Gastro-oesophageal adenocarcinoma represents a group of malignancies comprising gastric, oesophageal, and gastro-oesophageal junction adenocarcinomas. Gastro-oesophageal adenocarcinoma remains one of the most prevalent cancers worldwide, accounting for over 1·4 million new cases and approximately 1 million deaths globally in 2022. Patients with gastro-oesophageal adenocarcinoma are typically diagnosed with advanced disease and have a poor prognosis.

Approximately 20% of patients with gastro-oesophageal adenocarcinoma have human epidermal growth factor receptor 2 (HER2)-positive tumours (defined by immunohistochemistry [IHC] 3+ or IHC 2+ with fluorescence in-situ hybridisation [FISH] positivity). In the phase 3 Trastuzumab for Gastric Cancer (ToGA) trial, Trastuzumab, a HER2-targeted monoclonal antibody, plus Platinum-fluoropyrimidine chemotherapy was associated with an objective response rate of 47% with a median progression-free survival of 6·7 months (95% CI 6–8; hazard ratio [HR] 0·71 vs chemotherapy alone) and a median overall survival of 13·8 months (95% CI 12–16; HR 0·74) as first-line treatment of patients with HER2-positive advanced gastric or gastro-oesophageal junction adenocarcinoma. These results established Trastuzumab plus Platinum-based and fluoropyrimidine-based chemotherapy as first-line standard of care. Moreover, nationally and regionally recognised practice guidelines recommend HER2 testing at the time of diagnosis of metastatic disease to identify patients who might benefit from HER2-targeted therapies.

In 2023, the phase 3 KEYNOTE-811 trial demonstrated that adding Pembrolizumab to Trastuzumab-based combination regimens in patients with HER2-positive advanced gastric or gastro-oesophageal junction adenocarcinomas that also expressed PD-L1 (combined positive score greater than or equal to 1) improved survival versus Trastuzumab plus chemotherapy alone (median progression-free survival 10·9 months vs 7·3 months, HR 0·73; median overall survival 20·1 months vs 15·7 months, HR 0·79).

Despite this advancement, a high unmet need remains for first-line treatments that could further improve survival outcomes for patients with HER2-positive advanced gastro-oesophageal adenocarcinoma while also maintaining a manageable safety profile.

Zanidatamab, a dual HER2-targeted bispecific antibody, binds to two non-overlapping domains on HER2 (the juxtamembrane and dimerisation domains) in trans (between molecules) to initiate distinct HER2 reorganisation. In preclinical studies, Zanidatamab was shown to drive multiple antitumour mechanisms of action, including facilitation of HER2 internalisation and subsequent degradation, inhibition of HER2 homo-dimerisation and hetero-dimerisation, and activation of immune-mediated effects (complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity and phagocytosis).

In a phase 1 trial, Zanidatamab as a monotherapy and in combination with chemotherapy demonstrated encouraging antitumour activity (objective response rates of 32% and 49%, respectively), with a manageable safety profile in heavily pretreated patients with HER2-expressing gastro-oesophageal adenocarcinoma.

In a new study, part 1 aimed to characterise the safety and tolerability of Zanidatamab and find the recommended dose when administered with combination chemotherapy, and part 2 aimed to evaluate the antitumour activity of Zanidatamab administered with combination chemotherapy in patients receiving first-line treatment for HER2-expressing advanced gastro-oesophageal adenocarcinoma.

This is the first global, phase 2 trial of Zanidatamab, a dual HER2-targeted bispecific antibody, that simultaneously targets both the HER2 juxtamembrane (ECD4) and dimerisation (ECD2) domains in trans (between molecules), in combination with standard chemotherapy regimens for the first-line treatment of patients with HER2-positive advanced gastro-oesophageal adenocarcinoma. This regimen provided clinically meaningful and sustained antitumour activity, with a robust response rate observed in the subset of patients with HER2-positive tumours (status confirmed by central laboratory assessment). The safety profile of the combination was manageable, with the incidence of grade 3 diarrhoea mitigated after the implementation of mandatory antidiarrhoeal prophylaxis for all patients and omission of the 5-Fluorouracil bolus for patients receiving modified FOLFOX (Leucovorin, 5-Fluorouracil, and Oxaliplatin) chemotherapy.

In conclusion, this study has provided evidence that Zanidatamab plus standard chemotherapy offers encouraging antitumour activity with sustained responses and a manageable safety profile in the first-line treatment of patients with HER2-positive advanced gastro-oesophageal adenocarcinoma. ( Xagena_2025 )

Elimova E et al, Lancet Oncol 2025;26(7):847-859

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