Abstract 850
Background
Anaplastic lymphoma kinase (ALK) rearrangements define a distinct molecular subtype of non-small cell lung cancer. Recently, the therapeutic landscape for advanced ALK+ NSCLC has been transformed by the development of increasingly potent and selective ALK inhibitors. Crizotinib was the first ALK inhibitor to enter clinical development. The mechanism of acquired resistance to crizotinib for the patients with ALK+ NSCLC is not yet fully identified. In this study, we performed mutational profiling in a cohort of 42 ALK+NSCLC patients at diagnosis and following acquired resistance to crizotinib using targeted NGS.
Methods
A total of 42 patients with stage IIIb-IV ALK+ NSCLC underwent tumor biopsies or blood withdrawal by the time of acquiring resistance to crizotinib, including 19 formalin-fixed paraffin-embedded (FFPE) samples, 12 serum samples and 11 serous effusions. We used targeted NGS to detect the gene status of patients.
Results
In total, we identified 92 genetic alterations with a median of 2.2 mutations per patient. 83% of patients still exhibit fusions, and 29% of patients acquired ALK point mutations. Besides other known resistance mechanisms, we identified KRAS mutations in 14% of patients, and EGFR mutations in 12%. Interestingly, we also observed IGF1R, GPR133, CDH18and HSD17B3 mutations in ALK point mutation-negative patients, which were restricted to crizotinib resistance.
Conclusions
Our study uncovered mutational profiles of ALK+NSCLC patients with crizotinib resistance with potential therapeutic implications, and this study also comprehensively depicted the genetic landscape in a Chinese ALK+NSCLC population resistant to crizotinib. Our analysis demonstrates new perspectives for further study of resistance and suggests corresponding relevant tactics against the challenge of disease progression.
Clinical trial identification
Legal entity responsible for the study
Chunwei Xu.
Funding
Has not received any funding.
Editorial Acknowledgement
Disclosure
All authors have declared no conflicts of interest.
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