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

Yongchang Zhang, Xiangyu Zhang, Ruiguang Zhang, Qinqin Xu, Haiyan Yang, Analyn Lizaso, Chunwei Xu, Jun Liu, Wenxian Wang, Sai-Hong Ignatius Ou, Jiexia Zhang, Zhengbo Song, Nong Yang, Yongchang Zhang, Xiangyu Zhang, Ruiguang Zhang, Qinqin Xu, Haiyan Yang, Analyn Lizaso, Chunwei Xu, Jun Liu, Wenxian Wang, Sai-Hong Ignatius Ou, Jiexia Zhang, Zhengbo Song, Nong Yang

Abstract

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.

Keywords: Concomitant mutations; Crizotinib; Progression associated efficacy; ROS1 gene rearrangements.

Conflict of interest statement

Analyn Lizaso declared that she is employed by Burning Rock Biotech. Sai-Hong Ignatius Ou has stock ownership and was on the scientific advisory board of Turning Point Therapeutics Inc (until Feb 28, 2019), is a member of the SAB of Elevation Oncology and has stock ownership in Elevation Oncology, and has received speaker honorarium from Merck, Roche/Genentech, Astra Zeneca, Takeda/ARIAD and Pfizer; has received advisory fees from Roche/Genentech, Astra Zeneca, Takeda/ARIAD, Pfizer, Foundation Medicine Inc, Spectrum, Daiichi Sankyo, Jassen/JNJ, and X-Covery. All the other authors declare no conflict of interest.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Study design schematic. Flow chart illustrating the study design. A total of 21,747 treatment-naïve patients diagnosed with lung cancer were retrospectively screened for ROS1 fusion variants. Among them, 447 were detected with ROS1 rearrangements using various methods including NGS (n = 264), FISH (n = 105), and ARMS (n = 78). Clinical outcomes were further analyzed for the 235 patients with ROS1-rearranged locally advanced to advanced lung cancer who received either chemotherapy (n = 67) or crizotinib (n = 168) as first-line therapy
Fig. 2
Fig. 2
ROS1-rearranged NSCLCs had better objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) with first-line crizotinib therapy than chemotherapy. A Distribution of various ROS1 fusions detected using NGS-based method in 235 patients with locally advanced to advanced disease who received first-line therapy. B Treatment outcomes of patients with ROS1-rearranged NSCLCs who received either chemotherapy (red) or crizotinib therapy (green) in the first-line setting. C, D Kaplan-Meier survival curves illustrating the significantly better PFS for patients with ROS1-rearranged NSCLC (D) who received crizotinib (green) as compared to those who received chemotherapy (red) in the first-line setting; and (E) who received crizotinib and had non-CD74 ROS1 fusions (green) as compared to those with single CD74-ROS1 (red). The risk table below summarizes the number of patients included per time point
Fig. 3
Fig. 3
The presence of concomitant mutations is associated with poor prognosis. Kaplan-Meier survival curves illustrating the PFS for (A) patients with only ROS1 fusions (green), for those with concurrent driver mutations (red), and with concomitant mutations in tumor suppressor genes (blue), and (B) patients with (red) and without (green) concomitant TP53 mutations. The risk table below summarizes the number of patients included per time point
Fig. 4
Fig. 4
Patients with ROS1-rearranged NSCLC who had baseline brain metastasis still benefit from first-line crizotinib than chemotherapy. Kaplan-Meier survival curves illustrating the PFS for patients with ROS1-rearranged NSCLC who had non-brain metastasis (green) and brain metastasis (red) at baseline and received chemotherapy (A) and crizotinib (B) as first-line therapy. C Plot comparing the cumulative incidence of CNS progression in patients receiving crizotinib (green) and chemotherapy (red). D–E Crizotinib-treated patients with ROS1-rearranged NSCLC who experienced CNS only progression had a better prognosis than those who experienced non-CNS progression. D-E. Kaplan-Meier survival curves comparing the PFS of crizotinib-treated patients with ROS1-rearranged NSCLC who had non-CNS only progression (red), CNS only progression (green) and the whole cohort (blue) (D); E crizotinib-treated patients without baseline CNS metastasis who had CNS only progression (green) and non-CNS only progression (pink) and patients with baseline CNS metastasis who had CNS only progression (blue) and non-CNS only progression (red). The risk table below summarizes the number of patients included per time point

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