Background: Mutations in exon 9 of calreticulin (mutCALR) are found in ~30% of pts with MF. INCA033989 (‘989‘), a novel, fully human, Fc-silenced, IgG1 monoclonal antibody, selectively inhibits oncogenic signaling and proliferation of cells expressing mutCALR and thrombopoietin receptor. INCA033989-101 (NCT05936359) and -102 (NCT06034002) are studies evaluating 989 in pts with MF or essential thrombocythemia (ET) expressing mutCALR. Dose escalation data from pts with MF receiving 989 monotherapy (MF mono) or in combination with ruxolitinib (rux; MF combo) are presented.

Methods: Pts had primary/post-ET MF and a pathogenic CALR mutation. Pts in MF mono were intolerant to JAK inhibitor (JAKi) treatment (tx) or resistant after ≥12 wks (n=35) or were ineligible for JAKi tx (n=12). Pts in MF combo had prior rux tx for ≥12 wks, a suboptimal spleen response, and received 989 with ongoing rux. Pts received 989 (24-2500 mg) intravenously every 2 wks. The primary endpoint was safety and tolerability. Efficacy assessments included spleen volume reduction ≥25% (SVR25) and ≥35% (SVR35); anemia response (Tefferi A. Blood. 2024;114:1813); change in MPN-SAF total symptom score (TSS); mutCALR variant allele frequency (VAF) reduction.

Results: As of May 8, 2025, 47 pts were treated in MF mono. Median (range) exposure was 28 wks (0.4, 85); 85% of pts continued on tx. Median (range) age was 60 y (34, 76); 66% of pts were male. Median (range) baseline mutCALR VAF was 36% (31, 53); spleen volume was 1229 mL (257, 3970); hemoglobin (Hb) was 100 g/L (70, 143); MPN-SAF TSS was 23 (0, 65). No dose-limiting toxicities (DLTs) were observed; maximum tolerated dose (MTD) was not reached. Two pts discontinued due to adverse events (AEs) (mantle cell lymphoma [MCL; 400 mg]; neutropenia [750 mg]). Forty-three pts (91%) had tx-emergent AEs (TEAEs) of any grade, most commonly anemia (34%; 9% Gr ≥3), fatigue (28%; 0% Gr ≥3), and thrombocytopenia (26%; 6% Gr ≥3). In total, 16 (34%) had a Gr ≥3 TEAE, most commonly neutropenia (11%); 29 (62%) had tx-related AEs (TRAEs), most commonly leukopenia (19%). Three pts had serious TEAEs (abdominal pain and tendonitis [70 mg; tendonitis was tx-related]; MCL and small intestinal obstruction [400 mg]; arthritis [1500 mg]). Two pts (50 and 750 mg) had dose reductions and 2 (70 and 400 mg) had infusion interruptions due to TEAEs. At 24 wks, 10/27 pts (37%) had SVR25, including 8/27 (30%) with SVR35. Anemia responses occurred in 12/22 pts (55%); 9 (41%) responses were major (1/4 pts with baseline transfusion-dependent anemia [TDA]; 8/18 with non-TDA); 3 (14%) were minor (1/4 pts with TDA; 2/18 with non-TDA). Mean (SD) MPN-SAF TSS change from baseline was –6 (7.9) at 12 wks (n=38); –4.7 (8.5) at 24 wks (n=24). Most pts (31/39; 79%) had a postbaseline mutCALR VAF reduction; 5 (13%) had ≥20% reduction. Exploratory single cell analyses showed rapid reductions of mutCALR+ hematopoietic stem/progenitor cell fractions, confirming impact on target cells.

In MF combo, 14 pts were treated. Median (range) exposure was 19 wks (4, 40); 93% of pts continued on tx. Median (range) age was 62 y (51, 82); 71% of pts were male. Median (range) baseline mutCALR VAF was 37% (30, 50); spleen volume was 1853 mL (848, 3533); Hb was 92 g/L (72, 118); MPN-SAF TSS was 17 (6, 56). No DLTs were observed; MTD was not reached and only 1 pt discontinued (AE of diffuse large B-cell lymphoma [DLBCL]; 70 mg). Twelve pts (86%) had any grade TEAEs, most commonly anemia (36%; 21% Gr ≥3) and thrombocytopenia (36%; 7% Gr ≥3). In total, 7 pts (50%) had Gr ≥3 TEAEs, most commonly anemia; 8 (57%) had TRAEs, most commonly thrombocytopenia (21%). Two pts had serious TEAEs considered unrelated to tx (DLBCL [70 mg]; stomatitis [750 mg]). At 24 wks, 2/4 pts (50%) had SVR25, including 1/4 (25%) with SVR35; 1/8 pts (13%) had a major anemia response (non-TDA). Mean (SD) MPN-SAF TSS change from baseline was –12 (20.2) at 12 wks (n=7); –12.3 (15.4) at 24 wks (n=3). Most pts (6/8; 75%) had a postbaseline mutCALR VAF reduction; 1 (13%) had ≥20% reduction.Conclusions: As monotherapy in pts with MF intolerant, resistant or ineligible for JAKi tx, and in combination with rux, 989 was well-tolerated with no DLTs and few tx discontinuations. Promising spleen and anemia responses and symptom improvements occurred in both cohorts despite advanced disease and limited follow-up. VAF reductions and single cell analyses further support the potential disease-modifying impact of 989.

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2025
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