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MATCHING-ADJUSTED INDIRECT COMPARISON (MAIC) OF PELABRESIB (CPI-0610) IN COMBINATION WITH RUXOLITINIB VS RUXOLITINIB OR FEDRATINIB MONOTHERAPY IN PATIENTS WITH INTERMEDIATE OR HIGH-RISK MYELOFIBROSIS
Author(s): ,
Vikas Gupta
Affiliations:
Princess Margaret Cancer Centre, University of Toronto,Toronto,Canada;Princess Margaret Cancer Centre, University of Toronto,Toronto,Kanada;Princess Margaret Cancer Centre, University of Toronto,Toronto,Canada;Princess Margaret Cancer Centre, University of Toronto,Toronto,Canada;Princess Margaret Cancer Centre, University of Toronto,Toronto,Canadá;Princess Margaret Cancer Centre, University of Tor
,
John Mascarenhas
Affiliations:
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,États-unis;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,Vereinigte Staaten;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,Stati Uniti;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,United States;Tisch Cancer Institute, Icahn School
,
Marina Kremyanskaya
Affiliations:
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,États-unis;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,Vereinigte Staaten;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,Stati Uniti;Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai,New York, NY,United States;Tisch Cancer Institute, Icahn School
,
Raajit K Rampal
Affiliations:
Memorial Sloan Kettering Cancer Center,New York, NY,États-unis;Memorial Sloan Kettering Cancer Center,New York, NY,Vereinigte Staaten;Memorial Sloan Kettering Cancer Center,New York, NY,Stati Uniti;Memorial Sloan Kettering Cancer Center,New York, NY,United States;Memorial Sloan Kettering Cancer Center,New York, NY,Estados Unidos;Memorial Sloan Kettering Cancer Center,New York, NY,Verenigde Staten;
,
Moshe Talpaz
Affiliations:
University of Michigan Comprehensive Cancer Center,Ann Arbor, MI,États-unis;University of Michigan Comprehensive Cancer Center,Ann Arbor, MI,Vereinigte Staaten;University of Michigan Comprehensive Cancer Center,Ann Arbor, MI,Stati Uniti;University of Michigan Comprehensive Cancer Center,Ann Arbor, MI,United States;University of Michigan Comprehensive Cancer Center,Ann Arbor, MI,Estados Unidos;Univ
,
Jean-Jacques Kiladjian
Affiliations:
Hôpital Saint-Louis, Université de Paris,Paris,France;Hôpital Saint-Louis, Université de Paris,Paris,Frankreich;Hôpital Saint-Louis, Université de Paris,Paris,Francia;Hôpital Saint-Louis, Université de Paris,Paris,France;Hôpital Saint-Louis, Université de Paris,Paris,Francia;Hôpital Saint-Louis, Université de Paris,Paris,Frankrijk;Hôpital Saint-Louis, Université de Paris,Paris,França;Hôpital Saint
,
Alessandro Vannucchi
Affiliations:
Azienda Ospedaliero-Universitaria Careggi, University of Florence,Florence,Italie;Azienda Ospedaliero-Universitaria Careggi, University of Florence,Florence,Italien;Azienda Ospedaliero-Universitaria Careggi, University of Florence,Florence,Italia;Azienda Ospedaliero-Universitaria Careggi, University of Florence,Florence,Italy;Azienda Ospedaliero-Universitaria Careggi, University of Florence,Floren
,
Srdan Verstovsek
Affiliations:
University of Texas MD Anderson Cancer Center,Houston, TX,États-unis;University of Texas MD Anderson Cancer Center,Houston, TX,Vereinigte Staaten;University of Texas MD Anderson Cancer Center,Houston, TX,Stati Uniti;University of Texas MD Anderson Cancer Center,Houston, TX,United States;University of Texas MD Anderson Cancer Center,Houston, TX,Estados Unidos;University of Texas MD Anderson Cancer
,
Gozde Colak
Affiliations:
Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,États-unis;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Vereinigte Staaten;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Stati Uniti;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,United States;Constellation Pharmaceuticals a MorphoSys Company,Boston, MA,Estados Unidos;Constellation Pharmaceut
,
Debarshi Dey
Affiliations:
MorphoSys AG,Planegg,Allemagne;MorphoSys AG,Planegg,Deutschland;MorphoSys AG,Planegg,Germania;MorphoSys AG,Planegg,Germany;MorphoSys AG,Planegg,Alemania;MorphoSys AG,Planegg,Duitsland;MorphoSys AG,Planegg,Alemanha;MorphoSys AG,Planegg,Германия;MorphoSys AG,Planegg,Tyskland
Claire Harrison
Affiliations:
Guy's and St Thomas' NHS Foundation Trust,London,Royaume-uni;Guy's and St Thomas' NHS Foundation Trust,London,Vereinigtes Königreich;Guy's and St Thomas' NHS Foundation Trust,London,Regno Unito;Guy's and St Thomas' NHS Foundation Trust,London,United Kingdom;Guy's and St Thomas' NHS Foundation Trust,London,Reino Unido;Guy's and St Thomas' NHS Foundation Trust,London,Verenigd Koninkrijk;Guy's and St
(Abstract release date: 05/12/22) EHA Library. Gupta V. 06/10/22; 357888; P1029
Vikas Gupta
Vikas Gupta
Contributions
Abstract
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

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

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

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

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