CONTEXT: Among patients with MF, approximately 25-35% of patients harbor calreticulin mutations (mutCALR). INCA033989 is a novel, fully human, Fc-silenced, IgG1 monoclonal antibody that selectively targets mutCALR complexed with thrombopoietin receptor, inhibiting oncogenic signaling and cell proliferation. INCA033989-101 (NCT05936359) and INCA033989-102 (NCT06034002) are phase 1 studies evaluating INCA033989 in MF or essential thrombocythemia.

OBJECTIVE: To evaluate safety and efficacy of INCA033989 monotherapy or combined with ruxolitinib (MF combo).

PATIENTS: Patients had MF with mutCALR and spleen volume (SV) ≥450 mL or palpable splenomegaly ≥5 cm. Monotherapy patients were relapsed/resistant/intolerant/ineligible for JAK inhibitor (JAKi) treatment. MF combo patients had received ruxolitinib ≥12 weeks with suboptimal response.

OUTCOMES: Endpoints were safety and tolerability (primary); SV reduction (≥25% [SVR25]; ≥35% [SVR35]); anemia response (Tefferi. Blood. 2024); MPN-SAF total symptom score (TSS); reduction in mutCALR variant allele frequency (VAF).

RESULTS: As of Jan 5, 2026, monotherapy doses were 24-3500mg. No DLTs were observed; MTD was not reached. Seventy patients were enrolled; 59%, 21%, and 20% harbored Type 1, Type 2, or other mutCALR, respectively. Treatment-emergent adverse events (TEAEs) occurred in 66 patients (94%); grade ≥3 TEAEs in 21 (30%) patients, most frequently anemia (9%) and neutropenia (7%). Seven patients (10%) had serious AEs. At week 24, 20/45 patients (44%) achieved SVR25; 14/45 (31%) SVR35; and 14/38 (37%) TSS50. Of 36 patients with anemia and ≥12 weeks’ treatment, 21 (58%) achieved anemia response. VAF reduction occurred in 51/56 (91%). In MF combo (n=20; median daily ruxolitinib 40mg), 60%, 35%, and 5% harbored Type 1, Type 2, and other mutCALR, respectively. All patients experienced TEAEs. Grade ≥3 TEAEs occurred in 13 (65%) patients, most commonly anemia (35%); 5 patients had serious AEs. At week 24, 10/16 patients (63%) achieved SVR25; 6/16 (38%) SVR35; and 4/13 (31%) TSS50. Of 16 patients with anemia and ≥12 weeks’ treatment, 5 (31%) achieved anemia response. VAF reduction occurred in 18 patients (95%).

CONCLUSIONS: INCA033989 alone or with ruxolitinib showed favorable safety in patients with MF relapsed/resistant/intolerant/ineligible for JAKi treatment, or suboptimal response to ruxolitinib. Robust spleen, symptom, and anemia responses were observed and correlated with mutCALR reduction.