P1061: INDIRECT TREATMENT COMPARISONS OF FEDRATINIB VERSUS NAVITOCLAX PLUS RUXOLITINIB: EFFECT ON SPLEEN VOLUME AND SYMPTOMS IN RUXOLITINIB-EXPOSED MYELOFIBROSIS PATIENTS

Abstract

Background: Myelofibrosis (MF) is a life-threatening myeloproliferative neoplasm characterized by stem cell-derived clonal myeloproliferation, bone marrow fibrosis, anemia, and splenomegaly. The Janus kinase (JAK) pathway is the critical pathway in its pathogenesis. Ruxolitinib (RUX), a JAK1/2 inhibitor, was the first therapy for intermediate- and high-risk MF approved in the United States; however, a high unmet need remains for alternative treatment options for patients who discontinue or are no longer responding to RUX. The efficacy and safety of fedratinib (FEDR), a JAK2 inhibitor approved by the US Food and Drug Administration in 2019, was investigated post RUX in the single-arm JAKARTA2 trial (NCT01523171). Clinical data from a similar population treated with navitoclax plus RUX (NAV+RUX) have been reported. The efficacy of FEDR relative to NAV+RUX in patients with MF previously treated with RUX has not been evaluated. Aims: To explore the comparative efficacy of FEDR versus NAV+RUX in patients with MF previously treated with RUX for the binary endpoints of ≥35% spleen volume reduction (SVR) from baseline to the end of cycle 6 (EOC6; 24 weeks) and ≥50% reduction in total symptom score (TSS) from baseline to the EOC6. Methods: Evidence for FEDR was informed by JAKARTA2 patient-level data, and evidence for NAV+RUX was informed by known reported evidence from the REFINE study (NCT03222609). The suitability of these studies for indirect treatment comparison (ITC) was assessed by considering the comparability of study design, population, intervention, and outcomes. Given the lack of a common comparator in the identified studies, unanchored ITCs were performed for SVR using matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC) methods. MAICs used effective sample size (ESS) of the FEDR cohort as an indicator of the amount of overlap. Univariable and multivariable regression models were used to identify potential prognostic factors to adjust for in the ITCs. Additionally, all Dynamic International Prognostic Scoring System (DIPSS)-Plus criteria reported were considered. Results: A subgroup of 58 JAKARTA2 patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 and intermediate-2 or high-risk disease most closely aligned with the REFINE population (N=34) was used in the analyses. Baseline mean platelet count was similar between subgroups. Across all analyses, results suggested FEDR consistently increased the odds/risk of a spleen response compared with NAV+RUX. The MAIC, matching on ECOG PS score, suggested that the odds of having an SVR for patients in the FEDR group was 2.19 times that of the NAV+RUX group (95% confidence interval [CI], 1.26 to 3.66), and the risk of having an SVR for patients in the FEDR group was 17.6% higher (95% CI, −2.1 to 37.0) (Figure). The results from the MAIC that additionally matched on all possible DIPSS-Plus criteria (age, hemoglobin, and platelet count) were consistent. Results from the 2 methods (MAIC and STC) were also consistent. For TSS reduction, the sample size (N=20) in REFINE was considered too small to perform a meaningful ITC; however, the absolute response rates for TSS reduction were similar across the 2 groups (29% [16/56] in the FEDR group and 30% [6/20] in the NAV+RUX group). Image:Summary/Conclusion: In patients with MF previously treated with RUX, these analyses suggest treatment with FEDR was associated with a greater proportion of patients achieving a spleen response compared with NAV+RUX. Limited data were available for comparison of TSS.