Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML
David A. Sallman, Rami S. Komrokji, Amy E. DeZern, Marie Sébert, Guillermo Garcia‐Manero, Ramy Rahmé, Eric S. Winer, Jacqueline Lehmann‐Che, Gail J. Roboz, Isabelle Madelaine, Mikkael A. Sekeres, Pierre Péterlin, Onyee Chan, Odile Beyne‐Rauzy, Andrew Kuykendall, Christian Récher, Amy F. McLemore, Aspasia Stamatoullas, Ling Zhang, Lise Willems, Qianxing Mo, Emmanuel Raffoux, Lisa Nardelli, Céline Berthon, Najla H. Al Ali, Bruno Quesnel, Eric Padron, Hagop M. Kantarjian, Alan F. List, Lionel Adès, Jeffrey E. Lancet, Pierre Fenaux, Thomas Cluzeau
Abstract
Abstract TP53 gene mutations (m TP53 ) represent a distinct molecular cohort with poor outcomes. Eprenetapopt (APR‐246) is a novel, first‐in‐class small molecule that reactivates p53 and targets cellular redox balance, ultimately inducing apoptosis and ferroptosis in m TP53 cancer cells. This is a multicenter, international collaboration of the US myelodysplastic syndromes/neoplasms (MDS) clinical research symposium and the Groupe Francophone des Myelodysplasies (GFM) of hypomethylating agents‐naïve m TP53 higher risk MDS and oligoblastic acute myeloid leukemia (AML; ≤30% blasts; NCT03072043/NCT03588078). Patients received eprenetapopt 4500 mg iv (Days 1–4) + azacitidine 75 mg/m 2 sc/iv × 7 days in 28‐day cycles. The primary objective was the complete remission (CR) rate by International Working Group (IWG) 2006 criteria. In total, 100 patients were enrolled with a median age of 68 years (34–87; 47% male). Febrile neutropenia occurred in 37% of patients. Thirty‐ and 60‐day mortality was 1% and 7%, respectively. By intention‐to‐treat, overall response rate by IWG was 69% with 41% CR. The median duration of CR was 10.2 months (95% CI 8.7–11.8). With a median follow‐up of 52 months, median overall survival (OS) was 11.8 months (95% CI 9.4–14.3). Although allogeneic hematopoietic cell transplantation (allo‐HCT) was borderline predictive of OS in the overall cohort by landmark analysis (14.7 vs. 14.4 months; P = 0.046), OS was significantly improved in allo‐HCT patients based on CR/ TP53 next‐generation sequencing (NGS) negativity (P = 0.00085; 2‐year OS of 54%). In this international, combined analysis of Phase 2 eprenetapopt + azacitidine patients, the combination was well‐tolerated with synergistic response rates in m TP53 MDS/AML. Quality of response and NGS negativity strongly predicted OS, particularly in the setting of allo‐HCT, validating NGS clearance as a critical biomarker of allo‐HCT outcomes in m TP53 patients.