A multi-center, single-arm, phase Ib study of pembrolizumab (MK-3475) in combination with chemotherapy for patients with advanced colorectal cancer: HCRN GI14-186

• Type of Material: Article
• Authors: Cameron J Herting, Emory University; Matthew R Farren, Emory University; Yan Tong, Indiana University; Ziyue Liu, Indiana University; Bert O'Neil, Indiana University; Tanios Bekaii-Saab, Mayo Clinic; Anne Noonan, Ohio State University; Christopher McQuinn, Ohio State University; Thomas A Mace, Ohio State University; Walid Shaib, Emory University; Christina Wu, Emory University; Bassel El-Rayes, Emory University; Safi Shahda, Indiana University; Gregory Lesinski, Emory University
• Language: English
• Date: 2021-06-23
• Publisher: SPRINGER
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1007/s00262-021-02986-5
• Title of Journal or Parent Work: CANCER IMMUNOLOGY IMMUNOTHERAPY
• Volume: 70
• Issue: 11
• Start Page: 3337
• End Page: 3348
• Grant/Funding Information: Research reported in this publication was supported in part by the Cancer Tissue and Pathology shared resource and the Pediatrics/Winship Flow Cytometry Core of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292.; Research funding for the clinical trial and correlative research studies was provided to investigators through a sponsored research agreement between Merck and Co., Inc and Emory University or The Ohio State University.
• Keywords: FOLFOX; LIVER METASTASIS; Clinical trial; 2ND-LINE TREATMENT; Life Sciences & Biomedicine; Immunology; COLON-CANCER; Oncology; mCRC; EFFICACY; SUPPRESSOR-CELLS; T-CELLS; Immunotherapy; PROGNOSIS; BEVACIZUMAB; Pembrolizumab; Science & Technology; THERAPY; Colorectal cancer; mFOLFOX6

Abstract

Modified FOLFOX6 is an established therapy for patients with metastatic colorectal cancer (mCRC). We conducted a single-arm phase Ib study to address the hypothesis that addition of pembrolizumab to this regimen could safely and effectively improve patient outcomes (NCT02375672). The relationship between immune biomarkers and clinical response were assessed in an exploratory manner. Patients with mCRC received concurrent pembrolizumab and modified FOLFOX6. The study included safety run-in for the first six patients. The primary objective was median progression-free survival (mPFS), with secondary objectives including median overall survival, safety, and exploratory assessment of immune changes. To assess immunological impact, peripheral blood was collected at baseline and during treatment. The levels of soluble factors were measured via bioplex, while a panel of checkpoint molecules and phenotypically defined cell populations were assessed with flow cytometry and correlated with RECIST and mPFS. Due to incidences of grade 3 and grade 4 neutropenia in the safety lead-in, the dose of mFOLFOX6 was reduced in the expansion cohort. Median PFS was 8.8 months and median OS was not reached at data cutoff. Best responses of stable disease, partial response, and complete response were observed in 43.3%, 50.0%, and 6.7% of patients, respectively. Several soluble and cellular immune biomarkers were associated with improved RECIST and mPFS. Immunosuppressive myeloid and T cell subsets that were analyzed were not associated with response. Primary endpoint was not superior to historic control. Biomarkers that were associated with improved response may be informative for future regimens combining chemotherapy with immune checkpoint inhibitors.