The combination of BMS-986158, a potent BET (bromodomain and extra-terminal) inhibitor, and JAK inhibitors ruxolitinib or fedratinib yielded robust sustained viral response (SVR) and deepened responses following continued treatment in patients with intermediate to high-risk myelofibrosis (MF), according to findings from a phase 1/2 dose escalation study. 

At the 2022 ASH Annual Meeting and Exposition in New Orleans, Louisiana, Rosa Ayala, Complutense University, CIBERONC, Madrid, Spain, presented this data from the phase 1a/b study. 

“Bromodomain and extra-terminal proteins play a role in cancer-cell proliferation, survival, and oncogenic progression, providing a rationale for using inhibitors of BET as anti-cancer drugs,” Dr. Ayala and colleagues wrote, adding, “combined inhibition of BET-mediated pathways and the JAK-STAT pathway has shown additional benefits for patients with MF.”

A total of 13 patients with primary or secondary myelofibrosis were evaluated in this study, which consisted of 2 parts (part 1a/1b and part 2a/2b). Part 1a involved treating patients who were ruxolitinib naive at a median of 66 years of age, ranging from 36 to 81, with a combination of BMS-986158 and ruxolitinib. Part 1b involved treating patients who had previously received ruxolitinib, at a median of 62 years of age, ranging from 37 to 77, with a combination of BMS-986158 and fedratinib. Part 2a/2b of this study are dose-expansion phases, which evaluated the combination of BMS-986158 and ruxolitinib or BMS-986158 and fedratinib at the recommended phase 2 dose, and are currently ongoing . 

As of May 31, 2022, results showed that BMS-986158, either alone or in combination with ruxolitinib or fedratinib, yielded safe toleration rates among patients with myelofibrosis. The most common grade 3 treatment-related adverse events (TRAEs) occurring in part 1a were thrombocytopenia (n=2), neutropenia (n=1), and hypertension (n=1). The most common grade 3 TRAEs occurring in part 1B were anemia (n=2) and thrombocytopenia (n=1). No serious TRAEs lead to treatment discontinuation. A significant number of patients achieved SVR, with 80% of part 1a reaching SVR35 at week 12 and 100% at week 24, and 0% and continued to deepen at week 24, and 50% of part 1b reaching SVR35 at week 24. 

“BMS-986158 in combination with [ruxolitinib] or [fedratinib] produced robust SVR in pts with MF, with responses that deepened beyond Week 12 under continued treatment,” Dr. Ayala and colleagues concluded, adding, “enrollment is continuing in the dose-escalation cohorts to establish RP2D for both combinations.” 

Source: 

Ayala R, Lopez N, Abulafia A, et al. BMS-986158, a Potent BET Inhibitor, As Monotherapy and in Combination with Ruxolitinib or Fedratinib in Intermediate- or High-Risk Myelofibrosis: First Results from a Phase 1/2 Study. Presented at ASH Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 4346.