Enasidenib (ENA) Monotherapy in Patients with IDH2 mutated Myelodysplastic Syndrome (MDS), the Ideal Phase 2 Study By the GFM and Emsco Groups

Introduction: ENA, a selective inhibitor of IDH2 mutated protein, is FDA approved for the treatment of patients with relapsed/refractory IDH2 mutated (IDH2m) AML. There are limited data on its efficacy as a single agent in patients with IDH2m MDS. Here we report the preliminary results of a Phase 2 trial evaluating the safety and efficacy of ENA in three different cohorts of MDS: Higher risk (HR-) MDS having failed HMA (cohort A), untreated HR- MDS without life threatening cytopenias (cohort B) and lower risk MDS having failed ESA (cohort C). (ClinicalTrials.gov NCT03744390).

Methods: Subjects were enrolled in cohort A, B, or C received continuous 28-day cycles of ENA - 100 mg PO QD. In cohort B, in the absence response after 3 cycles, Azacitidine (AZA, 75 mg/m2/d x 7 days, SC) was added to ENA. A Fleming single stage phase 2 trial, used the best overall hematological response (OR, including CR, PR, stable disease or marrow CR with HI according to IWG 2006) as the primary endpoint for cohort A and B, aiming to demonstrate a OR>20%; and a safety endpoint in cohort C. All patients who achieved OR could continue treatment until loss of response. Secondary endpoints included safety, duration of response, EFS, overall survival (OS) and translational studies evaluating the role of biomarkers on response.

Results: Between February 2019 and November 2022, 95 patients were screened, 69 were included (28, 30 and 11 in cohort A, B and C, respectively). Median age at screening was 76 years (IQR 71-81) and 36% were female. According to WHO 2016, 4 (6%) had MDS-SLD (including 3 MDS-RS-MLD), 7 (10%) MDS-MLD (including 5 MDS-RS-MLD), 13 (19%) MDS-EB1, 26 (38%) MDS-EB2, one (1%) MDS-U, 3 (4%) CMML and 15 (22%) low-blast AML. IPSS-R was low, intermediate, high and very high in 8 (12%), 16 (23%), 34 (49%) and 11 (16%) respectively. IDH2m variants were p.R140L/Q/W (85%) and p.R172K/W (15%). The median VAF of IDH2m in bone marrow at screening was 36.6% (IQR 22.2-42.2).

In cohort A, best OR after 3 or 6 cycles was achieved in 12/28 (42.9%) patients (95%CI, 24.5-62.8) (p=0.007), including 5 (42%) CR, and 7 (58%) HI, with a median DOR of 6.9 months. All responders achieved a response at 3 cycles. At data cut-off (Jan. 2024), 21 patients had died (mainly from disease) and 2 are still alive on therapy (after 28 and 41 cycles). With a median FU of 13.7 months, median OS was 14.9 months, and the 12-month OS rate was 57.1% (95%CI, 41.5-78.8).

In cohort B, primary endpoint was achieved in 13/30 (43.3%) patients (95%CI 25.5-62.6) (p=0.004), including 5 (38%) CR, 2 (15%) PR and 6 (46%) HI, with a median DOR of 12.2 months. AZA was added to ENA in 4 patients after 3 cycles leading to one additional response. Two patients were bridged to transplant. At data cut-off, 17 patients had died, and 2 are still alive on therapy (after 33 and 54 cycles). With a median follow-up of 19.8 months, median OS was 25.5 months and the 12-month OS rate was 85.8% (95%CI, 73.9-99.7).

With 72 grade 3 or more (3+) adverse events (AE), mainly related to cytopenia and occurring in 45/58 (78%) patients of HR-MDS cohorts (A and B), ENA was well tolerated. None of the 87 severe AE (SAE) were related to ENA in these two cohorts. Differentiation syndromes were manageable and reported in 5/58 (8.6%) patients.

In cohort C, one patient without IDH2m discontinued treatment after one cycle. Five patients had grade 3+ AE, related to ENA in two patients (thrombocytopenia and increasing bilirubin level), all resolved after drug temporary interruption. None of the four SAE reported in four patients were related to ENA and no differentiation syndrome was reported in this LR-MDS cohort. In intention to treat analysis, 6/11 (55%) patients achieved CR with transfusion independency, with a median time to response of 3 cycles. At data cut-off, none of the responders had lost response, two were bridged to transplant after 4 and 7 cycles and only one patient died (not related to disease or ENA). The median FU was 29.9 months and the median OS was not reached.

Conclusion: In IDH2m HR-MDS patients, we reported an overall response of 43.1% (95%CI, 30.2-56.8) (p<0.001) with ENA monotherapy, leading to an OS of 14.9 and 25.5 months in R/R and first-line treated patients respectively. In both HR-MDS cohorts, ENA was well tolerated in this frail population. Results from 11 IDH2m LR-MDS patients included in this study show that ENA has no limiting toxicity and can provide durable response in more than half of the patients.