Margetuximab–Pembrolizumab Trialled For HER2-Positive Gastro-Oesophageal Cancer

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: The combination of margetuximab and pembrolizumab is tolerable in previously treated patients with locally advanced or metastatic HER2-positive gastro-oesophageal adenocarcinoma, indicate phase Ib/II trial findings published in The Lancet Oncology. 

“These findings serve as proof of concept of synergistic antitumour activity with the combination of an 

Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab)”, say Daniel Catenacci, from The University of Chicago Medical Center & Biological Sciences in Illinois, USA, and co-authors. 

The single-arm CP-MGAH22-05 study recruited patients who had progressed after trastuzumab plus chemotherapy for HER2-positive, unresectable gastric or gastro-oesophageal junction cancer. The patients were not selected by PD-L1 status, the researchers explain. 

The dose-escalation phase of the trial was conducted with nine patients and showed no dose-limiting toxicities, leading to a recommended phase II regimen of margetuximab 15 mg/kg plus pembrolizumab 200 mg, both given intravenously every 3 weeks. 

After a median 19.9 months of follow-up, 20% of 95 patients in the full safety cohort had grade 3–4 treatment-related adverse events (TRAES), most commonly anaemia (4%) and infusion-related reactions (3%). Serious TRAEs included grade 3 or more severe autoimmune hepatitis in two patients and individual cases of grade 3 or higher pneumonitis, hyponatraemia, dehydration, diabetic ketoacidosis and hypotension , as well as a serious grade 2 incidence of dizziness. 

Eight patients discontinued treatment because of emerging AEs, half of which were TRAEs, but the majority (72%) did so because of progressive disease, the researchers say. 

Objective responses occurred in 18.5% of the 92 response-evaluable participants given the recommended dosage and lasted a median of 12.1 months, with a disease control rate of 53%. 

The objective response rate (ORR) varied with PD-L1 and HER2 immunohistochemistry (IHC) status, Daniel Catenacci et al observe. 

For example, the ORR was 33% for the 33 PD-L1-positive versus 7% for the 43 PD-L1-negative patients, and 24% for the 71 HER2 IHC3-positive patients but 0% for the 21 with HER2 IHC2-positive disease. The highest ORR was 60% among the 15 patients who were positive for both PD-L1 and HER2 IHC3 and also showed HER2 amplification in circulating tumour (ct)DNA. 

Further analysis showed that patients with HER2 amplification in ctDNA were a significant 7.3 times more likely to respond to treatment than those without, the researchers note. 

“Enhanced antibody-dependent cellular cytotoxicity with the Fc-engineered monoclonal antibody margetuximab possibly facilitated cross-talk between innate and adaptive immune responses, which were enhanced by checkpoint inhibition, resulting in promising antitumour activities, which were further enriched in patients with relevant biomarkers”, the investigators hypothesise. 

They conclude: “Given the activity and safety profile observed in this study, the phase 2–3 MAHOGANY study (NCT04082364) is underway to investigate the safety and efficacy of margetuximab plus checkpoint inhibitors with or without chemotherapy in the first-line setting for patients with HER2-positive gastro-oesophageal adenocarcinoma.” 

Reference 

Catenacci DVT, Kang Y-K, Park H, et al. Margetuximab plus pembrolizumab in patients with previously treated HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b–2 trial. Lancet Oncol; Advance online publication 9 July 2020. https://doi.org/10.1016/S1470-2045(20)30326-0