Type II ROS1 Inhibition Overcomes Type I Inhibitor Resistance in ROS1 Fusion-Positive Lung Cancers: A Phase II Trial of Cabozantinib.

Authors

Jaime Rubio-Perez, Matteo Repetto, Ling Feng Ye, Rebecca Repetti, Clare Wilhelm, Jeeban P Das, Christina Falcon, Meghanne Lomibao, Guilherme Harada, Mark G Kris, Alexander Drilon

Published in

Clinical cancer research : an official journal of the American Association for Cancer Research. Oct 05, 2026. Epub Oct 05, 2026.

Abstract

All targeted therapies approved for ROS1-fusion-positive non-small cell lung cancer (NSCLC) are type I inhibitors. These TKIs may induce resistance amenable to type II inhibition. Cabozantinib is a type II ROS1/MET tyrosine kinase inhibitor with preclinical activity against on-target ROS1 resistance mutations and MET alterations.
This single-center, open-label, phase 2 study (NCT01639508) enrolled patients with pre-treated ROS1 fusion-positive NSCLC. The primary endpoint was the overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. The first phase of the Simon two-stage design is reported.
7 ROS1 TKI pre-treated patients were enrolled. Previous treatment included crizotinib, entrectinib, repotrectinib and zidesamtinib. The ORR was 43% (95% CI, 10-81.5%). The best response was -92% partial response (PR) in a ROS1 D2033N mutant cancer patient. Two additional PRs were achieved, one (-49%) in a ROS1 G2032R/L2086F mutant cancer. The median PFS was 4.5 months (95% CI, 4-NE) with a median duration of response and OS of 8.0 (3-13) and 11 months (95% CI, 6-NE), respectively. Resistance mechanisms to cabozantinib were identified in two patients: MET overexpression and MET D1228N. The most frequent treatment-related toxicities observed were fatigue, nausea, and hypertension. Grade 3 treatment-related adverse events occurred in 57%, mostly palmar-plantar erythrodysesthesia and transaminitis. All patients required a dose reduction.
Cabozantinib achieved responses in pre-treated ROS1 fusion-positive NSCLCs, even in the presence of multi-drug-resistant mutations, highlighting the potential utility of type II ROS1 TKI therapy.

PMID:
42832369
Bibliographic data and abstract were imported from PubMed on 06 Oct 2026.

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