Efficacy and safety of HER2-targeted tyrosine kinase inhibitors in <i>HER2</i> -mutant non–small cell lung cancer: A systematic review and meta-analysis.

Abstract

e20772 Background: HER2-targeted tyrosine kinase inhibitors (TKIs) represent a new oral targeted therapy class in HER2-mutant non–small cell lung cancer (NSCLC), a rare molecular subset with historically poor outcomes. In 2025, zongertinib and sevabertinib each received FDA accelerated approval for HER2 TKD-mutant NSCLC after prior systemic therapy, expanding precision treatment options. Methods: A systematic search of major databases was conducted to identify studies evaluating HER2-targeted tyrosine kinase inhibitors in HER2-mutant non–small cell lung cancer; pooled analyses were performed using Stata version 18.0, and risk of bias was assessed using the ROB 2.0 tool. Results: A total of five studies were included, comprising 335 patients with advanced or metastatic HER2-mutant NSCLC. Of these, 209 patients received sevabertinib and 126 received zongertinib. Among sevabertinib-treated patients, 73 were treatment-naïve, 81 were previously treated but HER2-TKI–naïve, and 55 had prior HER2-directed ADC exposure. Among zongertinib-treated patients, 75 had previously treated TKD-mutant disease, 31 had prior ADC exposure, and 20 had non-TKD HER2 mutations. Relative to a historical ORR benchmark of 30%, sevabertinib demonstrated significant efficacy in treatment-naïve patients (OR 5.58, 95% CI 3.44–9.06) and previously treated HER2-TKI–naïve patients (OR 4.08, 95% CI 2.55–6.53), with reduced activity post-ADC (OR 1.43, 95% CI 0.78–2.61). Zongertinib showed robust efficacy in previously treated TKD-mutant disease (OR 5.58, 95% CI 3.50–8.90) and retained post-ADC activity (OR 2.14, 95% CI 1.11–4.12). Grade ≥3 adverse events were significantly reduced with sevabertinib (HR 0.65, 95% CI 0.51–0.82) and zongertinib (HR 0.36, 95% CI 0.21–0.60). Treatment discontinuation was lower with sevabertinib (HR 0.12, 95% CI 0.05–0.28), and no interstitial lung disease was reported. Conclusions: Both selective HER2-targeted TKIs demonstrated significant efficacy, with sevabertinib showing broader activity in treatment-naïve and HER2-TKI–naïve patients and zongertinib exhibiting superior tolerability with retained post-ADC efficacy; overall risk of bias across included studies was low.