PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Open accessAbstract
BACKGROUND: Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. METHODS: We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. RESULTS: The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02). CONCLUSIONS: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).
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In a 2015 phase II trial, pembrolizumab produced durable responses in more than 50% of patients with dMMR/MSI-H mCRC but not in pMMR/MSS mCRC.
“A seminal phase II trial from 2015 showed that ICB with the anti-PD-1 antibody pembrolizumab resulted in durable responses in more than 50% of patients with dMMR/MSI-H but not in pMMR/MSS mCRC.100”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [100]
Anti-PD-1-treated patients with colorectal cancers that were mismatch-repair deficient or non-small cell lung cancers with high mutation rates had better outcomes.
“This was particularly noted in anti-CTLA-4-treated melanoma patients whose tumors displayed neo-antigens (87) and similarly in anti-PD-1-treated patients with colorectal cancers or non-small cell lung cancers that were mismatch-repair deficient or had high mutation rates, respectively (78, 86).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [78]
Anti-PD-1 therapies are approved for tumors with microsatellite instability-high/mismatch-repair deficiency or high tumor mutational burden regardless of tumor type.
“Anti-PD-1 therapies have also received approval for treatment of patients with cancer who are diagnosed with tumors that have microsatellite instabilityhigh (MSI-H )/mismatch-repair defi ciency (dMMR; refs.47,48 ) or high tumor mutational burden (TMB-high) regardless of tumor type ( 49 ).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [47]
An initial colorectal cancer study found significantly higher response rates to pembrolizumab in dMMR patients than in MMR-proficient patients.
“An initial study in patients with colorectal cancer demonstrated significantly higher rates of response to pembrolizumab in dMMR patients compared with MMR-proficient patients (47), a finding that was later extended to multiple tumor types (48).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [47]
The total number of somatic coding mutations in a cancer genome correlates with response to immune checkpoint blockade.
“Previous reports have shown that the total number of somatic coding mutations in a cancer genome correlates with response to ICB (7, 8, 10–12, 17).”
From Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy (2018) · cites this paper as [8]
Response rates to ICIs vary widely across cancers, from >80% in refractory Hodgkin's lymphoma to little or no response in mismatch repair-proficient colorectal cancer, with many indications at 20-40%.
“Response rates to ICI treatment vary widely among different cancers, ranging from greater than 80% in patients with refractory Hodgkin's lymphoma to little or no response in patients with mismatch repair-proficient colorectal cancer (76, 77); many tumor indications fall within a response rate range of 20% to 40% (78).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [77]
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Naidoo, J., Wang, X., Woo, K. M., Iyriboz, T., Halpenny, D., Cunningham, J., Chaft, J. E., Segal, N. H., Callahan, M. K., Lesokhin, A. M., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2016.68.2005 · Cited by 1,215 · see citing works
- Authors
- Le, D. T., Uram, J. N., Wang, H., Bartlett, B. R., Kemberling, H., Eyring, A. D., Skora, A. D., Luber, B. S., Azad, N. S., Laheru, D., Biedrzycki, B., Donehower, R. C., Zaheer, A., Fisher, G. A., Crocenzi, T. S., Lee, J. J., Duffy, S. M., Goldberg, R. M., de la Chapelle, A., Koshiji, M., Bhaijee, F., Huebner, T., Hruban, R. H., Wood, L. D., Cuka, N., Pardoll, D. M., Papadopoulos, N., Kinzler, K. W., Zhou, S., Cornish, T. C., Taube, J. M., Anders, R. A., Eshleman, J. R., Vogelstein, B., & Diaz, L. A.
- Affiliations
- Swim Across America (US)
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- Providence Portland Medical Center (US)
- University of Pittsburgh (US)
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- From the Swim Across America Laboratory (D.T.L., J.N.U., B.R.B., L.A.D.), Sidney Kimmel Comprehensive Cancer Center (D.T.L., J.N.U., H.W., H.K., A.D.E., A.D.S., B.S.L., N.S.A., D.L., B.B., R.C.D., D.M.P., N.P., K.W.K., S.Z., B.V., L.A.D.), Ludwig Center and Howard Hughes Medical Institute (B.R.B., A.D.S., N.P., K.W.K., S.Z., B.V., L.A.D.), and the Departments of Radiology (A.Z.) and Pathology (F.B., T.H., R.H.H., L.D.W., N.C., T.C.C., J.M.T., R.A.A., J.R.E.), Johns Hopkins University School of Medicine,...
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- ORCID
- Le, Dung T.
- Wang, Hao
- Bartlett, Bjarne R.
- Kemberling, Holly
- Skora, Andrew D.
- Azad, Nilofer S.
- Donehower, Ross C.
- Zaheer, Atif
- Fisher, George A.
- Crocenzi, Todd S.
- Lee, James J.
- Duffy, Steven M.
- Goldberg, Richard M.
- Bhaijee, Feriyl
- Huebner, Thomas
- Hruban, Ralph H.
- Wood, Laura D.
- Pardoll, Drew M.
- Papadopoulos, Nickolas
- Kinzler, Kenneth W.
- Zhou, Shibin
- Cornish, Toby C.
- Taube, Janis M.
- Anders, Robert A.
- Eshleman, James R.
- Vogelstein, Bert
- Diaz, Luis A.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2015-06-25
- Volume
- 372
- Issue
- 26
- Pages
- 2509-2520
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4481136
- OpenAlex
- W1940241680
- Cited by
- 9,377
- References
- 59
- Citations by year
- 2026: 450 · 2025: 577 · 2024: 680 · 2023: 864 · 2022: 958 · 2021: 1155 · 2020: 1123 · 2019: 911 · 2018: 935 · 2017: 878 · 2016: 668 · 2015: 167 · 2014: 5 · 2013: 1
- FWCI
- 382.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA67941, CA163672, CA16058, CA 57345, CA43460, K23CA163672, U01CA067941, R37CA043460, R01CA057345, R01CA067941, P50CA062924, R37CA057345, P30CA016058, P30CA006973)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- anti-PD-1 therapy, pembrolizumab, mismatch repair deficiency, immune checkpoint inhibitors, somatic mutations, tumor mutational burden, colorectal cancer, metastatic carcinoma, predictive biomarkers, exome sequencing, cancer immunotherapy, progression-free survival, overall survival
- MeSH terms
- Adenocarcinoma, Adult, Aged, Antineoplastic Agents, Female, Humans, Male, Middle Aged, Neoplasm Metastasis, Colorectal Neoplasms, Disease-Free Survival, Kaplan-Meier Estimate, DNA Mismatch Repair, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized
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