Dr Mascarenhas on CALR-Directed Agents and Investigational Targeted Therapies in MPNs

We might see an era of molecularly defined treatment approaches that drive the treatment paradigm, because right now, it’s really one-size-fits-all with a type I JAK inhibitor for most patients, but I do see that changing.

John O. Mascarenhas, MD, a professor of Medicine at the Icahn School of Medicine, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and a member of The Tisch Cancer Institute at Mount Sinai, discussed the ongoing investigation of targeted therapies for patients with myeloproliferative neoplasms (MPNs), including agents targeting CALR mutations.

At the 2025 ASH Annual Meeting and Exposition, Mascarenhas and colleagues presented findings from the phase 1 INCA033989-101 (NCT05936359) and INCA033989-102 (NCT06034002) trials, which evaluated INCA033989 in patients with CALR exon 9–mutated myelofibrosis who were resistant or intolerant to prior JAK inhibitor therapy, or were ineligible for JAK inhibitor therapy. Findings showed that in patients treated with INCA033989 alone (n = 52), no dose-limiting toxicities were reported. Additionally, no DLTs were observed with the addition of INCA033989 to ruxolitinib (Jakafi; n = 20).

As monotherapy (n = 36), 41.7% of patients treated with INCA033989 achieved a spleen volume reduction of at least 25% (SVR25) at week 24, and 33.3% of patients had an SVR of at least 35% (SVR35) at week 24. For evaluable patients treated with INCA033989 plus ruxolitinib (n = 12), the SVR25 and SVR35 rates at week 24 were 50% and 25%, respectively.

Within the MPN space, targeted approaches have garnered recent attention, Mascarenhas explained. Regarding approaches targeting CALR mutations, Mascarenhas explained that these alterations are aberrantly expressed on the surfaces of MPN cells in the context of the thrombopoietin receptor, fueling the rationale for developing targeted agents such as the monoclonal antibody INCA033989 and bispecific T-cell engagers.

He explained that preliminary dose-escalation data for INCA033989 appear promising, with the agent displaying tolerability both as a single agent and in combination with ruxolitinib. These approaches also yielded on-target activity, rapid normalization of platelet counts in patients with essential thrombocythemia, and improvements in spleen, symptoms, and anemia in patients with myelofibrosis.

Mascarenhas said he expects therapies targeting CALR mutations to continue to evolve, although questions still remain regarding optimal scheduling and administration for these targeted therapies. Along with CALR-targeted approaches, other investigational approaches using novel JAK inhibitors are poised to help push the MPN treatment paradigm to more molecularly driven approaches, Mascarenhas concluded.

This video was supported in part by Incyte. Content independently developed and published by OncLive.