Oral Revumenib-Based Combo Produces Responses in R/R AML

Acute Myeloid Leukemia

Data from the phase 1/2 SAVE study (NCT05360160) demonstrated that teatment with the combination of revumenib (Revuforj), decitabine/cedazuridine (ASTX727), and venetoclax (Venclexta) led to high remission rates in patients with relapsed/refractory acute myeloid leukemia (AML).

Findings presented at the 2024 ASH Annual Meeting by Ghayas C. Issa, MD, an assistant professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, showed that the benefit was seen in those with KMT2A rearrangements (KMT2Ar), NPM1 mutations (NPM1mt), and NUP98 rearrangements (NUP98r).

The overall response rate (ORR) was 82% in the 33 patients enrolled in this study. When assessed by genetic alterations and mutations, the rates were 88% in patients with KMT2Ar, 67% in those with NPM1mt, and 100% in patients with NUP98r. For all the patients in the study, 48% achieved complete remission (CR) or a CR with partial hematologic recovery (CRh), and 39% achieved complete remission. These responses were seen across genetic variants.

Of the patients who responded, minimal residual disease (MRD) negativity by multicolor flow cytometry (MFC) was observed in 65% of patients. In particular, MRD negativity occurred in 88% of patients with CR/CRh.

During a median follow-up of 9.3 months (IQR, 7.6-12.5; n = 33), researchers observed a largely stable mutational landscape at progression on targeted sequencing except for those with FLT3-ITD expansion and phenotype switch of the B-cell acute lymphoblastic leukemia (B-ALL) plus acute myeloid leukemia (AML). The median time to first morphologic response was 28 days (range, 14-70), and bone marrow blasts less than 5% at day 14 occurred in 56% of patients (9/16).

During follow-up, the 6-month complete response duration (CRD) rate was 74% (95% CI, 44%-90%), and the median duration of response (DOR) was not reached. The 6-month overall survival (OS) rate was 68% (95% CI, 47%-80%), and the median OS was not reached.

The most common grade 3 or higher treatment-emergent adverse events (TEAEs) were febrile neutropenia (33%), lung infection (33%), elevated AST/ALT (18%), sepsis (18%) respiratory failure (18%), and decreased platelets (18%). Of note, 9% of patients experienced grade 3 or higher QT prolongation, and 3% of patients had grade 3 or higher differentiation syndrome.

“All cases of differentiation syndrome and QT prolongation were considered at least possibly related to revumenib,” Issa said.

Of the 33 patients in this study, 39% (n = 13) remain on study, of whom 30% have ongoing response without hematopoietic stem cell transplant (HSCT) and 9% are receiving maintenance post-HSCT. In addition, 6% (n = 2) completed the study including maintenance post-HSCT, 39% (n = 13) proceeded to HSCT, and 54% (n = 7) proceeded to maintenance therapy. Eighteen patients are off study for reasons including progression or no response (n = 10), unrelated death (n = 4), AE (n = 2) and other (n = 2).

Study Design

In this phase 1/2 study, researchers included patients aged 12 years and older with relapsed/refractory AML or myeloid mixed-lineage acute leukemia; KMT2Ar, NPM1mt, or NUP98r; an ECOG score of 2 or lower, and adequate organ function. Dose escalation in the study followed a 3+3 design, according to the abstract.

Decitabine/cedazuridine was administered at 35 mg/100 mg orally per day on days 1 to 5, venetoclax at 400 mg orally per day on days 1 through 14, and revumenib at 113 mg or 163 mg orally every 12 hours. On days 1 through 28, patients either received posaconazole or voriconazole. Patients then received revumenib monotherapy after HSCT for 1 year of maintenance therapy. An amendment was made to the study protocol that recommended holding revumenib after day 21 if bone marrow at cycle 1, day 14 showed bone marrow blasts of fewer than 5%.

MRD was assessed with MFC at a sensitivity of 10^-4.

Background

The rationale behind the SAVE study was to assess a combination of revumenib, ASTX727 and venetoclax in patients with relapsed/refractory AML to potentially improve chances of responses and decrease relapse risk, according to the presentation. Issa noted in the presentation that hypomethylating agents plus venetoclax is a standard treatment for older or unfit patients with AML. In addition, oral ASTX727 is currently approved for patients with myelodysplastic syndromes and chronic myelomonocytic leukemia, and has demonstrated equivalent efficacy as intravenous decitabine. KMT2Ar or NPM1mt leukemias are prone to apoptosis via BCL2 inhibition. Lastly, BCL2 plus menin inhibition has demonstrated the potential to eradicate bulk and stem/progenitor cells and improve survival in preclinical models.

Reference

Issa GC, Cuglievan B, Daver N, et al. Phase I/II Study of the All-Oral Combination of Revumenib (SNDX-5613) with Decitabine/Cedazuridine (ASTX727) and Venetoclax (SAVE) in R/R AML. Presented at: 2024 ASH Annual Meeting; December 7-10, 2024; San Diego, California. Abstract 216.