Revumenib has shown favorable efficacy in patients with relapsed or refractory NPM1-mutated acute myeloid leukemia (AML), according to updated findings from the phase 2 AUGMENT-101 trial. The drug, developed by Syndax Pharmaceuticals, met its primary endpoint of complete remission and complete remission with partial hematological recovery (CR/CRh). These results pave the way for a supplemental New Drug Application (NDA) filing expected in the first half of 2025.
Efficacy Data
The AUGMENT-101 trial (NCT04065399) revealed a CR/CRh rate of 23% (95% CI, 14%-36%; P = .0014) among patients with relapsed/refractory NPM1-mutated AML. This included 12 patients achieving CR and 3 achieving CRh. Notably, 64% (n = 9/14) of evaluable patients who achieved CR/CRh had negative minimal residual disease (MRD) status. The overall response rate (ORR) in this patient population was 47% (n = 30/64; 95% CI, 34%-60%), with 5 (17%) undergoing hematopoietic stem cell transplant (HSCT) following treatment.
Patient Population and Treatment History
The efficacy analysis included 64 patients with relapsed/refractory NPM1-mutated AML. The median age was 65 years (range, 19-84), and patients were heavily pretreated, with a median of 2 prior lines of therapy; 36% had received 3 or more prior lines. A significant 75% of the NPM1-mutated AML cohort had prior treatment with venetoclax.
Safety Profile
The safety population consisted of 84 adult and pediatric patients within the NPM1-mutated cohort. The safety data were consistent with previously reported data. Treatment-related adverse events (TRAEs) leading to discontinuation occurred in 4 patients (5%). Grade 3 TRAEs occurring in more than 10% of patients included QTc prolongation (21%), anemia (14%), febrile neutropenia (13%), differentiation syndrome (DS; 13%), and decreased platelet counts (11%). There were 9 (11%), 2 (2%), and 0 (0%) instances of grade 3, 4, and 5 DS, respectively, and 16 (19%), 2 (2%), and 0 (0%) instances of grade 3, 4, and 5 QTc prolongation among patients with NPM1-mutated AML.
Clinical Significance
"Relapsed or refractory [NPM1-mutated] AML is a very challenging disease with a poor prognosis and an urgent need for new treatments," said Eytan M. Stein, MD, chief of the Leukemia Service at Memorial Sloan Kettering Cancer Center. "The positive results for revumenib in this heavily pre-treated population, which included more than 75% who previously [progressed on] venetoclax [Venclexta], are encouraging. In particular, the robust rates of overall response, including deep molecular remissions and low discontinuation rates, highlight the tremendous promise of revumenib in the treatment of [patients with relapsed/refractory NPM1-mutated] AML."
Future Directions
Pending potential FDA approval of revumenib in relapsed/refractory KMT2A-rearranged acute leukemia, Syndax Pharmaceuticals anticipates filing a supplemental NDA for the NPM1-mutated AML indication in the first half of 2025. Michael A. Metzger, chief executive officer of Syndax, stated that the company is well-positioned to meaningfully impact the estimated 40% of patients with AML who have these two genetic alterations.
