Encouraging results for new mutation-specific targeted therapy in CALR-mutated ET

The experimental agent INCA33989 delivered swift and sustained haematologic responses in patients with essential thrombocythemia (ET). This mutation-specific targeted therapy was not associated with dose-limiting toxicities, supporting further investigation in a clinical trial programme.

“Mutations of calreticulin [CALR] in exon 9 are found in approximately 25% of the patients with ET,” outlined Prof. John Mascarenhas (Mount Sinai, NY, USA) [1]. “Current treatment options for these patients are directed at controlling blood counts, preventing vascular complications, and improving symptoms, but are limited by toxicity or poor activity since they are not targeted at driver mutations.” INCA33989 is a mutation-specific targeted therapy for patients with CALR mutations. The INCA33989-101 and -102 trials are phase 1 studies that evaluated this agent in patients with CALR-mutated high-risk ET. The studies enrolled 49 patients, who were exposed to doses ranging from 24 mg to 2,500 mg, intravenously administered, every 2 weeks [2].

“We did not see any dose-limiting toxicities,” stated Prof. Mascarenhas. There were 3 serious treatment-emergent adverse events (AEs): a case of asymptomatic lipase increase, a case of visceral venous thrombosis, and a case of diverticulitis. “The most frequently observed grade ≥3 AE was transient, asymptomatic lipase increase (6.1%), but this event had no correlation to dose,” said Prof. Mascarenhas.

Of the participants who received at least 400 mg (n=22), 86% had a response, and 82% achieved a complete response, defined as a platelet count <400x10⁹/L and leukocytes <10x10⁹/L. Importantly, a reduction in mutated CALR variant allele frequency (VAF) was reported in 89% of the participants; 47% achieved >20% reduction in VAF and 21% achieved >50% reduction in VAF.

“These findings support the potential of the mutation-specific targeted therapy INCA33989 in patients with CALR-mutated ET,” decided Prof. Mascarenhas. “It was associated with durable haematologic responses in the study population and may modify the disease.”

1. Guglielmelli P, et al. Blood. 2024;1310-1314.
2. Mascarenhas J, et al. INCA33989 is a novel, first-in-class, mutant calreticulin-specific monoclonal antibody that demonstrates safety and efficacy in patients with essential thrombocythemia (ET). LB4002, EHA2025 Congress, 12–15 June, Milan, Italy.

Medical writing support was provided by Robert van den Heuvel.
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Posted on 17 June 2025