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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

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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.

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Availability of data and material

All raw data and materials used to generate this manuscript and the included figures are available upon request from the corresponding author.

Code availability

Code utilized for the biostatistical analysis of this work is available from the corresponding author upon reasonable request.

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Acknowledgements

The authors are grateful for all the patients and families who participated in this clinical trial. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding

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. 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.

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Author notes

  1. Cameron J. Herting and Matthew R. Farren have contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, 1365 Clifton Road NE, Atlanta, GA, 30322, USA

    Cameron J. Herting, Matthew R. Farren, Walid Shaib, Christina Wu, Bassel F. El-Rayes & Gregory B. Lesinski

  2. Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN, USA

    Yan Tong, Ziyue Liu, Bert O’Neil & Safi Shahda

  3. Mayo Clinic, Scottsdale, AZ, USA

    Tanios Bekaii-Saab

  4. Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH, USA

    Anne Noonan, Christopher McQuinn & Thomas A. Mace

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Contributions

GBL, BFE, and SS conceptualized this project and obtained funding for the execution. MRF and TAM generated the raw data for each figure. BO, TB, AN, CM, WS, CW, BFE, and SS conducted the clinical work associated with this trial. CJH, YT, and ZL analyzed the data. CJH wrote the original draft. All authors participated in revisions of the manuscript.

Corresponding author

Correspondence to Gregory B. Lesinski.

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Conflict of interest

MRF, CJH, YT, ZL, AN, CM, and TAM have no conflicts of interest to declare. BO has consulted for Genentech, Amgen, and Merck. The terms of these arrangements have been reviewed and approved by Indiana University in accordance with its conflict-of-interest policies. TBS has consulted for Ipsen, Array Biopharma, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, and Merck through his institution. TBS has also consulted for Boehringer Ingelheim, Janssen, Eisai, Daichii Sankyo, Natera, TreosBio, Celularity, Exact Science, and Sobi and has been compensated for these services. TBS has received research funding from Agios, Arys, Boston Biomedical, Bayer, Amgen, Merck, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Array Biopharma, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, and BMS. The terms of these arrangements have been reviewed and approved by Mayo Clinic in accordance with their conflict-of-interest policies. WS has received honoraria from Merck, BMS, Lexicon, Mylan, Ipsen, Blueprint Medicine, Signatera, and Exilexis. Dr. Shaib has also received research support from Lexicon, Eli Lilly, and GSK. The terms of these arrangements have been reviewed and approved by Emory University in accordance with its conflict-of-interest policies. CW has consulted for Natera and Array Biopharma as well as received clinical trial funding from Vaccinex, Rapt Therapeutics, INBHRX, Boston Biomedical Inc., Seattle Genetics, Lycera, and Symphogen. The terms of these arrangements have been reviewed and approved by Emory University in accordance with its conflict-of-interest policies. BFE has consulted for Ipsen, Merck and Co., Bayer, AstraZeneca, Bristol-Myers Squibb, Inc. and been a speaker for Lexicon, Inc. He serves as a consultant to Merck and Co., and receives compensation for these services. He has also received research funding through a sponsored research agreement between Emory University and Bristol-Myers Squibb, Boston Biomedical, Novartis, Merck and Co, Bayer, Exelixis, Pfizer, AstraZeneca/Medimmune, Incyte, and EUSA. The terms of these arrangements have been reviewed and approved by Emory University in accordance with its conflict-of-interest policies. SS is currently employed by Eli Lilly. GBL has consulted for ProDa Biotech, LLC and received compensation. He has also received research funding through a sponsored research agreement between Emory University and Merck and Co., Bristol-Myers Squibb, Boerhinger-Ingelheim, and Vaccinex. The terms of these arrangements have been reviewed and approved by Emory University in accordance with its conflict-of-interest policies.

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All authors and relevant funding sources have read and approved the final version of this manuscript and consent its publication.

Ethics approval and consent to participate

This study was conducted in accordance with the IRB procedures at Emory University (IRB00080442), Indiana University (1502701251), and The Ohio State University and was approved by their Ethics Boards. All patients were consented prior to participation in this trial (NCT02375672).This study was conducted in accordance with the IRB procedures at Emory University (IRB00080442), Indiana University (1502701251), and The Ohio State University and was approved by their Ethics Boards. All patients were consented prior to participation in this trial (NCT02375672).

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Precis: We show that combining mFOLFOX and pembrolizumab is safe in patients with metastatic colorectal cancer. Correlative analyses identified immunotherapeutic targets, including LAG3, that warrant future investigation.

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Herting, C.J., Farren, M.R., Tong, Y. et al. 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. Cancer Immunol Immunother 70, 3337–3348 (2021). https://doi.org/10.1007/s00262-021-02986-5

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