CONTEXT: ET is a myeloproliferative neoplasm associated with increased thrombotic risk, hemorrhage, and transformation to myelofibrosis. About 25% of patients harbor calreticulin mutations (mutCALR). INCA033989, a novel, fully human, Fc-silenced, IgG1 monoclonal antibody selectively targets mutCALR in complex with thrombopoietin receptor and inhibits oncogenic signaling and cell proliferation. INCA033989-101 (NCT05936359) and INCA033989-102 (NCT06034002) are phase 1 studies evaluating INCA033989 in patients with ET or myelofibrosis.

OBJECTIVE: To evaluate safety and efficacy of INCA033989 in patients with mutCALR ET.

PATIENTS: Eligible patients had high-risk ET harboring mutCALR, resistance/intolerance to prior cytoreductive treatment, and platelet count (PLT) >450 G/L.

OUTCOMES: The primary endpoint was safety/tolerability. Efficacy endpoints included hematologic response: PLT ≤400 G/L (complete hematologic response [CHR]) or ≤600 G/L (partial hematologic response [PHR]) with leukocyte count <10 G/L. Reduction in mutCALR variant allele frequency (VAF) was evaluated.

RESULTS: As of Jan 5, 2026, 110 patients were enrolled in dose escalation (24-2500mg) and expansion. No DLTs were observed; MTD was not reached. Median age was 61.5 years (23, 89); 60% were female. Treatment-emergent adverse events (TEAEs) occurred in 94 patients (85%); most frequently fatigue (24%) and headache (20%). Grade ≥3 TEAEs occurred in 18 patients (16%). Seven serious AEs occurred in 3 patients; 1 venous thrombosis event (24mg) led to discontinuation; 1 diverticulitis event (400mg) led to dose reduction. Across all doses, 75 (68%) patients achieved CHR and 93 (85%) achieved CHR/PHR, with median duration of 15 (0.14, 95) weeks. Median time to durable (≥12 weeks) CHR was 2.1 (1.1, 64) weeks. At C7D1 (~24 weeks), doses ≥750mg resulted in PLT <600 G/L in 100% of Type 1 and 47% of non-Type 1 patients, and PLT <400 G/L in 92% and 33%, respectively. A ≥25% VAF reduction correlated with durable CHR (P<0.0001); among 38 patients with durable CHR and post-baseline VAF assessment, 71% achieved ≥25% VAF reduction. Bone marrow analysis showed reduced megakaryocyte clustering from baseline to C7D1, correlating with a ≥25% VAF reduction (P=0.02).

CONCLUSIONS: INCA033989 demonstrated favorable safety and efficacy in patients with mutCALR ET resistant/intolerant to cytoreductive treatment. Most patients achieved rapid, durable CHR correlating with decreased mutCALR VAF.