Activity Shown With Revumenib in KMT2Ar AML/ALL Leads to Early Trial Completion

Photomicrograph of bone marrow aspirate showing myeloblasts of AML: © David A Litman - stock.adobe.com

Revumenib (SNDX-5613), a first-in-class Menin inhibitor, produced complete remissions (CRs) with a CR with partial hematologic recovery (CRh) rate of 23% (95% CI, 12.7%-35.8%; P = .0036) in adult and pediatric patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) harboring KMT2A rearrangements. With these results, the primary end point of the phase 1/2 AUGMENT-101 trial (NCT04065399) has been met.¹

In addition to the 57 efficacy-evaluable patients in the KMT2A-rearranged acute leukemia cohort who experienced a CR, an additional 14% of patients proceeded to transplant without achieving CR/CRh. Patients with R/R AML (n = 49) achieved a CR/CRh rate of 24.5%. Additionally, overall response rates (ORRs) were 63% (95% CI, 49.3%-75.6%) among patients in the overall cohort and 65% for patients with R/R AML.

Both the overall population and patients with AML had durable CR/CRh responses with a 6.4-month (95% CI, 3.4-NR) median duration as of the July 24, 2023, data cut-off, and 46% remained in response. Ten of the 13 patients who achieved CR/CRh had minimal residual disease (MRD) status assessed, and 70% were MRD-negative.

A total of 14 (39%) of all evaluable responders who reached an overall response underwent hematopoietic stem cell transplant (HSCT), including 8 patients who did not achieve a CR or CRh prior to HSCT. Following transplant, half of the patients who underwent HSCT (n = 7) received revumenib maintenance, and 3 additional patients were in follow-up and eligible to restart revumenib in the maintenance setting.

Further accrual in the KMT2A-rearranged cohorts will be stopped, based on the recommendation of an independent data monitoring committee and these positive topline data.

“Acute leukemias with KMT2A rearrangements have a good response rate when patients are given Menin inhibitors. Their response rates are in the range of 50%. These responses are very deep, meaning that even by the most sensitive methods we have to detect acute leukemia…were unable to detect these abnormalities being the patients are in a very deep remissions,” Eytan M. Stein, MD, chief of the leukemia service and director of the Program for Drug Development in Leukemia, Division of Hematologic Malignancies, at Memorial Sloan Kettering Cancer Center in New York, New York, told Targeted Oncology^TM.

“We are thrilled to report positive results for revumenib in KMT2A-rearranged acute leukemia that demonstrate the utility of its practice-changing clinical profile and highlight revumenib's potential as a first- and best-in-class agent," Michael A. Metzger, chief executive officer of Syndax, stated in a news release.

Previously in December 2022, the FDA granted a breakthrough therapy designation to revumenib for adult and pediatric patients with R/R acute leukemia who harbor a KMT2A rearrangement.² Phase 1 data from the AUGMENT-101 trial, an open-label, dose-escalation and dose-expansion study evaluating revumenib, supported this decision, as 10 of 37 patients (27%) with age and phenotype agnostic KMT2A rearranged acute leukemia who were treated achieved CR, as measured by a CR/CRh.

Investigators sought to assess patients at least 30 days old with R/R leukemias, including those harboring an MLL/KMT2A rearrangement or NPM1 mutation.3 To participate, all patients needed to have a white blood cell count below 25,000/µL at enrollment, an ECOG performance status of 0 to 2 or a Karnofsky/Lansky score of at least 50, and adequate organ function.

In the phase 1 dose-escalation portion of the study, patients were enrolled based on concomitant treatment with a strong CYP3A4 inhibitor and randomized into 1 of 6 arms to receive escalating doses of oral revumenib. In the phase 2 portion, patients with R/R NPM1-mutant AML, KMT2A-rearranged AML, or KMT2A-rearranged ALL are included and being treated at the recommended phase 2 dose.³

For the phase 2 cohorts, the primary end point is CR plus CRh rate, with secondary end points of duration of response (DOR) and overall survival (OS) being evaluated.

Additional findings showed that 94 patients with acute leukemia were enrolled in the AUGMENT-101 study and made up the safety population. Fifty-seven patients comprised the efficacy-evaluable population. A total of 56% of patients relapsed after receiving treatment with at least 1 salvage regimen, with 46% having undergone prior stem cell transplant, and 72% who were previously treated with venetoclax (Venclexta).

For safety, treatment-related adverse events (TRAEs) leading to dose reductions and treatment discontinuations occurred in 9% and 6% of patients, respectively, in the KMT2A-rearranged acute leukemia cohort and R/R AML cohort. Any-grade TRAEs most commonly reported in more than 20% of patients included nausea (28%), differentiation syndrome (27%), and QTc prolongation (23%).

Moreover, 15% of patients experienced grade 3 differentiation syndrome, and 1 patient (1%) had grade 4 differentiation syndrome. A total of 14% of patients had grade 3 QTc prolongation, and there were no instances of grade 4 or 5 QTc prolongation or grade 5 differentiation syndrome observed. No patients discontinued treatment due to QTc prolongation or differentiation syndrome.

“With revumenib, the biggest [adverse events] that we've seen was the prolongation of the QT interval. That hasn't led to any significant arrhythmias, but we do see that prolongation,” added Stein.

Additional data from AUGMENT-101 are expected to be presented at an upcoming medical meeting.

REFERENCES

1. Syndax announces pivotal AUGMENT-101 trial of revumenib in relapsed/refractory KMT2Ar acute leukemia meets primary endpoint and stopped early for efficacy following protocol-defined interim analysis. News release. Syndax Pharmaceuticals. October 2, 2023. Accessed October 3, 2023. https://tinyurl.com/yc3zwppa

2. Syndax announces US FDA breakthrough therapy designation granted for revumenib for the treatment of adult and pediatric patients with relapsed or refractory KMT2A- rearranged (MLLr) acute leukemia. News release. Syndax Pharmaceuticals. December 5, 2022. Accessed October 3, 2022. https://tinyurl.com/m6xhdksk

3. A study of SNDX-5613 in R/R leukemias including those with an MLLr/KMT2A gene rearrangement or NPM1 mutation (AUGMENT-101). ClinicalTrials.gov. Updated August 21, 2023. Accessed October 3, 2023. https://tinyurl.com/5n8p4d53