Revumenib Meets CR/CRh End Point in KMT2A-Rearranged Relapsed/Refractory AML/ALL

Treatment with the first-in-class menin inhibitor revumenib (SNDX-5613) generated complete remissions (CRs) or CRs with partial hematological recovery (CRh) in adult and pediatric patients with relapsed/refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) harboring KMT2A rearrangements, meeting the primary end point of the phase 1/2 AUGMENT-101 trial (NCT04065399).¹

Efficacy-evaluable patients in the KMT2A-rearranged acute leukemia cohort (n = 57) experienced a CR/CRh rate of 23% (95% CI, 12.7%-35.8%; P = .0036). Specifically, those with relapsed/refractory AML (n = 49) achieved a CR/CRh rate of 24.5%. The overall response rates (ORRs) were 63% (95% CI, 49.3%-75.6%) for the overall cohort and 65% for patients with AML (FIGURE).

Thirty-nine percent of all evaluable responders (n = 14) underwent hematopoietic stem cell transplant (HSCT), including 8 patients who did not achieve a CR or CRh prior to HSCT. Half of patients who underwent HSCT (n = 7) received revumenib maintenance following transplant, and 3 additional patients were in follow-up and eligible to restart revumenib in the maintenance setting.

Following the positive topline data from protocol-defined interim analysis and based on the recommendation of an independent data monitoring committee, further accrual in the KMT2A-rearranged cohorts will be stopped, according to Syndax Pharmaceuticals, the developer of revumenib.

“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.

In December 2022, the FDA granted a breakthrough therapy designation to revumenib for the treatment of adult and pediatric patients with relapsed/refractory acute leukemia harboring a KMT2A rearrangement.2 “Breakthrough therapy designation has enabled us to work closely with the FDA to submit an new drug application by year-end,” Metzger said. “Enrollment in the [NPM1-mutated] cohort of AUGMENT-101 is also progressing well, and we are rapidly advancing that program to an anticipated filing following KMT2A rearrangements...”

AUGMENT-101 is an open-label, dose-escalation and -expansion study evaluating revumenib in patients at least 30 days old with relapsed/refractory 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.

Key exclusion criteria included active acute promyelocytic leukemia, isolated extramedullary relapse; active central nervous system disease, detectable HIV within 6 months of enrollment, or hepatitis B or C.

In the phase 1 dose-escalation portion of the study, patients were enrolled based on concomitant treatment with a strong CYP3A4 inhibitor. Phase 1 included 6 arms:

1. Arm A: Patients not receiving any strong CYP3A4 inhibitor/inducers or fluconazole
2. Arm B: Patients receiving any strong CYP3A4 inhibitors for antifungal prophylaxis
3. Arm C: Patients receiving SNDX-5613 and cobicistat (Tybost)
4. Arm D: Patients receiving fluconazole for antifungal prophylaxis
5. Arm E: Patients not receiving any weak, moderate, or strong CYP3A4 inhibitors/inducers
6. Arm F: Patients receiving isavuconazole (Cresemba) for antifungal prophylaxis

The pivotal phase 2 portion included patients with relapsed/refractory NPM1-mutant AML, KMT2A-rearranged AML, or KMT2A-rearranged ALL.1 After revumenib received breakthrough therapy designation from the FDA, Syndax elected to pool data from cohorts of patients with relapsed/refractory KMT2Ar-rearranged AML and ALL.

Patients treated in phase 1 received escalating doses of oral revumenib, and those in phase 2 are being treated at the recommended phase 2 dose.³

The primary end point for the phase 2 cohorts is CR plus CRh rate. Secondary end points include duration of response (DOR) and overall survival (OS).¹

As of the data cutoff date of July 24, 2023 for the interim analysis, 94 patients with acute leukemia were enrolled onto AUGMENT-101 and comprised the safety population. Within the efficacy-evaluable population (n = 57), 56% relapsed following treatment with at least 1 salvage regimen, 46% had undergone prior stem cell transplant, and 72% received prior treatment with venetoclax (Venclexta).

Additional efficacy data showed that the median DOR was 6.4 months (95% CI, 3.4-not reached), and 6 of 13 patients had ongoing responses at data cutoff. Furthermore, in patients who achieved a CR/CRh and were evaluated for minimal residual disease (MRD; n = 10), the MRD negativity rate was 70%.

Regarding safety, treatment-related adverse effects (TRAEs) led to dose reductions and treatment discontinuations in 9% and 6% of patients, respectively. The most common any-grade TRAEs reported in more than 20% of patients included nausea (28%), differentiation syndrome (27%), and QTc prolongation (23%).

Notably, 15% of patients experienced grade 3 differentiation syndrome, and 1 patient (1%) experienced grade 4 differentiation syndrome. Fourteen percent of patients had grade 3 QTc prolongation. No instances grade 4 or 5 QTc prolongation or grade 5 differentiation syndrome were observed, and no patients discontinued treatment due to QTc prolongation or differentiation syndrome.

“This pivotal dataset of revumenib monotherapy in heavily pretreated R/R patients is very compelling in that it demonstrates significant clinical benefit that includes deep molecular remissions and is well tolerated,” Ibrahim Aldoss, MD, assistant attending physician and associate professor in the Division of Leukemia of the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, and principal investigator of AUGMENT-101, said in a news release. “The responses were durable with a high proportion of patients proceeding to potentially curative transplant and re-starting revumenib therapy. This is especially impressive given that these patients would generally not have an option for transplant with the current treatment options.”

Additional data from AUGMENT-101 will 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 2, 2023. https://ir.syndax.com/news-releases/news-release-details/syndax-announces-pivotal-augment-101-trial-revumenib
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 2, 2022. https://ir.syndax.com/news-releases/news-release-details/syndax-announces-us-fda-breakthrough-therapy-designation-granted
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 2, 2023. https://clinicaltrials.gov/ct2/show/NCT04065399