The Menin Inhibitor SNDX-5613 (revumenib) Leads to Durable Responses in Patients (Pts) with <i>KMT2A</i>-Rearranged or <i>NPM1</i> Mutant AML: Updated Results of a Phase (Ph) 1 Study

Issa, Ghayas C.; Aldoss, Ibrahim; DiPersio, John F.; Cuglievan, Branko; Stone, Richard; Arellano, Martha; Thirman, Michael J.; Patel, Manish R.; Dickens, David; Shenoy, Shalini; Shukla, Neerav; Rosen, Galit; Meyers, Michael L.; Madigan, Kate; Ordentlich, Peter; Gu, Yu; Smith, Steven D.; McGeehan, Gerard M.; Stein, Eytan M.

doi:10.1182/blood-2022-164849

Cited by 24 publications

(22 citation statements)

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“…Apart from the R/R setting and the assessment of Menin inhibition in combination with standard first-line therapies, the efficacy of Menin inhibitors as a maintenance therapy, both after conventional (chemo-) therapy and allo SCT, should be investigated. The results from the AUGMENT-101 trial seem promising, with 2 out of 3 patients that received maintenance therapy with revumenib following allo SCT in a compassionate use setting remaining in remission at the data cut off [61].…”

Section: The Future Use Of Menin Inhibitorsmentioning

confidence: 99%

The future of HOXA-expressing leukemias: Menin inhibitor response and resistance

Wenge,

Armstrong

2023

Current Opinion in Hematology

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Purpose of review We provide an update on the successes and ongoing challenges of Menin inhibition as a novel approach for the treatment of patients with acute leukemias that express HOXA cluster genes including leukemias with KMT2A-rearrangements, NPM1 mutations or NUP98-rearrangements. Initial clinical trials show promising response rates in heavily pretreated patients suggesting these inhibitors may have a significant impact on patient outcome. Furthermore, the development of resistance mutations that decrease drug binding affinity, validates Menin as a therapeutic target in human cancers. Therapeutic strategies aiming at overcoming and preventing resistance, are of high clinical relevance. Recent findings Several Menin inhibitor chemotypes have entered clinical trials. Acquired point mutations have recently been described as a mechanism of resistance towards Menin inhibitors. However, resistance can develop in absence of these mutations. Combination therapies are currently being investigated in preclinical models and in early phase clinical trials. Summary Given the remarkable overall response rates, shedding light on treatment options for patients whose leukemias develop resistance to Menin inhibitors is an imminent clinical need. Studying the underlying mechanisms to inform clinical decision making, and to potentially prevent the development of resistance is of outmost importance.

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Section: The Future Use Of Menin Inhibitorsmentioning

confidence: 99%

The future of HOXA-expressing leukemias: Menin inhibitor response and resistance

Wenge,

Armstrong

2023

Current Opinion in Hematology

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“…This has led to the opening of multiple phase 1/2 studies in patients with R/R AML with KMT2A-rearrangement or NPM1 -mutation using the menin-MLL inhibitor KO-539 (NCT04067336) or menin inhibitor SNDX-5613 (NCT04065399, NCT05326516, NCT05406817, NCT05360160, NCT03013998) which are currently enrolling patients or opening soon. Early data from NCT04067336 and NCT04065399 suggest similar CR/CRh rates (25–30%) and MRD negativity rates in responding patients (75–78%) with either KO-539 or SNDX-5613, respectively [ 182 – 184 ]. Toxicities include QTc prolongation with SNDX-5613 and differentiation syndrome, particularly with KO-539.…”

Section: Investigational Agents and Future Directionsmentioning

confidence: 99%

Recent advances in targeted therapies in acute myeloid leukemia

2023

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Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While survival for younger patients over the last several decades has improved nearly sixfold with the optimization of intensive induction chemotherapy and allogeneic stem cell transplantation (alloHSCT), this effect has been largely mitigated in older and less fit patients as well as those with adverse-risk disease characteristics. However, the last 10 years has been marked by major advances in the molecular profiling of AML characterized by a deeper understanding of disease pathobiology and therapeutic vulnerabilities. In this regard, the classification of AML subtypes has recently evolved from a morphologic to a molecular and genetic basis, reflected by recent updates from the World Health Organization and the new International Consensus Classification system. After years of stagnation in new drug approvals for AML, there has been a rapid expansion of the armamentarium against this disease since 2017. Low-intensity induction therapy with hypomethylating agents and venetoclax has substantially improved outcomes, including in those previously considered to have a poor prognosis. Furthermore, targeted oral therapies against driver mutations in AML have been added to the repertoire. But with an accelerated increase in treatment options, several questions arise such as how to best sequence therapy, how to combine therapies, and if there is a role for maintenance therapy in those who achieve remission and cannot undergo alloHSCT. Moreover, certain subtypes of AML, such as those with TP53 mutations, still have dismal outcomes despite these recent advances, underscoring an ongoing unmet need and opportunity for translational advances. In this review, we will discuss recent updates in the classification and risk stratification of AML, explore the literature regarding low-intensity and novel oral combination therapies, and briefly highlight investigative agents currently in early clinical development for high-risk disease subtypes.

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“…In this heavily pretreated population (median four prior therapies, 46% prior transplant), the overall response rate (ORR, included CR/CRh/CRp/ CRi/MLFS) was 53% (32/60) with a CRc rate (CR/CRh/ CRp) of 38% (23/60), of which 78% were MRD (minimal DiNardo et al Journal of Hematology & Oncology (2023) 16:17 residual disease) negative. Notable side effects included asymptomatic QTc prolongation and grade 2 or less differentiation syndrome in 16% (11/68) of patients [3].…”

Section: Menin Inhibitors In Amlmentioning

confidence: 99%

Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting

2023

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Developments in investigational agents and novel regimens in acute myeloid leukemia (AML) were reported in the 2022 American Society of Hematology (ASH) annual meeting. Encouraging efficacy data were presented from first-in-human studies of two investigational menin inhibitors, SNDX-5613 and KO-539, in relapsed and refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangement or mutant NPM1, with overall response rates (ORR) of 53% (32/60) and 40% (8/20), respectively. The addition of the novel drug pivekimab sunirine, a first-in-class antibody–drug conjugate targeting CD123, to azacitidine and venetoclax in R/R AML resulted in an ORR of 45% (41/91), which rose to 53% in those who were venetoclax naïve. Additional novel triplet treatment combinations included the addition of magrolimab, an anti-CD47 antibody, to azacitidine and venetoclax, with an ORR of 81% (35/43) in newly diagnosed AML, including an ORR of 74% (20/27) in TP53 mutated AML. The addition of the FLT3 inhibitor gilteritinib to azacitidine/venetoclax was also featured, with an ORR of 100% (27/27) in newly diagnosed AML and an ORR of 70% (14/20) in R/R AML.

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The Menin Inhibitor SNDX-5613 (revumenib) Leads to Durable Responses in Patients (Pts) with KMT2A-Rearranged or NPM1 Mutant AML: Updated Results of a Phase (Ph) 1 Study

Cited by 24 publications

References 0 publications

The future of HOXA-expressing leukemias: Menin inhibitor response and resistance

The future of HOXA-expressing leukemias: Menin inhibitor response and resistance

Recent advances in targeted therapies in acute myeloid leukemia

Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting

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