Intracranial Efficacy of Crizotinib and Postprogression Therapeutic Strategies in Advanced c-ros Oncogene 1 (ROS1)-Positive Non-Small Cell Lung Cancer (NSCLC), a Multicenter Real-World Study.

Intracranial efficacy of crizotinib and optimal postprogression therapies in c-ros oncogene 1 (ROS1)-positive non-small cell lung cancer(NSCLC) remain under-explored. We performed a multicenter real-world study across 17 Chinese hospitals (2015-2024) in 325 ROS1-positive NSCLC patients to evaluate the intracranial efficacy of crizotinib and postprogression treatment strategies. Crizotinib achieved an overall response rate(ORR) of 78.5% and a median progression-free survival (PFS) of 22.4 months. Patients with baseline brain metastases had a 66.7% intracranial response rate and a median central nervous system (CNS)-PFS of 22.2 months, demonstrating intracranial benefit. After progression, next-generation ROS1 inhibitors (active against the G2032R resistance mutation, for example, taletrectinib and repotrectinib) significantly prolonged PFS compared to older-generation targeted agents (median 13.9 vs. 4.4 months), especially among patients with secondary ROS1 resistance mutations (ORR 66.7% vs. 14.3%). However, due to greater availability in China, earlier agents like lorlatinib and entrectinib were commonly used after crizotinib failure. In our cohort, lorlatinib demonstrated superior efficacy to entrectinib, with a trend toward longer PFS and higher overall (34% vs. 7%) and intracranial (50% vs. 0%) response rates. This large real-world study confirms crizotinib's intracranial benefit and underscores the importance of next-generation ROS1 inhibitors and older-generation agents like lorlatinib-for improved patient outcomes after crizotinib resistance.