The latest study results from multiple trials of revumenib (also known as SNDX-5613)*, a highly selective, oral menin inhibitor being developed by Syndax, in combination with the current standard of care agents in patients with nucleophosmin mutant (mNPM1) and KMT2A-rearranged (KMT2r) relapsed/refractory (R/R) acute leukemias, shows positive results.

Poor prognosis
Rearrangements of the KMT2A (mixed lineage leukemia or MLL) gene give rise to KMT2Ar acute leukemia which is known to have a poor prognosis.  KMT2A genes produce fusion proteins that require interaction with the protein called menin to drive leukemic cancer growth.

The disruption of the menin-KMT2Ar interaction has been shown to halt the growth of KMT2Ar leukemic cells.  KMT2Ar acute leukemia can phenotypically appear as AML, ALL, or mixed phenotype acute leukemia (MPAL) and is routinely diagnosed through currently available cytogenetic or molecular diagnostic techniques.

The KMT2Ar genetic abnormality is found in about 10% of acute leukemias and can occur in several types of leukemia in both children and adults.

The median overall survival (OS) after the standard-of-care first-line treatment, including intensive chemotherapy and transplant, is less than one year and the majority of patients suffer relapse within five years. With third-line treatment or beyond, less than 5% of patients achieve complete remission (CR), and the median OS is less than three months.

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Although a stem cell transplant is the only known curative treatment for aggressive and hard-to-treat KMT2Ar cancers, there are currently no approved therapies indicated for KMT2A-rearranged acute leukemia.[1]

“Any time you have relapsed or refractory acute leukemia, the only cure is transplant, but to do that, you have to have a response,” noted Ibrahim Aldoss, MD, associate professor in the Department of Hematology and Stem Cell Transplant at City of Hope National Medical Center, the study’s lead author.

“We observed encouraging durable and meaningful responses, and many of these patients were able to proceed successfully to transplant. We have not seen this level of activity with any other available treatment in this advanced disease setting.”

NPM1-Mutant AML
NPM1-mutant AML, which is distinguished by mutations in the NPM1 gene that drive the leukemic phenotype, is the most common type of cytogenetically normal adult AML and represents approximately 30% of all adult AML cases. This subtype of AML has a five-year overall survival rate of approximately 50%.

Similar to KMT2A-rearranged acute leukemia, NPM1-mutant AML is highly dependent on the expression of specific developmental genes shown to be negatively impacted by inhibitors of the menin-KMT2A interaction.

NPM1-mutant AML is routinely diagnosed through currently available screening techniques. There are currently no approved therapies indicated for NPM1-mutant AML.[2][3]

ASH 2023
The outcomes presented at the 65th American Society of Hematology (ASH) Annual Meeting & Exposition shows

  • A potential of combining revumenib with venetoclax (Venclexta®; AbbVie and Genentech)/hypomethylating agents in both the frontline and R/R acute myeloid leukemia (AML) settings, as well as with fludarabine/cytarabine (FLA) chemotherapy in a heavily pretreated R/R pediatric AML population, including in patients who relapsed on FLA.
  • In addition to supporting the expansion of ongoing trials and advancement into additional combination trials currently in planning, the new combination data positions revumenib to become a cornerstone of treatment across a range of acute leukemia populations.

In three clinical trials, patients are now receiving the full monotherapy recommended Phase 2 dose in combination with the standard of care agents. The new combination data collectively highlight revumenib’s potential to safely combine with the current standard of care agents across the acute leukemia treatment landscape, and support the expansion of ongoing trials and advancement into additional combination trials currently in planning.

“Given the urgent need for novel, effective solutions for acute leukemia patients, we’re excited to show clinical data demonstrating tolerability and compelling clinical responses when revumenib is added to current treatment regimens,” noted Michael A. Metzger, Syndax’ Chief Executive Officer.

“The potential to safely combine with the standard of care positions revumenib to become a cornerstone of treatment across a range of acute leukemia populations. In addition, current response rates seen across all three trials strengthen revumenib’s already robust clinical profile as a monotherapy and furthers our conviction that revumenib could be a first- and best-in-class treatment for both KMT2Ar and mNPM1 acute leukemias,” Metzger added.

SAVE AML Trial
Results from the SAVE AML trial of revumenib in combination with venetoclax-decitabine/cedazuridine in R/R AML were featured during an oral session at the 65(th) American Society of Hematology (ASH) Annual Meeting. The dose escalation phase of the trial tested revumenib at doses of 113 mg and 163 mg every 12 hours (q12h) in combination with azole antifungals known to strongly inhibit CYP3A4 enzymes.

As of a data cutoff date of November 1, 2023, nine patients with KMT2Ar, mNPM1 or NUP98r AML or mixed phenotypic acute leukemia (MPAL) were enrolled and response evaluable at the time of the data cut. Patients received a median of three prior lines of therapy, including 56% who received prior venetoclax and 67% who received prior hypomethylating agents (HMA) or underwent prior stem cell transplant or both.

All nine patients attained a morphologic remission for an overall response rate of 100%, 78% of whom achieved a CRc(1) including 44% who achieved a CR/CRh. 67% (6/9) of patients in the trial attained minimal residual disease (MRD) negative status. Five patients transitioned to hematopoietic stem-cell transplantation (HSCT) following response. Two patients initiated post-transplant maintenance with revumenib and continue in remission for over 11 months.

The combination was well tolerated in this relapsed and refractory population, with no new safety signals observed beyond those reported for venetoclax-HMA. Grade >=3 treatment related adverse events (TRAEs) included febrile neutropenia (56%), decreased platelets count (22%), decreased neutrophil count (22%) and lung infection (22%). There was one dose-limiting toxicity (DLT) at each dose level, Grade 4 thrombocytopenia that resolved after a dosing hold. There were no deaths due to TRAEs and no Grade 3 or higher QTc prolongation occurred.

BEAT AML Trial
The Company also announced data from the BEAT AML trial of revumenib in combination with venetoclax/azacitidine in newly diagnosed mNPM1 or KMT2Ar AML patients. The dose escalation phase of the trial tested revumenib at doses of 113 mg and 163 mg q12h in combination with azole antifungals known to strongly inhibit CYP3A4 enzymes. As of the data cutoff date of December 1, 2023, 13 newly diagnosed mNPM1 (n=8) or KMT2Ar (n=5) AML patients were efficacy evaluable. In the efficacy evaluable population, the CRc was 100% (13/13) after 1 — 2 cycles of induction. Eleven (85%) of 13 patients attained a CR/CRh and 92% (12/13) attained MRD negative status. Two patients proceeded to transplant.

No new safety signals were identified when revumenib was added to the standard venetoclax/azacitidine doublet in newly diagnosed AML patients. One patient at the lowest dose level, 113 mg q12h, experienced a DLT of decreased platelet counts; no DLTs were observed in the 163 mg q12h dose cohort. 31% of patients experienced differentiation syndrome or QTc prolongation, each included one (8%) Grade 3 event. All were managed without dose reductions.

Cytopenias were manageable across the treatment experience with continuous dosing of venetoclax and revumenib. There were no increased safety issues outside of known adverse events reported for venetoclax/azacitidine toxicities.

An expansion cohort is planned to further evaluate safety and activity of this combination, and the full BEAT AML data will be presented at a future medical conference.

AUGMENT-102 Trial
The Company announced data from the AUGMENT-102 trial of revumenib in combination with fludarabine/cytarabine in a predominantly pediatric relapsed/refractory mNPM1 (n=1), NUP98r (n=1) and KMT2Ar (n=13) AML population. The dose-escalation phase of the trial tested revumenib at doses of 113 mg and 163 mg every 12 hours in combination with azole antifungals known to strongly inhibit CYP3A4 enzymes.

As of the data cutoff date of September 20, 2023, 15 AML patients were efficacy evaluable, including three patients treated at 113 mg q12h and 12 patients treated at 163 mg q12h. The 163 mg q12hr cohort was comprised of primarily pediatric patients (median age of four), who had received a median of four prior lines of therapy.

Across both dose groups, 50% of patients had failed prior treatment with fludarabine/cytarabine. Among the 12 patients treated at 163 mg q12h, four (33%) patients achieved a CRc including three (25%) patients that achieved a CR; four (33%) proceeded to transplant, including one mNPM1 patient who received a five-day course of decitabine prior to transplant.

The triplet of revumenib-fludarabine-cytarabine had an adverse event profile consistent with that observed with fludarabine-cytarabine alone, and no new safety signals were identified in the trial. Grade >=3 TRAEs in over 30% of patients included decreased platelets (53%), decreased white blood cells (40%) and anemia (33%).

In this study, participants whose cancer responded to the treatment, 39% proceeded to a stem cell transplant and half had initiated post-transplant maintenance treatment with revumenib at the time of the data cutoff. Based on these results, researchers say revumenib provides a promising avenue to allow more patients to proceed to a stem cell transplant.
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Note: * Revumenib is a potent, selective, small molecule inhibitor of the menin-KMT2A binding interaction that is being developed for the treatment of KMT2A-rearranged, also known as mixed lineage leukemia rearranged or MLLr, acute leukemias including ALL and AML, and NPM1-mutant AML. The investigational drug was granted Orphan Drug Designation by the FDA and European Commission for the treatment of patients with AML, and Fast Track designation by the FDA for the treatment of adult and pediatric patients with R/R acute leukemias harboring a KMT2A rearrangement or NPM1 mutation. Revumenib was also granted BTD by the FDA for the treatment of adult and pediatric patients with R/R acute leukemia harboring a KMT2A rearrangement.

Clinical trials
Testing the Addition of an Anti-cancer Drug, SNDX-5613, to the Standard Chemotherapy Treatment (Daunorubicin and Cytarabine) for Newly Diagnosed Patients With Acute Myeloid Leukemia That Has Changes in NPM1 or MLL/​KMT2A Gene – ClinicalTrials.gov ID NCT05886049
Study of Revumenib, Azacitidine, and Venetoclax in Pediatric and Young Adult Patients With Refractory or Relapsed Acute Myeloid Leukemia – ClinicalTrials.gov ID NCT06177067
A Study of SNDX-5613 in Combination With Chemotherapy in Participants With R/​R Acute Leukemia – ClinicalTrials.gov ID NCT05326516

ASH Abstract
Aldoss I, Issa GC, Thirman M, DiPersio J, Arellano M, Blachly JS, Mannis GN, Perl A, Dickens DS, McMahon CM, Traer E, Zwaan CM, Grove C, Stone R, Shami PJ, Ioannis Mantzaris I, Greenwood M, Shukla N, Cuglievan B, Gu Y, Bagley RG, Madigan K, Sunkaraneni S, Van Nguyen H, McNeer N and Stein EM. LBA-5: Revumenib Monotherapy in Patients with Relapsed/Refractory KMT2Ar Acute Leukemia: Topline Efficacy and Safety Results from the Pivotal Augment-101 Phase 2 Study. Presented on Tuesday, December 12, 2023, 9:00 AM-10:30 AM during the 65th annual meeting of the American Society of Hematology, held December 9 – 12, 2023 in San Diego, CA. [Abstract]

Reference
[1]Issa GC, Zarka J, Sasaki K, Qiao W, Pak D, Ning J, Short NJ, Haddad F, Tang Z, Patel KP, Cuglievan B, Daver N, DiNardo CD, Jabbour E, Kadia T, Borthakur G, Garcia-Manero G, Konopleva M, Andreeff M, Kantarjian HM, Ravandi F. Predictors of outcomes in adults with acute myeloid leukemia and KMT2A rearrangements. Blood Cancer J. 2021 Sep 29;11(9):162. doi: 10.1038/s41408-021-00557-6. PMID: 34588432; PMCID: PMC8481264.
[2] Falini B, Brunetti L, Sportoletti P, Martelli MP. NPM1-mutated acute myeloid leukemia: from bench to bedside. Blood. 2020 Oct 8;136(15):1707-1721. doi: 10.1182/blood.2019004226. PMID: 32609823.
[3] Issa GC, Bidikian A, Venugopal S, Konopleva M, DiNardo CD, Kadia TM, Borthakur G, Jabbour E, Pemmaraju N, Yilmaz M, Short NJ, Maiti A, Sasaki K, Masarova L, Pierce S, Takahashi K, Tang G, Loghavi S, Patel K, Andreeff M, Bhalla K, Garcia-Manero G, Ravandi F, Kantarjian H, Daver N. Clinical outcomes associated with NPM1 mutations in patients with relapsed or refractory AML. Blood Adv. 2023 Mar 28;7(6):933-942. doi: 10.1182/bloodadvances.2022008316. PMID: 36322818; PMCID: PMC10027507.

Featured image by John Schnobrich on Unsplash. Used with permission.

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