398P - Real-world mechanism of crizotinib-resistance in MET exon 14 skipping mutations non-small-cell lung cancer using next generation sequencing: A multicenter study

Background

MET exon 14 skipping is a potential driver alteration in lung cancer targetable. Treatment with crizotinib can cause dramatic responses in patients whose cancers have MET exon 14 skipping. The mechanism of acquired resistance to crizotinib for the patients with MET exon 14 skipping NSCLC is not yet fully identified. In this study, we performed mutational profiling in a cohort of MET exon 14 skipping NSCLC patients at diagnosis and following acquired resistance to crizotinib using targeted NGS.

Methods

We screened 2926 patients with NSCLC for MET exon 14 skipping mutation. Among them, 14 patients received crizotinib treatment, and a total of 9 patients with stage IIIb-IV MET exon 14 skipping mutation NSCLC underwent tumor biopsies or blood withdrawal by the time of acquiring resistance to crizotinib, including 3 formalin-fixed paraffin-embedded (FFPE) samples, 4 serum samples and 2 serous effusions. We used targeted NGS to detect the gene status of patients.

Results

In total, we identified 41 genetic alterations with a median of 4.6 mutations per patient. 88.9% of patients still exhibit MET exon 14 skipping mutation, and 22.2% of patients acquired MET point mutations. Besides other known resistance mechanisms, we identified HRAS mutation in 11.1% of patients, and EGFR mutation in 11.1%. Interestingly, we also observed NUP93, MS4A1 and ELAC2 mutations in MET acquired point mutation-negative patients, which were restricted to crizotinib resistance.

Conclusions

MET exon 14 skipping patients acquired resistance mutational profiles were uncovered, and this study also comprehensively depicted the genetic landscape in a Chinese MET exon 14 skipping NSCLC population resistant to crizotinib. Precision methods, such as NGS for oncogenic alteration detection for further study of resistance and suggests corresponding relevant tactics against the challenge of disease progression.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Chun-wei Xu.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.