FDA Grants Margetuximab Orphan Drug Status for Gastric Cancer


The FDA has granted margetuximab an Orphan Drug designation for the treatment of patients with gastric and gastroesophageal junction cancer.

The FDA has granted margetuximab an Orphan Drug designation for the treatment of patients with gastric and gastroesophageal junction (GEJ) cancer, according to MacroGenics, Inc., the manufacturer of the Fc-engineered monoclonal antibody.1

The designation will expedite the development and review of margetuximab in this setting. Margetuximab has shown positive clinical activity in a phase 2 trial (NCT02689284) when combined with pembrolizumab (Keytruda) in previously treated patients with gastric/GEJ cancer. The antibody is currently being explored in the phase 2/3 MAHOGANY trial (NCT04082364) in which patients with treatment-naïve HER2-positive gastric/GEJ cancer are receiving margetuximab in combination with a checkpoint inhibitor with or without chemotherapy.

“We are pleased that the FDA has granted orphan status to margetuximab,” Scott Koenig, MD, PhD, president and CEO of MacroGenics, stated in a press release. “We believe that our immune-enhancing antibody targeting HER2 has the potential to improve upon the clinical activity of existing standard of care for patients with gastric or gastroesophageal cancer.”

Findings from the phase 2 open-label, dose-escalation and -expansion trial of margetuximab plus pembrolizumab were presented at the 2019 European Society for Medical Oncology (ESMO) Annual Congress.2 The study accrued patients with HER2-positive gastric/GEJ cancer who had previously received treatment with chemotherapy and trastuzumab (Herceptin) in the metastatic setting. The results presented at ESMO included 92 patients, comprising 61 with gastric cancer and 31 with GEJ cancer. Enrollment was allowed, regardless of PD-L1 status. Patients received the recommended phase 2 dose, which was established as 15 mg/kg of margetuximab every 3 weeks and 200 mg of pembrolizumab every 3 weeks.

The results showed that among patients who were HER2 IHC3+/PD-L1+ (n = 25), the objective response rate (ORR) was 48% (n = 12) and the median overall survival (OS) was 20.5 months. The disease control rate was 76% (n = 19) and the median progression-free survival (PFS) was 4.8 months. Among all 92 patients, the ORR was 21.7% (n = 20) and the median OS was 12.5 months. The disease-control rate was 54.4% (n = 50) and the median PFS was 2.7 months.

Regarding safety, the study investigators reported that the toxicity was manageable. Grade ≥3 treatment-related adverse events were observed in 19.6% of patients.

The FDA is currently reviewing a Biologics License Application (BLA) for margetuximab for use in combination with chemotherapy as a treatment for patients with previously treated metastatic HER2-positive breast cancer.

The BLA is based on data from the phase 3 SOPHIA trial. Data from a prespecified second interim OS analysis presented at the 2019 San Antonio Breast Cancer Symposium (SABCS) showed that at a median follow-up of 15.6 months, the median OS in the intent-to-treat (ITT) population was 21.6 months (95% CI, 18.86-24.05) with margetuximab plus chemotherapy compared with 19.8 months (95% CI, 17.54-22.28) with trastuzumab plus chemotherapy (HR, 0.89; 95% CI, 0.69-1.13; P = .326).3,4

At the analysis, the investigator-assessed PFS showed a 29% reduction in risk of disease progression or death. The median PFS was 5.7 months (95% CI, 5.22-6.97) in the margetuximab arm compared with 4.4 months (95% CI, 4.14-5.45) in the trastuzumab arm (HR, 0.71; 95% CI, 0.58-0.86; P = .0006).


  1. MacroGenics Announces Margetuximab Granted Orphan Drug Designation in the U.S. for Gastric Cancer. Posted June 5, 2020. https://bit.ly/2MwAlhh. Accessed June 5, 2020.
  2. MacroGenics Presents Margetuximab Data in Gastroesophageal Cancer at the ESMO 2019 Congress. Posted September 30, 2019. https://bit.ly/2MwAlhh. Accessed June 5, 2020.
  3. Rugo HS, Im S-A, Cardoso F, et al. Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: second interim overall survival analysis. Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract GS1-02.
  4. Rugo HS, Im S-A, Wright GLS, et al. SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Oncol. 2019;37(15 suppl; abstr 1000). doi: 10.1200/JCO.2019.37.15_suppl.1000
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