Paper Details

ABSTRACT

Background and significance: Essential thrombocythemia (ET) is a clonal hematopoietic stem cell disorder characterized by excessive platelet production, an increased risk for thrombotic and hemorrhagic complications, and disease progression to myelofibrosis (MF), myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML). About 30% of patients (pts) with ET exhibit calreticulin exon 9 frameshift mutations (mutCALR) as the oncogenic driver of their disease. In comparison with Janus kinase 2 (JAK2)-mutant ET, mutCALR-driven ET exhibits distinctive clinical features: higher platelet counts, increased bleeding risk, and lower thrombosis risk. In addition, pts with Type 1 mutCALR have a higher risk of transformation to MF.

INCA033989 is a first-in-class, mutCALR-specific, Fc-silenced, fully human recombinant monoclonal antibody that demonstrated a favorable safety profile and disease-modifying potential in 2 ongoing phase 1 studies (NCT06034002 and NCT05936359: 95% (108/114) of enrolled pts with ET continued INCA033989 treatment for a median duration of 8.1 months (range, 0.59?27.0 months) and 87% (99/114) obtained a Complete Hematologic Response (CHR: platelet count ≤400 × 10⁹/L and WBC count <10 × 10⁹/L) or a Partial Hematologic Response (PHR: platelet count ≤600 × 10⁹/L and WBC count <10 × 10⁹/L) with 70% (80/114) achieving a CHR. Median duration of CHR/PHR was 23 weeks (range, 0.14?107 weeks) with a median time to onset of durable CHR of 2.1 weeks (range, 1.1?68 weeks). Durable (≥12 weeks) responses were observed in pts with Type 1 mutCALR at ≥750 mg (CHR 81%; 21/26), and in non–Type 1 mutCALR at 2500 mg (CHR/PHR 50%; 3/6). Among 45 pts who achieved a durable CHR and had ≥1 postbaseline mutCALR variant allele frequency (VAF) assessment, 73% (33/45) achieved a ≥25% reduction in VAF. Analysis at Week 24 demonstrated a reduction of mutCALR megakaryocytes in the bone marrow and a decrease of mutCALR myeloid cells in peripheral blood mononuclear cells as further evidence for INCA033989´s disease-modifying capacity. These data support the initiation of a phase 3 trial evaluating safety and efficacy of INCA033989 in comparison to best available therapy (BAT).

Study design and methods: EXCALIBUR-ET2 (NCT07623200) is a global, multicenter, randomized, open-label phase 3 trial, enrolling adult pts with mutCALR-positive high-risk ET with a platelet count ≥450× 10?/L after inadequate response to ≥1 prior cytoreductive therapy. High-risk ET is defined as one of the following: age ≥60 years, platelet count >1500 × 10?/L, previous thrombosis (including transient ischemic attack), hemorrhage related to ET/acquired von Willebrand disease, erythromelalgia or ET-related migraine or concomitant diabetes or hypertension requiring pharmacological therapy. Key exclusion criteria include the presence of any hematologic malignancy other than ET, major bleeding or thrombosis within the last 3 months prior to enrollment, and prior allogeneic or autologous stem cell transplantation. The study will randomize approximately 426 pts 2:1 to INCA033989 treatment or BAT. BAT options include hydroxyurea, anagrelide, PEG interferon alfa-2a, and ropeginterferon alfa-2b. Stratification factors are the type of mutCALR, platelet count, and Total Symptom Score. Treatment in the experimental arm consists of infusions of INCA033989 given at a starting dose of 750 mg on Days 1 and 15 of each 28-day treatment cycle. INCA033989 dosage may be increased to 2500 mg if platelets remain above 400 × 109/L at the start of the second treatment cycle. Pts randomized to the BAT arm have the option to crossover to the INCA033989 treatment arm after Week 48. The primary endpoint is defined as durable clinicohematologic response (DCR) at Week 24. DCR is defined as a durable (≥12 weeks) reduction of platelet counts to ≤400 × 10?/L, the absence of WBC count ≥10 × 10?/L, as well as the absence of any major thrombotic or hemorrhagic events or disease progression to MF, MDS, or AML. Reduction of mutCALR VAF is evaluated as a secondary endpoint. The primary endpoint will be analyzed using stratified Cochran-Mantel-Haenszel test. The study is currently enrolling pts in ~180 investigational sites across 18 countries.