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<p>Early-generation TRK tyrosine kinase inhibitors (TKIs) approved for treating <i>NTRK</i> fusion–positive (<i>NTRK</i><sup>+</sup>) solid tumors provide clinical benefit; however, resistance emerges. Repotrectinib is a next-generation ROS1/TRK TKI with a compact macrocyclic structure designed to improve durability of response. TRIDENT-1 is a registrational phase 1/2 trial assessing repotrectinib, a next-generation ROS1/TRK TKI, in adults with advanced solid tumors, including <i>NTRK</i><sup>+</sup> disease. The primary endpoint was confirmed objective response; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival and safety. Median follow-up ranged between 21.3 months and 25.7 months. In the TKI-naive cohort (<i>n</i> = 51; 95% confidence interval (CI)), the response rate was 59% (44–72); the median DOR was not estimable (NE); and the median PFS was 30.3 months (9.0–NE). In the TKI-pretreated cohort (<i>n</i> = 69; 95% CI), the response rate was 48% (36–60); the median DOR was 9.8 months (7.4–13.0); and the median PFS was 7.4 months (3.9–9.7). Of 30 TKI-pretreated patients with <i>NTRK</i> solvent front mutations, 16 had a response (53%; 95% CI: 34–72). Intracranial responses were observed in two of three TKI-naive patients and in four of six TKI-pretreated patients with measurable intracranial disease at baseline. Among all treated patients (<i>n</i> = 565), the most common any-grade treatment-related adverse event (TRAE) was dizziness (57%); most TRAEs were low grade; and 4% discontinued repotrectinib due to a TRAE. Here repotrectinib demonstrated durable systemic and intracranial responses with generally low-grade adverse events in patients with <i>NTRK</i><sup>+</sup> solid tumors, including those with previous TRK TKI treatment and solvent front mutations. These results support the use of repotrectinib to treat patients with <i>NTRK</i><sup>+</sup> solid tumors. ClinicalTrials.gov identifier: <a href="https://www.clinicaltrials.gov/study/NCT03093116">NCT03093116</a>.</p>

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Repotrectinib in NTRK fusion–positive advanced solid tumors: a phase 1/2 trial

  • 期刊论文

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  • 发表日期：

    2026年2月4日

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  • Benjamin Besse,
  • Jessica J. Lin,
  • Lyudmila Bazhenova,
  • Koichi Goto,
  • Adrianus Johannes de Langen,
  • Dong-Wan Kim,
  • Jürgen Wolf,
  • Christoph Springfeld,
  • Sanjay Popat,
  • Darren W. T. Lim,
  • Misako Nagasaka,
  • Jung Yong Hong,
  • Christina S. Baik,
  • Alice Hervieu,
  • Victor Moreno,
  • Nong Yang,
  • Kanthi Kollengode,
  • Haisu Yang,
  • Yuanfang Xu,
  • Christophe Y. Calvet,
  • Yong Yuan,
  • Amy B. Hammell,
  • Alexander Drilon,
  • Benjamin J. Solomon

摘要

Early-generation TRK tyrosine kinase inhibitors (TKIs) approved for treating NTRK fusion–positive (NTRK+) solid tumors provide clinical benefit; however, resistance emerges. Repotrectinib is a next-generation ROS1/TRK TKI with a compact macrocyclic structure designed to improve durability of response. TRIDENT-1 is a registrational phase 1/2 trial assessing repotrectinib, a next-generation ROS1/TRK TKI, in adults with advanced solid tumors, including NTRK+ disease. The primary endpoint was confirmed objective response; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival and safety. Median follow-up ranged between 21.3 months and 25.7 months. In the TKI-naive cohort (n = 51; 95% confidence interval (CI)), the response rate was 59% (44–72); the median DOR was not estimable (NE); and the median PFS was 30.3 months (9.0–NE). In the TKI-pretreated cohort (n = 69; 95% CI), the response rate was 48% (36–60); the median DOR was 9.8 months (7.4–13.0); and the median PFS was 7.4 months (3.9–9.7). Of 30 TKI-pretreated patients with NTRK solvent front mutations, 16 had a response (53%; 95% CI: 34–72). Intracranial responses were observed in two of three TKI-naive patients and in four of six TKI-pretreated patients with measurable intracranial disease at baseline. Among all treated patients (n = 565), the most common any-grade treatment-related adverse event (TRAE) was dizziness (57%); most TRAEs were low grade; and 4% discontinued repotrectinib due to a TRAE. Here repotrectinib demonstrated durable systemic and intracranial responses with generally low-grade adverse events in patients with NTRK+ solid tumors, including those with previous TRK TKI treatment and solvent front mutations. These results support the use of repotrectinib to treat patients with NTRK+ solid tumors. ClinicalTrials.gov identifier: NCT03093116.