Final Results of the Phase Ib/II Study Evaluating Enasidenib in Combination with Venetoclax in Patients with <i>IDH2</i>-Mutated Relapsed/Refractory Myeloid Malignancies

BACKGROUND: Theisocitrate dehydrogenase 2 ( IDH2) gene is mutated in ∼10-15% cases of acute myeloid leukemia (AML) and ∼5% cases of myelodysplastic syndromes (MDS). Enasidenib (ENA) is an oral selective IDH2 inhibitor used for treatment of IDH2-mutated (m IDH2) relapsed/refractory (R/R) AML. Preclinical studies showed that m IDH2 AML cells are particularly sensitive to BCL2 inhibition with venetoclax (VEN) and combination of ENA and VEN is more effective than single agents in patient-derived xenograft models of m IDH2 AML. Based on this rationale, we conducted a phase Ib/II trial evaluating the safety and efficacy of ENA plus VEN in patients (pts) with m IDH2 R/R AML or MDS (NCT04092179). METHODS: This single-arm phase Ib/II trial was conducted at the Princess Margaret Cancer Centre and the University of Alberta Hospital in Canada. Pts ≥ 18 years with m IDH2 R/R AML or MDS, adequate organ function and ECOG performance status ≤ 2 were eligible. Participants were not eligible if they had prior exposure to IDH2 or BCL2 inhibitors. Pts were treated continuously by 28-day cycles of VEN 400 mg daily starting with a 3-day ramp-up on cycle 1 day 1 and with ENA 100 mg daily starting on cycle 1 day 15. The primary endpoints were safety, tolerability and recommended phase 2 dose (RP2D) for the phase Ib part and overall response rate (ORR) for the phase II part. ORR included complete remission (CR), CR with partial hematological recovery (CRh), CR with incomplete hematological recovery (CRi), morphologic leukemia-free state (MLFS) and partial remission (PR) as defined by the European Leukemia Network (ELN). Duration of response (DOR), overall survival (OS), pharmacokinetic (PK) analysis for VEN and bone marrow (BM) IDH2 variant allele frequency (VAF) by droplet digital PCR (ddPCR) were also evaluated. RESULTS: From November 2020 to July 2022, 27 pts were enrolled: 12 in the phase Ib and 15 in the phase II. Almost all pts had AML, except one with MDS who progressed on treatment with azacitidine. The data cutoff date was June 30, 2023. The median age was 70 years (range, 23 - 84) ( Table 1). Patients had a median of 1 prior line of treatment (range, 1-2) including 5 (19%) who had previously undergone allogeneic stem cell transplant (HSCT). Fifteen (56%) and 12 (44%) pts had R140Q and R172K/W IDH2 mutation (mut), respectively. The median BM IDH2 VAF at baseline was 23.4 (range 2.3 - 49.9). The most common (≥ 20%) grade 3-5 treatment emergent adverse events (TEAEs), regardless of attribution, were febrile neutropenia (41%), lung infection (22%) and thrombocytopenia (26%). Nausea, vomiting and diarrhea occurred each in 41% of pts, but were primarily grade 1-2 (only 1 pt with grade 3 diarrhea). Hyperbilirubinemia of any grade occurred in 48% pts, including grade 3 in 15%. No case of IDH inhibitor associated differentiation syndrome (IDH-DS) occurred in this study. Grade 3 leukocytosis without IDH-DS occurred in 2 (8%) pts. No patient discontinued ENA because of an adverse event and no treatment-related death was reported. The PK profile of VEN was not altered by ENA, and the RP2D was VEN 400 mg daily plus ENA 100 mg daily. Among 23 pts with R/R AML evaluable for response, the ORR was 70% (16/23), including 57% (13/23) CR ( Figure 1). In pts with R172 mut, the ORR and CR rates were 83% (10/12) and 67% (8/12), respectively, versus 55% (6/11) and 45% (5/11) in pts with R140 mut. m IDH2 VAF at baseline was similar between responders and non-responders. On follow-up BM samples, there was an association between response and decrease in m IDH2 VAF. Clearance of m IDH2 was observed in 47% (7/15) of analyzed responders. The median time to initial response was 1 month (range, 0.9 - 5.7), and the median time to best response was 2.8 months (range, 0.9 - 12.5). The median DOR was 16.6 months (95% CI 5.0 - NR) and pts received a median of 7 cycles of treatment (range, 1 - 32). With a median follow-up of 17.1 months (range, 0.9 - 31.4), 10 (38%) pts were alive, including 9 (35%) in ongoing remission. The median OS was 9.4 months (95% CI, 8.2 - NR) and the 2-year OS rate was 42% (95% CI, 27 - 66). Four pts proceeded to HSCT after achieving remission, of whom 2/4 (50%) are alive in remission on last follow-up. CONCLUSIONS: The combination of ENA and VEN is safe and well tolerated in pts with R/R m IDH2 myeloid malignancies. The ENA-VEN combination compares favorably to ENA single-agent in this patient population. Further studies of targeted combination therapies using IDH2 and BCL2 inhibitors are warranted.

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