An All-Oral Revumenib Combination Achieves 100% ORR Patients with R/R AML

Findings from the small phase 1/2 SAVE study (NCT05360160) showcased a 100% objective response rate (ORR) in patients with relapsed/refractory acute myeloid leukemia (AML) when treated with the all-oral combination of revumenib (SNDX-5613), decitabine/cedazuridine, and venetoclax (Venclexta), according to data presented at the 2023 American Society of Hematology (ASH) Annual Meeting. Acceptable safety was also achieved with the use of this combination for this population.¹

Of the 9 patients currently enrolled on the SAVE trial, the complete response (CR)/complete response with partial hematologic recovery (CRh) rate with the regimen was 44% and the CR rate was 33%. The CRh, CR with incomplete platelet recovery (CRp), partial response (PR), and morphologic leukemia-free state (MLFS) rates were 11%, 33%, 11%, and 11%, respectively. Sixty-seven percent of patients were minimal residual disease (MRD) negative, 4 of which were of the 4 CRs. Sixty-three percent had a complete cytogenetic remission by fluorescence in situ hybridization (FISH).

At 6 months, the RFS rate was 62.2% (95% CI, 21.3%-86.4%) and the OS rate was 71.1% (95% CI, 23.1%-92.2%). The median RFS and OS have not yet been reached, but Ghayas C. Issa, MD, noted that 2 patients have ongoing remission beyond 11 months.

“Early results of the all-oral combination of the menin inhibitor revumenib, oral decitabine, and venetoclax indicate acceptable safety and high efficacy in children and adults with relapsed/refractory AML susceptible to menin inhibition,” said Issa, lead study aauthor, a medical oncologist of the Department of Leukemia in the Division of Pediatrics, The University of Texas MD Anderson Cancer Center in Houston, said in an oral presentation during the meeting.

Menin-KMT2A interaction is dependent in KMT2Ar, NUP98r, or NPM1 mutant leukemias, and revumenib is a potent, oral selective menin-KMT2A inhibitor. Previous data have shown that revumenib elicited a 53% ORR, 30% CR/CRh rate, and a 78% MRD-negativity rate in patients with relapsed/refractory AML who harbor KMT2A rearrangements and NPM1 mutations.² However, there remains a need to improve responses and lower the risk of relapse in this patient population.

Additionally, hypomethylating agents (HMAs) and venetoclax comprise a standard regimen available for patients who are older or unfit with AML, and the oral formulation of decitabine/cedazuridine is approved for patients with myelodysplastic syndromes.³ Adding BCL-2 inhibition to menin inhibition, Issa explained, preclinically showed it can eradicate bulk and stem/progenitor cells while improving survival. KMT2Ar or NPM1-mutant leukemias are susceptible to apoptosis through BCL-2 inhibition, he added.

In the phase 1/2 SAVE trial, investigators used a 3+3 design with a dose-escalation phase to administer revumenib at 113 mg at dose level 0 or 163 mg at dose level 1, the latter of which was determined as the recommended phase 2 dose (RP2D) of revumenib. Both doses were given every 12 hours on days 1 through 28, along with a strong CYP3A4 inhibitor, Issa said. In addition to revumenib, patients received 1 tablet of 35 mg of decitabine and 100 mg of cedazuridine daily for days 1 to 5, plus venetoclax at a 400-mg target dose, adjusted for azoles, with ramp up on days 1 to 14. All treatments were given orally. On day 14, bone marrow was assessed for early response. Revumenib was given as maintenance for 1 year following hematopoietic stem cell transplant (HSCT).

To be eligible for enrollment, patients must be aged 12 years or older with relapsed/refractory AML or myeloid mixed phenotype acute leukemia (MPAL), have a KMT2A or NUP98 rearrangement or a NPM1 mutation, an ECOG performance status of 0 to 2, and adequate organ function.

The primary end points in the phase 1 portion are safety, maximum-tolerated dose, and RP2D; in the phase 2 portion, the primary outcome measure is efficacy. Secondary end points are overall survival (OS), relapse-free survival (RFS), CRD, and MRD.

Regarding baseline characteristics of the patients enrolled thus far, the median age was 30 years (range, 12-63), and 3 patients were between the ages of 12 and 18 years. Seven of the 9 patients were female, and the bone marrow blast rate was 24% (AML, 89%; MPAL, 11%). One patient had both medullary and extramedullary disease and 2 had therapy-related AML. Five patients had KMT2A rearrangements, 3 had NUP98 rearrangements, and 1 had an NPM1 mutation. Cooccurring mutations also occurred with WT1 (n = 4), RAS (n = 3), IDH2 (n = 2), and FLT3 (n = 1). The median number of prior therapies was 3 (range, 1-5), and included venetoclax (n = 5), a menin inhibitor (n = 1), and HSCT (n = 6).

In the phase 1 dose-escalation portion, there was one dose-limiting toxicity (DLT) at the dose level 0 (113 mg) of grade 4 prolonged thrombocytopenia, which resolved after dose hold, Issa said. After escalation to dose level 1 of 163 mg, there was another DLT of grade 4 prolonged thrombocytopenia, which also resolved after dose hold, “leading to a delay in count recovery,” he added.

Of the 9 patients enrolled, 5 patients are ongoing and received consolidation therapy with HSCT after response, 1 is in an ongoing response without HSCT, 2 have resumed maintenance revumenib, 2 have not yet started maintenance therapy, and 1 patient—who had a NUP98 rearrangement and a PR—had progressive disease at 6 months of treatment. Two deaths occurred that were unrelated to treatment (sepsis, n = 1; acute respiratory distress syndrome posttransplant, n = 1), and 1 had an adverse effect (AE) that was also not related to therapy.

The most common any-grade treatment-emergent AEs were febrile neutropenia (n = 5), nausea (n = 5), and hyperphosphatemia (n = 5). Any-grade treatment-related AEs, which were related to any of the agents used in the SAVE regimen, included nausea (n = 5), hyperphosphatemia (n = 5), vomiting (n = 4), QT prolongation (n = 3), and differentiation syndrome (n = 2). Grade 3 or higher treatment-related AEs were febrile neutropenia (n = 5), and neutropenia, thrombocytopenia, and lung infection (n = 2 each). Leukocytosis occurred in 1 patient, and no cases of grade 3 or higher QTc prolongation, nor severe cases of differentiation syndrome, were reported.

The myelosuppression is confounded by the expected risk with HMA and venetoclax in the relapsed/refractory AML setting, Issa explained.

“Future mitigation measures could minimize the risk of myelosuppression, include exploring intermittent revumenib dosing, which is unlikely to comprise efficacy, giving clearance of leukemia by day 14 so far observed,” he said.

The data cutoff date was November 1, 2023. The median follow-up was 6.4 months (range, 0.4-12.3); the median time to response was 28 days (range, 14-55), and bone marrow on day 14 was less than 5% in 6 of the 6 evaluable patients.

Additional efficacy data showed that 3 of the CR/CRh rates were in the KMT2A (n = 3) and NUP98 rearrangement (n = 1) subgroups. Three CRs and 2 CRp were of the KMT2A subgroup (n = 5); the MRD-negativity rate and complete cytogenetic remission by FISH were both 80%. In the NUP98 rearrangement subgroup (n = 3), there was 1 CRh, 1 PR, 1 MLFS, a 33% MRD-negativity rate, and a 33% complete cytogenetic remission by FISH. In the NPM1-mutant subgroup (n = 1), the patient had a CRp and they achieved MRD negativity as well as a complete cytogenetic remission by FISH.

Furthermore, pharmacokinetic analysis demonstrated that the dose-normalized, steady-state plasma concentrations of revumenib in the SAVE regimen are comparable with the agent alone.

Issa concluded that the trial is continuing to accrue patients.

REFERENCES:

1. Issa GC, Cuglievan B, DiNardo CD, et al. Early results of the Phase I/II study investigating the all-oral combination of the Menin inhibitor revumenib (SNDX-5613) with decitabine/cedazuridine (ASTX727) and venetoclax in acute myeloid leukemia (SAVE). Blood. 2023;142 (suppl 1):58. doi:10.1182/blood-2023-182337

2. Issa GC, Aldoss I, DiPersio J, et al. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature. 2023;615:920-924. doi:10.1038/s41586-023-05812-3

3. FDA approves oral combination of decitabine and cedazuridine for myelodysplastic syndromes. News release. FDA. July 7, 2020. Accessed September 20, 2023. https://bit.ly/3pHeQhk