Combination Margetuximab, Retifanlimab, Tebotelimab, and Chemotherapy Phase 2/3 Trial in HER2+ Gastric/GEJ Cancer

A Phase 2/3 Trial to Evaluate Margetuximab in Combination With INCMGA00012 and Chemotherapy or MGD013 and Chemotherapy in Patients With Metastatic or Locally Advanced, Treatment-naïve, HER2-Positive Gastric or Gastroesophageal Junction Cancer

This is a Phase 2/3, randomized, open-label study for the treatment of patients with HER2-positive Gastric cancer (GC) or Gastroesophageal Junction (GEJ) cancer conducted in two parts.

Part A is a single-arm cohort (Cohort A, 40 to 110 participants) will evaluate safety and efficacy of margetuximab plus retifanlimab.

Part B Part 1 has 4 arms (50 patients/arm). Participants will be randomized to margetuximab plus retifanlimab plus chemotherapy, margetuximab plus tebotelimab, plus chemotherapy, margetuximab plus chemotherapy, or trastuzumab plus chemotherapy.

Key Inclusion Criteria:

• Histologically confirmed diagnosis of previously untreated locally advanced unresectable or metastatic HER2+ GC or GEJ adenocarcinoma

  1. Prior systemic perioperative treatment is allowed; however the participants must have had a disease-free interval of at least 6 months from end of chemo/surgery
  2. Participants receiving perioperative anti-HER2 therapy require testing of HER2 status for eligibility
  3. Cohort A: HER2-positive (by IHC 3+) and PD-L1-positive (by IHC with 22C3 CPS ≥ 1%) per central review
  4. Cohort B: HER2-positive (by IHC 3+ or IHC 2+ in combination with FISH+) by local review. PD -L1 status is not required for enrollment.

• Availability of formalin-fixed, paraffin-embedded tumor specimen, unstained slides or contemporaneous biopsy for tumor target testing

• Eastern Cooperative Oncology Group performance status of 0 or 1, verified within 3 days of Day 1

• Life expectancy ≥ 6 months

• At least one radiographically measurable target lesion

• Acceptable laboratory parameters and adequate organ function

Key Exclusion Criteria:

• Other malignancy that is progressing or required treatment within the past 5 years, with certain exceptions

  • Participants with known MSI-H status

• History of allogeneic stem cell or tissue/solid organ transplant

• Central nervous system metastases

• Clinically significant cardiovascular disease, gastrointestinal disorders, pulmonary compromise

  • Prior neoadjuvant or adjuvant treatment with immunotherapy