Pivotal Results Show Revumenib Holds Promise for Patients With KMT2Ar Acute Leukemia

Patients with KMT2Ar acute leukemia, who until now have lacked a therapy targeting their condition, may have hope with news of phase 2 results for revumenib, which blocks the protein interactions that put cells on the path to developing into leukemia.

Ibrahim T. Aldoss, MD | Image credit: City of Hope

Ibrahim T. Aldoss, MD, a hematologist/oncologist at City of Hope National Medical Center, presented results Tuesday for AUGMENT-101 (NCT04065399), which is evaluating revumenib in a pair of leukemias, during the late-breaking session of the 65th American Society of Hematology Annual Meeting and Exposition (ASH) in San Diego, California.

Revumenib, developed by Syndax, is being studied in several related blood disorders, with results presented earlier during ASH. Preliminary efficacy and safety were previously demonstrated in a phase 1 study, described in Nature, that examined both relapsed/refractory (R/R) KMT2Ar and nucleophosmin 1-mutated (NPM1m) acute leukemias. At the late-breaking session, Aldoss presented results from an interim analysis for R/R KMT2Ar acute leukemia.

Patients in the trial with R/R KMT2Ar acute leukemia had high overall response rates; despite being heavily pretreated, 40% were able to proceed to transplant and the KMT2Ar cohort was stopped early.

This could be quite a turn of events for these patients: right now, those diagnosed with histone-lysine N-methyltransferase 2A (KMT2A)-rearranged acute leukemia are treated with chemotherapy and hematopoietic stem cell transplant (HSCT), but nearly all relapse; complete remission rates are quite low at 5%.

As Aldoss reminded the audience during the late-breaking session, KMT2Ar accounts for 10% of all acute leukemias, and is the most common type of acute leukemia in children.

“It's a disease with unmet therapeutic needs,” Aldoss said in a press briefing prior to the late-breaking session. “These patients are at high risk of relapse after transplant and after chemotherapy.”

He elaborated in an interview with The American Journal of Managed Care®. “There have been different attempts at targeting therapy for KMT2A, but so far, nothing has shown to be effective. So, we’re very excited by revumenib, because it is already showing us, in patients who have chemorefractory disease, have relapsed, and are heavily pretreated, that a single agent is able to actually achieve responses in these patients with a manageable safety profile.”

Mechanism of Action. As Aldoss explained, acute leukemia occurs when menin interacts with KMT2A, driving cell behavior during the immature phase, causing the cells’ failure to differentiate and become active. When this happens, the immature cells also take the space of healthy cells. Revumenib targets menin to disrupt the interaction that triggers this process, he said, allowing “the immature ones to become actually mature, healthy, functioning cells.”

The concept of blocking the mechanism that prevents differentiation is not new, but it can cause adverse effects known as differentiation syndrome (DS). Thus, AUGMENT-101 would seek not only to evaluate efficacy but also safety including whether DS occurs in patients receiving the drug.

Methods. Patients diagnosed at least 30 days prior with R/R KMT2Ar acute leukemia were enrolled in cohort A, which was mixed phenotype acute leukemia (MPAL); cohort B, which was acute myeloid leukemia (AML), or cohort C, which continues to enroll patients with NPMIm and will be reported later. Patients received 163 mg of revumenib (or 95 mg/m², if they weighed less than 40 kg) every 12 hours with an antibiotic in 28-day cycles. Treatment continued until unacceptable toxicity or lack of at least morphological leukemia-free state after 4 cycles.

Primary endpoints were safety and tolerability of revumenib and complete response (CR) plus complete response with partial hematological recovery (CRh). Key secondary endpoints included the composite CR rate (CRc), the CRc with incomplete platelet recovery (CRp), the CRc with incomplete count recovery (CRi), and overall response rate (ORR).

A planned interim analysis (IA) of pooled adult and pediatric patients took place. The 94 patients evaluated as of July 24, 2023, after receiving at least 1 dose of the study drug were included in the safety analysis. According to the abstract, the IA efficacy analysis included all patients in phase 2 with centrally confirmed KMT2Ar acute leukemia and at least 5% blasts in the bone marrow at baseline who received at least 1 dose of study drug before the 38th adult AML efficacy evaluable patient The IA was specified to occur when 57 patients had been followed for 6 months.

Results. The results of the safety analysis were as follows:

• Median age was 37 years, with a range from 1.3 to 75 years; 24.5% were younger than 18 years and 13.8% were at least 65 years of age. 17.5% were non-White.
• 78 patients (83%) had AML and 16 (17.0%) had ALL/MPAL.
• Patients were heavily pretreated, with a median of 2 prior lines of therapy (range, 1-11), and 43.6% of patients had at least 3 prior lines of therapy, with 57.4% unresponsive to their most recent salvage treatment.
• 50% had prior HSCT.
• Treatment-related adverse events were seen in 81.9% of the safety group, with the most common being nausea (more than 27%), DS (26.6%), and QTc prolongation (23.4%). Grade 3 or higher TRAEs were seen in 54.3% of patients with the most common being DS (16%), febrile neutropenia (13.8%), and QTc prolongation (13.8%).
• 6.4% of patients stopped therapy due to TRAEs, but none stopped due to DS or QTc prolongation.

Results from the interim efficacy analysis were as follows:

• After a median follow-up of 6.1 months, 13 patients (22.8%) achieved CR+CRh, which investigators said surpassed the predefined IA efficacy boundary for the KMT2Ar group (95% CI, 12.7-35.8).
• Median duration of CR+CRh was 6.4 months (95% CI, 3.4-not reached).
• CRc was 43.9% (95% CI, 30.7-57.6)
• ORR was 63.2% (95% CI, 49.3-75.6)
• Minimal residual disease (MRD) status: Most patients with a CR or CRh response who had MRD reported also achieved MRD negativity (15/22, 68.2%).
• 14 of the 36 patients who responded to treatment were able to proceed to HSCT, with half resuming treatment with revumenib after transplant.

Aldoss said revumenib is being studied in combination with other therapies and also in earlier lines of care. “The next step is, how can we better combine this agent with other standard treatments? How can we give it more post-transplant to reduce the risk of relapse?”

Giving it to patients in earlier lines of care could prove critical; in response to a question, Aldoss said that patients who had received venetoclax had much lower response rates than those who had not received this therapy.

In a statement, officials from Syndax said they remain on track to submit a New Drug Application to FDA for revumenib for the treatment of R/R KMT2Ar acute leukemia by the end of the year.

Reference

Aldoss I, Issa GC, Thirman M, et al. Revumenib monotherapy in patients with relapsed/refractory KMT2Ar acute leukemia: Topline efficacy and safety results from the pivotal augment-101 phase 2 study. Presented at: 65th American Society of Hematology Annual Meeting and Exposition, San Diego, CA: December 9-12, 2023. Abstract LBA-5.

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