grade adverse events, consistent with previous reports,” lead study author Benjamin Besse, MD, PhD, director of Clinical Research at the Gustave Roussy Institute and a professor of Medical Oncology at Paris-Saclay University, wrote with coauthors in the publication.¹ “This evidence supports repotrectinib as a new treatment option for patients with [NTRK fusion-positive] solid tumors.”

As part of the TRIDENT-1 trial, 2 cohorts of patients with NTRK fusion-positive solid tumors, as well as 4 cohorts with ROS1-positive non–small cell lung cancer, received repotrectinib at the recommended phase 2 dose of 160 mg once daily for 14 days followed by 160 mg twice daily. The primary end point of phase 2 was the confirmed objective response rate per blinded independent central review using RECIST v1.1 criteria. Secondary end points included DOR, PFS, OS, intracranial response, and safety. Patients 18 years and older with tumors harboring an NTRK fusion were eligible for enrollment on the phase 1 portion of the trial; those 12 years and older were able to enroll on the phase 2 portion.

The median age was 61 years (range, 25-84) in the TKI-naive population and 56 years (range, 18-81) in the TKI-pretreated group, and most patients from each respective cohort were not Hispanic or Latino (90% vs 93%). Most patients in each respective group had an ECOG performance status of 1 (55% vs 61%), stage IV metastatic disease at study entry (96% vs 91%), no intracranial disease (80% vs 77%), and 1 (35% vs 26%) or 2 prior lines of systemic therapy (24% vs 33%).

Among 144 patients with NTRK fusion-positive disease, any-grade treatment-emergent adverse effects (TEAEs) and treatment-related AEs (TRAEs) occurred in 99% and 97% of patients, respectively; grade 3 or higher TEAEs and TRAEs affected 58% and 34% of the population. The most common TEAEs and TRAEs of any grade in this population included dizziness (63% vs 58%), dysgeusia (56% vs 54%), and constipation (41% vs 27%).

Any-grade TEAEs led to treatment discontinuation, dose reduction, and dose interruption in 10%, 45%, and 53% of patients, respectively; TRAEs resulted in these events for 3%, 44%, and 42% of patients. A total of 6% and 1% of patients died due to TEAEs and TRAEs in the NTRK fusion-positive cohort, respectively.

In June 2024, the FDA granted accelerated approval to repotrectinib for patients 12 years and older with NTRK fusion-positive solid tumors based on prior findings from the TRIDENT-1 trial.²

References

1. Besse B, Lin JJ, Bazhenova L, et al. Repotrectinib in NTRK fusion–positive advanced solid tumors: a phase 1/2 trial. Nat Med. Published online February 4, 2026. doi:10.1038/s41591-025-04079-7
2. FDA grants accelerated approval to repotrectinib for adult and pediatric patients with NTRK gene fusion-positive solid tumors. News release. FDA. June 13, 2024. Accessed February 11, 2026. https://tinyurl.com/yfb6ctnn