Paper Details

ABSTRACT

Background: Myelofibrosis (MF) is characterized by progressive deterioration of bone marrow (BM) function resulting in cytopenias, splenomegaly, and debilitating symptoms. Frameshift mutations in exon 9 of calreticulin (mutCALR) are present in 25-35% of cases. INCA033989 (989) is a novel, fully human, Fc-silenced, IgG1 monoclonal antibody that specifically targets mutCALR and inhibits oncogenic signaling. The phase 1 studies INCA033989-101 (NCT05936359) and -102 (NCT06034002) are evaluating 989 in patients (pts) with MF or essential thrombocythemia (ET). The efficacy of 989 as monotherapy (mono) or combined with ruxolitinib (rux) in pts with MF relapsed/refractory/intolerant (R/R/I) or with suboptimal responses to JAK inhibitor treatment (JAKi tx) is reported.

Methods: Enrolled pts had primary or post-ET MF with mutCALR and spleen volume (SV) of ≥450 mL or palpable splenomegaly ≥5 cm below the costal margin. 989 mono was studied in pts R/R/I to JAKi tx after ≥12 weeks. 989 added to rux was studied in pts with suboptimal response to rux after ≥12 weeks. Efficacy, including SV reduction (≥25% [SVR25], ≥35% [SVR35]), hemoglobin (Hb) or anemia response (Tefferi, Blood. 2024), MPN-SAF total symptom score (TSS), and reduction in mutCALR variant allele frequency (VAF), are reported for pts with postbaseline assessments or who discontinued treatment.

Results: The median (range) 989 exposure in the R/R/I (mono) cohort (n=65) was 38 (8,137) weeks. As best response, SVR25 and SVR35 were observed in 52% (28/54) and 35% (19/54) of pts, respectively, and 52% (31/60) achieved TSS50. At week 24, SVR25, SVR35, and TSS50 were 34% (16/47), 21% (10/47), and 34% (15/44), respectively. Of the 60% of pts who were anemic at baseline, 69% (22/32) of evaluable pts had an anemia response (19 major, 3 minor). Of evaluable non-anemic pts, 50% (12/24) had an increase in Hb ≥1g/dL.

In the suboptimal cohort (989 added to rux, n=22), median (range) exposure was 48 (4, 94) weeks. As best response, 76% (16/21) and 57% (12/21) achieved SVR25 and SVR35, respectively, and 68% (13/19) achieved TSS50. At week 24, SVR25, SVR35, and TSS50 were 52% (11/21), 29% (6/21), and 29% (5/17), respectively. Of the 82% pts anemic at baseline, 53% (9/17) of evaluable pts had an anemia response (5 major, 4 minor). Of evaluable non-anemic pts, 25% (1/4) had an increase in Hb ≥1.0 g/dL.

Among R/R/I pts with available peripheral blast data, 35% (12/34) had blast counts of >1% at baseline; of these, 17% (2/12) were >1% at C7D1. For evaluable R/R/I pts, 89% (58/65) had lactate dehydrogenase (LDH) >300 U/L at baseline (median [range], 691 [309, 2252]); 66% (38/58) of those decreased to ≤300 U/L (median [range], 231 [129, 1752]) at last assessment. In the suboptimal group, 46% (6/13) of pts had peripheral blasts counts >1% at baseline; of these, 50% (3/6) were >1% at C7D1. For evaluable suboptimal pts, 100% (22/22) had LDH >300 U/L at baseline (median [range], 1098 [409, 5412]); 32% (7/22) of those decreased to ≤300 U/L (median [range], 403 [148, 1989]) by last assessment.

Digital pathology assessment of BM fibrosis (Ground Truth) in evaluable pts showed an improvement in 69% (22/32) of pts, with a ~22% per pt average relative reduction of fibrosis score (Ryou, Leukemia. 2023). Single cell analysis of peripheral blood mononuclear cells (n=26) revealed reduction of mutCALR CD34⁺/CD38⁺/TPOR⁺ cells posttreatment, with 73% reaching ≤1% at C7D1 vs 39% ≤1% at baseline. A best decrease in whole blood VAF of >10% was observed in 57% (mono) and 25% (suboptimal group) of pts.

To evaluate simultaneous response to multiple disease outcomes, best SVR was measured together with blasts with an average ≤1%; Hb with average ≥10 g/dL and PLT with an average ≥75 G/L across all postbaseline assessments. In evaluable pts, 77% (20/26) with SVR25 also achieved blast, Hb, and PLT responses.