AF8c

ERBB2 (HER2)-mutant NSCLC, most commonly driven by exon 20 insertions, has historically shown limited benefit from early pan-ERBB inhibitors. Although multiple HER2-targeted agents have since emerged, the relationship between objective response, disease control, and durability remains incompletely defined across heterogeneous single-arm studies.

We conducted a systematic review and single-arm meta-analysis of HER2-targeted monotherapies in advanced HER2-mutant NSCLC. Objective response rate (ORR) and disease control rate were pooled using random-effects meta-analysis of proportions with logit transformation. PFS was summarized descriptively because time-to-event outcomes were not consistently reported in a form suitable for pooling. Prespecified analyses evaluated outcomes by drug class and TKI generation, with additional analyses restricted to ERBB2 exon 20 insertion-mutant disease.

Twenty studies (n = 1489) met eligibility criteria; 7 prospective cohorts (n = 524) formed the main analysis. The pooled ORR was 0.51 (95% CI, 0.33-0.68; I² = 89.8%). The pooled disease control rate was 0.88 (95% CI, 0.69-0.96) with limited separation across TKI generations. Median PFS ranged from approximately 5.5-11.5 months. Twelve-month overall survival estimates were similar between pyrotinib and trastuzumab deruxtecan. In exon 20-restricted analyses (n = 392), the pooled ORR was 0.52 (95% CI, 0.28-0.74).

Next-generation HER2-selective TKIs achieved higher ORRs than older inhibitors, particularly in ERBB2 exon 20 insertion-mutant disease; however, differences in durability-related outcomes were less distinct in currently available later-line studies. These findings are exploratory and support prospective studies to better define durability and optimize sequencing strategies for HER2-mutant NSCLC.

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 the secondary T790M mutation, other resistance mechanisms to afatinib remain to be explored.

This study retrospectively included 37 NSCLC patients harboring either EGFR or ERBB2 activating mutations, who had received afatinib as first‐line treatment. Targeted next‐generation sequencing data on the baseline and post‐progression samples were subjected to analysis. Comparative analyses of clinical parameters and genomic features were performed.

Overall, the progression‐free survival of the EGFR ‐mutated patients on first‐line afatinib was longer than that of the ERBB2 ‐positive patients (hazard ratio = 0.35 [95% confidence interval = 0.15–0.79], p  = 0.008). Primary resistance was associated with the presence of exon 20 insertion mutation ( p  = 0.011), higher tumor mutational burden ( p  = 0.009), and higher proportion of APOBEC signature ( p  = 0.012), which were all enriched in the ERBB2 ‐mutated cohort. We further characterized acquired resistance to afatinib and discovered that baseline EGFR exon 19 deletions and higher levels of chromosomal instability and age‐related mutational signatures would contribute to the development of known resistance mechanisms such as EGFR T790M or MET amplification. We also report gaining EGFR activating mutations and losing CDKN2A , NF1 , or the original ERBB2 mutations as novel resistance mechanisms to afatinib for ERBB2 ‐mutated patients.

The study identified multiple genomic characteristics associated with primary and secondary resistance to first‐line afatinib treatment in EGFR ‐ and ERBB2 ‐positive subpopulations.