Home Blog of Signal Transduction Autophagy Autophagy MPN-379 Matching-Adjusted Indirect Comparison (MAIC) of Pelabresib (CPI-0610) in Combination With Ruxolitinib vs. JAK Inhibitor Monotherapy in Patients With Intermediate or High-Risk Myelofibrosis

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MPN-379 Matching-Adjusted Indirect Comparison (MAIC) of Pelabresib (CPI-0610) in Combination With Ruxolitinib vs. JAK Inhibitor Monotherapy in Patients With Intermediate or High-Risk Myelofibrosis

Context: Pelabresib (CPI-0610) combined with ruxolitinib showed encouraging spleen and symptom responses in Janus kinase inhibitor (JAKi)-naïve patients with intermediate or high-risk myelofibrosis in Arm 3 of the Phase 2 MANIFEST study (NCT02158858). Cross-trial comparisons with JAKi monotherapy have limitations due to potential imbalances in baseline characteristics.

Objective: Matching-adjusted indirect comparison (MAIC) analysis was conducted to correct for potential imbalances in baseline characteristics, comparing primary (SVR35) and secondary (TSS50) endpoints at Week 24 for pelabresib and ruxolitinib (MANIFEST Arm 3) with JAKi monotherapy from Phase 3 studies (COMFORT-I and II, SIMPLIFY-1, and JAKARTA).

Methods: Individual patient-level data were available for MANIFEST Arm 3 vs. only published summary data for the four comparator studies. Unanchored MAIC was conducted, adjusting for imbalances in gender, myelofibrosis subtype, International Prognostic Scoring System risk status, previous hydroxyurea use, platelet count, hemoglobin levels, spleen volume, and JAK2 V617F status. Weighted mean outcomes of treatment effects were estimated; weights were also used to calculate the effective sample size. Treatment effect outcomes for SVR35 and TSS50 are presented in terms of response rates (RRs) and response rate ratios (RRRs, RR in MANIFEST Arm 3/RR in comparator arm; RRR >1 favors MANIFEST Arm 3). Bias due to potential unmeasured differences in baseline characteristics cannot be excluded.

Results: Complete summary-level balance in weighted distributions of prognostic factors was achieved. For SVR35 at Week 24, significant MAIC-adjusted RRRs (95% CI) were 1.57 (1.10-2.24; p=0.012), 1.82 (1.17-2.83; p=0.008), 2.13 (1.51-3.02; p<0.0001), 2.26 (1.57-3.27; p<0.0001), 1.76 (1.16-2.66; p=0.008) and 1.55 (1.06-2.27; p=0.023) for MANIFEST Arm 3 (pelabresib with ruxolitinib) versus COMFORT-I, COMFORT -II, SIMPLIFY-1 (ruxolitinib), SIMPLIFY-1 (momelotinib), JAKARTA (fedratinib 400 mg), and JAKARTA (fedratinib 500 mg), respectively, consistent with the significant results of unadjusted analyses. RRRs >1 were observed for TSS50 at Week 24 for all comparisons.

Conclusions: Results suggest that MAIC-adjusted improvements observed in SVR35 and TSS50 at Week 24 with pelabresib and ruxolitinib vs. ruxolitinib, fedratinib, or momelotinib monotherapy were consistent with unadjusted comparisons. Phase 3 MANIFEST-2 (NCT04603495), assessing pelabresib or placebo combined with ruxolitinib in JAKi-naïve patients with myelofibrosis, is ongoing.

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