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Background   ROS1 -rearranged lung cancers benefit from first-line crizotinib therapy; however, clinical and molecular factors that could affect crizotinib efficacy in  ROS1 -rearranged lung cancers are not yet well-elucidated. Our retrospective study aimed to compare the efficacy of chemotherapy and crizotinib in the first-line treatment of  ROS1 -rearranged advanced lung cancer and evaluate various clinical and molecular factors that might impact crizotinib efficacy in real-world practice.    Methods  Treatment responses, survival outcomes, and patterns of disease progression were analyzed for 235 patients with locally advanced to advanced disease who received first-line chemotherapy ( n  = 67) or crizotinib ( n  = 168).    Results  The overall response rate was 85.7% (144/168) for first-line crizotinib and 41.8% (28/67) for chemotherapy. Patients treated with first-line crizotinib ( n  = 168) had significantly longer median progression-free survival (PFS) than chemotherapy ( n  = 67) (18.0 months vs. 7.0 months,  p  < 0.001). Patients harboring single  CD74-ROS1  ( n  = 90) had significantly shorter median PFS with crizotinib than those harboring non- CD74 ROS1  fusions ( n  = 69) (17.0 months vs. 21.0 months;  p  = 0.008). Patients with baseline brain metastasis ( n  = 45) had a significantly shorter PFS on first-line crizotinib than those without brain metastasis ( n  = 123) (16.0 months vs. 22.0 months;  p  = 0.03). At progression, intracranial-only progression ( n  = 40), with or without baseline CNS metastasis, was associated with longer median PFS than those with extracranial-only progression ( n  = 64) (19.0 months vs. 13.0 months,  p  < 0.001).  TP53  mutations were the most common concomitant mutation, detected in 13.1% (7/54) of patients with  CD74-ROS1  fusions, and 18.8% (6/32) with non- CD74 ROS1  fusions .  Patients with concomitant  TP53  mutations (n=13) had significantly shorter PFS than those who had wild-type  TP53  ( n  = 81) (6.5 months vs. 21.0 months;  p  < 0.001). PFS was significantly shorter for the patients who harbored concomitant driver mutations ( n  = 9) (11.0 months vs 24.0 months;  p  = 0.0167) or concomitant tumor suppressor genes (i.e.,  TP53 ,  RB1 , or  PTEN ) ( n  = 25) (9.5 months vs 24.0 months;  p  < 0.001) as compared to patients without concomitant mutations ( n  = 58).    Conclusion  Our results demonstrate that baseline brain metastatic status and various molecular factors could contribute to distinct clinical outcomes from first-line crizotinib therapy of patients with  ROS1 -rearranged lung cancer.    Clinical trials registration  CORE, NCT03646994    Supplementary Information  The online version contains supplementary material available at 10.1186/s12916-021-02082-6.

bmc medicine

Clinical and molecular factors that impact the efficacy of first-line crizotinib in ROS1-rearranged non-small-cell lung cancer: a large multicenter retrospective study