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

Abstract

EGFR exon 20 insertions (EGFR e20ins) account for up to 10% of EGFR mutations in lung cancer; however, tumors with EGFR e20ins had poor response rates to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib, afatinib, and osimertinib, and the heterogeneity of EGFR 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 EGFR 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 TP53 mutations frequently coexisted with p.H773dup (77.8%, P = 0.0558) and p.A767_V769dup (62.8%, P = 0.0325), while RB1 mutations usually co-occurred with p.H773_V774insAH (33.3%, P = 0.0551), implying that different EGFR e20ins variants might require distinct genomic context for tumorigenesis and/or maintenance. Despite that treatment regimens were highly diverse for EGFR 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 EGFR e20ins variants (P = 0.017), and EGFR p.A763_Y764insF-QEA was associated with better PFS than other EGFR e20ins when treating with various EGFR TKIs. Some EGFR e20ins variants showed at least partial response to first-generation EGFR TKIs, including p.A767_V769dup, p.S768_D770dup, p.N771_H773dup, p.A763_Y764insF-QEA, 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 EGFR e20ins were highly diversified in terms of insertion patterns and co-occurring mutations and these EGFR e20ins variants showed different clinical responses to various EGFR TKIs,

Case Report: Afatinib Treatment in a Patient With NSCLC Harboring a Rare EGFR Exon 20 Mutation

“…The other patient received afatinib in the context of a global compassionate use program and had progressive disease ( 19 , 20 ). It is not uncommon for patients to have concurrent mutations alongside exon 20 insertions ( 21 ); therefore, we speculate that the difference in afatinib response could be owing to the presence of an additional mutation. For example, TP53 mutations are one of the most common concurrent mutations alongside exon 20 insertion ( 21 ) and is possibly associated with a lower likelihood of response to EGFR TKIs ( 22 ).…”

“…It is not uncommon for patients to have concurrent mutations alongside exon 20 insertions ( 21 ); therefore, we speculate that the difference in afatinib response could be owing to the presence of an additional mutation. For example, TP53 mutations are one of the most common concurrent mutations alongside exon 20 insertion ( 21 ) and is possibly associated with a lower likelihood of response to EGFR TKIs ( 22 ). Overall, these findings are particularly interesting and suggest that afatinib may provide a new therapeutic option for the particular type of mutation discussed here.…”

Extensive functional evaluation of exon 20 insertion mutations of EGFR

“…Fourth, there are extremely rare exon 20 insertions that we did not assess their drug sensitivity. Finally, our study did not take into account other gene mutations such as the PIK3CA mutation, which can possibly co-occur in cancers harboring EGFR mutations and may affect drug sensitivity [24,48].…”

“…There are not enough data on each exon 20 insertion, but we analyzed the available data to assess the concordance between this study and the clinical information. For the overall response rate (ORR), we defined sensitive as more than 50 % patients showing partial response (PR) or long stable disease (over eight months), partially sensitive as 50 % or less but not less than 20 %, and resistant as less than 20 %, according to the Response Evaluation Criteria in Solid Tumors (RECIST) [24,40].…”

“…Patients with EGFR exon 20 insertions fundamentally have a shorter survival time compared with those who have common EGFR mutations due to the general lack of sensitivity to EGFR kinase inhibitors [19]. The sensitivity of several exon 20 insertions has been examined for EGFR TKIs [23][24][25][26][27][28][29][30][31][32][33][34]; however, little is known about the clinical significance of individual variants. Clinical trials have gathered the data about the activity of TKIs in NSCLC harboring uncommon EGFR mutations [35].…”