Oxaliplatin-Based Versus Alkylating Agent in Neuroendocrine Tumors According to the O 6 -Methylguanine-DNA Methyltransferase Status: A Randomized Phase II Study (MGMT-NET)

Alkylating agents (ALKY) are the main chemotherapies used for advanced neuroendocrine tumors (NETs). O6-Methylguanine-DNA methyltransferase (MGMT) status, as proficient (p) or deficient (d), may predict the response to ALKY. 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. 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. Despite the fact that the primary end point was not reached, ALKY has clinical activity in patients with dMGMT-NETs.