INCA033989 for mutCALR MF: Ongoing phase I studies

Results from INCA033989-101 (NCT05936359) and INCA033989-102 (NCT06034002), two ongoing phase I, first-in-human, multicenter, open-label trials evaluating INCA033989 monotherapy or INCA033989 + ruxolitinib in adults with calreticulin-mutated (mutCALR) myelofibrosis (MF), were presented by Claire Harrison at the European Hematology Association (EHA) 2026 Congress, June 11–14, 2026, Stockholm, SE. Patients received INCA033989 monotherapy (n = 83) or INCA033989 + ruxolitinib (n = 21). Patients were intolerant of, resistant to, or ineligible for Janus kinase inhibitor (JAKi) treatment (monotherapy) or had a suboptimal response to ruxolitinib (combination). The primary endpoints were dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs). 

Key data: No DLTs were observed, and the maximum tolerated dose (MTD) was not reached. With monotherapy, any-grade TEAEs occurred in 91.6% of patients, including Grade ≥3 TEAEs in 26.5%, serious TEAEs in 8.4%, and no fatal TEAEs; corresponding rates with INCA033989 + ruxolitinib were 100%, 66.7%, 28.6%, and 0%. The most common Grade ≥3 TEAEs were thrombocytopenia (monotherapy, 6.0%; combination, 9.5%) and anemia (monotherapy, 7.2%; combination, 33.3%). Best monotherapy responses included spleen volume reduction ≥25% (SVR25) in 55%, spleen volume reduction ≥35% (SVR35) in 39%, and total symptom score reduction ≥50% (TSS50) in 53% of patients; anemia response was reported in 60% of evaluable anemic patients (n = 40). At Week 24, SVR35 and TSS50 rates were 27% and 32% with monotherapy vs 30% and 31% with combination therapy, respectively; anemia response occurred in 35% of evaluable anemic patients receiving combination therapy (n = 17). Among evaluable monotherapy patients, 81% had ≥25% reduction in mutCALR peripheral blood mononuclear cells (PBMCs) and 89% had reduced whole-blood mutCALR variant allele frequency (VAF). 

Key learning: INCA033989 demonstrated a manageable safety profile with clinical, hematologic, and molecular activity, including anemia responses, across monotherapy and combination cohorts, supporting continued evaluation in mutCALR MF.