Mutation Variants and Co-Mutations as Genomic Modifiers of Response to Afatinib in HER2-Mutant Lung Adenocarcinoma

Abstract

Background Human epidermal growth factor receptor 2 (HER2)‐mutant lung cancer remains an orphan of specific targeted therapy. The variable responses to anti‐HER2 therapies in these patients prompt us to examine impact of HER2 variants and co‐mutations on responses to anti‐HER2 treatments in lung cancer. Patients and Methods Patients with stage IV/recurrent HER2‐mutant lung cancers identified through next‐generation sequencings were recruited from seven hospitals. The study comprised a cohort A to establish the patterns of HER2 variants and co‐mutations in lung cancer and a cohort B to assess associations between HER2 variants, co‐mutations, and clinical outcomes. Results The study included 118 patients (cohort A, n = 86; cohort B, n = 32). Thirty‐one HER2 variants and 35 co‐mutations were detected. Predominant variants were A775_G776insYVMA (49/118, 42%), G778_P780dup (11/118, 9%), and G776delinsVC (9/118, 8%). TP53 was the most common co‐mutation (61/118, 52%). In cohort B, objective response rates with afatinib were 0% (0/14, 95% confidence interval [CI], 0%–26.8%), 40% (4/10, 14.7%–72.6%), and 13% (1/8, 0.7%–53.3%) in group 1 (A775_G776insYVMA, n = 14), group 2 (G778_P780dup, G776delinsVC, n = 10), and group 3 (missense mutation, n = 8), respectively (p = .018). Median progression‐free survival in group 1 (1.2 months; 95% CI, 0–2.4) was shorter than those in group 2 (7.6 months, 4.9–10.4; hazard ratio [HR], 0.009; 95% CI, 0.001–0.079; p < .001) and group 3 (3.6 months, 2.6–4.5; HR, 0.184; 95% CI, 0.062–0.552; p = .003). TP53 co‐mutations (6.317; 95% CI, 2.180–18.302; p = .001) and PI3K/AKT/mTOR pathway activations (19.422; 95% CI, 4.098–92.039; p < .001) conferred additional resistance to afatinib. Conclusion G778_P780dup and G776delinsVC derived the greatest benefits from afatinib among HER2 variants. Co‐mutation patterns were additional response modifiers. Refining patient population based on patterns of HER2 variants and co‐mutations may help improve the efficacy of anti‐HER2 treatment in lung cancer. Implications for Practice Human epidermal growth factor receptor 2 (HER2)‐mutant lung cancers are a group of heterogenous diseases with up to 31 different variants and 35 concomitant genomic aberrations. Different HER2 variants exhibit divergent sensitivities to anti‐HER2 treatments. Certain variants, G778_P780dup and G776delinsVC, derive sustained clinical benefits from afatinib, whereas the predominant variant, A775_G776insYVMA, is resistant to most anti‐HER2 treatments. TP53 is the most common co‐mutation in HER2‐mutant lung cancers. Co‐mutations in TP53 and the PI3K/AKT/mTOR pathway confer additional resistance to anti‐HER2 treatments in lung cancer. The present data suggest that different HER2 mutations in lung cancer, like its sibling epidermal growth factor receptor, should be analyzed independently in future studies.

A narrative review of advances in treatment and survival prognosis of HER2-positive malignant lung cancers

“…In a recent study, genotype G778_P780dup and G776delinsVC was found achieving greatest benefit from afatinib (25). In this study, ORR and DCR of afatinib were 15.6% and 68.8%.…”

An ErbB2 splice variant lacking exon 16 drives lung carcinoma

“…Clinical trial results have suggested efficacy of anti-ERBB2 antibody-drug conjugates in lung cancers with ERBB2 mutations (45,46), while TKIs are efficacious in preclinical models of ERBB2-driven NSCLC (23,39), although their performance in the clinic has been variable (47,48). Heterogeneous responses to ERBB2 targeted therapies in lung cancer are thought to be at least partially due to properties unique to specific molecular alterations in ERBB2 (49,50). Our work provides a basis for further studies examining the available suite of ERBB2 targeted therapies and other modalities, such as immunotherapies, to identify effective strategies for cancers driven by ERBB2ΔEx16.…”

Genomic characteristics of driver genes in Chinese patients with non‐small cell lung cancer

“…Afatinib, pyrotinib and poziotinib are regarded as HER2‐TKIs. Certain variants, G778_P780dup and G776delinsVC, derive sustained clinical benefits from afatinib, whereas the predominant variant, A772_G775dupYVMA, is resistant to most anti‐ HER2 treatments 12 . In one study, chemotherapy was found to achieve better outcomes than afatinib for YVMA insertions 13 .…”