Efficacy of Perioperative Pembrolizumab in Mismatch Repair Deficient/Microsatellite Unstable Localized Colorectal Cancers: Results of the Phase II Trial IMHOTEP

Author(s): Christelle de la Fouchardière, MD^1,2; Aziz Zaanan, MD, PhD^3,4; Aymeric de Montfort, MSc⁵; Romain Cohen, MD, PhD^6,7; Samuel Le Sourd, MD⁸; David Tougeron, MD, PhD⁹; Emilie Soularue, MD¹⁰; Olivier Dubreuil, MD¹¹; Nicolas Williet, MD, PhD¹²; Emmanuelle Samalin-Scalzi, MD¹³; Guillaume Piessen, MD, PhD¹⁴; Vincent Hautefeuille, MD¹⁵; Marine Jary, MD, PhD¹⁶; Meher Ben Abdelghani, MD¹⁷; Ludovic Evesque, MD¹⁸; Philippe Rochigneux, MD¹; Ellen Blanc, MSc⁵; David Pérol, MD⁵; Frederic Bibeau, MD, PhD¹⁹; Clélia Coutzac, MD, PhD^2,20;

Source: DOI: 10.1200/JCO-25-02169

Dr. Maen Hussein's Thoughts

One or 2 doses pre op then completing a year of therapy lead to pCR in 53% of patients with MSI, the pCR increased from 46% after one dose to 68% after 2 doses.

PURPOSE

Mismatch repair deficiency (dMMR) or microsatellite instability (MSI) represents a distinct phenotype among solid tumors resulting in the generation of highly immunogenic neoantigens. Pembrolizumab has been approved in first-line unresectable or metastatic dMMR/MSI colorectal cancers (CRC). We aimed to assess efficacy and tolerance of perioperative pembrolizumab in dMMR/MSI CRC.

PATIENTS AND METHODS

The prospective multicenter phase II trial IMHOTEP enrolled patients with localized resectable dMMR/MSI CRC to receive one or two cycles of IV pembrolizumab 400 mg once every 6 weeks before surgery and 1-year total duration thereafter. The primary end point was pathologic complete response (pCR) rate (ypT0N0). Secondary objectives included safety, event-free survival, and overall survival.

RESULTS

IMHOTEP enrolled 81 patients with dMMR/MSI CRC who received least one cycle of pembrolizumab from November 26, 2021, to February 22, 2023: median age was 66 (21-89) years, 46 (52%) were women, and 63 (71%) had clinical stage III disease baseline. Out of the 72 patients included in the efficacy population, 38 patients (52.7% [95% CI, 41.4 to 63.9]) achieved a pCR. The exploratory post hoc analysis showed a pCR rate increased from 46% (23/50) after one cycle to 68.2% (15/22) after two cycles of neoadjuvant pembrolizumab (P = .0125). With a median follow-up of 24.5 (95% CI, 23.3 to 25.6) months, three disease recurrences occurred. Grade ≥3 immune-related toxicities were reported in 14 (15.7%) patients including one grade 5 (myasthenia).

CONCLUSION

The IMHOTEP trial showed promising results, with pCR achieved after one or two cycles of neoadjuvant pembrolizumab in 53% of patients with dMMR/MSI CRC. To our knowledge, this prospective study is the first to demonstrate the feasibility and the safety of perioperative pembrolizumab.

Author Affiliations

¹Medical Oncology Department, Paoli-Calmettes Institute, Aix-Marseille University, Marseille, France; ²Department of Medical Oncology, Centre Léon Bérard, Lyon, France; ³Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Paris University, Paris, France; ⁴Assistance Publique-Hôpitaux de Paris, Paris, France; ⁵Department of Clinical Research and Innovation, Centre Léon Bérard, Lyon, France; ⁶Department of Medical Oncology, Sorbonne University, Hôpital Saint-Antoine, AP-HP, Paris, France; ⁷INSERM UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée Par la Ligue Nationale Contre le Cancer, SIRIC CURAMUS, Centre de Recherche Saint Antoine, Paris, France; ⁸Medical Oncology, Centre Eugène Marquis, Rennes, France; ⁹Department of Hepato-gastroenterology, Centre Hospitalo-Universitaire Poitiers, Poitiers, France; ¹⁰Department of Oncology, Institute Mutualiste Montsouris, Paris, France; ¹¹Department of Digestive Oncology, Groupe Hospitalier Diaconesses Croix Saint Simon, Paris, France; ¹²Department of Hepato-Gastroenterology and Gastrointestinal Oncology, University Institute of Cancerology and Hematology of Saint-Etienne (ICHUSE), Saint-Etienne, France; ¹³Department of Medical Oncology, Institut Régional du Cancer de Montpellier (ICM), Université Montpellier, Montpellier, France; ¹⁴CNRS, Inserm, Chu Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, University Lille, Lille, France; ¹⁵Department of Hepato-Gastroenterology and Gastrointestinal Oncology, CHU d'Amiens, Amiens, France; ¹⁶Department of Digestive and Oncological Surgery, CHU Estaing, Clermont-Ferrand, France; ¹⁷Department of Medical Oncology, Paul Strauss Center, Strasbourg, France; ¹⁸Department of Medical Oncology, Centre Antoine Lacassagne, Nice, France; ¹⁹Department of Pathology, Besançon University Hospital, Besançon, France; ²⁰Gastroenterology and Technologies for Health (Université Claude Bernard Lyon 1, INSERM U1052, CNRS UMR5286, Centre Léon Bérard), Cancer Research Center of Lyon, Lyon, France

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