Outcomes of patients with HER2+ breast or gastroesophageal cancer are greatly improved with standard anti-HER2 antibody therapies, principally trastuzumab; however, resistance and disease relapse are common. The results of a first-in-human phase I study of a novel anti-HER2 antibody, margetuximab, indicate that enhanced immune-system engagement via antibody-dependent cell-mediated cytotoxicity (ADCC) might further improve outcomes.

ADCC is triggered by the binding of antibodies to Fc receptors on immune effector cells. As lead author Yung-Jue Bang explains, “retrospective data have revealed unfavourable outcomes of trastuzumab treatment in patients expressing low-affinity alleles of the CD16A and CD32A Fc receptors, suggesting a role for ADCC in the antitumour activity of this agent; notably, most people are heterozygous or homozygous for these low-affinity isoforms.” He adds, “margetuximab has been Fc-modified to bind all allelic forms of CD16A and CD32A with increased affinity and, thus, to have greater potential to induce ADCC.”

margetuximab...was active in these patients, two-thirds of whom had received prior anti-HER2 therapy

Margetuximab was evaluated in 66 patients with HER2+ breast or gastric cancer. A maximum tolerated dose was not reached and the drug was well tolerated, with mostly grade ≤2 adverse events, each at a frequency of <24%. Importantly, Bang emphasizes, “margetuximab, as a monotherapy, was active in these patients, two-thirds of whom had received prior anti-HER2 therapy.” Among 60 response-evaluable patients, the partial response and disease-stabilization rates were 12% and 50%, respectively; 23 of 30 women with breast cancer (78%) had tumour shrinkage, some for >30 weeks.

Margetuximab is currently in phase II and phase III testing, in combination with an anti-PD-1 antibody for the second-line treatment of patients with HER2+ gastroesophageal cancer, and in women with heavily pretreated HER2+ metastatic breast cancer, respectively. Bang concludes, “we hope that margetuximab will overcome failures with trastuzumab, owing to its potential to enhance ADCC while retaining antagonistic activity on HER2.”