AUGMENT-101 Trial of Revumenib Meets Primary End Point in KMT2Ar Acute Leukemia

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The first-in-class Menin inhibitor revumenib (SNDX-5613) generated high remission rates and was well tolerated among patients with relapsed or refractory (R/R) KMT2A-rearranged acute leukemia, according to findings from the AUGMENT-101 trial (NCT04065399).^1,2

A total of 94 patients were evaluated in the AUGMENT-101 t study from October 1, 2021, to July 24, 2023, and the trial met its primary end point at the protocol-defined interim analysis with a complete remission (CR) or a CR with partial hematologic recovery (CRh) rate of 23% (95% CI, 12.7%-35.8%; P =.0036) among the 57 efficacy-evaluable patients in the KMT2Ar acute leukemia population.¹ In adult patients, the CR and CRh rate was 23% (10/44; 95% CI, 11.5%-37.8%) and 23% in pediatric patients (3/13; 95% CI, 5.0%-53.8%).

In the overall efficacy-evaluable population, the median time to CR and CRh was 1.9 months (range, 0.9-4.6). These responses were durable with a median duration of 6.4 months (95% CI, 3.4-not reached). Additionally, 46% (6/13) of patients remained in response at the time of data cutoff. In 10 of the 13 patients who achieved a CR and CRh, 70% were minimal residual disease (MRD)-negative.

"Publication of the pivotal AUGMENT-101 dataset in KMT2Ar acute leukemia allows for a broader dissemination of these important data and highlights revumenib's impressive and consistent clinical profile that has led to meaningful results for these advanced patients," said Neil Gallagher, MD, PhD, president, head of research and development at Syndax Pharmaceuticals, in a press release.¹ "These data serve as the foundation for the [new drug application] filing that is currently being reviewed by the FDA under its [real-time oncology review program]. As we approach the potential FDA approval of revumenib, we are actively preparing for a successful commercial launch to enable us to deliver this important medicine to patients in need."

Among the efficacy-evaluable patients, the overall response rate was 63% (95% CI, 49.3%-75.6%). The composite response rate (CRc) was 44%, as seen in 25 of 57 patients. MRD status was assessed in 22 of the 25 patients who achieved a CRc, and of these patients, 68% (n = 15) were MRD-negative.

The observed responses were seen across all major subgroups. This included across a range of the number of prior treatments and prior hematopoietic stem cell transplant (HSCT), and across patients aged 1 year to 75 years. Fourteen (39%) patients who achieved an overall response underwent HSCT and 8 did not reach a CR or CRh before the transplant. Moreover, 7 of the 14 patients who had an HSCT continued treatment with revumenib posttransplant, and the median overall survival at the time of data cutoff was 8.0 months (95% CI, 4.1-10.9).

Looking at safety, the safety profile of revumenib was similar to previously reported data. Of the 94 patients included in the safety population of the trial, grade 3 or greater treatment-emergent adverse events (TEAEs) seen in ≥10% of patients consisted of febrile neutropenia (37%), neutropenia (29%), thrombocytopenia (21%), anemia (18%), differentiation syndrome (16%), QTc prolongation (14%), sepsis (12%), and hypokalemia (11%). TEAEs led to dose reductions in 9.6% of patients and discontinuation in 12.8%.

Fourteen patients had grade 3 differentiation syndrome, 1 patient had grade 4 differentiation syndrome, and no patients experienced grade 5 differentiation syndrome. Further, there were no grade 4 or 5 QTc events and, as of the July 2023 data cutoff, no patients discontinued treatment due to differentiation syndrome, cytopenias, or QTc prolongation.

"Despite an increased understanding of the mechanisms governing development of KMT2Ar acute leukemia, no available therapies adequately serve this population," said Ghayas C. Issa, MD, assistant professor, department of leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, in a press release.¹ "The high rate of deep, MRD-negative responses along with a safety profile that supports prolonged time on therapy and maintained remission post-stem cell transplant gives me confidence that revumenib could serve as a paradigm-changing treatment."

In March 2024, the FDA granted priority review for the new drug application for revumenib for the treatment of adult and pediatric patients with relapsed/refractory (R/R) KMT2Ar acute leukemia. A Prescription Drug User Fee Act target action date of December 26, 2024, has been set.

The final AUGMENT-101 pivotal trial cohort of patients with R/R mutant nucleophosmin acute myeloid leukemia also completed enrollment in March 2023, and topline data are expected in the fourth quarter of 2024.

REFERENCES:

1. Syndax announces publication in the journal of clinical oncology of data from the pivotal AUGMENT-101 trial of revumenib in relapsed/refractory KMT2Ar acute leukemia. News release. Syndax Pharmaceuticals. August 12, 2024. Accessed August 12, 2024. https://tinyurl.com/2p8hmbf2

2. Issa GC, Aldoss I, Thirman MJ, et al. Menin inhibition with revumenib for KMT2A-rearranged relapsed or refractory acute leukemia (AUGMENT-101). J Clin Oncol. Published online August 9, 2024. doi:10.1200/JCO.24.00826