Becotatugvedotin Plus Pucotenlimab in EGFR-Positive Advanced Gastric/GEJ Adenocarcinoma

Advanced gastric cancer (AGC) and gastroesophageal junction (GEJ) adenocarcinoma remain associated with poor prognosis after failure of first-line systemic therapy. Although immune checkpoint inhibitor-based chemoimmunotherapy has become the standard first-line treatment for HER2-negative advanced disease, most patients eventually experience disease progression. Current second-line treatment options provide limited clinical benefit, highlighting the need for novel therapeutic strategies.

Epidermal growth factor receptor (EGFR) is overexpressed in approximately 20-30% of gastric cancers and is associated with aggressive tumor biology and poor prognosis. Previous studies evaluating anti-EGFR monoclonal antibodies or tyrosine kinase inhibitors in unselected gastric cancer populations failed to demonstrate survival benefit, largely because of the lack of biomarker-based patient selection and the limited efficacy of conventional EGFR-targeted agents. Becotatug vedotin (MRG003), an EGFR-directed antibody-drug conjugate (ADC) carrying monomethyl auristatin E (MMAE), exerts potent cytotoxic activity through EGFR-mediated internalization and intracellular payload release. In addition, MMAE-containing ADCs may induce immunogenic cell death and remodel the tumor immune microenvironment, providing a strong biological rationale for combination with programmed cell death protein-1 (PD-1) blockade. Pucotenlimab is a humanized anti-PD-1 monoclonal antibody with demonstrated antitumor activity and favorable safety in multiple solid tumors.

This is a prospective, single-center, open-label, single-arm phase II investigator-initiated trial designed to evaluate the efficacy and safety of becotatug vedotin in combination with pucotenlimab as second-line treatment in patients with EGFR-positive unresectable locally advanced, recurrent, or metastatic gastric or gastroesophageal junction adenocarcinoma who have progressed after standard first-line therapy. Approximately 28 patients will be enrolled. Participants will receive becotatug vedotin (2.0 mg/kg, intravenous infusion, every 3 weeks) plus pucotenlimab (200 mg, intravenous infusion, every 3 weeks) until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision.

The primary endpoint is objective response rate (ORR) assessed according to RECIST version 1.1. Secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DoR), time to response (TTR), and safety. Exploratory analyses will evaluate the association between treatment outcomes and biomarkers including EGFR expression, PD-L1 expression, tumor mutational burden, microsatellite instability/mismatch repair status, and immune-related biomarkers, aiming to identify patients most likely to benefit from this combination therapy.