Abstract 1262P
Background
Crizotinib as an ALK/ROS1/MET inhibitor, is highly effective against ROS1-rearranged lung cancer. However, similar to other oncogene-driven lung cancers, ROS1-rearranged lung cancers treated with crizotinib eventually acquired resistance. In our study, we examined the profiles of ROS1 resistance mutations and co-occurring genetic alterations after crizotinib treatment.
Methods
Using targeted gene capture and next-generation sequencing (NGS) technologies, we analyzed the somatic mutations from18 patients (pts) with crizotinib treatment.
Results
Among 18 patients, 88.9% of patients (16/18) received first-line/second-line crizotinib and mPFS was 11 months (5m∼22m). 28% of patients (5/18) were developed ROS1 resistance point mutations, including G2032R (4 pts) and L2026M (1 pts). Specifically, G2032R was the commonest type of ROS1-dependent secondary kinase-domain mutations, which is consistent with the analysis results in this study. Activated bypass signaling may be a potential ROS1-independent resistance mechanism. In 13 patients who did not have secondary ROS1 mutations at PD, co-occurring genomic alterations include TP53 (56%, 4 pts), LRP1B (22.2%, 4 pts), SLX4 (16.7%, 3 pts), NF1 (11.1%, 2 pts), DNMT3A (11.1%, 2 pts), CDKN2A (11.1%, 2 pts), etc. The driver mutations may inhibit crizotinib response. In addition to the MET (5.6%, 1 pts) and ERBB2 (5.6%, 1 pts) that has been reported, we also found EGFR (11.1%, 2 pts) and ALK (5.6%, 1 pts) in our study, and EGFR-TKI treatment was long-lasting and effective in one of the 2 patients (PFS = 19m). In 7 patients who detected pre - and post-treatment samples, the frequency of mutations of post-treatment samples was higher than baseline, and the most common mutations were all TP53. 2 of the 7 patients developed ROS1 resistance point mutation (G2032R), implying the resistance mechanisms.
Conclusions
In lung cancer patients, ROS1 resistant point mutation G2032R was significantly developed in post-crizotinib, and L2026M point mutation type was also detected. In addition, the co-occurring genetic alterations in TP53, MET, ERBB2, EGFR or ALK mutations after crizotinib treatment may provide a direction for further treatment of patients.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Geneplus-Beijing.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.