PII-067 - EXPOSURE RESPONSE (E-R) RELATIONSHIPS OF FEDRATINIB IN PATIENTS WITH INTERMEDIATE-2 TO HIGH-RISK MYELOFIBROSIS WITH OR WITHOUT PRIOR RUXOLITNIB EXPOSURE.

Y. Chen¹, Y. Li¹, Y. Xue¹, P. Brown¹, C. Hernandez¹, S. Rose¹, R. Pilot¹, G. Krishna², K. Ogasawara¹; ¹Bristol Myers Squibb, NJ, United States, ²N/A, NJ, United States.

Background: Fedratinib is a potent, oral, Janus kinase inhibitor (JAKi) for the treatment of myelofibrosis (MF). Fedratinib has demonstrated compelling efficacy as both a first line and second line JAKi in randomized phase 3 studies. The recommended dose of fedratinib is 400 mg once daily. Pharmacokinetics (PK) of fedratinib is characterized by a biphasic disposition with an effective half-life of 41 hours, a terminal half-life of approximately 114 hours, and apparent clearance of 13 L/hr in MF patients. This is the first report to describe the exposure-response (E-R) analyses of fedratinib based on pooled data from multiple phase 2-3 studies in patients with intermediate-2 or high-risk MF, with or without prior ruxolitinib exposure.

Methods: The PK exposures were derived from the population PK analysis. Efficacy endpoints included spleen volume reduction ≥35% (SVR35) and total symptom score reduction ≥50% (TSS response) at the end of cycle 6. Safety endpoints included frequency of grade ≥3 anemia or grade ≥3 thrombocytopenia, any grade nausea/vomiting, and any grade diarrhea. The E-R models were developed using logistic regression.

Results: Fedratinib exposure was positively associated with SVR35 (P <.001) and TSS response (P <.001) after adjusting for covariates. Baseline spleen volume was inversely associated with SVR35 (P=.029). Prior ruxolitinib exposure was not associated with SVR35 (P=.090) or TSS response (P=.326). Although, numerically higher incidence of adverse events was observed in patients with higher fedratinib exposure, there was no statistically significant association between fedratinib exposure and any safety related endpoints. Lower baseline hemoglobin level ( < 10 g/dL) and platelet count ( < 100 × 109/L) were associated with patients experiencing grade ≥3 anemia (P <.001) and thrombocytopenia (P <.001), respectively. Prior ruxolitinib exposure was associated with patients experiencing grade ≥3 thrombocytopenia (P=.004). Antiemetic prophylaxis was associated with lower rates of nausea/vomiting (P <.001).

Conclusion: Fedratinib exposure is positively correlated to efficacy of spleen volume reduction and TSS responses without having significant impact to safety. Fedratinib 400 mg once daily is the appropriate dose for patients with MF regardless of ruxolitinib exposure.