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

Myriam Chalabi*, Lorenzo F. Fanchi, Krijn K. Dijkstra, Jose G. van den Berg, Arend G. Aalbers, Karolina Sikorska, Marta Lopez-Yurda, Cecile Grootscholten, Geerard L. Beets, Petur Snaebjornsson, Monique Maas, Marjolijn Mertz, Vivien Veninga, Gergana Bounova, Annegien Broeks, Regina G. Beets-Tan, Thomas R. de Wijkerslooth, Anja U. van Lent, Hendrik A. Marsman, Elvira NuijtenNiels F. Kok, Maria Kuiper, Wieke H. Verbeek, Marleen Kok, Monique E. Van Leerdam, Ton N. Schumacher, Emile E. Voest*, John B. Haanen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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,

Original languageEnglish
Pages (from-to)566-576
Number of pages21
JournalNature Medicine
Volume26
Issue number4
DOIs
Publication statusPublished - Apr 2020

Keywords

  • DNA MISMATCH REPAIR
  • COLORECTAL-CANCER
  • PD-1 BLOCKADE
  • GENERATION
  • TUMORS
  • NIVOLUMAB
  • SURVIVAL
  • THERAPY
  • EVASION
  • CELLS

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