Revumenib Meets CR/CRh End Point in NPM1+ R/R AML

Treatment with the oral, small molecule menin inhibitor revumenib (SNDX-5613) led to a complete remission (CR) plus CR with partial hematological recovery (CRh) rate of 23% (95% CI, 14%-36%; P = .0014) in patients with relapsed/refractory acute myeloid leukemia (AML) harboring NPM1 mutations, meeting the primary end point of the phase 2 AUGMENT-101 trial (NCT04065399).¹

Findings showed that among those who achieved CR/CRh (n = 15), 12 patients had a CR, and 3 patients had a CRh. Additionally, the median duration of CR/CRh was 4.7 months (95% CI, 1.2-8.2), and 3 patients had ongoing responses at data cutoff. Among patients who achieved a CR or CRh and were evaluable for minimal residual disease (MRD; n = 14), 64% were MRD negative.

In the evaluable population (n = 64), the overall response rate (ORR) was 47% (95% CI, 34%-60%); 17% of responders underwent hematopoietic stem cell transplant following treatment, and 3 of these patients resumed revumenib after transplant.

“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 Pharmaceuticals, stated in a news release. “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] patients with these 2 genetic alterations.”

In March 2024, the FDA granted priority review to the new drug application seeking the approval of revumenib for the treatment of adult and pediatric patients with relapsed/ refractory acute leukemia harboring KMT2A rearrangements, based on prior data from AUGMENT-101.²

In July 2024, the FDA extended the Prescription Drug User Fee Act target action date for the NDA to December 26, 2024.³

The open-label, multicenter AUGMENT-101 trial is evaluating safety, tolerability, pharmacokinetics, and efficacy in a dose-escalation and -expansion format.¹ In the dose-escalation portion of the study, investigators identified a revumenib dose with and without a strong CYP3A4 inhibitor. Dose expansion was designed to evaluate revumenib in relapsed/refractory KMT2A-rearranged acute leukemias and NPM1-mutated AML.

The primary end points were CR/CRh rate and short- and long-term safety and tolerability. Duration of response and overall survival served as secondary end points.

The efficacy-evaluable population for the phase 2 protocol-defined NPM1-mutated cohort included 64 patients with a median age of 65 years (range, 19-84). Notably, 36% of the population had received 3 or more prior lines of therapy, and the median prior lines of therapy was 2. Additionally, 75% of patients were previously treated with venetoclax (Venclexta).

“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 Leukemia Service at Memorial Sloan Kettering Cancer Center, in New York, New York, stated in the news release. “The positive results for revumenib in this heavily pretreated population, which included more than 75% who previously [progressed on or after] venetoclax, are very encouraging. In particular, the robust [ORR], 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 safety population included 84 adult and pediatric patients with relapsed/refractory disease, and data showed a consistent safety profile with previously reported data for revumenib. Treatment-related adverse effects (TRAEs) led to discontinuations in 5% of patients. TRAEs of grade 3 or higher that occurred in more than 10% of patients included QTc prolongation (21%), anemia (14%), febrile neutropenia (13%), differentiation syndrome (DS; 13%), and decreased platelet count (11%).

Furthermore, grade 3 and 4 treatment-related DS was observed in 11% and 2% of patients, respectively, although no grade 5 DS was reported. Grade 3 treatment-related QTc prolongation was observed in 19% of patients; 2% of patients had grade 4 events, and no patients had grade 5 treatment-related QTc prolongation.

Further data for revumenib will be presented at the 2024 ASH Annual Meeting.

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 12, 2024. https://ir.syndax.com/news-releases/news-release-details/syndax-announces-positive-pivotal-topline-results-relapsed-or
2. Syndax announces FDA priority review of NDA for revumenib for the treatment of relapsed/refractory KMT2Ar acute leukemia. News release. Syndax Pharmaceuticals. March 26, 2024. Accessed November 12, 2024. https://ir.syndax.com/news-releases/news-release-details/syndax-announces-fda-priority-review-nda-revumenib-treatment
3. Syndax announces PDUFA action date extension for revumenib NDA for relapsed or refractory KMT2Ar acute leukemia. News release. Syndax Pharmaceuticals. July 29, 2024. Accessed November 12, 2024. https://ir.syndax.com/news-releases/news-release-details/syndax-announces-pdufa-action-date-extension-revumenib-nda