Investigational Menin Inhibitor Levmenib Produces Encouraging Responses in Relapsed or Refractory Patients KMT2A– rearrange or NPM1– Mutant acute leukemia in first-in-human study of oral formulation.
In a phase 1 trial of 60 patients, more than half responded to levmenib, with 18 achieving complete or near-complete remission at a median of 9 months. Of the 18 patients, 14 had undetectable levels of residual disease.
“This trial was the last hope for many of our enrolled patients,” said Ghayas Issa, M.D., director of the study at the Leukemia Division at the University of Texas MD Anderson Cancer Center in Houston. Medscape medical news. “This is a breakthrough that demonstrates the importance of the menin protein in certain leukemia subtypes, and the implications of targeting menin with oral therapies such as levmenib, the drug tested in this study. It’s the first clinical validation of a long-standing science that shows it leads to clinical response.”
Mikkael Sekeres, M.D., Ph.D., director of the Department of Hematology at the University of Miami Sylvester Comprehensive Cancer Center in Florida, was not involved in the study but was impressed with the results. He said this was an “exciting” proof-of-concept study with “impressive” response rates and duration of response for this heavily pretreated population treated with a single drug.
Results from the AUGMENT-101 trial publish online March 15th Nature.
NPM1 It is the most common genetic alteration in adult acute myeloid leukemia (AML), found in up to 30% of patients.rearrangement of genes KMT2A It occurs in approximately 80% of infants with acute lymphoblastic leukemia (ALL) and up to 15% of children and adults with acute leukemia (both ALL and AML).
Prognosis of patients with acute leukemia KMT2A Rearrangement is poor, with a 5-year overall survival rate of less than 25%.
However, there are currently no targeted therapies approved for these two— KMT2A– rearrange or NPM1-mutant — genetic subtype of acute leukemia.
of KMT2A– rearrange or NPM1– Mutant acute leukemia, interaction with menin protein KMT2A Promotes the expression of leukemia-promoting genes. Targeting menin disrupts the gene transcription machinery, shifting 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 menin.KMT2A Interactions and phase 1 data “establish menin inhibition as a therapeutic strategy” for these acute leukemia subtypes, the authors say.
The AUGMENT-101 study enrolled 68 adults and 10-month-old children with relapsed/refractory advanced disease KMT2A– rearrange or NPM1– Mutant acute myeloid or lymphocytic leukemia. The patient received a median of 4 treatments and 46% received allogeneic stem cell transplantation.
Subtypes include AML (82%), ALL (16%), and mixed acute leukemia (2%).About two-thirds (68%) KMT2A Reorganization, 21% had NPM1 mutation, and 12% had other genotypes.
Thirty-two of the 60 patients responded to levumenib for an overall response rate of 53%. Eighteen patients (30%) achieved complete remission or complete remission with partial hematologic recovery (CR/CRh), of which 14 (78%) achieved clearance of measurable residual disease .
These response rates, especially clearance rates of residual disease, are “the highest we’ve seen with monotherapy used for these resistant leukemia subsets,” Issa said in a statement.
Morphological remission occurred in 27 of 49 (55%) patients with AML, 4 of 10 (40%) patients with ALL, and 1 patient with mixed phenotype acute leukemia. Morphological remission was seen in 4 of 8 pediatric patients and 28 of 52 adults (54%).
None of the 8 patients who lacked either KMT2A rearrange or NPM1 The mutation was drug responsive, consistent with our hypothesis about how menin inhibitors work.
Median time to CR/CRh was 1.9 months, and median follow-up for patients who achieved CR/CRh was 11.9 months. The median duration of response was 9.1 months. Median overall survival was 7 months, regardless of remission status.
Twelve patients responded to levmenib and then underwent consolidation allogeneic stem cell transplantation, with 9 patients in remission at the time of data cutoff, 7 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-negative rate in 78% of patients who achieve remission is a big step forward,” said Leukemia Services chief, Memorial Sloan, New York. Kettering Cancer Center’s Leukemia Drug Development Program said: Medscape medical news.
No patients discontinued treatment due to treatment-related adverse events. The most common treatment-related adverse event was asymptomatic prolongation of her QT interval, with a grade 3 rate of 13%.
Differentiation syndrome—common with antileukemic therapies that result in the differentiation of leukemic cells into normal hematopoietic cells—occurred in 11 patients, all grade 2. All cases of differentiation syndrome recovered after treatment with corticosteroids with or without hydroxyurea.
“As with all differentiation factors, differentiation syndromes that can lead to capillary leak and its sequelae should be noted, and if differentiation syndromes are present, they should be treated with corticosteroids.” explained Stein.
Alice S. Mims, MD, head of the Acute Leukemia/Myelogenous Tumor Division at The Ohio State University Comprehensive Cancer Center in Columbus, said revumenib is a “new approach,” and other menin inhibitors are being investigated as well. said that
Mims, who was not involved in the study, said that since levumenib is a substrate for cytochrome P450 3A4, “it will be important if this goes forward to assess the co-medications patients are taking for drug interactions. would,’ he said.
“A future step is to combine levumenib with standard treatments such as azacitidine/venetoclax and intensive induction chemotherapy,” Stein said.
“I’m excited to see the study of this drug in an expanded patient population and to eventually use it in combination with other aggressive anti-leukemia treatments,” Sequeres said.
This study was supported by Syndax Pharmaceuticals. Issa and Stein are consultants for Syndax Pharmaceuticals. Sekeres has not made any disclosures related to this study. Bristol-Myers He has been an advisor to Squibb, Novartis and Krome. Mims has no relevant disclosures.
Nature. Published online on March 15, 2023. full text
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