Antitumor Activity of First-Line Crizotinib in ROS1-Rearranged Non-Small-Cell Lung Cancers: A Large Cohort, Multi-Center, Retrospective Study

Abstract

Background: Lung tumors harboring genomic rearrangements involving ROS1 clinically benefits from crizotinib therapy. Our retrospective study aims to compare the efficacy of chemotherapy and crizotinib in the first-line setting and evaluate other clinical and molecular factors that might impact crizotinib efficacy in real-world practice. Methods: ROS1 rearrangements were retrospectively analyzed from NGS data of 21,747 treatment-naive patients diagnosed with lung cancer at various hospitals from 4 provinces of China. Treatment response and survival outcomes were analyzed in 235 patients with locally advanced to advanced disease who received first-line chemotherapy (n=67) or crizotinib (n=168). Findings: A total of 233 different ROS1 fusion partners were detected from 264 patients, with CD74 as the most common partner. The overall response rate was 85.7% (144/168) for front-line crizotinib and 41.8% (28/67) for chemotherapy. Patients treated with front-line crizotinib had significantly longer median progression-free survival (mPFS) than chemotherapy (18.0 months vs. 7.0 months, p<0.001). Patients harboring CD74-ROS1 fusion had significantly shorter mPFS with crizotinib than those harboring non-CD74-ROS1 fusions (17.0 months vs. 21.0 months; p=0.008). Baseline brain metastasis contributed to decreased efficacy of crizotinib (16.0 months vs. 22.0 months; p=0.02). The presence of CNS progression (n=61) with or without baseline CNS metastasis was associated with longer mPFS than those with non-CNS progression (n=48, 19.0 months vs. 11.5 months, p<0.001). Crizotinib as front-line therapy provided significantly longer mPFS than as second-line therapy (18.0 months vs. 11.0 months; p=0.028). The emergence of secondary ROS1 mutations mediated the crizotinib resistance of a majority of our cohort (54.8%, 23/42), particularly those with non-CNS metastasis at baseline (67.9%, 19/28; p=0.015). Interpretation: Our results demonstrate that patients with different ROS1 fusion variants have distinct clinical outcomes to crizotinib therapy due to baseline clinical and molecular factors that could affect the efficacy of crizotinib. Trial Registration: This study was also registered as a clinical trial (CORE, NCT03646994). Funding Statement: This work received financial support from the Natural Science Foundation of Hunan Province (2018RS3106, 2018SK50901, 2019-TJ-N04, 2019JJ50357, 2019SK4010, and 2020JJ3025), and CAS “Light of West China Program”. Declaration of Interests: Analyn Lizaso and Hao Liu declare that they are employees of Burning Rock Biotech. All the other authors declare no conflict of interest. Ethics Approval Statement: Approval was obtained from the Hunan Cancer Hospital Institutional Review Board Committee (2017YYQ-SSB-026).