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Randomized Controlled Trial
. 2020 Apr;26(4):566-576.
doi: 10.1038/s41591-020-0805-8. Epub 2020 Apr 6.

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

Myriam Chalabi  1   2   3 , Lorenzo F Fanchi #  4   5 , Krijn K Dijkstra #  4   5 , José G Van den Berg #  6 , Arend G Aalbers  7 , Karolina Sikorska  8 , Marta Lopez-Yurda  8   9 , Cecile Grootscholten  10 , Geerard L Beets  7   11 , Petur Snaebjornsson  6 , Monique Maas  12 , Marjolijn Mertz  13 , Vivien Veninga  4   5 , Gergana Bounova  5   14 , Annegien Broeks  15 , Regina G Beets-Tan  11   12 , Thomas R de Wijkerslooth  10 , Anja U van Lent  16 , Hendrik A Marsman  17 , Elvira Nuijten  8 , Niels F Kok  7 , Maria Kuiper  10 , Wieke H Verbeek  10 , Marleen Kok  18   19 , Monique E Van Leerdam  10 , Ton N Schumacher  4   5 , Emile E Voest #  20   21   22 , John B Haanen #  4   18
Affiliations
Randomized Controlled Trial

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

Myriam Chalabi et al. Nat Med. 2020 Apr.

Abstract

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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