Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study
Open accessAbstract
BACKGROUND: Pembrolizumab demonstrated durable antitumor activity in 233 patients with previously treated advanced microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors in the phase II multicohort KEYNOTE-158 (NCT02628067) study. Herein, we report safety and efficacy outcomes with longer follow-up for more patients with previously treated advanced MSI-H/dMMR noncolorectal cancers who were included in cohort K of the KEYNOTE-158 (NCT02628067) study. PATIENTS AND METHODS: Eligible patients with previously treated advanced noncolorectal MSI-H/dMMR solid tumors, measurable disease as per RECIST v1.1, and Eastern Cooperative Oncology Group performance status of 0 or 1 received pembrolizumab 200 mg Q3W for 35 cycles or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as per RECIST v1.1 by independent central radiologic review. RESULTS: Three hundred and fifty-one patients with various tumor types were enrolled in KEYNOTE-158 cohort K. The most common tumor types were endometrial (22.5%), gastric (14.5%), and small intestine (7.4%). Median time from first dose to database cut-off (5 October 2020) was 37.5 months (range, 0.2-55.6 months). ORR among 321 patients in the efficacy population (patients who received ≥1 dose of pembrolizumab enrolled ≥6 months before the data cut-off date) was 30.8% [95% confidence interval (CI) 25.8% to 36.2%]. Median duration of response was 47.5 months (range, 2.1+ to 51.1+ months; '+' indicates no progressive disease by the time of last disease assessment). Median progression-free survival was 3.5 months (95% CI 2.3-4.2 months) and median overall survival was 20.1 months (95% CI 14.1-27.1 months). Treatment-related adverse events (AEs) occurred in 227 patients (64.7%). Grade 3-4 treatment-related AEs occurred in 39 patients (11.1%); 3 (0.9%) had grade 5 treatment-related AEs (myocarditis, pneumonia, and Guillain-Barre syndrome, n = 1 each). CONCLUSIONS: Pembrolizumab demonstrated clinically meaningful and durable benefit, with a high ORR of 30.8%, long median duration of response of 47.5 months, and manageable safety across a range of heavily pretreated, advanced MSI-H/dMMR noncolorectal cancers, providing support for use of pembrolizumab in this setting.
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Existing predictive biomarkers (PD-L1 expression, TMB, microsatellite instability, and mismatch repair deficiency) have clinical utility in specific contexts, but their predictive accuracy varies considerably across tumor histologies and patient populations.
“While these markers have clinical utility in specific contexts, their predictive accuracy varies considerably across tumor histologies and patient populations.”
From PathTIGR: A pathway topology-informed graph representation learning framework for immunotherapy response prediction (2026) · cites this paper as [18]
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Cites
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Li, X., He, Y., Wu, J., Wang, Z., Zhao, X., Zhang, Y., Pan, B., Tang, Y., & Han, J. (2026) · PubMed · doi:10.1126/sciadv.aed6373 · Cited by 1 · see citing works
“Now, researchers have proposed several predicted biomarkers, including programmed death-ligand 1 (PD-L1) expression ( 10 – 12 ), tumor mutational burden (TMB) ( 13 – 16 ), microsatellite instability ( 17 , 18 ), and mismatch repair deficiency status ( 19 – 21 ).”
- Authors
- Maio, M., Ascierto, P. A., Manzyuk, L., Motola-Kuba, D., Penel, N., Cassier, P. A., Bariani, G. M., De Jesus Acosta, A., Doi, T., Longo, F., Miller, W. H., Oh, D.-Y., Gottfried, M., Xu, L., Jin, F., Norwood, K., & Marabelle, A.
- Affiliations
- University of Siena (IT)
- Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
- Russian Cancer Research Center NN Blokhin (RU)
- Université de Lille (FR)
- Centre Léon Bérard (FR)
- Universidade de São Paulo (BR)
- National Cancer Center Hospital East (JP)
- Instituto Ramón y Cajal de Investigación Sanitaria (ES)
- Jewish General Hospital (CA)
- Seoul National University (KR)
- Meir Medical Center (IL)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Inserm (FR)
- Corresponding author
- Maio, M.
- ORCID
- Venue
- Annals of Oncology
- Publisher
- Elsevier BV
- Published
- 2022-09
- Volume
- 33
- Issue
- 9
- Pages
- 929-938
- ISSN
- 0923-7534 (ISSN-L)
- OpenAlex
- W4281630256
- Cited by
- 472
- References
- 4
- Citations by year
- 2026: 92 · 2025: 139 · 2024: 146 · 2023: 79 · 2022: 9 · 2021: 4 · 2020: 2 · 2014: 1
- FWCI
- 39.13
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Annals of Oncology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc-nd)
- LillOA (Université de Lille (University Of Lille)) (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Use Siena air (University of Siena) (submittedVersion, other-oa)
- Funders
- Sanofi
- Chugai Pharmaceutical
- AbbVie
- Daiichi-Sankyo
- Meso Scale Diagnostics
- Boehringer Ingelheim
- Novartis
- Merck Sharp and Dohme
- AstraZeneca
- GlaxoSmithKline
- Amgen
- Bristol-Myers Squibb
- Janssen Pharmaceuticals
- 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
- pembrolizumab, microsatellite instability-high, immune checkpoint inhibitors, KEYNOTE-158, endometrial cancer, gastric cancer, small intestine neoplasms, objective response rate, progression-free survival, overall survival, treatment-related adverse events, durable response, long-term follow-up
- MeSH terms
- Antineoplastic Agents, Immunological, Humans, Neoplasms, Microsatellite Instability, DNA Mismatch Repair, Antibodies, Monoclonal, Humanized
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