Enasidenib Elicits Clinical Efficacy in High-Risk, IDH2-Mutated MDS

Sangeetha Venugopal, MD

The IDH2 inhibitor enasidenib (Idhifa) demonstrated promising efficacy in combination with azacitidine and as a single agent in patients with high-risk, IDH2-mutated myelodysplastic syndrome (MDS), according to findings from a phase 2 study (NCT03383575) that were presented during the 2021 ASCO Annual Meeting and subsequently published in the Journal of Clinical Oncology.¹

Enasidenib in combination with azacitidine induced an overall response rate (ORR) of 84% in patients with hypomethylating agent (HMA)–naïve, high-risk MDS (n = 25). Of these responses, 24% (n = 6) were complete responses (CRs), 8% (n = 2) were partial responses (PRs), 44% (n = 11) were bone marrow CRs, and 8% (n = 2) were hematological improvements.

When used as a single agent, enasidenib induced an ORR of 43% in patients who previously failed an HMA (n = 21). Of these responses, 24% (n = 5) were CRs, 5% (n = 1) were PRs, 5% (n = 1) were marrow CRs, and 10% (n = 2) were hematological improvements.

IDH2 mutations are present in 5% to 10% of patients with MDS.

“[The IDH2-mutant] phenotype is characterized by normal karyotype, increased bone marrow blast count, [and] neutropenia, but with sustained platelet count,” said lead study author Sangeetha Venugopal, MD, a clinical fellow in leukemia in the MD Anderson Cancer Center Leukemia Fellowship Program at The University of Texas MD Anderson Cancer Center, in a virtual presentation of the data.

Enasidenib is a selective, oral, IDH2 inhibitor that is FDA approved to treat patients with relapsed/refractory IDH2-mutated acute myeloid leukemia (AML).

Findings from the phase 1 AG221-C-001 study (NCT01915498) demonstrated a 53% response rate and a median overall survival (OS) of 16.9 months with enasidenib among patients with relapsed/refractory IDH2-mutant MDS.

In the ongoing, multicenter, open-label phase 2 trial, patients with HMA-naïve, high-risk MDS (arm A) received 75 mg/m2 of intravenous azacitidine daily or subcutaneous azacitidine on days 1 through 7 of 28-day cycles plus 100 mg of daily, oral enasidenib on days 1 through 14. Patients who previously failed HMA treatment (arm B) received single-agent, continuous enasidenib at 100 mg daily.

High-risk MDS was defined by high- or very high–risk per Revised International Prognostic Scoring System (IPSS-R) for Myelodysplastic Syndromes Risk Assessment criteria or the presence of high-risk mutations, such as TP53, ASXL1, EZH2, or RUNX1, explained Venugopal.

“The median survival in patients with higher-risk MDS treated with standard-of-care [HMAs] is less than 2 years, which decreases to less than 6 months in the setting of HMA failure where no standard-of-care treatment options are available,” Venugopal said.

In the overall population (n = 46), the median patient age was 73 (range, 46-83) and 77% (n = 36) of patients were 65 years of age or older.

Per the World Health Organization 2017 criteria, 30% (n = 14) of patients had a diagnosis of MDS with multilineage dysplasia (MDS-MLD)/MDS-myeloproliferative neoplasm, unclassifiable (MDS-MPN-U), 59% (n = 27) had a diagnosis of MDS with excessive blasts (MDS-EB)/AML with myelodysplasia-related changed (AML-MRC), and 11% (n = 5) had a diagnosis of chronic myelomonocytic leukemia (CMML).

The majority of patients (50%; n = 23) had good cytogenetics. ASXL1, SRSF2, and RUNX1 mutations, which confer poor prognosis, were identified in 37% (n = 17), 43% (n = 20), and 17% (n = 8) of patients, respectively, Venugopal said.

Finally, per IPSS-R classification, 59% (n = 27) of patients had high- or very high–risk disease and 39% (n = 18) had low- or intermediate-risk disease.

In the overall population, the ORR was 68% and was comprised of CRs (24%; n = 11), PRs (7%; n = 3), marrow CRs (26%; n = 12), and hematologic improvement only responses (9%; n = 4). The median time to first response was 1 month (range, 0.9-3.7) and the time to best response was 3.1 months (range, 0.9-7.6). Moreover, 35% (n = 16) of patients had no response to treatment, 30% (n = 14) achieved stable disease (SD), and 4% (n = 2) developed progressive disease.

In arm A, the median time to first response was 0.9 months (range, 0.9-3.4) and the median time to best response was 1.6 months (range, 0.9-3.7). In this cohort, 16% of patients (n = 4) did not respond to enasidenib/azacitidine, 16% (n = 4) achieved SD, and no patients developed progressive disease.

In arm B, the median time to first response was 1 month (range, 0.9-3.7) and the median time to best response was 4.6 months (range, 2.8-7.6). In this cohort, 57% of patients (n = 12) did not respond to single-agent enasidenib, 48% (n = 10) achieved SD, and 10% (n = 2) developed progressive disease.

With a median follow-up of 12.6 months, the median OS was 32.2 months in Arm A and 21.3 months in Arm B.

“[The survival data reported] are much better than the reported OS in single-agent HMA or post-HMA failure settings,” added Venogopal.

Regarding safety, any-grade adverse effects (AEs) included infection (26%; n = 12), pneumonia (26%; n = 12), neutropenic fever (17%; n = 8), nausea (46%; n = 21), constipation (44%; n = 20), diarrhea (15%; n = 7), differentiation syndrome (17%; n = 8), fatigue (35%; n = 16), hyperbilirubinemia (20%; n = 9), liver function test abnormalities (15%; n = 7), electrolyte/metabolic abnormalities (28%; n = 13), and intracranial bleeding (6%; n = 3).

Grade 3 or 4 AEs included infection (13%; n = 6), pneumonia (13%; n = 6), neutropenic fever (17%; n = 8), nausea (2%; n = 1), diarrhea (2%; n = 1), differentiation syndrome (13%; n = 6), fatigue (7%; n = 3), hyperbilirubinemia (9%; n = 4), liver function test abnormalities (2%; n = 1), and electrolyte/metabolic abnormalities (2%; n = 1).

Regarding differentiation syndrome, the median time to onset was 1.4 months (range, 1.2-1.8) in arm A and 1.2 months (range, 1.0-8.4 months) in arm B. One patient with grade 2 differentiation syndrome did not require treatment, whereas 5 patients with grade 3 differentiation syndrome were successfully treated with dexamethasone. One patient with grade 3 differentiation syndrome was treated with hydroxyurea but progressed to AML.

Grade 5 AEs included infection (2%; n = 1), pneumonia (13%; n = 6), and intracranial bleeding (2%; n = 1).

“This study continues to accrue patients and, hopefully, with longer follow-up in a larger dataset, we will confirm these promising results of enasidenib in IDH2-mutated HR-MDS,” concluded Venugopal.

Reference

1. Venugopal S, DiNardo CD, Takahashi K, et al. Phase II study of the IDH2-inhibitor enasidenib in patients with high-risk IDH2-mutated myelodysplastic syndrome (MDS). J Clin Oncol. 2021;39(suppl 15):7010. doi:10.1200/JCO.2021.39.15_suppl.7010