Efficacy and Safety of HER2-Directed Therapies for Advanced HER2-Mutant NSCLC: A Systematic Review and Meta-Analysis

Recently, both human epidermal growth factor receptor (HER2) tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs) targeting HER2 have reported clinically meaningful activity and received regulatory approval for advanced HER2-mutant NSCLC, although the evidence is primarily derived from single-arm trials with modest sample sizes and a lack of direct comparative data. The preferred choice and sequencing of HER2-directed therapy, particularly across distinct clinical contexts, require further studies. We searched multiple biomedical databases for prospective trials evaluating the efficacy and safety of HER2 TKIs and ADCs approved in at least one country for advanced HER2-mutant NSCLC. The primary outcome was objective response rates (ORRs). Secondary outcomes included ORRs in prespecified subgroups, progression-free survival, and adverse events. Meta-analyses were performed using a fixed-effect model. A total of 916 patients from seven trials were included in the analysis. The pooled ORR was 65% (95% confidence interval: 61%-69%) for HER2 TKIs and 57% (95% confidence interval: 52%-61%) for ADCs. In patients with HER2 Y772_A775dupYVMA insertion, ORRs were 74% with TKIs and 57% with ADCs; in those with non-YVMA insertion tyrosine kinase domain mutations, ORRs were 57% and 60% with TKIs and ADCs, respectively; and in those with non-tyrosine kinase domain mutations, ORRs were 31% and 33% with TKIs and ADCs, respectively. The ORR in those with TKI and prior ADC exposure seemed diminished, whereas ADC efficacy seemed maintained after TKI treatment. Notably, ADCs were associated with a higher incidence of grade 3 or higher adverse events than TKIs. The findings suggest that HER2 TKIs may be the preferred initial option over ADCs in advanced HER2 mutated NSCLC, given their higher response rates, particularly in patients with YVMA insertions, a more favorable safety profile, and preserved ADC efficacy after TKI exposure. Prospective validation is warranted.