Sotatercept (ACE-011) Alone and in Combination with Ruxolitinib in Patients (pts) with Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis (MF) and Anemia

Introduction Anemia is common in MPN-associated MF and current treatment options are unsatisfactory. Furthermore, anemia is often worsened by ruxolitinib (rux), the only FDA-approved therapy for MF, frequently leading to premature discontinuation of rux/impairing dose optimization. Sotatercept is a first-in-class, activin receptor IIA ligand trap that improves anemia by sequestering TGF-β superfamily ligands, e.g., growth and differentiation factor 11 (GDF11), which suppress terminal erythroid differentiation. Early results from this phase 2 study (NCT01712308) were presented previously (Bose, ASH 2016). Here, we report updated results from the sotatercept monotherapy cohort and the first results from the rux/sotatercept combination cohort.

Methods Eligible pts are adults with primary, post-polycythemia vera (PPV) or post-essential thrombocythemia (PET) MF with hemoglobin (Hgb) <10 g/dL on every determination during the 84 days preceding study entry, Hgb <10 g/dL with sporadic RBC transfusions, or transfusion-dependent (TD) as defined by IWG-MRT 2013 criteria. Sotatercept is administered subcutaneously every 3 weeks at a dose of either 0.75 mg/kg or 1 mg/kg in the monotherapy cohort and 0.75 mg/kg in combination with rux. The overall response rate (ORR) is a composite of the rate of transfusion independence (TI), as defined by the IWG-MRT 2013 criteria, and Hgb response (increase from baseline of ≥1.5 g/dL on every determination consecutively over ≥12 weeks without RBC transfusions). Pts in the rux combination cohort must have been on rux for ≥6 months with a stable dose during the preceding ≥2 months.

Results To date, 33 pts have been treated, 24 in the monotherapy cohort and 9 in the rux combination cohort.

Monotherapy cohort : Of the 24 pts, 10 were female and 14 male, with a median age of 66.5 (47-83) years. Twenty had primary MF (PMF), 3 PET MF and 1 PPV MF. JAK2^V617F was detected in 16, MPL^W515L in 3, and CALR exon 9 indels in 3; 1 pt was "triple negative" and driver mutation status was unknown in 1. All were DIPSS intermediate (int)-2 (n=19) or high (n=5) risk. Bone marrow (BM) fibrosis grade was 3 in 15 pts, 2 in 8 pts and 1 in 1 pt. Five pts were previously untreated; 19 had received 1-5 prior therapies (median 1). Median time from diagnosis was 1.2 (0.2-5.8) years. Eleven pts received 0.75 mg/kg and 13, 1 mg/kg. Five pts remain on study and have received a median of 15 (2-29) cycles; 19 pts are off study (median no. of cycles 5, range 1-23). Reasons for discontinuation include: no response (7), SCT (3), patient decision (3), hypertension (1), progressive MF necessitating alternate therapy (3), transformation to AML (1), and unrelated medical complications (1). Six of 17 (35%, exact 95% CI: 14% - 62%) evaluable patients (on study for ≥84 days) responded. Two responses occurred at the 1 mg/kg dose, and 4 at 0.75 mg/kg. Hgb rose by ≥1.5 g/dL in 2 other pts who only received 2 cycles each and were, thus, not evaluable. Responses occurred in previously treated and treatment-naïve pts, across driver mutation types and in both RBC TD and -independent pts.

Rux combination cohort : Nine pts, 4 female and 5 male, with a median age of 67 (57-75) years have been treated. Six have PMF, 2 PPV MF and 1 MDS/MPN. One pt each had a MPL and a CALR mutation; the rest had JAK2^V617F. DIPSS risk was int-2 in 8 pts and int-1 in 1 pt. BM fibrosis grade was 3 in 5 pts, 2 in 3 pts and 1 in 1 pt. Median time from diagnosis was 1.9 (0.4-11) years, and pts had received 1-4 (median 2) prior therapies. The rux dose at study entry was 10 mg bid in 6 pts, 20 mg bid in 2 and 5 mg bid in 1. Six pts remain on study; 3 have come off for lack of response (1) or to move to SCT (2). One of 8 evaluable pts (12.5%, exact 95% CI: 0.3% - 52.7%) has responded thus far.

Sotatercept was very well tolerated. Two pts, 1 in each cohort, reported grade 2 bilateral lower limb pain possibly related to sotatercept. Hypertension was felt to be possibly related to sotatercept in 1 pt. A number of responders had to have the drug held on multiple occasions due to Hgb levels ≥11.5 g/dL and resumed upon their return to ≤11 g/dL, as defined in the protocol.

Conclusions As a single agent , sotatercept is effective in improving anemia in pts with MPN-associated MF. Efficacy is also possible in the setting of concurrent rux use, but more experience is required in this setting. Enrollment continues to both cohorts of this trial. A similarly designed trial (NCT03194542) of a closely related drug, luspatercept (ACE-536), will soon open to accrual.