INCA033989 Is Safe and Produces Spleen, Symptom, Anemia, and Molecular Responses in CALR-Mutated Myelofibrosis

INCA033989, a novel mutant calreticulin (mutCALR)–targeted monoclonal antibody, was deemed well tolerated by investigators and demonstrated rapid and durable spleen, symptom, anemia, and molecular responses both as monotherapy and in combination with ruxolitinib (Jakafi) in patients with myelofibrosis harboring a CALR exon 9 mutation, according to data from the phase 1 INCA033989-101 (NCT05936359) and INCA033989-102 (NCT06034002) studies presented at the 2026 EHA Congress.¹

Among safety-evaluable patients in the monotherapy arm (n = 83), any treatment-emergent adverse effects (TEAEs) were reported in 91.6%, with 57.8% of patients experiencing TEAEs that were considered treatment related. Grade 3 or higher TEAEs occurred in 26.5% of patients, and serious TEAEs were reported in 8.4% of patients; no fatal TEAEs were reported. Discontinuation due to TEAEs occurred in 2.4% of patients, and dose reduction due to TEAEs was also reported in 2.4% of patients. Infusion interruption occurred in 6.0% of patients, and dose delay was reported in 20.5% of patients.

In the monotherapy arm, at a data cutoff of March 6, 2026, 55% of evaluable patients (n = 38/69) achieved a best spleen volume reduction (SVR) of at least 25% (SVR25), and 39% of patients (n = 27/69) achieved a best SVR of at least 35% (SVR35). Among evaluable anemic patients (n = 40), 60% experienced an anemia response, most of whom achieved a major response. Additionally, 53% of patients in the monotherapy arm achieved a 50% or greater reduction in total symptom score (TSS50) as a best response. mutCALR variant allele frequency (VAF) was reduced in 89% of patients (type 1 myelofibrosis population, n = 35/39; non-type 1 population, n = 23/26), and 40% of patients had improved bone marrow fibrosis grade by cycle 7 day 1.

All safety-evaluable patients in the combination arm (n = 21) experienced at least 1 TEAE; treatment-related TEAEs were seen in 66.7% of patients, grade 3 or higher TEAEs occurred in 66.7% of patients, serious TEAEs were seen in 28.6% of patients, and no fatal TEAEs were reported. Discontinuation of INCA033989 due to TEAEs occurred in 14.3% of patients. TEAE-associated dose reductions of INCA033989 (9.5%), infusion interruptions (4.8%), and dose delays of INCA033989 (42.9%) were also reported.

At week 24, patients in the combination arm achieved an SVR25 of 55% (n = 11/20), an SVR35 of 30% (n = 6/20), a TSS50 of 31% (n = 5/16), and an anemia response rate of 35% (n = 6/17).

“INCA033989 administered as monotherapy or in combination [with ruxolitinib] continues to show a highly favorable safety profile in patients with myelofibrosis who are relapsed/refractory [to], intolerant to, or ineligible for JAK inhibitor therapy,” Claire Harrison, MD, stated in a presentation of the data. “There were no dose-limiting toxicities, the maximum tolerated dose was not reached, and there were no new emergent safety signals.”

Harrison is a professor of myeloproliferative neoplasms and a clinical director at Guy’s and St Thomas’ NHS Foundation Trust in London, United Kingdom.

What is the rationale for targeting mutCALR in myelofibrosis?

Mutations in exon 9 of calreticulin are found in approximately 25% to 35% of patients with myelofibrosis, with approximately 71.9% classified as type 1.^2,3 Patients with myelofibrosis harboring mutCALR have distinct clinical and biological features and experience inferior responses to current therapies, including lower symptom and spleen responses and higher anemia rates, compared with ruxolitinib-treated patients with JAK2 V617F–mutated disease, according to Harrison.¹ Current myelofibrosis treatments are not targeted toward mutations and therefore, their efficacy at reducing mutCALR VAF is limited. Additionally, JAK inhibitors manage clinical features of the disease with limited effect on the stem and progenitor cells that initiate and sustain the disease.

INCA033989 is a novel, fully human, high-affinity, Fc-silenced IgG1 monoclonal antibody that selectively targets mutCALR in complex with the thrombopoietin receptor, inhibiting oncogenic signaling and cell proliferation.

What were the enrollment criteria for the INCA033989 phase 1 studies?

The myelofibrosis dose-escalation portions of the 2 parallel phase 1, first-in-human, multicenter, open-label studies (INCA033989-101, outside the US; INCA033989-102, US only) enrolled patients at least 18 years of age with primary or post-essential thrombocythemia myelofibrosis harboring a CALR exon 9 mutation and a spleen volume per imaging of at least 450 mL or palpable splenomegaly of at least 5 cm. For the monotherapy arm, patients were required to be intolerant, resistant after at least 12 weeks, or ineligible for JAK inhibitor treatment. For the combination arm, patients needed to have received prior ruxolitinib treatment for at least 12 weeks with a suboptimal response. INCA033989 was administered intravenously every 2 weeks at doses ranging from 24 mg to 3500 mg (monotherapy arm) or 70 mg to 2500 mg (combination arm). The dose-expansion phase evaluated the agent at doses of 250 mg and 2000 mg.

In the monotherapy arm, the JAK inhibitor–relapsed/refractory/intolerant cohort (n = 62) had a median age of 60 years (range, 38.0-81.0) and a median time from diagnosis of 6.6 years (range, 0.1-26.2); the JAK inhibitor–ineligible cohort (n = 21) had a median age of 64 years (range, 34.0-82.0). The median spleen volumes were 1396 mL (range, 226-5060) and 1225 mL (range, 450-3970), respectively. The median mutCALR VAFs were 37% (range, 30%-73%) and 36% (range, 24%-53%), respectively. CALR type 1 mutations were present in 59.7% of the JAK inhibitor–relapsed/refractory/intolerant cohort and 52.4% of JAK inhibitor–ineligible cohort.

In the combination arm (n = 21), the median age was 61 years (range, 38-82), the median spleen volume was 2376 mL (range, 848-5338), and the median baseline ruxolitinib daily dose was 40 mg (range, 10-50).

What additional spleen and symptom responses have been observed with INCA033989 in myelofibrosis?

In the monotherapy arm, at week 24, SVR25 was achieved in 39% of evaluable patients (n = 24/62), and SVR35 was achieved in 27% of evaluable patients (n = 17/62). Among JAK inhibitor–ineligible patients, SVR35 at week 24 was achieved in 60% of patients with type 1 disease (n = 6/10) and 29% of those with non–type 1 disease (n = 2/7). Among JAK inhibitor–relapsed/refractory/intolerant patients, SVR35 at week 24 was achieved in 31% of patients with type 1 (n = 8/26) and 5% of those with non-type 1 (n = 1/19) disease. Notably, baseline spleen imaging was performed without JAK inhibitor washout in 61% of patients in the JAK inhibitor–relapsed/refractory/intolerant cohort.

Among evaluable patients in the monotherapy arm, at week 24, TSS50 was achieved in 32%, with rates of 29% in JAK inhibitor–ineligible patients with all disease types (n = 4/14), 44% in patients with JAK inhibitor–ineligible type 1 disease (n = 10/23), 33% in those with all types of JAK inhibitor–relapsed/refractory/intolerant disease (n = 14/42), and 44% in those with JAK inhibitor–relapsed/refractory/intolerant type 1 disease (n = 10/23).

What anemia and molecular responses did INCA033989 produce in patients with myelofibrosis?

In the monotherapy arm, improvement in anemia was observed in 63% (n = 31/49) of patients with JAK inhibitor–relapsed/refractory/intolerant disease and 55% (11/20) of JAK inhibitor–ineligible patients. Mean hemoglobin levels improved progressively over time across both anemic and non-anemic subgroups in both the JAK inhibitor–relapsed/refractory/intolerant and JAK inhibitor–ineligible populations.

Among patients evaluable for peripheral blood mononuclear cell (PBMC) analysis, 81% (n = 21/26) had at least a 25% reduction in mutCALR PBMCs, with 62% (n = 13/21) harboring type 1 and 38% (n = 8/21) non–type 1 mutCALR. A molecular response of at least 25% VAF reduction was achieved as a best molecular response in 12.3% of patients. Peripheral blast reductions and reductions in mutCALR hematopoietic stem and progenitor cells were observed across both type 1 and non–type 1 populations.

What were the additional safety findings with INCA033989 in myelofibrosis?

In the monotherapy arm, the most common TEAEs (occurring in ≥ 15% of patients) were thrombocytopenia (any-grade, 30.1%; grade ≥ 3, 6.0%), anemia (28.9%; 7.2%), arthralgia (25.3%; 0%), fatigue (20.5%; 0%), headache (20.5%; 0%), neutropenia (20.5%; 6.0%), cough (16.9%; 0%), diarrhea (15.7%; 0%), leukopenia (15.7%; 6.0%), nausea (15.7%; 0%), and pruritus (15.7%; 0%). Grade 3 or higher cytopenias typically occurred in patients with pre-existing cytopenias. No dose relationship with TEAEs was observed.

In the combination arm, the most common TEAEs (occurring in ≥ 15% of patients) were thrombocytopenia (any-grade, 42.9%; grade ≥ 3, 9.5%), anemia (38.1%; 33.3%), diarrhea (23.8%; 0%), fatigue (23.8%; 0%), increased alanine aminotransferase levels (19.0%; 4.8%), and increased aspartate aminotransferase levels (19.0%; 0%).

Overall, 84% of patients in the monotherapy arm and 76% of those in the combination arm remained on study treatment at the time of data cutoff.

“These data support the disease modification potential of this agent and initiation of a phase 3 program in patients with myelofibrosis,” Harrison concluded.

The findings from these 2 phase 1 trials add to a growing body of EHA 2026 evidence in the myelofibrosis setting, which has also shown that the first-in-class type II JAK2 inhibitor AJ1-11095 produced SVR35 in 70% of patients with post–type I JAK inhibitor myelofibrosis in the phase 1 AJX-101 trial (NCT06343805) trial, and that luspatercept-aamt (Reblozyl) produced clinically meaningful anemia improvements in patients with myelofibrosis-associated anemia in the phase 3 INDEPENDENCE trial (NCT04717414), though the primary end point for statistical significance was missed.^4,5

Disclosures: Harrison reported receiving consulting fees from Keros, Novartis, Syntara, and Takeda; receiving research funding from Novartis GSK Constellation; and receiving honoraria from AOP, Bristol-Myers Squibb, DISC, Galecto, GSK, Incyte, Johnson & Johnson, Kartos, Karyopharm, Keros, Novartis, Pharma&, Silence, Sobi, Syntara, and Takeda.

References

1. Harrison C, Gupta V, Al-Ali HK, et al. Mutant calreticulin–specific monoclonal antibody, INCA033989, is well tolerated and achieves robust spleen, anemia, and molecular responses in patients with myelofibrosis. Presented at: 2026 EHA Congress; June 11–14, 2026; Stockholm, Sweden. Abstract S216.
2. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-90. doi:10.1056/NEJMoa1311347
3. Guglielmelli P, Maccari C, Sordi B, et al. Phenotypic correlations of CALR mutation variant allele frequency in patients with myelofibrosis. Blood Cancer J. 2023;13(1):21. doi:10.1038/s41408-023-00786-x
4. Wahner A. AJ1-11095 shows spleen responses and symptom improvement in post–type I JAK inhibitor myelofibrosis. OncLive.com. June 13, 2026. Accessed June 13, 2026. https://www.onclive.com/view/aj1-11095-shows-spleen-responses-and-symptom-improvement-in-post-type-i-jak-inhibitor-myelofibrosis
5. OncLive Staff. Luspatercept misses primary RBC-TI end point but shows clinically meaningful improvement for anemia in myelofibrosis. OncLive.com. June 13, 2026. Accessed June 13, 2026. https://www.onclive.com/view/luspatercept-misses-primary-rbc-ti-end-point-but-shows-clinically-meaningful-improvement-for-anemia-in-myelofibrosis