A meta-analysis on outcomes of zanidatamab plus chemotherapy in patients with advanced HER2-gastroesophageal adenocarcinoma.

Abstract

e16076 Background: Zanidatamab is a novel HER2-targeted antibody that binds to two non-overlapping extracellular domains of the HER2 receptor (EC2 and EC4). Early-phase trials have shown clinical benefit of first-line zanidatamab in patients with advanced HER2-positive gastroesophageal adenocarcinoma (GEA). We performed a meta-analysis to evaluate the efficacy and safety of zanidatamab in this patient population. Methods: We searched PubMed, Embase, Cochrane, ASCO, and ESMO databases for studies examining zanidatamab as first-line treatment in patients with HER2-positive advanced GEA. Outcomes of interest included progression-free survival (PFS); objective response rate (ORR); disease control rate (DCR); duration of response (DOR); and incidence of adverse events (AEs). Analyses were presented as median or proportions in percentages with 95% confidence intervals (CIs). Random-effect models were used for analysis. Results: Three clinical trials (HERIZON-GEA-01, Elimova et al [2025], Lee et al [2025]) involving 685 patients with advanced HER2-positive GEA treated with zanidatamab plus chemotherapy and/or anti-PD1 were included. These comprised: a phase 2 single-arm trial (Elimova et al) of zanidatamab plus chemotherapy (capecitabine/oxaliplatin, fluorouracil/cisplatin, or mFOLFOX6) in 46 patients (non-randomized); a phase 1b/2 single-arm trial (Lee et al) of zanidatamab plus tislelizumab plus capecitabine/oxaliplatin in 33 patients (cohorts A/B with different dosing, non-randomized); and the phase 3 HERIZON-GEA-01 trial, randomizing patients to zanidatamab plus chemotherapy plus tislelizumab (cohort B, n = 302), zanidatamab plus chemotherapy plus placebo (cohort C, n = 304), or trastuzumab plus chemotherapy plus placebo (not in meta-analysis). Overall, 70% (95% CI, 67%-74%) achieved an ORR, and 96% (95% CI, 78%-100%) a DCR. Median PFS was 12.6 months (95% CI, 10.9-14.7), and median DOR 17.1 months (95% CI, 13.1-22.4). AEs led to dose reductions from treatment-related diarrhea in 16% (95% CI, 1%-75%). Treatment discontinuation rate was 20% (95% CI, 3%-44%): 6% (95% CI, 1%-15%) due to zanidatamab. Serious treatment-emergent AEs occurred in 66% (95% CI, 50%-81%). Grade ≥3 TRAEs affected 65% (95% CI, 58%-71%), with grade ≥3 diarrhea in 26% (95% CI, 19%-34%) and nausea in 5% (95% CI, 2%-13%). Other important AEs: immune-mediated (25%), left ventricular dysfunction (6%), non-infectious pulmonary toxicity (4%). Conclusions: Zanidatamab shows meaningful activity as first-line treatment for advanced HER2-positive GEA, but with notable toxicity, mainly diarrhea. Future randomized studies will refine its profile. Main outcomes of this meta-analysis. Pooled proportion/median (95% CI) ORR 70% (67-74%) DCR 96% (78-100%) mPFS 12.6 months (10.9-14.7) mDOR 17.1 months (13.1-22.4) All-grade diarrhea 89% (75-98%) High-grade diarrhea 26% (19-34%)