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INCA033989 given with or without ruxolitinib was well tolerated and yielded spleen and anemia responses in myelofibrosis with CALR exon 9 mutations
Treatment with INCA033989 as monotherapy or in combination with ruxolitinib (Jakafi) was well tolerated and led to spleen and anemia responses 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, according to data from the phase 1 INCA033989-101 (NCT05936359) and INCA033989-102 (NCT06034002) trials.1
Findings presented at the 2025 ASH Annual Meeting and Exposition demonstrated that no dose-limiting toxicities (DLTs) were reported in patients treated with INCA033989 monotherapy (n = 52). Treatment-emergent adverse effects (TEAEs) of any grade occurred in 96.2% of patients, including 57.7% who had any-grade treatment-related AEs (TRAEs), 30.8% who had grade 3 or higher TEAEs, and 9.6% who had serious TEAEs. TEAEs led to treatment discontinuation and dose reductions in 3.8% of patients each, infusion interruption in 5.8% of patients, and dose delays in 23.1% of patients.
In patients treated with INCA033989 plus ruxolitinib (n = 20), all had any-grade TEAEs, including 65.0% with any-grade TRAEs, 55.0% with grade 3 or higher TEAEs, and 25.0% with serious TEAEs. No DLTs were reported with the combination. TEAEs led to treatment discontinuation in 10.0% of patients, dose reductions in 5.0% of patients, infusion interruption in 5.0% of patients, and dose delays in 40.0% of patients.
Regarding efficacy, INCA033989 monotherapy (n = 36) yielded a spleen volume reduction of at least 25% (SVR25) at week 24 in 41.7% of patients and an SVR of at least 35% (SVR35) at week 24 in 33.3% of patients. Best SVR was 47.9% for SVR25 and 31.3% for SVR35. In patients without any prior JAK inhibitor exposure (n = 7), the 24-week SVR25 and SVR35 rates were 71.4% and 57.1%, respectively. In patients who were relapsed/refractory or intolerant to a JAK inhibitor (n = 29), these respective rates were 34.5% and 27.6%.
For patients treated with the combination, evaluable patients at week 24 (n = 12) experienced SVR25 and SVR35 rates of 50% and 25%, respectively. A best SVR of SVR25 occurred in 11 total patients; SVR35 was reported in 8 patients.
“INCA033989 is really well tolerated both as monotherapy and in combination with ruxolitinib,” lead study author John O. Mascarenhas, MD, said in a presentation of the data. “We saw rapid spleen and anemia responses in both cohorts.”
Mascarenhas is a professor of medicine at the Icahn School of Medicine at Mount Sinai in New York, New York, where he also serves as director of the Center of Excellence for Blood Cancers and Myeloid Disorders. He is also a member of The Tisch Cancer Institute, where he is director of the Adult Leukemia Program and leader of clinical investigation in the Myeloproliferative Disorders Program.
Mascarenhas reported that approximately 25% to 35% of patients with myelofibrosis harbor CALR exon 9 mutations, and higher CALR variant allele frequency (VAF) has been associated with more advanced disease featuring anemia and elevated peripheral blasts.
INCA033989—a novel, fully human, high-affinity, Fc-silenced, immunoglobulin G1 monoclonal antibody—is a therapy designed to target CALR exon 9 mutations through selective targeting in complex with the thrombopoietin receptor.
INCA033989-101 is being conducted outside the United States (US), while INCA033989-102 is including US patients specifically. Both studies are enrolling patients at least 18 years of age with primary or post–essential thrombocythemia myelofibrosis harboring CALR exon 9 mutations.1-3
Patients need to have a spleen volume of at least 450 mL or palpable splenomegaly of at least 5 cm.1 To be included in the monotherapy arm, patients need to be intolerant to a JAK inhibitor, resistant to a JAK inhibitor for at least 12 weeks, or ineligible for a JAK inhibitor. Those in the combination arm needed to have a suboptimal response to ruxolitinib given for at least 12 weeks of prior treatment.
During dose escalation, patients in both arms received INCA033989 at 24 mg to 2500 mg intravenously once every 2 weeks. The dose-expansion portion of the study includes monotherapy and combination arms, along with a randomized portion where JAK inhibitor–naive patients are being randomly assigned to INCA033989 with or without ruxolitinib.
The primary end points of dose escalation are evaluating the incidence of DLTs and TEAEs. Secondary end points comprised SVR25 and SVR35 at weeks 12 and 24; anemia response; symptom improvement; and change in CALR exon 9 VAF.
In the monotherapy and combination arms, the median age was 59.5 years (range, 34-76) and 61.0 years (range, 38-82), respectively. The rates of female patients were 32.7% and 20.0%, respectively, and patients had respective median times from initial diagnosis of 7.4 years (range, 0-25.3) and 3.1 years (range, 0.4-16.4). CALR exon 9 mutation type included type 1 (monotherapy arm, 57.7%; combination arm, 60.0%), type 2 (21.2%; 35.0%), and other (21.2%; 5.0%). The median CALR VAF was 36% (range, 24%-53%) in the monotherapy arm and 39% (range, 30%-85%) in the combination arm.
In the monotherapy arm, 93.3% of evaluable patients (n = 45) experienced symptom improvements, and 60.0% achieved at least a 50% reduction in total symptom score (TSS50).
For those evaluable for anemia response (n = 25), best responses comprised major response (40.0%), minor response (16.0%), stable anemia (32.0%), progressive anemia (8.0%), and missing (4.0%). In patients with transfusion-dependent anemia, best responses were major response (20.0%), minor response (40.0%), stable anemia (20.0%), and progressive anemia (20.0%). Those without transfusion-dependent anemia (n = 20) had best anemia responses of major response (45.0%), minor response (10.0%), stable anemia (35.0%), progressive anemia (5.0%), and missing (5.0%).
Notably, a reduction of CALR exon 9 mutation VAF occurred in 89.4% of evaluable patients in the monotherapy arm (n = 47), and 10.6% of patients achieved a best reduction of at least 25%.
In the combination arm, 81.3% of patients (n = 16) experienced symptom improvements, and 33.3% (n = 9) achieved TSS50 at week 24. In evaluable patients (n = 14), 86% had stable anemia during the study, and 1 patient had a major anemia response.
In the INCA033989 monotherapy group, the most common any-grade TEAEs reported in at least 15% of patients included anemia (30.8%), fatigue (26.9%), thrombocytopenia (25.0%), arthralgia (21.2%), increased aspartate aminotransferase (AST; 21.2%), cough (21.2%), diarrhea (21.2%), headache (21.2%), leukopenia (21.2%), nausea (21.2%), pruritus (21.2%), hyperglycemia (19.2%), neutropenia (19.2%), nasal congestion (15.4%), and extremity pain (15.4%).
In the combination arm, the most frequent TEAEs of any grade that occurred in at least 15% of patients consisted of anemia (45.0%), thrombocytopenia (35.0%), increased alanine aminotransferase levels (20.0%), diarrhea (20.0%), fatigue (20.0%), increased AST (15.0%), and cough (15.0%).
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