Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability–high/mismatch repair–deficient metastatic colorectal cancer: KEYNOTE-164
Open accessAbstract
PURPOSE: KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) colorectal cancer (CRC). METHODS: This phase II open-label study involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti–vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability. RESULTS: A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in ≥ 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A. CONCLUSION: Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC.
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The efficacy of ICIs in phase II studies with dMMR/MSI and BRAFV600E tumors versus dMMR/MSI and BRAF wild type tumors was similar.
“Additionally, the efficacy of ICIs in phase II studies with dMMR/MSI and BRAFV600E tumors versus dMMR/MSI and BRAF wild type was similar [53,54,55,56].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [55]
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- Authors
- Le, D. T., Kim, T. W., Van Cutsem, E., Geva, R., Jäger, D., Hara, H., Burge, M., O’Neil, B., Kavan, P., Yoshino, T., Guimbaud, R., Taniguchi, H., Elez, E., Al-Batran, S.-E., Boland, P. M., Crocenzi, T., Atreya, C. E., Cui, Y., Dai, T., Marinello, P., Diaz Jr, L. A., & André, T.
- Affiliations
- Johns Hopkins University (US)
- Asan Medical Center (KR)
- University Hospitals Gasthuisberg Leuven, KU Leuven, Leuven, Belgium
- Tel Aviv Sourasky Medical Center (IL)
- National Center for Tumor Diseases (DE)
- Saitama Cancer Center (JP)
- Royal Brisbane and Women's Hospital (AU)
- Indiana University Health (US)
- McGill University Health Centre (CA)
- National Cancer Center Hospital East (JP)
- Centre Hospitalier Universitaire de Toulouse (FR)
- Aichi Cancer Center Hospital (JP)
- Vall d’Hebron Institute of Oncology, Barcelona, Spain
- Krankenhaus Nordwest, Frankfurt, Germany
- Roswell Park Comprehensive Cancer Center (US)
- Providence Portland Medical Center (US)
- University of California, San Francisco (US)
- MSD (China) Investment Co., Ltd. (China) (CN)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Memorial Sloan Kettering Cancer Center, New York, NY
- Sorbonne Université (FR)
- Corresponding author
- Le, Dung T.
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2020-01-01
- Volume
- 38
- Issue
- 1
- Pages
- 11-19
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC7031958
- OpenAlex
- W2983284890
- Cited by
- 1,005
- References
- 13
- Citations by year
- 2026: 75 · 2025: 125 · 2024: 144 · 2023: 193 · 2022: 176 · 2021: 181 · 2020: 108 · 2019: 3
- FWCI
- 48.83
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Journal of Clinical Oncology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Cancer Institute (P30CA008748)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- pembrolizumab, metastatic colorectal cancer, microsatellite instability-high, mismatch repair deficiency, immune checkpoint inhibitors, treatment-refractory cancer, objective response rate, progression-free survival, overall survival, immune-related adverse events, anti-PD-1 therapy, predictive biomarkers, tumor-infiltrating lymphocytes, tumor mutational burden, PD-L1
- MeSH terms
- Antineoplastic Agents, Immunological, Adult, Aged, Aged, 80 and over, Drug Administration Schedule, Female, Humans, Infusions, Intravenous, Male, Middle Aged, Colorectal Neoplasms, Cohort Studies, Treatment Outcome, Microsatellite Instability, DNA Mismatch Repair, Young Adult, Antibodies, Monoclonal, Humanized
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