Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers
Open accessAbstract
PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86-100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8-55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8+PD-1+ T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data.
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In the NICHE study, patients with dMMR/MSI-H cancer responded better than pMMR/MSS patients, but an efficacy signal was also noticed in the pMMR/MSS group in a non-metastatic, locally advanced setting.
“Patients with dMMR/MSI-H cancer responded better, but an efficacy signal was also noticed in the pMMR/MSS group,105 although this was in a non-metastatic, locally advanced setting.”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [105]
Dual ICB is already established as effective in primary dMMR/MSI-H and second or later line treatment of dMMR/MSI-H mCRC.
“in addition to the already established effectiveness of this combination in primary dMMR/MSI-H and second or later line treatment of dMMR/MSI-H mCRC.105 106”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [105]
Infiltration of PD1-positive CD8+ T cells predicted response to combinatorial immune checkpoint blockade with nivolumab and ipilimumab in patients with pMMR/MSS colorectal cancer in the NICHE study.
“In line with both scores, the infiltration of PD1-positive CD8+ T cells predicted the response to combinatorial ICB with nivolumab and ipilimumab in patients with pMMR/MSS in the NICHE (Neoadjuvant Immune Checkpoint Inhibition and Novel IO Combinations in Early-Stage Colon Cancer) study.105”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [105]
Neoadjuvant immune checkpoint therapy trials have demonstrated clinical benefit in multiple tumor types including melanoma, Merkel cell carcinoma, NSCLC, MMR-deficient colorectal cancer, urothelial carcinoma, and breast cancer.
“Clinical trials with ICT in the neoadjuvant setting have now demonstrated clinical benefit in multiple tumor types, including melanoma (173, 174), Merkel cell carcinoma (175), NSCLC (176), MMRdeficient colorectal cancer (177), urothelial carcinoma (21, 178), and breast cancer (179-181).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [177]
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- Authors
- Chalabi, M., Fanchi, L. F., Dijkstra, K. K., Van den Berg, J. G., Aalbers, A. G., Sikorska, K., Lopez-Yurda, M., Grootscholten, C., Beets, G. L., Snaebjornsson, P., Maas, M., Mertz, M., Veninga, V., Bounova, G., Broeks, A., Beets-Tan, R. G., de Wijkerslooth, T. R., van Lent, A. U., Marsman, H. A., Nuijten, E., Kok, N. F., Kuiper, M., Verbeek, W. H., Kok, M., Van Leerdam, M. E., Schumacher, T. N., Voest, E. E., & Haanen, J. B.
- Affiliations
- The Netherlands Cancer Institute (NL)
- OLVG (NL)
- Corresponding author
- Chalabi, Myriam
- Voest, Emile E.
- ORCID
- Chalabi, Myriam
- Fanchi, Lorenzo F.
- Dijkstra, Krijn K.
- Aalbers, Arend G.
- Sikorska, Karolina
- Grootscholten, Cecile
- Beets, Geerard L.
- Snaebjornsson, Petur
- Maas, Monique
- Mertz, Marjolijn
- Veninga, Vivien
- Broeks, Annegien
- Marsman, Hendrik A.
- Kok, Niels F.
- Verbeek, Wieke H.
- Kok, Marleen
- Schumacher, Ton N.
- Voest, Emile E.
- Haanen, John B.
- Venue
- Nature Medicine
- Published
- 2020-04
- Volume
- 26
- Issue
- 4
- Pages
- 566-576
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W3015035400
- Cited by
- 1,417
- References
- 16
- Citations by year
- 2026: 162 · 2025: 241 · 2024: 261 · 2023: 287 · 2022: 219 · 2021: 173 · 2020: 67 · 2015: 2 · 2014: 1
- FWCI
- 68.36
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Amsterdam University Medical Centers
- Universiteit Leiden
- Rijksuniversiteit Groningen
- Universiteit van Amsterdam
- Radboud Universiteit
- Universiteit Maastricht
- 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
- neoadjuvant immunotherapy, early colon cancer, mismatch repair deficiency, ipilimumab, nivolumab, celecoxib, anti-PD-1 therapy, CTLA-4 blockade, pathological complete response, CD8+ T cell infiltration, predictive biomarkers, treatment safety and feasibility
- MeSH terms
- Antineoplastic Agents, Immunological, Ipilimumab, Nivolumab, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Cells, Cultured, Colonic Neoplasms, Combined Modality Therapy, Drug Administration Schedule, Feasibility Studies, Female, Humans, Immunotherapy, Male, Middle Aged, Neoplasm Staging, Digestive System Surgical Procedures, Treatment Failure, Neoadjuvant Therapy, DNA Mismatch Repair
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