Novel Drug Leads to 'Impressive' Responses in Advanced Leukemia

Megan Brooks

March 20, 2023

Revumenib, an investigational menin inhibitor, yielded encouraging responses in patients with relapsed or refractory KMT2A-rearranged or NPM1-mutant acute leukemia in the first-in-human test of the oral agent.

In the phase 1 trial of 60 patients, more than half responded to revumenib, and 18 achieved complete or near-complete remission over a median of 9 months. Among the 18 patients, 14 had undetectable levels of residual disease.

"This trial was the last hope for many patients enrolled," study investigator Ghayas Issa, MD, with the Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, told Medscape Medical News. "This is a breakthrough and the first clinical validation of years of science showing that the protein menin is critical for certain leukemia subtypes and that targeting menin with an oral therapy like revumenib, the drug we tested in this study, can lead to meaningful clinical responses."

Mikkael Sekeres, MD, chief of the Division of Hematology, at the University of Miami Sylvester Comprehensive Cancer Center in Florida, who was not involved in the study, was struck by the results. This is an "exciting" proof-of-concept study with "impressive" response rates and duration of response for this heavily pretreated population treated with a single drug, he said.

The results of the AUGMENT-101 study were published online March 15 in Nature.

NPM1 is the most common genetic alteration in adult acute myeloid leukemia (AML), seen in up to 30% of patients. Rearrangements of the gene KMT2A occur in about 80% of infants with acute lymphoblastic leukemia (ALL) and in up to 15% of children and adults with acute leukemia — both ALL and AML.

The prognosis for patients with acute leukemias harboring KMT2A rearrangements is poor, with 5-year overall survival rates of less than 25%.

However, there are currently no targeted therapies approved for these two — KMT2A-rearranged or NPM1-mutant — genetic subtypes of acute leukemia.

In KMT2A-rearranged or NPM1-mutant acute leukemias, the interaction of the menin protein with KMT2A drives expression of leukemia-promoting genes. Targeting menin disrupts the gene transcription machinery and shifts gene expression in cancer cells from a leukemia pattern to a normal pattern, ultimately leading to remission, the researchers explained.

Revumenib (formerly SNDX-5613) is a potent and selective oral inhibitor of the menin-KMT2A interaction and the phase 1 data "establish menin inhibition as a therapeutic strategy" for these acute leukemia subtypes, the authors said.

The AUGMENT-101 study enrolled 68 adults and children as young as 10 months with relapsed/refractory advanced KMT2A-rearranged or NPM1-mutant acute myeloid or lymphoid leukemias. Patients had received a median of four prior lines of therapy, and 46% had a prior allogeneic stem cell transplant.

Disease types included AML (82%), ALL (16%), and mixed phenotype acute leukemia (2%). Roughly two thirds (68%) had KMT2A rearrangements, 21% had NPM1 mutations, and 12% had other genotypes.

Thirty-two of 60 patients responded to revumenib — an overall response rate of 53%. Eighteen patients (30%) had complete remission or complete remission with partial hematologic recovery (CR/CRh), with 14 of those patients (78%) achieving clearance of measurable residual disease.

These response rates, especially rates of residual disease clearance, are "the highest we have seen with any monotherapy used for these resistant leukemia subsets," Issa said in a statement.

Morphologic remissions occurred in 27 of 49 patients (55%) with AML, four of 10 patients (40%) with ALL, and in one patient with a mixed-phenotype acute leukemia. Morphologic remission was noted in four of eight pediatric patients and in 28 of 52 adults (54%).

None of the eight patients who lacked either a KMT2A rearrangement or NPM1 mutation responded to the drug, consistent with hypothesis on how menin inhibitors work.

The median time to CR/CRh was 1.9 months, with median follow-up of 11.9 months in patients who achieved CR/CRh; the median duration of response was 9.1 months. Median overall survival, regardless of remission status, was 7 months.

Twelve patients received an allogeneic stem cell transplant as consolidation after response to revumenib, with nine patients in remission at the time of the data cutoff, seven of whom have been in remission for over 6 months.

"Having a targeted therapy that promotes myeloid differentiation and leads to a rate of measurable disease negativity in 78% of the patients who achieve a remission is a major advance forward," study investigator Eytan Stein, MD, chief of the Leukemia Service and director of the Program for Drug Development in Leukemia, Memorial Sloan Kettering Cancer Center, New York, told Medscape Medical News.

No patient discontinued treatment due to treatment-related adverse events. The most common treatment-related adverse event was asymptomatic prolongation of the QT interval, with a grade 3 rate of 13%.

Differentiation syndrome — a common occurrence with antileukemia therapies that leads to differentiation of leukemia cells into normal hematopoietic cells — occurred in 11 patients, all grade 2. All cases of differentiation syndrome resolved after treatment with corticosteroids with or without hydroxyurea.

"As with all differentiation agents, one needs to look out for differentiation syndrome that can cause capillary leak and its sequelae and if differentiation syndrome is seen, treat with corticosteroids," Stein explained.

Alice S. Mims, MD, who heads the acute leukemia/myeloid malignancies section at The Ohio State University Comprehensive Cancer Center in Columbus, said that revumenib represents a "novel approach" and noted that other menin inhibitors are being explored as well.

Mims, who wasn't involved in the study, also noted that because revumenib is a substrate of cytochrome P450 3A4 "it will be important if this moves forward to assess concurrent medications a patient is taking due to drug-drug interactions."

Stein noted that "future steps are to combine revumenib with standard of care therapies like azacitidine/venetoclax and intensive induction chemotherapy."

Sekeres said that he is "excited to see studies of this drug in expanded patient populations, and eventually in combination with other active anti-leukemic therapies."

The study was supported by Syndax Pharmaceuticals. Issa and Stein serve as consultants to Syndax Pharmaceuticals. Sekeres has no disclosures related to this study. He has served as an advisor to Bristol-Myers Squibb, Novartis, and Kurome. Mims has no relevant disclosures.

Nature. Published online March 15, 2023. Full text

For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.