On July 9, 2020 MacroGenics, Inc. (NASDAQ: MGNX), a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported that Lancet Oncology has published results from a Phase 2 study of margetuximab plus pembrolizumab as a chemotherapy-free regimen for patients with advanced HER2-positive gastroesophageal adenocarcinoma (GEA) who have previously been treated with chemotherapy and trastuzumab. Margetuximab is an investigational, Fc-engineered, monoclonal antibody targeting HER2. Pembrolizumab is an anti-PD-1 monoclonal antibody (Press release, MacroGenics, JUL 9, 2020, View Source [SID1234561792]).

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"Current standard of care treatment for patients with metastatic gastroesophageal adenocarcinoma is heavily dependent on the use of cytotoxic chemotherapy," said Stephen Eck, M.D., Ph.D., Senior Vice President, Clinical Development & Chief Medical Officer. "The published data suggest that a chemotherapy-free regimen combining the immune-enhancing properties of margetuximab with checkpoint blockade may improve upon clinical outcomes for certain first-line patients with metastatic HER2-positive gastroesophageal adenocarcinoma and provide a strong rationale for the ongoing Phase 2/3 MAHOGANY study."

The Phase 2 study enrolled patients with gastric cancer (GC) or gastroesophageal junction (GEJ) cancer whose tumors were IHC3-positive or IHC2-positive/FISH-positive at diagnosis. Enrollment was regardless of PD-L1 expression status, which was subsequently determined from available archived tumor tissue.

Tolerability of margetuximab and pembrolizumab was acceptable in patients treated in this study. Grade 3 or higher treatment-related adverse events (TRAEs) were reported in 20% of patients, with anemia (4%) and infusion-related reactions (3%) being the most common. No treatment-related deaths were reported.

Patients who had received margetuximab at the recommended Phase 2 dose of 15 mg/kg every three weeks were evaluable for response. In this overall population, the objective response rate (ORR) was 18% (17/92 patients), including complete responses (CR) and partial responses (PR). The disease control rate (DCR), which includes CR, PR, and stable disease (SD), was 53% (49/92 patients). Median progression-free survival (PFS) was 2.7 months (95% CI 1.6–4.3) and median overall survival (OS) was 12.5 months (95% CI 9.1–14.1).

Activity of margetuximab and anti-PD-1 in this study was more pronounced in key biomarker-positive subgroups. The most pronounced benefit was observed in patients whose tumors had high HER2 expression at diagnosis (HER2 IHC3-positive) and were PD-L1-positive. In this double-positive subgroup, the ORR was 44% (11/25 patients) and the DCR was 72% (18/25 patients). Median PFS was 4.8 months (95% CI 1.6–13.9) and median OS was 20.5 months (95% CI 8.1–NR).

Patients with initial HER2-positive GEA may lose HER2 expression after trastuzumab-based therapy. In this second-line study, HER2 amplification was not detectable in circulating tumor DNA (ctDNA) in 42% of patients who were tested, suggesting loss of HER2 following prior trastuzumab and before treatment with margetuximab and pembrolizumab. The presence of HER2 amplification in ctDNA was associated with better response rates in this study. HER2amp-positive/HER2 IHC3-positive/PD-L1-positive ORR was 60% (9/15 patients) and DCR was 80% (12/15 patients).

Consistent with prior studies of margetuximab in other tumor types, correlative analyses of samples from GEA patients treated in the study showed an increase in anti-HER2 specific T-cell immunity, suggesting the potential for engagement of both innate and adaptive immune responses.

These data in second-line patients who were refractory to trastuzumab provide the rationale for the ongoing Phase 2/3 MAHOGANY clinical trial of margetuximab in combination with checkpoint blockade, with or without chemotherapy, as a potential first-line treatment for patients with HER2-positive GC or GEJ cancer (NCT04082364). The data published in Lancet Oncology are reported as of July 10, 2019 and were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress in September 2019.

About Gastric and Gastroesophageal Junction Cancer

Cancer of the stomach (gastric cancer) or the gastroesophageal junction (where the esophagus joins the stomach) is collectively known as gastroesophageal adenocarcinoma. According to the American Cancer Society, approximately 27,600 new cases of gastric cancer will be diagnosed in the U.S in 2020 and more than 11,000 people will die from the disease. Both GC and GEJ cancer are often diagnosed at an advanced stage and therefore have very poor prognosis, with a 5-year survival of 5-20%. Chemotherapy is the standard of care for first-line therapy and may be combined with trastuzumab for the approximately 20% of patients whose tumors are HER2-positive.

About Margetuximab

Margetuximab is an Fc-engineered, monoclonal antibody that targets the HER2 oncoprotein. HER2 is expressed by tumor cells in breast, gastroesophageal and other solid tumors. Margetuximab was designed to provide HER2 blockade and has similar HER2 binding and antiproliferative effects as trastuzumab. In addition, margetuximab has been engineered using MacroGenics’ Fc Optimization technology to enhance the engagement of the immune system. A Biologics License Application (BLA) for margetuximab for the treatment of patients with metastatic HER2-positive breast cancer in combination with chemotherapy is under review by the FDA, with a Prescription Drug User Fee Act (PDUFA) goal date of December 18, 2020. A Phase 2/3 MAHOGANY clinical trial in of margetuximab in combination with checkpoint inhibition, with or without chemotherapy, as a potential first-line treatment for patients with HER2-positive GC or GEJ cancer (NCT04082364) is ongoing. Margetuximab has been granted an orphan drug designation by the FDA for the treatment of GC or GEJ cancer.