New advanced leukemia drug leads to ‘impressive’ responses

Revumenib, an Investigational Menin Inhibitor, Shows Encouraging Responses in Relapsed or Refractory Patients KMT2A-rearranged or MNP1-mutant acute leukemia in the first human test of the oral agent.

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

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

Mikkael Sekeres, MD, chief of the division of hematology at the Sylvester Comprehensive Cancer Center at the University of Miami 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 single-drug population, he said.

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

MNP1 is the most common genetic alteration in adult acute myeloid leukemia (AML), seen in up to 30% of patients. Gene rearrangements 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 of patients with acute leukemia harboring KMT2A rearrangements is poor, with overall 5-year survival rates below 25%.

However, there are currently no approved targeted therapies for these two – KMT2A-rearranged or MNP1-mutant — genetic subtypes of acute leukemia.

In KMT2A-rearranged or MNP1-mutant acute leukaemias, the interaction of the menin protein with KMT2A stimulates the 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 meningitis inhibitorKMT2A the interaction and phase 1 data “establish menin inhibition as a therapeutic strategy” for these acute leukemia subtypes, the authors said.

The AUGMENT-101 study recruited 68 adults and children as young as 10 months of age with an advanced relapsed/refractory stage KMT2A-rearranged or MNP1– mutant acute myeloid or lymphoid leukaemia. Patients had received a median of four prior lines of treatment and 46% had previously undergone allogeneic stem cell transplantation.

Disease types included AML (82%), ALL (16%) and mixed phenotype acute leukemia (2%). About two-thirds (68%) had KMT2A rearrangements, 21% had MNP1 mutations and 12% had other genotypes.

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

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

Morphological remissions occurred in 27 of 49 patients (55%) with AML, four of 10 patients (40%) with ALL, and one patient with mixed phenotype acute leukemia. Morphological 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 MNP1 mutation responded to the drug, consistent with the hypothesis about the functioning of menin inhibitors.

The median time to CR/CRh was 1.9 months, with a 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 allogeneic stem cell transplantation after a response to revumenib, with nine patients in remission at the time of data closure, seven of whom have been in remission for more than 6 months.

“Having a targeted therapy that promotes myeloid differentiation and leads to a measurable disease negativity rate in 78% of patients who achieve remission is a major breakthrough,” said study investigator Eytan Stein, MD, lead of the Leukemia Service and Director of the Leukemia Drug Development Program, Memorial Sloan Kettering Cancer Center, New York, said Medscape Medical News.

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

Differentiation syndrome – a common phenomenon with antileukemic therapies that leads to the differentiation of leukemic cells into normal haematopoietic 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 differentiating agents, look for differentiating syndrome which can cause capillary leak and its sequelae and if differentiating syndrome is observed, treat with corticosteroids,” explained Stein.

Alice S. Mims, MD, who directs the acute leukemia/myeloid malignancies section at The Ohio State University’s Comprehensive Cancer Center in Columbus, said revumenib represents a “new approach” and noted that other inhibitors of menin are also under study.

Mims, who was not involved in the study, also noted that revumenib being a substrate of cytochrome P450 3A4 “will be important if this advances in evaluating concomitant medications a patient is taking due to drug interactions.” .

Stein noted that “the next steps are to combine revumenib with standard therapies like azacitidine/venetoclax and intensive induction chemotherapy.”

Sekeres said he was “excited to see studies of this drug in expanded patient populations, and possibly in combination with other active anti-leukemic therapies.”

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

Nature. Published online March 15, 2023. Full Text

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