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Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer
Open accessAbstract
BACKGROUND: Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown. METHODS: In this phase 3, open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil-based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival. RESULTS: At the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.80; P = 0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group. CONCLUSIONS: Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer, with fewer treatment-related adverse events. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 ClinicalTrials.gov number, NCT02563002.).
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“Among patients with a response, treatment responses were durable at 24 months in 83% of patients treated with pembrolizumab versus 33.1% among patients who received standard chemotherapy.”
From Update on Targeted Therapy and Immunotherapy for Metastatic Colorectal Cancer (2024) · cites this paper as [76]
In the citing paper
“Pembrolizumab was associated with improved progression-free survival (median 16.5 months versus 8.2 months, HR 0.60, p < 0.001) and mean overall survival (13.7 months versus 10.8 months).”
From Update on Targeted Therapy and Immunotherapy for Metastatic Colorectal Cancer (2024) · cites this paper as [76]
In the citing paper
“In 2020, the phase III Keynote-177 trial confirmed the superiority of pembrolizumab compared with chemotherapy with or without anti-VEGF/anti-EGFR in the first-line treatment of metastatic dMMR/MSI-H CRC.101”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [101]
In the citing paper
“careful analysis of clinical trials shows that a relevant proportion of patients with metastatic dMMR/MSI-H CRC still do not respond to immune checkpoint blockade101 107 with tumour progression within the first 6 months (up to 50% and up to 25% in single and double agent ICB therapy, respectively)”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [101]
In the citing paper
“However, despite the high rate of durable responses, a fraction of them will develop immune resistance that can outweigh prolonged survival outcomes (approximately 15–29%) [12,15,16].”
From Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy (2024) · cites this paper as [15]
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Metadata
- Authors
- André, T., Shiu, K.-K., Kim, T. W., Jensen, B. V., Jensen, L. H., Punt, C., Smith, D., Garcia-Carbonero, R., Benavides, M., Gibbs, P., de la Fouchardiere, C., Rivera, F., Elez, E., Bendell, J., Le, D. T., Yoshino, T., Van Cutsem, E., Yang, P., Farooqui, M. Z. H., Marinello, P., & Diaz, L. A.
- Affiliations
- University College Hospital (GB)
- From Sorbonne Université and Hôpital Saint Antoine, Paris (T.A.), Bordeaux University Hospital, Bordeaux (D.S.), and Léon Bérard Center, Lyon (C.F.) — all in France; University College Hospital, NHS Foundation Trust, London (K.-K.S.); Asan Medical Center, University of Ulsan, Seoul, South Korea (T.W.K.); Herlev and Gentofte Hospital, Herlev (B.V.J.), and University Hospital of Southern Denmark, Vejle (L.H.J.) — both in Denmark; Amsterdam University Medical Center, University of Amsterdam, Amsterdam ...
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2020-12-03
- Volume
- 383
- Issue
- 23
- Pages
- 2207-2218
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W3110528877
- Cited by
- 3,099
- References
- 27
- Citations by year
- 2026: 522 · 2025: 536 · 2024: 526 · 2023: 587 · 2022: 554 · 2021: 367 · 2020: 4
- FWCI
- 136.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion, other-oa)
- Lirias (submittedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion)
- Digital Access to Libraries (submittedVersion, other-oa)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
- Funders
- Merck (N/A)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- pembrolizumab, microsatellite instability-high, mismatch repair deficiency, advanced colorectal cancer, metastatic colorectal cancer, anti-PD-1 therapy, immunotherapy, first-line therapy, 5-fluorouracil chemotherapy, bevacizumab, cetuximab, progression-free survival, overall survival, treatment-related adverse events, immune-related adverse events
- MeSH terms
- Antineoplastic Agents, Immunological, Progression-Free Survival, Immune Checkpoint Inhibitors, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Brain Neoplasms, Female, Fluorouracil, Humans, Male, Middle Aged, Mutation, Neoplastic Syndromes, Hereditary, Biomarkers, Tumor, Colorectal Neoplasms, Kaplan-Meier Estimate, Microsatellite Instability, Antibodies, Monoclonal, Humanized
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