Triplet With Menin-KMT2A Inhibitor Safe, Effective in AML With Genetic Aberrations

By Andrew Moreno - Last Updated: June 30, 2024

A multicenter, phase 1b study is currently underway to evaluate the use of combination JNJ-75276617, venetoclax, and azacitidine in adults with relapsed or refractory acute myeloid leukemia (AML) with KMT2A or NPM1 aberrations. The first analysis of this study, presented at the European Hematology Association 2024 Hybrid Congress, shows the triplet has acceptable safety and is effective even in patients previously exposed to venetoclax.

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JNJ-75276617 is an agent that inhibits the interactions between scaffolding protein menin and methyltransferase KMT2A, which drive the above AML types. In this study, it was administered orally in ≥15 mg BID doses continuously in combination with a 28-day cycle of venetoclax and seven days/cycle of azacitidine.

The study had a safety dataset comprising 45 patients, with a median age of 60 years and a median of two prior therapies. A total of 56% of patients had prior venetoclax. The study’s efficacy dataset included 21 patients, focusing on those whose JNJ-75276617 dose levels were ≥50 mg BID.

In the safety dataset, 87% of patients experienced one or more treatment-related adverse event (TRAE), the most common being nausea, vomiting, and thrombocytopenia. Grading TRAEs according to the Common Terminology Criteria for Adverse Events, the investigators found 60% of the dataset experienced grade ≥3 TRAEs. Thrombocytopenia, leukopenia, neutropenia, and febrile neutropenia were the most common. A total of 22% of the dataset had a TRAE of any grade that was attributed solely to JNJ-75276617. No differentiation syndrome, dose-limiting toxicity, QTcF prolongation, or tumor lysis syndrome was reported.

In the efficacy dataset, the median time to first response was 23 days, and the overall objective response rate (ORR) was 86%. Investigators found the ORR to be similar across genetic profiles and that it was 82% in patients with prior venetoclax exposure.

Reference

Wei AH, Searle E, Aldoss I, et al. Phase 1b study of the menin-KMT2A inhibitor JNJ-75276617 in combination with venetoclax and azacitidine in relapsed/refractory acute myeloid leukemia with alterations in KMT2A or NPM1. Abstract S133. Presented at the European Hematology Association 2024 Hybrid Congress; June 13-16, 2024; Madrid, Spain.

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