Afatinib, an irreversible pan-ErbB family inhibitor, has demonstrated promising efficacy in non-small cell lung cancer (NSCLC) patients with uncommon EGFR activating mutations. However, besides the acquisition of secondary T790M mutation, other resistance mechanisms to afatinib remained to be explored.
This study retrospectively included 40 NSCLC patients harboring either EGFR or ERBB2 activating mutations, who had received afatinib as first-line treatment. Targeted next-generation sequencing (NGS) data on the baseline and post-treatment samples were subjected to analysis. Comparative analyses of genetic features and clinical parameters were performed.
Overall, the progression-free survival (PFS) of the EGFR-positive patients on first-line afatinib was longer than that of the ERBB2-positive patients (P=0.01). In the EGFR-positive subgroup, primary resistance was associated with the presence of EGFR exon 20 insertion mutation (P=0.02), higher tumor mutational burden (TMB, P=0.02), higher proportion of APOBEC signature (P=0.001) and higher tumor heterogeneity (P=0.01). Secondary resistance mainly involved EGFR T790M and MET amplification. Patients with 19del were more likely to acquire T790M mutation compared with those harboring L858R or other EGFR mutations (57.1%, 33.3% and 0%, respectively). On the other hand, no significant difference was observed in the distribution of MET amplification among different EGFR subgroups. In the ERBB2-positive subgroup, patients with the p.Y772_A775dup mutation tended to have a longer PFS than those harboring ERBB2 mutations (HR=0.19, 95%CI, 0.02-1.56, P=0.09). In addition, alterations in PIK3CA or genes in the cell cycle pathway were associated with primary resistance to afatinib in the ERBB2-positive patients. Secondary resistance mechanisms included alterations in ERBB4, EGFR, TSC2, NF1 and CDKN2A that participate in the bypass or downstream pathway of ERBB2 and the cell cycle pathway.
This study identified multiple genetic factors associated with afatinib efficacy and resistance. In addition, genomic characteristics such as TMB, tumor heterogeneity and APOBEC signature might serve as biomarkers for afatinib response.
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Y. Shao, X. Wu, Q. Hu, Q. Meng, J.C. Yin, Q. Ou, X. Wu: Financial Interests, Personal, Full or part-time Employment: Nanjing Geneseeq Technology Inc. All other authors have declared no conflicts of interest.