Revumenib Elicits Favorable Efficacy in mNPM1 Acute Myeloid Leukemia

Developers are expected to file a supplemental NDA for revumenib in NPM1-mutated AML in the first half of 2025.

Revumenib met its primary end point of complete remission and complete remission with partial hematological recovery (CR/CRh) rate and achieved responses in patients with relapsed or refractory NPM1-mutant acute myeloid leukemia (AML), according to a press release from the drug’s developer, Syndax Pharmaceuticals.¹

Updated findings from the phase 2 AUGMENT-101 trial (NCT04065399) reveal that the CR/CRh rate was 23% (95% CI, 14%-36%; P = .0014) among patients with relapsed/refractory NPM1-mutated AML, including 12 patients with a CR and 3 with a CRh. Additionally, of the 15 who achieved a CR/CRh, 64% (n = 9/14) of evaluable patients had negative minimal residual disease (MRD) status. Furthermore, the overall response rate (ORR) in this patient population was 47% (n = 30/64; 95% CI, 34%-60%), with 5 (17%) having underwent hematopoietic stem cell transplant (HSCT) following treatment.

Pending the potential FDA approval of revumenib in relapsed/refractory KMT2A-rearranged acute leukemia, Syndax is expected to file a supplemental new drug application (NDA) for a NPM1-mutated AML indication in the first half of 2025.

"Relapsed or refractory [NPM1-mutated] AML is a very challenging disease with a poor prognosis and an urgent need for new treatments," Eytan M. Stein, MD, chief of the Leukemia Service at Memorial Sloan Kettering Cancer Center, said in the press release.¹ "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."

The phase 2 AUGMENT-101 trial enrolled patients with KMT2A-rearranged acute lymphoblastic leukemia (ALL) or mixed phenotype cute leukemia (MPAL), KMT2A AML, and NPM1-mutated AML to receive oral revumenib.² In patients evaluable for efficacy with relapsed/refractory NPM1-mutated AML (n = 64), the median age was 65 (range, 19-84), and patients were heavily pretreated, with a median of 2 prior lines of therapy and 36% having received 3 or more prior lines. Additionally, 75% of the NPM1-mutated AML cohort received prior treatment with venetoclax.

The safety population consisted of adult and pediatric patients within the NPM1-mutated cohort (n = 84). The safety data reported in this cohort aligned with previously reported data.

Median duration of CR/CRh responses was 4.7 months (95% CI, 1.2-8.2) at data cutoff, with 3 patients remaining in response. Of the 5 patients who underwent HSCT following treatment, 3 continued revumenib post-transplant.

Safety data reveal that treatment-related adverse events (TRAEs) leading to discontinuation occurred in 4 patients (5%) evaluable for safety. Additionally, 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.

"We are thrilled to report positive pivotal data in [patients with relapsed/refractory NPM1-mutated] AML treated with revumenib, which has shown compelling and notably consistent results across treatment settings for both [NPM1-mutated] AML and KMT2A-rearranged acute leukemias," Michael A. Metzger, chief executive officer of Syndax, said in the press release.¹ "With the anticipated FDA approval of revumenib for the treatment of [relapsed/refractory] KMT2A-rearranged acute leukemias this quarter, and this second positive pivotal data readout, we are well-positioned to meaningfully impact the estimated 40% of [patients with] AML with these two genetic alterations."

References

1. Syndax announces positive pivotal topline results from relapsed or refractory mNPM1 AML cohort in AUGMENT-101 trial of revumenib. News release. Syndax Pharmaceuticals. November 12, 2024. Accessed November 13, 2024. https://tinyurl.com/mcnk8mux
2. A study of revumenib in R/​R leukemias including those with an MLL/​KMT2A gene rearrangement or NPM1 mutation (AUGMENT-101). Updated October 16, 2024. Accessed November 13, 2024. https://tinyurl.com/2t48nmns