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.

backgroundROS1-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.

methodsTreatment 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).

resultsThe 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).

conclusionOur 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.