Clinical Summary: 

• Design/Population: Two phase 1 studies evaluated INCA033989, a mutant CALR-targeted monoclonal antibody, in patients with high-risk CALR-mutant essential thrombocythemia who were resistant or intolerant to prior cytoreductive treatment and had persistent thrombocytosis.
• Key Outcomes: Most patients achieved complete or partial hematologic responses, with complete responses occurring rapidly and remaining durable. Higher doses produced particularly strong platelet control, and reductions in mutant CALR variant allele frequency correlated with durable complete hematologic response.
• Clinical Relevance: These findings provide early evidence that directly targeting mutant CALR may achieve both hematologic control and molecular responses in essential thrombocythemia, potentially offering a disease-directed strategy for patients with limited options after cytoreductive therapy.

Results from phase 1 studies demonstrated that INCA033989 produced rapid, durable hematologic responses and reductions in mutant CALR variant allele frequency among patients with CALR-mutant essential thrombocythemia who were resistant or intolerant to previous cytoreductive therapy.

These results were presented by Haris Ali, MD, City of Hope Medical Center, Duarte, California, at the Society of Hematological Oncology (SOHO) Annual Meeting in Houston, Texas. 

The INCA033989-101 and INCA033989-102 phase 1 studies enrolled 110 patients with high-risk CALR-mutant essential thrombocythemia and a platelet count above 450 G/L despite resistance or intolerance to prior cytoreductive treatment to receive INCA033989 doses ranging from 24 mg to 2500 mg. 

The primary end point was safety and tolerability. Efficacy assessments included complete hematologic response, defined as a platelet count of 400 G/L or less with a leukocyte count below 10 G/L, and partial hematologic response, defined as a platelet count of 600 G/L or less with a leukocyte count below 10 G/L. Changes in mutant CALR variant allele frequency (VAF) were also assessed.

Across all dose levels, 68% of patients achieved complete hematologic response and 85% achieved either complete hematologic response or partial hematologic response. Responses occurred rapidly, with a median time to durable complete hematologic response lasting at least 12 weeks of 2.1 weeks.

Greater platelet control was observed at doses of at least 750 mg. At approximately 24 weeks, all patients with type 1 CALR mutations treated at these dose levels achieved platelet counts below 600 G/L, compared with 47% of patients with non-type 1 mutations. Platelet counts below 400 G/L were achieved by 92% and 33% of these groups, respectively.

Hematologic responses were accompanied by molecular changes. A reduction of at least 25% in mutant CALR VAF was significantly associated with durable complete hematologic response (P < .0001). Among 38 patients with a durable complete hematologic response and evaluable post-baseline molecular assessments, 71% experienced a reduction in mutant CALR VAF of at least 25%.

Bone marrow assessments also demonstrated reduced megakaryocyte clustering between baseline and approximately 24 weeks. These changes correlated with reductions in mutant CALR VAF, further supporting a biological effect on the underlying mutant clone.

INCA033989 demonstrated a generally favorable safety profile. Treatment-emergent adverse events occurred in 85% of patients, with fatigue and headache reported most frequently. Grade ≥3 treatment-emergent adverse events occurred in 16% of patients.

Seven serious adverse events were reported among 3 patients. One venous thrombosis event in a patient receiving 24 mg led to treatment discontinuation, while one case of diverticulitis in a patient receiving 400 mg resulted in dose reduction. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached.

The findings suggest that selective inhibition of mutant CALR may provide more than conventional platelet control by directly targeting the disease-driving clone. The association between hematologic response, decreasing mutant CALR VAF, and changes in bone marrow megakaryocyte morphology supports further evaluation of INCA033989 as a potentially disease-modifying treatment for CALR-mutant essential thrombocythemia. 

Source: 

Ali H, Jain T, Gerds AT, et al. Mutant calreticulin-specific monoclonal antibody, INCA033989, is well tolerated and achieves rapid and sustained hematologic and molecular responses in patients with essential thrombocythemia. Presented at the SOHO Annual Meeting; September 9-12, 2026; Houston, Texas. Abstract MPN-481.