Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers

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 (ClinicalTria...

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Published in:	Nature medicine Vol. 26; no. 4; pp. 566 - 576
Main Authors:	Chalabi, Myriam, Fanchi, Lorenzo F., Dijkstra, Krijn K., Van den Berg, José G., Aalbers, Arend G., Sikorska, Karolina, Lopez-Yurda, Marta, Grootscholten, Cecile, Beets, Geerard L., Snaebjornsson, Petur, Maas, Monique, Mertz, Marjolijn, Veninga, Vivien, Bounova, Gergana, Broeks, Annegien, Beets-Tan, Regina G., de Wijkerslooth, Thomas R., van Lent, Anja U., Marsman, Hendrik A., Nuijten, Elvira, Kok, Niels F., Kuiper, Maria, Verbeek, Wieke H., Kok, Marleen, Van Leerdam, Monique E., Schumacher, Ton N., Voest, Emile E., Haanen, John B.
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01.04.2020 Nature Publishing Group
Subjects:	631/250 631/67 692/308/575 Adenocarcinoma - genetics Adenocarcinoma - pathology Adenocarcinoma - therapy Adult Aged Aged, 80 and over Antineoplastic Agents, Immunological - administration & dosage Antineoplastic Agents, Immunological - adverse effects Biomarkers Biomedical and Life Sciences Biomedicine Cancer Research CD8 antigen Celecoxib Cells, Cultured Colon Colon cancer Colonic Neoplasms - genetics Colonic Neoplasms - pathology Colonic Neoplasms - therapy Colorectal cancer Combined Modality Therapy Confidence intervals CTLA-4 protein Digestive System Surgical Procedures DNA Mismatch Repair - drug effects DNA Mismatch Repair - genetics Drug Administration Schedule Drug therapy Feasibility Studies Female Humans Immunotherapy Immunotherapy - adverse effects Immunotherapy - methods Infectious Diseases Ipilimumab Ipilimumab - administration & dosage Ipilimumab - adverse effects Lymphocytes Lymphocytes T Male Metabolic Diseases Metastases Middle Aged Mismatch repair Molecular Medicine Monoclonal antibodies Neoadjuvant Therapy - adverse effects Neoadjuvant Therapy - methods Neoplasm Staging Neurosciences Nivolumab - administration & dosage Nivolumab - adverse effects Patient outcomes Patients PD-1 protein Safety Surgery Targeted cancer therapy Treatment Failure Tumors Netherlands
ISSN:	1078-8956, 1546-170X, 1546-170X
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Summary:	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. Results from the NICHE study show remarkable pathological responses to neoadjuvant combination immunotherapy in patients with early-stage colon cancer and uncover potential biomarkers of response.
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ISSN:	1078-8956 1546-170X 1546-170X
DOI:	10.1038/s41591-020-0805-8