TQB3455 Plus Azacitidine in Patients with Newly Diagnosed, Mutant-IDH2 Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Phase 1 Trial

Introduction: TQB3455, a novel selective inhibitor of isocitrate dehydrogenase-2(IDH2) proteins, demonstrated well-tolerated and preliminary antitumor activity in relapsed/refractory acute myeloid leukemia(AML) and myelodysplastic syndromes(MDS). We evaluated the safety and efficacy of TQB3455 plus azacitidine in patients(pts) with newly diagnosed, mutant-IDH2 AML ineligible for intensive chemotherapy and MDS. Methods: This open-label, multicenter, phase 1 study enrolled AML or MDS pts with mIDH2. Eligible patients were 18 or older and had newly diagnosed, mutant-IDH2 AML and MDS, and an Eastern Cooperative Oncology Group performance status (ECOG) of 0-2. Pts received oral TQB3455 100 mg/day in continuous 28-day cycles, plus subcutaneous azacitidine 75 mg/m² per day for 7 days of each cycle. The primary endpoint was the overall response rate in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drug. Results: Between June 3, 2022, and May 31, 2024, 21 pts were enrolled in the study and had received at least one dose of TQB3455, 17 were AML and 4 were MDS. The median age was 61 years and 47.6% were male, including 2 pts with ECOG 2. There were 12 pts with R140 mutation and 9 pts with R172 mutation. The most frequently mutated genes in whole pts were DNMT3A (52.4%), ASXL1 (23.8%), and WT1 (19.1%). Eight patients had poor-risk cytogenetics in AML pts. The median follow-up was 7.62 months (95%CI 4.63, 9.17). Treatment was well tolerated in all pts. All pts experienced at least one treatment-emergent adverse event(TRAEs). The most common(≥20%) TRAEs were neutropenia (85.7%), leukopenia (66.7%), thrombocytopenia (66.7%), anemia (61.9%), white cell count increased (28.6%), pyrexia(23.8%). Grade 3 or higher TRAEs were neutropenia, leukopenia, thrombocytopenia, and anemia. The majority of these TRAEs could be recovered after supportive treatment. Serious treatment-related adverse events were reported in 8 (38.1%) pts, mainly pneumonia. Differentiation syndrome (DS) was not observed. Treatment-related deaths were reported in 1 AML pt. For efficacy, an overall response was 94.1%, and 50.0% was achieved in AML pts and MDS pts. CR+CRi rates were 82.4% in AML pts, and the median duration of response and median event-free survival was not reached. The median time to complete remission plus complete remission with partial hematological was 2.79 months (95%CI, 1.25-2.79). Additionally, the CR rate was 50% in MDS pts. Among CR pts, two of them received hematopoietic stem-cell transplantation. The median OS was not reached in all pts. Conclusion: TQB3455 plus azacitidine was a well-tolerated, and effective therapy for newly diagnosed, mutant-IDH2 AML ineligible for intensive chemotherapy and MDS. The randomized study will be launched soon to explore the superiority of the therapy.