Oxaliplatin-Based Versus Alkylating Agent in Neuroendocrine Tumors According to the O-Methylguanine-DNA Methyltransferase Status: A Randomized Phase II Study (MGMT-NET).

Christine Do Cao, Alice Durand, Laura Gerard, Marc Barritault, Elisabeth Gaye, Léa Saban-Roche, Maxime Bonjour, Benjamin Gibert, Thomas Aparicio, Jean-Yves Scoazec, Thierry Lecomte, Caroline Petorin, Olivia Hentic, Thomas Walter, Marine Perrier, Rosine Guimbaud, Vincent Hautefeuille, Julien Hadoux, Patricia Niccoli, Valérie Hervieu, Delphine Poncet, Mathieu Baconnier

Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2025;43(8):960-971

PMID: 39586038

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Abstract

PURPOSE

Alkylating agents (ALKY) are the main chemotherapies used for advanced neuroendocrine tumors (NETs). O-Methylguanine-DNA methyltransferase (MGMT) status, as proficient (p) or deficient (d), may predict the response to ALKY.

PATIENTS AND METHODS

MGMT-NET (ClinicalTrials.gov identifier: NCT03217097) was a phase II trial randomly assigning 1:1 for pMGMT or 2:1 for dMGMT-NETs to either ALKY or oxaliplatin (Ox). Inclusion criteria were a confirmed advanced pancreatic, thoracic, or unknown primary NETs with an indication for chemotherapy and tissue available. The primary aim was to detect a difference of 35% between the 3-month objective response rate (ORR) in pMGMT-NETs versus in dMGMT-NETs when treated with ALKY. A biomarker-stratified design was performed to compare ALKY and Ox in the dMGMT and pMGMT strata for the secondary end points. dMGMT was defined using pyrosequencing (PSQ; methylated ≥9%) and using immunochemistry (-score of MGMT <50) when PSQ was not interpretable.

RESULTS

From October 2018 to October 2021, 105 patients (55 pancreas, 38 thorax, 12 unknown) started either ALKY (n = 62) or Ox (n = 43). The median age was 63 years (range, 30-84), and 59% were males. NETs were G1 (19%), G2 (69%), or G3 (10%). Among patients with interpretable MGMT status, 56.9% (58 of 102) had a dMGMT-NET. The primary end point was not reached; the 3-month ORR was 10 (29.4%) versus 2 (8%), and the odds ratio was 3.5 (0.58-21.16), = .172. However, best ORR (18 [52.9%] 3 [11.5%]) and median progression-free survival (14.6 [95% CI, 7.2 to 22.1] 11.3 [9.4 to 13.2] months) were higher for dMGMT-NETs versus pMGMT-NETs. MGMT status does not seem to affect the Ox efficacy.

CONCLUSION

Despite the fact that the primary end point was not reached, ALKY has clinical activity in patients with dMGMT-NETs.

Address: Department of Medical Oncology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.; Gastroenterology and Technologies for Health, INSERM UMR 1052 CNRS UMR 5286, Cancer Research Center of Lyon, University of Lyon, Lyon, France.; Department of Hepatogastroenterology and Digestive Oncology, Tours University Hospital, Tours, France.; Inserm UMR 1069, Nutrition, Croissance et Cancer, University of Tours, Tours, France.; Departement of Endocrine Oncology, Gustave Roussy, Villejuif, France.; Oncology Department, Institut Paoli Calmette, Marseille, France.; Oncology Department, Lucien Neuwirth Cancer Institute, Saint Priest en Jarez, France.; Oncology Department, Oscar Lambret, Lille, France.; Department of Digestive Medical Oncology, CHU de Toulouse, Toulouse, France.; Departement of Hepato-gastroenterology and Digestive Oncology, Annecy Hospital, Annecy, France.; Departement of Hepato-gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France.; CHU Lille, Department of Endocrinology, Diabetology, and Metabolism, University Hospital of Lille, Lille, France.; Oncology Department, Estaing Hospital, Clermont-Ferrand, France.; Gastroenterology-Pancreatology Department, Hôpital Beaujon, Clichy, France.; Department of Hepatogastroenterology and Digestive Oncology, Hôpital Robert Debré, Reims, France.; Department of Gastroenterology and Digestive Oncology, Saint Louis Hospital, APHP, Université de Paris, Paris, France.; Department of Pathology, Gustave Roussy Cancer Campus, Villejuif, France.; Biostatistic Team of Hospices Civils of Lyon, Clinical Research Department UMR CNRS 5558, University Lyon 1, Lyon, France.; Gastroenterology and Technologies for Health, Research Unit INSERM UMR 1052 CNRS UMR 5286, Cancer Research Center of Lyon, Lyon, France.; Multi-site Institute of Pathology of the HCL-Est Site, GHE University Hospital, Bron, France.; Department of Molecular Biology, Institute of Multi-Site Pathology of the HCL-Est Site, GHE University Hospital, Bron, France.; Department of Medical Oncology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.

DOI: 10.1200/JCO.23.02724

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MeSH Terms: Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Antineoplastic Agents, Alkylating, Antineoplastic Combined Chemotherapy Protocols, DNA Modification Methylases, DNA Repair Enzymes, Neuroendocrine Tumors, O(6)-Methylguanine-DNA Methyltransferase, Oxaliplatin, Tumor Suppressor Proteins