Phase I trials: INCA033989 ± ruxolitinib for myelofibrosis

During the 67th American Society of Hematology (ASH) Annual Meeting and Exposition, December 6–9, 2025, Orlando, US, John Mascarenhas presented preliminary results from the global phase I INCA033989-101 (NCT05936359) and INCA033989-102 (NCT06034002) trials, investigating INCA033989, a monoclonal antibody targeting mutant calreticulin (CALR), as monotherapy (n = 52) or in combination with ruxolitinib (n = 20) in patients with CALR-mutated myelofibrosis (MF) who were intolerant or resistant to, or ineligible for Janus kinase inhibitor (JAKi) treatment. Primary endpoints were dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs).

Key data: INCA033989 monotherapy was well tolerated with no DLTs observed; Grade ≥3 TEAEs occurred in 30.8% of patients. Among evaluable patients at Week 24, 41.7% (n/N = 15/36) achieved ≥25% spleen volume reduction (SVR25), and 39.4% (n/N = 13/33) achieved ≥50% reduction in total symptom score (TSS50). A reduction in mutant CALR variant allele frequency (VAF) occurred in 89.4% of patients with ≥1 post-baseline VAF measurement. In the combination cohort, no DLTs were observed and Grade ≥3 TEAEs occurred in 55% of patients. Of evaluable patients, 50% (n/N = 6/12) achieved SVR25 and 33.3% (n/N = 3/9) achieved TSS50 at Week 24. 

Key learning: INCA033989 was well tolerated, both as monotherapy and in combination with ruxolitinib, in patients with CALR-mutated MF intolerant or resistant to, or ineligible for JAKi treatment. Reductions of mutant CALR VAF support the disease-modifying potential of INCA033989.