SEL24/MEN1703 Demonstrates Early Efficacy, Tolerability in R/R AML With IDH1/2 Mutations

The first-in-class dual PIM/FLT3 kinase inhibitor, SEL24/MEN1703, showcased encouraging efficacy and a tolerable safety profile in patients with acute myeloid leukemia (AML) whose tumors harbor a IDH1/2 mutation, according to data from an additional expansion cohort of the phase 1/2 DIAMOND-01 trial (NCT03008187) presented at the 2022 ASCO Annual Meeting.

Among 15 patients who completed at least 1 treatment cycle and were evaluable for efficacy, the agent elicited an objective response rate (ORR) of 13%. One patient with IDH2 and NMP1 mutations experienced a partial response to treatment at cycle 4, followed by a CR at cycle 13; the duration of response (DOR) was 177 days. Another patient with an IDH2 mutation achieved a CR with incomplete hematologic recovery at cycle 3, and they went on to undergo hematopoietic stem cell transplant; the DOR in this patient is 133 days.

“SEL24/MEN1703 was well tolerated, with only asthenia, nausea, and vomiting reported as the most frequent treatment-emergent adverse effects [TEAEs], possibly related to study drug,” Prof Giovanni Martinelli, of IRCCS Instituto Romagnolo per lo Studio dei Tumori “Dino Amadori” – IRST, and colleagues, wrote in a poster on the data. “SEL24/MEN1703 may be a feasible therapy in this difficult-to-treat population of patients with relapsed/refractory AML who harbor IDH1 mutations.”

Although advanced AML is an aggressive condition associated with high mortality rates, an increased understanding of the molecular and cytogenetic aspects of the disease has allowed for the development of effective targeted therapies for several patient subsets. FLT3 mutations are present in 21% to 34% of patients with de novo AML and are linked with a poor prognosis. In up to 30% of cases, IDH1 and IDH2 mutations can co-occur with FLT3 mutations.

Preclinical data have indicated that PIM inhibition restores sensitivity to FLT3 inhibitors in relapsed AML samples. The findings provided the rationale to explore approaches that can dually target PIM and FLT3 kinase pathways, such as SEL24/MEN1703. Preliminary data from the first-in-human DIAMOND-01 trial showed that the drug had promising antitumor activity, with 3 of 8 patients who had relapsed or refractory AML harboring IDH mutations experiencing a response to treatment.

DIAMOND-01 trial is comprised of 2 parts: dose escalation and cohort expansion; the additional expansion cohort of patients with IDH mutations is ongoing. The IDH-mutated cohort included patients who were 18 years of age or older and who had relapsed/refractory AML who harbored IDH mutations. These patients did not have standard therapeutic options available to them.

In part 1 of the 2 study, investigators identified the recommended dose of oral SEL24/MEN1703 to be 125 mg given once daily over the course of 14 days as part of a 21-day cycle. Treatment continued until disease progression, patient withdrawal, or unacceptable toxicity.

In addition to the primary end point of characterizing the safety profile of SEL24/MEN1703, secondary end points included examining the antileukemic activity of the inhibitor, which included ORR, CR, CR with incomplete hematologic recovery, CR with partial hematologic recovery, as well as morphologic leukemic-free state.

As of April 21, 2022, a total of 25 patients were enrolled to the IDH-mutated expansion cohort. The median age of these patients was 68 years (range, 33-79) and 64% of patients were male. Regarding disease type, 72% of patients had de novo disease and 24% had disease that was secondary to myelodysplastic syndrome; this information was not reported in 1 patient. Additionally, 8% of patients had favorable cytogenetic risk, 52% had intermediate risk, 4% had unfavorable risk, and this was not reported for 36% of patients.

Twenty-four percent of patients had refractory disease, and 72% of patients had relapsed disease; AML status was not reported for 4% of patients. Thirty-six percent of patients received 1 prior line of therapy, 36% received 2 prior lines, and 20% received 3 or more prior lines; this information was not reported in 8% of patients.

In terms of IDH mutational status, 56% of patients harbored IDH2 mutations, 36% harbored IDH1 mutations, 4% harbored IDH1/2 mutations, and this was not reported for 4% of patients. Concomitant mutational status with NPM1 (28%), FLT3-ITD (16%), DNMT3A (16%), RUNX1 (12%), ASXL1 (8%), EZH2 (8%), TP53 (4%), CEBPA (4%), BAALC (4%), SRSF2 (4%), or WT1 (4%) was also observed.

Overall, a total of 5 out of 25 patients continue to receive treatment on the study. The most common reason for treatment discontinuation was because of progressive disease (PD)/clinical PD/near PD/death for disease progression (n = 7), followed by an AE not associated with study treatment (n = 7), and other unspecified reasons (n = 6).

The median duration of treatment in evaluable patients was 2 cycles (range 1-13). The safety population comprised a total of 22 patients. The most common TEAEs of any grade were asthenia and nausea, which occurred in 8 and 7 patients, respectively. The most common grade 3 or higher TEAE was pneumonia, which occurred in 6 patients; however, all cases were determined to be unrelated to study treatment.

Four patients had grade 3 or higher asthenia (1 related to study drug), and 3 patients had grade 3 or higher thrombocytopenia (all unrelated). Serious TEAEs included pneumonia (n = 6) and sepsis/septic shock (n = 2), which were not related to the study treatment.

Investigators observed 1 liver injury that was determined to have potentially been induced by MEN1703 and other concomitant medications. However, the extent of the contribution of each suspected drug could not be defined by the investigators.

Three patients required a drug interruption due to treatment-related AEs (TRAEs) such as drug-induced liver injury, hyponatremia, and asthenia. Notably, however, no patients required drug discontinuation or died due to TRAEs. Moreover, no differentiation syndrome was reported

“[Additional] clinical trials are planned in order to better explore the potential of MEN1703 in combination with standard-of-care therapies in different AML patient populations,” the study authors concluded.

Reference

Martinelli G, Santoro A, Gambacorti-Passerini C, et al. Phase 1/2 study of SEL24/MEN1703, a first-in-class dual PIM/FLT3 kinase inhibitor, in patients with IDH1/2-mutated acute myeloid leukemia: the DIAMOND-01 trial. J Clin Oncol. 2022;40(suppl 16):7024. doi:10.1200/JCO.2022.40.16_suppl.7024