Margetuximab shows synergy with pembrolizumab in gastro-oesophageal adenocarcinoma

When combined with the anti-PD-1 checkpoint inhibitor pembrolizumab, the investigational anti-HER2 monoclonal antibody margetuximab demonstrates synergistic antitumour activity against HER2 gastro-oesophageal adenocarcinoma, according to the results of a phase Ib–II trial.

Conducted at centres in the US, Canada, and Asia (Korea, Taiwan, and Singapore), the trial included 95 patients with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma. All patients had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy.

In the dose-escalation phase, three patients received infusions of margetuximab 10 mg/kg, while six patients received the recommended dose of 15 mg/kg, in addition to intravenous pembrolizumab 200 mg every 3 weeks. Eighty-six patients were included in the cohort expansion and received the recommended margetuximab dose.

Over a median follow-up of 19.9 months, the combination therapy showed acceptable safety and tolerability; no dose-limiting toxicities were recorded in the dose-escalation phase. The most common grade 3–4 treatment-related adverse events were anaemia (n=4) and infusion-related reactions (n=3).

Nine patients developed serious treatment-related adverse events. There were no reports of treatment-related deaths.

Of the 92 evaluable patients, 17 showed objective response and 49 achieved disease control. The median progression-free survival was 2.73 months, and median overall survival was 12.48 months. The presence of HER2 amplification in ctDNA (n=48) was associated with better response (odds ratio, 7.3, 95 percent confidence interval, 1.5–71.4).

Based on the findings, the combination of margetuximab and pembrolizumab might offer a new chemotherapy-free treatment option for patients with gastro-oesophageal adenocarcinoma, researchers said. A phase II–III MAHOGANY study is underway to investigate the safety and efficacy of margetuximab plus checkpoint inhibitors with or without chemotherapy in the first-line setting.