Variability of EGFR exon 20 insertions in 24 468 Chinese lung cancer patients and their divergent responses to EGFR inhibitors

摘要

exon 20 insertions ( e20ins) account for up to 10% of mutations in lung cancer; however, tumors with e20ins had poor response rates to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib, afatinib, and osimertinib, and the heterogeneity of e20ins further complicates the clinical studies. Here, we retrospectively screened next‐generation sequencing (NGS) data from 24 468 lung cancer patients, and a total of 85 unique e20ins variants were identified in 547 cases (2.24%), with p.A767_V769dup (25.1%) and p.S768_D770dup (17.6%) being the most prevalent ones. Comprehensive genomic profiling revealed that mutations frequently coexisted with p.H773dup (77.8%,  = 0.0558) and p.A767_V769dup (62.8%,  = 0.0325), while mutations usually co‐occurred with p.H773_V774insAH (33.3%,  = 0.0551), implying that different e20ins variants might require distinct genomic context for tumorigenesis and/or maintenance. Despite that treatment regimens were highly diverse for e20ins‐positive patients, we observed an overall response rate of 14% and a disease control rate (DCR) of 38.4% in 65 patients who received at least one EGFR TKI. The progression‐free survival (PFS) differs significantly in six representative e20ins variants (  = 0.017), and p.A763_Y764insFQEA was associated with better PFS than other e20ins when treating with various EGFR TKIs. Some e20ins variants showed at least partial response to first‐generation EGFR TKIs, including p.A767_V769dup, p.S768_D770dup, p.N771_H773dup, p.A763_Y764insFQEA, and p.D770_N771insG. Poziotinib achieved higher DCR for p.S768_D770dup than for p.A767_V769dup, whereas osimertinib showed limited effects for these two insertions when used as the first‐line treatment. Overall, our results demonstrated that e20ins were highly diversified in terms of insertion patterns and co‐occurring mutations and these e20ins variants showed different clinical responses to various EGFR TKIs, suggesting the clinical importance of selecting proper EGFR TKI treatment based on the specific e20ins type.