Oxaliplatin-Based Versus Alkylating Agent in Neuroendocrine Tumors According to the O <sup>6</sup> -Methylguanine-DNA Methyltransferase Status: A Randomized Phase II Study (MGMT-NET)
Thomas Walter, Thierry Lecomte, Julien Hadoux, Patricia Niccoli, Léa Saban-Roche, Élisabeth Gaye, Rosine Guimbaud, Mathieu Baconnier, Vincent Hautefeuille, Christine Do Cao, Caroline Pétorin, Olivia Hentic, Marine Perrier, Thomas Aparicio, Jean‐Yves Scoazec, Maxime Bonjour, Benjamin Gibert, Valérie Hervieu, Delphine Poncet, Marc Barritault, Laura Gérard, Alice Durand, on behalf of the “Groupe d’étude des tumeurs endocrines (GTE)” and the French ENDOCAN-RENATEN network
Abstract
PURPOSE Alkylating agents (ALKY) are the main chemotherapies used for advanced neuroendocrine tumors (NETs). O 6 -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 MGMT ≥9%) and using immunochemistry ( H -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), P = .172. However, best ORR (18 [52.9%] v 3 [11.5%]) and median progression-free survival (14.6 [95% CI, 7.2 to 22.1] v 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.