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

Mark Yarchoan, Chiung Yu Huang, Qingfeng Zhu, Anna K. Ferguson, Jennifer N. Durham, Robert A. Anders, Elizabeth D. Thompson, Noah S. Rozich, Dwayne L. Thomas, Julie M. Nauroth, Christina Rodriguez, Arsen Osipov, Ana De Jesus-Acosta, Dung T. Le, Adrian G. Murphy, Daniel Laheru, Ross C. Donehower, Elizabeth M. Jaffee, Lei Zheng, Nilofer S. Azad

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalCancer medicine
DOIs
StateAccepted/In press - Jan 1 2019

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DNA Mismatch Repair
Cyclophosphamide
Colorectal Neoplasms
Colon
Carcinoembryonic Antigen
Disease-Free Survival
Programmed Cell Death 1 Receptor
Confidence Intervals
Survival
Hemolytic Anemia
Graft Rejection
Neoplasm Antigens
Regulatory T-Lymphocytes
Granulocyte-Macrophage Colony-Stimulating Factor
GVAX vaccine
pembrolizumab
Immunotherapy
Immunity
Necrosis
Therapeutics

Keywords

  • checkpoint inhibitor
  • colorectal cancer
  • immunotherapy
  • PD-1
  • vaccine

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer. / Yarchoan, Mark; Huang, Chiung Yu; Zhu, Qingfeng; Ferguson, Anna K.; Durham, Jennifer N.; Anders, Robert A.; Thompson, Elizabeth D.; Rozich, Noah S.; Thomas, Dwayne L.; Nauroth, Julie M.; Rodriguez, Christina; Osipov, Arsen; De Jesus-Acosta, Ana; Le, Dung T.; Murphy, Adrian G.; Laheru, Daniel; Donehower, Ross C.; Jaffee, Elizabeth M.; Zheng, Lei; Azad, Nilofer S.

In: Cancer medicine, 01.01.2019.

Research output: Contribution to journalArticle

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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 = "checkpoint inhibitor, colorectal cancer, immunotherapy, PD-1, vaccine",
author = "Mark Yarchoan and Huang, {Chiung Yu} and Qingfeng Zhu and Ferguson, {Anna K.} and Durham, {Jennifer N.} and Anders, {Robert A.} and Thompson, {Elizabeth D.} and Rozich, {Noah S.} and Thomas, {Dwayne L.} and Nauroth, {Julie M.} and Christina Rodriguez and Arsen Osipov and {De Jesus-Acosta}, Ana and Le, {Dung T.} and Murphy, {Adrian G.} and Daniel Laheru and Donehower, {Ross C.} and Jaffee, {Elizabeth M.} and Lei Zheng and Azad, {Nilofer S.}",
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T1 - A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer

AU - Yarchoan, Mark

AU - Huang, Chiung Yu

AU - Zhu, Qingfeng

AU - Ferguson, Anna K.

AU - Durham, Jennifer N.

AU - Anders, Robert A.

AU - Thompson, Elizabeth D.

AU - Rozich, Noah S.

AU - Thomas, Dwayne L.

AU - Nauroth, Julie M.

AU - Rodriguez, Christina

AU - Osipov, Arsen

AU - De Jesus-Acosta, Ana

AU - Le, Dung T.

AU - Murphy, Adrian G.

AU - Laheru, Daniel

AU - Donehower, Ross C.

AU - Jaffee, Elizabeth M.

AU - Zheng, Lei

AU - Azad, Nilofer S.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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KW - immunotherapy

KW - PD-1

KW - vaccine

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