Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 2026
Efficacy and safety of HER2 directed therapies for advanced HER2-mutant non-small-cell lung cancer - a systematic review and meta-analysis.
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Li Molly S C, Soon Yu Yang, Au-Yeung Pui Yin, Chan Andrew L S, Lee Jii-Bum, Nutzinger Jorn, Tateishi Akiko, Soo Ross
Аннотация
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.
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.