Contributions
Abstract: P1029
Type: Poster presentation
Session title: Myeloproliferative neoplasms - Clinical
Background
Pelabresib (CPI-0610), an investigational product, in combination with ruxolitinib (ruxo) has shown encouraging responses in terms of ≥35% reduction in spleen volume from baseline (SVR35) and ≥50% reduction in total symptoms score (TSS) from baseline (TSS50) in Janus kinase inhibitor (JAKi) treatment-naïve patients with intermediate or high-risk myelofibrosis (MF) in Arm 3 of the open-label Phase 2 MANIFEST study (NCT02158858). A cross-trial comparison with ruxo or fedratinib monotherapy has limitations in the presence of the potential imbalances in baseline characteristics.
Aims
Here we report findings from matching-adjusted indirect comparisons (MAICs), conducted to correct for potential imbalances in baseline characteristics, comparing the primary endpoint SVR35 and secondary endpoint TSS50 at Week (Wk) 24 for the combination of pelabresib and ruxo (MANIFEST Arm 3) with Phase 3 ruxo monotherapy (COMFORT-I and II, SIMPLIFY-1) and fedratinib monotherapy (JAKARTA) data.
Methods
Individual patient level data were available for MANIFEST Arm 3, while only published summary data were available for COMFORT-I and II, SIMPLIFY-1 and JAKARTA. An unanchored MAIC was conducted wherein patients in MANIFEST Arm 3 were reweighted to adjust for imbalances in the following key prognostic baseline characteristics: gender, MF subtype, International Prognostic Scoring System risk status, previous hydroxyurea use, platelet count, hemoglobin levels, spleen volume and JAK2V617F status. Weighted mean outcomes of the treatment effects were estimated together with their 95% confidence interval (CI) using robust sandwich estimators for variance. The weights were also used to calculate the Effective Sample Size (ESS). Treatment effect outcomes for SVR35 and TSS50 at Wk 24 are presented in terms of Response Rates (RR) and Response Rate Ratio (RRR, defined as RR in MANIFEST Arm 3/RR in comparator arm). An RRR >1 favors the pelabresib + ruxo arm in MANIFEST Arm 3 over the JAKi monotherapy comparator arm. A limitation of a MAIC is that bias due to potential unmeasured differences in patient baseline characteristics between trials cannot be excluded.
Results
The MAIC analysis resulted in complete summary-level balance in the weighted distributions of the prognostic factors in MANIFEST Arm 3 versus comparators. The figure presents the weighted (or MAIC-adjusted) and unweighted (or unadjusted) treatment effect comparisons along with their 95% CI for SVR35 and corresponding ESS at Wk 24. Statistically significant MAIC-adjusted (weighted) RRRs of 1.57 (95% CI 1.10, 2.24; p-value: 0.012), 1.82 (95% CI: 1.17, 2.83; p-value: 0.008), 2.13 (95% CI: 1.51, 3.02; p-value: <0.001), 1.76 (95% CI: 1.16, 2.66; p-value: 0.008) and 1.55 (95% CI: 1.06, 2.27; p-value: 0.023) were observed for MANIFEST Arm 3 (pelabresib + ruxo) versus COMFORT-I and -II and SIMPLIFY-1 (ruxo only) and JAKARTA (fedratinib 400 mg and 500 mg), respectively. These weighted analyses are consistent with statistically significant results of unadjusted analyses. RRRs >1 were also observed for TSS50 at Wk 24 for all the comparisons.
Conclusion
The MAIC analysis, adjusting for eight key baseline prognostic factors, suggests an improvement in SVR35 and TSS50 at Wk 24 for JAKi treatment-naïve patients with MF treated with a combination of pelabresib and ruxo over ruxo or fedratinib monotherapy. MANIFEST-2 (NCT04603495), a Phase 3 double-blind, randomized study assessing the efficacy and safety of pelabresib or placebo in combination with ruxo in patients with MF, is currently open for enrollment.
Keyword(s): Clinical trial, Janus Kinase inhibitor, Myelofibrosis
Abstract: P1029
Type: Poster presentation
Session title: Myeloproliferative neoplasms - Clinical
Background
Pelabresib (CPI-0610), an investigational product, in combination with ruxolitinib (ruxo) has shown encouraging responses in terms of ≥35% reduction in spleen volume from baseline (SVR35) and ≥50% reduction in total symptoms score (TSS) from baseline (TSS50) in Janus kinase inhibitor (JAKi) treatment-naïve patients with intermediate or high-risk myelofibrosis (MF) in Arm 3 of the open-label Phase 2 MANIFEST study (NCT02158858). A cross-trial comparison with ruxo or fedratinib monotherapy has limitations in the presence of the potential imbalances in baseline characteristics.
Aims
Here we report findings from matching-adjusted indirect comparisons (MAICs), conducted to correct for potential imbalances in baseline characteristics, comparing the primary endpoint SVR35 and secondary endpoint TSS50 at Week (Wk) 24 for the combination of pelabresib and ruxo (MANIFEST Arm 3) with Phase 3 ruxo monotherapy (COMFORT-I and II, SIMPLIFY-1) and fedratinib monotherapy (JAKARTA) data.
Methods
Individual patient level data were available for MANIFEST Arm 3, while only published summary data were available for COMFORT-I and II, SIMPLIFY-1 and JAKARTA. An unanchored MAIC was conducted wherein patients in MANIFEST Arm 3 were reweighted to adjust for imbalances in the following key prognostic baseline characteristics: gender, MF subtype, International Prognostic Scoring System risk status, previous hydroxyurea use, platelet count, hemoglobin levels, spleen volume and JAK2V617F status. Weighted mean outcomes of the treatment effects were estimated together with their 95% confidence interval (CI) using robust sandwich estimators for variance. The weights were also used to calculate the Effective Sample Size (ESS). Treatment effect outcomes for SVR35 and TSS50 at Wk 24 are presented in terms of Response Rates (RR) and Response Rate Ratio (RRR, defined as RR in MANIFEST Arm 3/RR in comparator arm). An RRR >1 favors the pelabresib + ruxo arm in MANIFEST Arm 3 over the JAKi monotherapy comparator arm. A limitation of a MAIC is that bias due to potential unmeasured differences in patient baseline characteristics between trials cannot be excluded.
Results
The MAIC analysis resulted in complete summary-level balance in the weighted distributions of the prognostic factors in MANIFEST Arm 3 versus comparators. The figure presents the weighted (or MAIC-adjusted) and unweighted (or unadjusted) treatment effect comparisons along with their 95% CI for SVR35 and corresponding ESS at Wk 24. Statistically significant MAIC-adjusted (weighted) RRRs of 1.57 (95% CI 1.10, 2.24; p-value: 0.012), 1.82 (95% CI: 1.17, 2.83; p-value: 0.008), 2.13 (95% CI: 1.51, 3.02; p-value: <0.001), 1.76 (95% CI: 1.16, 2.66; p-value: 0.008) and 1.55 (95% CI: 1.06, 2.27; p-value: 0.023) were observed for MANIFEST Arm 3 (pelabresib + ruxo) versus COMFORT-I and -II and SIMPLIFY-1 (ruxo only) and JAKARTA (fedratinib 400 mg and 500 mg), respectively. These weighted analyses are consistent with statistically significant results of unadjusted analyses. RRRs >1 were also observed for TSS50 at Wk 24 for all the comparisons.
Conclusion
The MAIC analysis, adjusting for eight key baseline prognostic factors, suggests an improvement in SVR35 and TSS50 at Wk 24 for JAKi treatment-naïve patients with MF treated with a combination of pelabresib and ruxo over ruxo or fedratinib monotherapy. MANIFEST-2 (NCT04603495), a Phase 3 double-blind, randomized study assessing the efficacy and safety of pelabresib or placebo in combination with ruxo in patients with MF, is currently open for enrollment.
Keyword(s): Clinical trial, Janus Kinase inhibitor, Myelofibrosis