Immunotherapy in MSI/dMMR tumors in the perioperative setting: The IMHOTEP trial

Clélia Coutzac; Frederic Bibeau; Meher Ben Abdelghani; Thomas Aparicio; Romain Cohen; Elodie Coquan; Olivier Dubreuil; Ludovic Evesque; François Ghiringhelli; Stefano Kim; Samuel Lesourd; Cindy Neuzillet; Jean-Marc Phelip; Guillaume Piessen; Philippe Rochigneux; Emmanuelle Samalin; Emilie Soularue; Yann Touchefeu; David Tougeron; Aziz Zaanan; Christelle de la Fouchardière

doi:10.1016/j.dld.2022.07.008

Immunotherapy in MSI/dMMR tumors in the perioperative setting: The IMHOTEP trial

Dig Liver Dis. 2022 Oct;54(10):1335-1341. doi: 10.1016/j.dld.2022.07.008. Epub 2022 Jul 28.

Authors

Clélia Coutzac¹, Frederic Bibeau², Meher Ben Abdelghani³, Thomas Aparicio⁴, Romain Cohen⁵, Elodie Coquan⁶, Olivier Dubreuil⁷, Ludovic Evesque⁸, François Ghiringhelli⁹, Stefano Kim¹⁰, Samuel Lesourd¹¹, Cindy Neuzillet¹², Jean-Marc Phelip¹³, Guillaume Piessen¹⁴, Philippe Rochigneux¹⁵, Emmanuelle Samalin¹⁶, Emilie Soularue¹⁷, Yann Touchefeu¹⁸, David Tougeron¹⁹, Aziz Zaanan²⁰, Christelle de la Fouchardière²¹

Affiliations

¹ Medical Oncology Department, Centre Léon Bérard, 28 rue Laennec, Lyon 69008, France; Cancer Research Center of Lyon (CRCL), UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, Lyon, France.
² Department of pathology, Besançon University Hospital, Besançon, France.
³ Department of Medical Oncology, Paul Strauss Center, Strasbourg, France.
⁴ AP-HP, Gastroenterology and Digestive Oncology Department, Saint Louis Hospital, Paris, France.
⁵ AP-HP, INSERM, Sorbonne University, Saint-Antoine Hospital, Unité Mixte de Recherche Scientifique 938, Paris 75012, France.
⁶ Department of Medical Oncology, Center François Baclesse, Caen, France.
⁷ Department of Digestive Oncology, Groupe hospitalier Diaconesses Croix Saint Simon, Paris, France.
⁸ Department of Medical Oncology, Centre Antoine Lacassagne, Nice, France.
⁹ Department of Medical Oncology, Georges François Leclerc, Dijon, France.
¹⁰ Department of Medical Oncology, University Hospital of Besançon, Besançon 25000, France.
¹¹ Medical Oncology, Centre Eugène Marquis, Rennes 35000, France.
¹² Department of Medical Oncology, Curie Institute, Versailles Saint-Quentin University (UVSQ) - Paris Saclay University, Saint-Cloud, France.
¹³ Centre Hospitalier Universitaire St Etienne, St Etienne, France.
¹⁴ Department of Digestive and Oncological Surgery, Claude Huriez University Hospital, Lille F-59000, France.
¹⁵ Medical Oncology Department, Paoli-Calmettes Institute, Aix-Marseille University, Marseille, France.
¹⁶ Department of medical Oncology, Institut régional du Cancer de Montpellier (ICM), Université Montpellier, Montpellier, France.
¹⁷ Department of Oncology, Institute Mutualiste Montsouris, Paris 75014, France.
¹⁸ CHU Nantes, Institut des Maladies de l'Appareil Digestif (IMAD), Hépato-Gastroentérologie, Inserm CIC 1413, Nantes Université, Nantes F-44000, France.
¹⁹ Department of Hepato-gastroenterology, Centre Hospitalo-Universitaire Poitiers, Poitiers 86000, France.
²⁰ Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris University, Assistance Publique-Hôpitaux de Paris, Paris, France.
²¹ Medical Oncology Department, Centre Léon Bérard, 28 rue Laennec, Lyon 69008, France; Cancer Research Center of Lyon (CRCL), UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, Lyon, France. Electronic address: christelle.delafouchardiere@lyon.unicancer.fr.

PMID: 35907691
DOI: 10.1016/j.dld.2022.07.008

Abstract

Background: Immune checkpoint inhibitors (ICI) targeting Programmed death-1 (PD-1) have shown their efficacy in advanced MSI/dMMR (microsatellite instability/deficient mismatch repair) tumors. The MSI/dMMR status predicts clinical response to ICI. The promising results evaluating ICI in localized MSI/dMMR tumors in neoadjuvant setting need to be confirmed in MSI/dMMR solid tumors. The aim of the IMHOTEP trial is to assess the efficacy of neoadjuvant anti-PD-1 treatment in MSI/dMMR tumors regarding the pathological complete response rate.

Methods: This study is a prospective, multicenter, phase II study including 120 patients with localized MSI/dMMR carcinomas suitable for curative surgery. A single dose of pembrolizumab will be administered before the surgery planned 6 weeks later. Primary objective is to evaluate the efficacy of neoadjuvant pembrolizumab according to pathological complete tumor response. Secondary objectives are to assess safety, recurrence-free survival and overall survival. Ancillary studies will assess molecular and immunological biomarkers predicting response/resistance to ICI. First patient was enrolled in December 2021.

Discussion: The IMHOTEP trial will be one of the first clinical trial investigating perioperative ICI in localized MSI/dMMR in a tumor agnostic setting. Assessing neoadjuvant anti-PD-1 is mandatory to improve MSI/dMMR patient's outcomes. The translational program will explore potential biomarker to improve our understanding of immune escape and response in this ICI neoadjuvant setting.

Keywords: Colorectal cancer; Endometrial cancer; Gastric cancer; Immune checkpoint inhibitor; MSI/dMMR; Perioperative immunotherapy.

Publication types

Clinical Trial, Phase II
Multicenter Study

MeSH terms

Antineoplastic Agents, Immunological* / therapeutic use
Colorectal Neoplasms* / drug therapy
DNA Mismatch Repair
Humans
Immune Checkpoint Inhibitors / therapeutic use
Immunologic Factors / therapeutic use
Immunotherapy / methods
Microsatellite Instability
Neoplasms* / drug therapy
Prospective Studies

Substances

Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors
Immunologic Factors