The recently approved menin inhibitor revumenib is poised to improve the treatment of acute myeloid leukemia (AML), specifically for disease with a KMT2A rearrangement. Promising results for other novel menin inhibitors now in development—with their unique safety and activity profiles—suggest the treatment landscape may further expand. Studies of these agents in combination with chemotherapy in both the newly diagnosed and advanced settings were presented at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition.
Newly Diagnosed AML: Ziftomenib
Amer Zeidan, MBBS, MHS, Professor of Medicine at Yale School of Medicine and Chief of the Hematologic Malignancies Division at Yale Cancer Center, maintained that the greatest contribution of the menin inhibitors will be in newly diagnosed AML. “That’s what our study is about,” he said. “Robust clinical activity was demonstrated with ziftomenib.”
The phase I KOMET-007 trial is evaluating ziftomenib plus 7+3 chemotherapy in newly diagnosed AML.1 Ziftomenib is a highly selective agent given orally once daily. It does not interact with azoles and does not cause QTc prolongation; thus, Dr. Zeidan suggested, “this drug is certainly one of the easier agents to deal with.”
The phase Ia portion of KOMET-007 included 51 adults with newly diagnosed AML with an NPM1 mutation (NPM1m) or KMT2A rearrangement (KMT2Ar). Ziftomenib, in escalating doses, was started on day 8 and given continuously; cytarabine was given on days 1 to 7; and daunorubicin was given on days 1 to 3; ziftomenib was also offered as maintenance and after transplantation.
In 46 patients evaluable for response, 100% of the NPM1m cohort achieved complete clinical remission, he reported, noting, “This is not a composite of complete remission plus complete remission with partial hematologic recovery, this is real complete remission, a full response…especially impressive in adverse-risk patients, who don’t typically do well.” Complete remission was achieved as well by 83% of the KMT2A-rearranged cohort. Measurable residual disease (MRD) negativity was achieved in about 75% of both mutational groups, Dr. Zeidan reported.
At 31 weeks of median follow-up, the median duration of response and the median overall survival had not been reached in either mutational subtype. A total of 15 patients had undergone transplantation, and about half of them are on ziftomenib maintenance. All of the patients with NPM1-mutated AML are alive, as are 96% of the KMT2A-rearranged cohort.
The safety profile of ziftomenib in combination with intensive chemotherapy was similar to that reported for 7+3 alone. One case of grade 3 differentiation syndrome (in a patient with NPM1-mutated disease receiving 600 mg, the highest dose) was successfully managed without treatment discontinuation. There was no QTc prolongation or dose-limiting toxicity.
“Taken together, these data support the continued advancement of ziftomenib in combination with intensive chemotherapy in patients with newly diagnosed NPM1m and KMT2Ar AML, with or without adverse risks,” Dr. Zeidan concluded. Dr. Zeidan further announced the planned launch of a registrational-intent phase III study based on these results.
Newly Diagnosed AML: Bleximenib
Bleximenib, a potent, selective inhibitor of the menin-KMT2A complex, was combined with intensive chemotherapy (7 + 3) in 28 newly diagnosed “fit” patients with KMT2A-rearranged or NPM1-mutated AML, in a phase Ib dose-finding study conducted by Christian Recher, MD, PhD, of the University Cancer Institute Toulouse Oncopole in Toulouse, France.2
Bleximenib was given at 30, 50, or 100 mg twice daily starting on day 4, following induction with cytarabine and anthracycline, and given continuously up to 12 cycles. Investigators documented complete remission, complete remission with partial hematologic recovery, and complete remission with incomplete hematologic recovery.
In the efficacy population of 21 patients receiving 50 to 100 mg twice daily, the following outcomes were reported:
- Overall response rate was 95%, the rate of composite complete remission/complete remission with partial hematologic recovery/complete remission with incomplete hematologic recovery was 86%, and the complete remission rate was 76%.
- Similar response rates were seen in both mutational cohorts.
- MRD negativity was achieved in eight of nine patients tested.
- Three patients proceeded to transplant, and all had KMT2A rearrangements.
- No relapse or deaths have been observed at this time.
“No key adverse events, including differentiation syndrome, were observed to date,” Dr. Recher said, noting that differentiation syndrome seems to be observed more often with monotherapy. Also, similar to other studies of bleximenib, QTc prolongation was not observed, and no clinically significant myelosuppression or dose-limiting toxicities were seen. “The addition of bleximenib did not seem to exacerbate the expected toxicity of the 7+3 backbone,” Dr. Recher said.
Novel Agents in the Relapsed Setting
Bleximenib is also being evaluated as monotherapy in the phase I dose-finding cAMeLot-1 trial of 146 patients with acute leukemias and KMT2A, NPM1, NUP98, or NUP214 alterations.3 The efficacy population included 52 patients with at least 5% bone marrow blasts with KMT2A-rearranged or NPM1-mutated disease receiving at least 45 mg twice daily. The recommended phase II dose was determined to be bleximenib at 100 mg twice daily, which was associated with a complete remission rate of 44% in the KMT2A-rearranged population and 33% in the NPM1-mutated population; the rate of complete remission/complete remission with partial hematologic recovery was 33% across both mutational types, with a median duration of 6 months. The higher dose necessitated more dose modifications and treatment discontinuations without clear improvement in efficacy or pharmacodynamic activity, said Emma Searle, MBChB, PhD, of the Christie NHS Foundation Trust and University of Manchester in the United Kingdom.
The most common toxicities reported with bleximenib were cytopenias and gastrointestinal disturbances. No QTc prolongation signal was observed, but 14% of patients developed differentiation syndrome across dose levels, including 10 patients with grade ≥ 3 toxicity and 2 deaths.
“Differentiation syndrome is emerging as a class effect,” Dr. Searle said. “We’ve been on a learning curve with these agents and have been vigilant about signs of differentiation syndrome. Strategies to mitigate this effect appear to be effective.” These strategies include temporary interruption of bleximenib with initiation of hemodynamic monitoring and systemic corticosteroids with or without hydroxyurea. Clinicians may consider resuming the drug when signs and symptoms resolve to grade 1 or baseline, she said.
Updated findings from a phase I study of enzomenib in 84 patients were reported by Joshua Zeidner, MD, of UNC Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine in Chapel Hill.4 Enzomenib was designed with a “unique chemical formula and favorable chemical properties when compared with other menin inhibitors,” which result in a low volume of distribution and minimal to no accumulation, potentially minimizing off-target toxicity, according to Dr. Zeidner. “We’ve seen promising clinical activity at optimized doses (≥ 200 mg twice daily), he added, with the following results reported by mutational subtype:
- KMT2A-rearragned: Overall response was 73%; the rate of complete remission and complete remission with partial hematologic recovery was 40% at 300 mg twice daily.
- NPM1-mutated: Overall response was 59%; the rate of complete remission and complete remission with partial hematologic recovery was 47% at 200 mg or 300 mg twice daily.
- Primary refractory: The rate of complete remission and complete remission with partial hematologic recovery was 57%.
- Some patients are responding to treatment beyond 7 to 8 months.
- A total of 34% of patients with KMT2A-rearranged disease proceeded to transplantation.
Differentiation syndrome developed in 11%, but this was “not severe and was self-limiting, without prophylaxis,” stated Dr. Zeidner. One patient had grade 3 acute QTc prolongation. Studies of enzomenib in combination with azacitidine plus venetoclax, and with gilteritinib, have been initiated.
Expert Point of View
Rory M. Shallis, MD, Assistant Professor (Internal Medicine) at Yale School of Medicine, predicted the field will soon be poised to choose among a number of menin inhibitors for acute leukemia, including revumenib, ziftomenib, bleximenib, and enzomenib, which are demonstrating “relatively comparable efficacy” in the relapsed or refractory monotherapy setting.
“The difficulty is that these encouraging single-arm data [as presented at the 2024 ASH Annual Meeting & Exposition] are derived from relatively small populations and are subject to variance in biology-centric inclusion criteria,” he said. For instance, baseline patient characteristics and study design (monotherapy, combinations) have differed among the studies, Dr. Shallis added. These imbalances, along with the absence of randomized data, “do not allow us to discern any true differences between these drugs just yet,” he added. “We await the several planned randomized front-line menin inhibitor combinations, either in combination with 7+3 or azacitidine + venetoclax, the latter of which may soon be the dominant strategy for patients outside of the most favorable–risk biologies.”
One concern is differentiation syndrome, which appears to be a feature of this class of agents and is evidence of on-target effects. Any suggestion of this phenomenon warrants vigilant monitoring and intervention, according to Dr. Shallis.
Moving Forward
“I am excited about the future of ziftomenib given the data we’ve seen presented thus far,” continued Dr. Shallis. “The agent has no appreciable impact on QTc or CYP3A4 inhibitory effect leading to drug-drug interactions,” he pointed out. “The data derived from the patients treated with front-line intensive therapy on KOMET-007 are very exciting, particularly given the extraordinarily high—in fact, perfect—rates of complete remission among patients with NPM1-mutated AML who also had to have an additional higher-risk feature, such as age ≥ 60, therapy-related disease, or another higher-risk mutation…. Bleximenib is similarly being studied in combination with front-line intensive therapy, and based on the data for the first two dozen patients presented at the ASH meeting, it appears to be on a similar footing with ziftomenib.”
Dr. Shallis shared these concluding comments: “Like many others, I am curious about how the secondary endpoint data, and specifically event-based endpoints such as overall survival, will look in these single-arm trials. Furthermore, a valuable surrogate with substantial clinical implications could be the rate or kinetics of measurable residual disease (MRD) negativity by polymerase chain reaction (PCR) for NPM1 among those patients with NPM1-mutated disease. The variability in MRD assays and reporting standards for these types of leukemia-specific PCR assays limits firm conclusions from nonrandomized data sets or those without central assessment and thus requires future efforts for standardization and harmonization.”
DISCLOSURE: Dr. Zeidan reported financial relationships with Servier, Rigel, Orum, ALX Oncology, Otsuka, Glycomimetics, Keros, Pfizer, Kura, Kyowa Kirin, AbbVie, Sumitomo Pharma, Medus, Lava Therapeutics, Takeda, Taiho, Syndax, Agios, Hikma, Faron, Karyopharm, Genentech, Daiichi Sankyo, Epizyme, Gilead Sciences, BioCryst, Notable, Bristol Myers Squibb/Celgene, Janssen, Boehringer Ingelheim, Treadwell, Chiesi, Novartis, Amgen, Astellas, BeiGene, Zentalis, Regeneron, Schroedinger, Geron, Syros, Vinerx, Akeso Pharma, and Lava Therapeutics. Dr. Recher has served as a consultant or advisor to AbbVie, Amgen, Astellas Pharma, BMS, Boehringer Ingelheim, Jazz Pharmaceuticals, Johnson & Johnson, and Servier Pharmaceuticals; has received research funding from AbbVie, Amgen, Astellas Pharma, BMS, Iqvia, and Jazz Pharmaceuticals; has received support for attending meetings and/or travel from AbbVie, Novartis, and Servier Pharmaceuticals. Dr. Searle has served on an advisory board for Sanofi, BMS, Johnson & Johnson, Syndax Pharmaceuticals, and Pfizer; has received reimbursement for travel from Johnson & Johnson, AbbVie, BeiGene, Menarini Group, and Stemline Therapeutics; has received speaker honoraria from Pfizer, AbbVie, Johnson & Johnson, Jazz Pharmaceuticals, and Astellas Pharma; and has served as a consultant to Shattuck Labs, Dark Blue Therapeutics, and Sanius Health. Dr. Zeidner has served as a consultant to Sumitomo Pharma, Shattuck Labs, Servier, Sellas Life Sciences, Novartis, Gilead Sciences, Genmab, Foghorn, Daiichi Sankyo, AbbVie, and Syndax. Dr. Shallis has received fees for serving as a consultant or advisor to Syndax Pharmaceuticals and Kura Oncology.
REFERENCES
1. Zeidan AM, Wang ES, Issa GC, et al: Ziftomenib combined with intensive induction (7+3) in newly diagnosed NPM1-m or KMT2A-r acute myeloid leukemia: Interim phase 1a results from KOMET-007. 2024 ASH Annual Meeting & Exposition. Abstract 214. Presented December 7, 2024.
2. Recher C, O’Nions J, Aldoss I, et al: Phase Ib study of menin-KMT2A inhibitor bleximenib in combination with intensive chemotherapy in newly diagnosed acute myeloid leukemia with KMT2Ar or NPM1 alterations. 2024 ASH Annual Meeting & Exposition. Abstract 215. Presented December 7, 2024.
3. Searle E, Recher C, Abdul-Hay M, et al: Bleximenib dose optimization and determination of RP2D from a phase 1 study in relapsed/refractory acute leukemia with KMT2A and NPM1 alterations. 2024 ASH Annual Meeting & Exposition. Abstract 212. Presented December 7, 2024.
4. Zeidner JF, Yuda J, Watts JM, et al: Phase I results: First-in-human phase 1/2 study of the menin-MLL inhibitor enzomenib (DSP-5336) in patients with relapsed or refractory acute leukemia. 2024 ASH Annual Meeting & Exposition. Abstract 213. Presented December 7, 2024.
