Zanidatamab with chemotherapy or tislelizumab achieves 70% objective response rate in HER2-positive gastroesophageal adenocarcinomaNew drug combination shows promise for advanced stomach cancer

BACKGROUND: Zanidatamab is a novel HER2-targeted antibody that binds to two non-overlapping extracellular domains of the HER2 receptor. Early-phase trials have shown clinical benefit of first-line Zanidatamab in patients with advanced HER2-positive esophageal 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, which were carried out using R software (v4.5.2). RESULTS: Three clinical trials involving 685 patients with advanced HER2-positive GEA treated with zanidatamab in combination with chemotherapy and/or tislelizumab were included. Overall, the reconstructed pooled median OS was 26.05 months (95% CI: 23.60-30.04), while the pooled median PFS was 12.61 months (95% CI: 11.05-14.60). The pooled ORR was 70% (95% CI, 67-74), DCR was 96% (95% CI, 78-100), and median DOR was 17.11 months (95% CI, 13.07-22.40). Treatment-related diarrhea leading to dose reduction was observed in 16% (95% CI, 1%-75%) of patients. Treatment discontinuation due to any cause rate was 20% (95% CI, 3%-44%). Serious treatment-emergent AEs occurred in 66% (95% CI, 50%-81%) of patients. Common any-grade AEs included diarrhea (89%; 95% CI, 75%-98%), nausea (60%; 95% CI, 45%-74%), and infusion-related reactions (30%; 95% CI, 19%-43%). Grade ≥ 3 diarrhea, nausea, and treatment-related AEs rates were as follows: 26% (95% CI, 19%-34%), 5% (95% CI, 2%-13%), and 65% (95% CI, 58%-71%), respectively. Other important AEs include immune-mediated AEs (25% incidence rate), left ventricular dysfunction (6% incidence rate), and non-infectious pulmonary toxicity (4% incidence rate). CONCLUSIONS: Our pooled analyses suggest that zanidatamab exhibits meaningful activity as first-line treatment of advanced HER2-positive GEA. Yet, concerning toxicity rates were also consistently reported across studies. Future randomized studies are needed to further explore its activity and safety profile in this population.