Margetuximab/Pembrolizumab for Previously Treated Patients With HER2-Positive Advanced Gastroesophageal Adenocarcinoma

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In a phase Ib/II trial reported in The Lancet Oncology, Daniel V.T. Catenacci, MD, and colleagues found that the combination of margetuximab and the anti–PD-1 therapy pembrolizumab showed evidence of activity in patients with previously treated HER2-positive gastroesophageal adenocarcinoma.

Daniel V.T. Catenacci, MD

Daniel V.T. Catenacci, MD

As stated by the investigators, margetuximab is a novel Fc-engineered anti-HER2 monoclonal antibody that is designed to more effectively potentiate innate immunity compared with trastuzumab.

Study Details

The study enrolled 95 patients with unresectable locally advanced or metastatic HER2-positive, PD-L1­–unselected disease. Patients had experienced progression after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, 3 patients received intravenous margetuximab at 10 mg/kg plus pembrolizumab at 200 mg every 3 weeks, and 6 received the recommended phase II dose of margetuximab at 15 mg/kg plus pembrolizumab every 3 weeks. An additional 86 patients enrolled in the phase II expansion cohort received the recommended phase II dose.


Median follow-up was 19.9 months. Among 92 evaluable patients who received the phase II dose, objective response was observed in 17 (18%), with disease control achieved in 49 (53%). Median duration of response was 12.09 months. Median progression-free survival was 2.73 months and median overall survival was 12.48 months. Objective response was observed in 11 (33%) of 33 patients with PD-L1–positive tumors.


  • Objective response was observed in 18% of patients.
  • Median duration of response was 12 months.

Adverse Events

No dose-limiting toxicities were observed in the dose-escalation phase. Among all 95 patients, treatment-related grade 3 or 4 adverse events occurred in 20%, with the most common being anemia (4%) and infusion-related reactions (3%). Serious treatment-related adverse events were reported in 9% of patients, and included autoimmune hepatitis in two and pneumonitis, hyponatremia, diabetic ketoacidosis, hypotension, infusion-related reaction, and dehydration in one patient each. Adverse events led to death in three patients, due to esophageal hemorrhage, peritonitis, and acute respiratory failure; none of the deaths was considered treatment-related.

The investigators concluded, “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).”

Dr. Catenacci, of the University of Chicago Medical Center, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by MacroGenics. For full disclosures of the study authors, visit

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