A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer

Cancer Med. 2020 Feb;9(4):1485-1494. doi: 10.1002/cam4.2763. Epub 2019 Dec 26.

Abstract

Background: Mismatch repair proficient (MMRp) colorectal cancer (CRC) has been refractory to single-agent programmed cell death protein 1 (PD1) inhibitor therapy. Colon GVAX is an allogeneic, whole-cell, granulocyte-macrophage colony-stimulating factor -secreting cellular immunotherapy that induces T-cell immunity against tumor-associated antigens and has previously been studied in combination with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells.

Methods: We conducted a single-arm study of GVAX/Cy in combination with the PD1 inhibitor pembrolizumab in patients with advanced MMRp CRC. Patients received pembrolizumab plus Cy on day 1, GVAX on day 2, of a 21-day cycle. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary objectives included safety, overall survival, progression-free survival, changes in carcinoembryonic antigen (CEA) levels, and immune-related correlates.

Results: Seventeen patients were enrolled. There were no objective responses, and the disease control rate was 18% by RECIST 1.1. The median progression-free survival was 82 days (95% confidence interval [CI], 48-97 days) and the median overall survival was 213 days (95% CI 179-441 days). Biochemical responses (≥30% decline in CEA) were observed in 7/17 (41%) of patients. Grade ≥ 3 treatment-related adverse events were observed in two patients (hemolytic anemia and corneal transplant rejection). Paired pre- and on-treatment biopsy specimens showed increases in programmed death-ligand 1 expression and tumor necrosis in a subset of patients.

Conclusions: GVAX/Cy plus pembrolizumab failed to meet its primary objective in MMRp CRC. Biochemical responses were observed in a subset of patients and have not previously been observed with pembrolizumab monotherapy in MMRp CRC, indicating that GVAX may modulate the antitumor immune response.

Keywords: PD-1; checkpoint inhibitor; colorectal cancer; immunotherapy; vaccine.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / adverse effects
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / therapy*
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / adverse effects
  • DNA Mismatch Repair
  • Female
  • Humans
  • Immunotherapy / adverse effects
  • Immunotherapy / methods*
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Progression-Free Survival
  • Response Evaluation Criteria in Solid Tumors
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology

Substances

  • Antibodies, Monoclonal, Humanized
  • Cancer Vaccines
  • GVAX vaccine
  • Cyclophosphamide
  • pembrolizumab