Efficacy and safety of HER2 directed therapies for advanced HER2-mutant non-small-cell lung cancer - a systematic review and meta-analysis.

INTRODUCTION Recently, both HER2 tyrosine kinase inhibitors (TKIs) and antibody drug conjugates (ADCs) targeting HER2 have demonstrated clinically meaningful activity and received regulatory approval for advanced HER2-mutant NSCLC, although evidence is primarily derived from single-arm trials with modest sample sizes and lacking direct comparative data. The preferred choice and sequencing of HER2-directed therapy, particularly across distinct clinical contexts, requires further studies.

Methods

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 include ORRs in prespecified subgroups, progression-free survival and adverse events. Meta-analyses were performed using a fixed-effect model.

Results

A total of 916 patients from seven trials were included in the analysis. The pooled ORR was 65% (95 CI 61-69%) for HER2 TKIs and 57% (95% CI 52-61%) for ADCs. In Y772_A775dupYVMA insertion, ORRs were 74% with TKIs and 57% with ADCs; in non-YVMA insertion tyrosine kinase domain (TKD) mutation, ORRs were 57% and 60%, respectively; and in non-TKD mutation, ORRs were 31% and 33%, respectively. ORR of TKI with prior ADC exposure appeared diminished while ADC efficacy appeared maintained after TKI treatment. ADCs were associated with a higher incidence of grade 3 or higher adverse events than TKIs.

Conclusion

HER2 TKIs may be the preferred initial option over ADCs in advanced HER2 mutated NSCLC, given their higher response rates, particularly in YVMA insertions, a more favorable safety profile, and preserved ADC efficacy following TKI exposure. Prospective validation is warranted.