IVOSIDENIB IMPROVES OVERALL SURVIVAL RELATIVE TO STANDARD THERAPIES IN RELAPSED OR REFRACTORY MUTANT IDH1 AML: RESULTS FROM MATCHED COMPARISONS TO HISTORICAL CONTROLS
Author(s): ,
Peter Paschka
Affiliations:
Universitätsklinikum Ulm,Ulm,Germany
,
Hervé Dombret
Affiliations:
Hôpital Saint-Louis,Paris,France
,
Xavier Thomas
Affiliations:
Centre Hospitalier Lyon-Sud,Pierre-Benite,France
,
Christian Recher
Affiliations:
IUCT-Oncopole, Centre Hospitalier Universitaire de Toulouse,Toulouse,France
,
Sylvain Chantepie
Affiliations:
Institut d'Hématologie de Basse-Normandie, Centre Hospitalier Universitaire de Caen,Caen,France
,
Pau Montesinos
Affiliations:
CIBERONC, Instituto Carlos III,Madrid,Spain;Hospital Universitario y Politécnico La Fe,Valencia,Spain
,
Evelyn Acuña-Cruz
Affiliations:
Hospital Universitario y Politécnico La Fe,Valencia,Spain
,
Paresh Vyas
Affiliations:
University of Oxford,Oxford,United Kingdom
,
Karl-Anton Kreuzer
Affiliations:
Uniklinik Köln,Köln,Germany
,
Michael Heuser
Affiliations:
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School,Hannover,Germany
,
Klaus H Metzeler
Affiliations:
Department of Medicine III,University Hospital, LMU Munich,Munich,Germany
,
Michael Dennis
Affiliations:
The Christie NHS Foundation Trust,Manchester,United Kingdom
,
Bruno Quesnel
Affiliations:
Centre Hospitalier Régional Universitaire de Lille,Lille,France
,
Mathilde Hunault-Berger
Affiliations:
CRCINA Centre Hospitalier Universitaire d'Angers,Angers,France
,
Mohamad Mohty
Affiliations:
Sorbonne University, Hôpital Saint-Antoine,Paris,France
,
Arnaud Pigneux
Affiliations:
CHU Bordeaux, Université de Bordeaux,Bordeaux,France
,
Stéphane de Botton
Affiliations:
Institut Gustave Roussy,Villejuif,France
,
Daniela Weber
Affiliations:
Universitätsklinikum Ulm,Ulm,Germany
,
Konstanze Döhner
Affiliations:
Universitätsklinikum Ulm,Ulm,Germany
,
Gary Milkovich
Affiliations:
RJM Group, LLC,Washington DC,United States
,
John Reitan
Affiliations:
RJM Group, LLC,Washington DC,United States
,
Sarah C MacDonald
Affiliations:
IQVIA,Seattle,United States
,
Deborah Casso
Affiliations:
IQVIA,Seattle,United States
,
Michael Storm
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Hua Liu
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Stephanie M Kapsalis
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Eyal C Attar
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Thomas Winkler
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
Hartmut Döhner
Affiliations:
Universitätsklinikum Ulm,Ulm,Germany
EHA Library. Paschka P. 06/12/20; 294458; EP540
Peter Paschka
Peter Paschka
Contributions
Abstract

Abstract: EP540

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background
Ivosidenib (IVO) monotherapy was approved by the FDA for the treatment of mutant isocitrate dehydrogenase 1 (mIDH1) relapsed/refractory (R/R) acute myeloid leukemia (AML) in 2018, and in newly diagnosed patients (pts) ≥75 y of age or pts ineligible for intensive therapies in 2019, based on the results of the open-label AG120-C-001 (NCT02074839) study.

Aims
To evaluate the comparative benefit of IVO, matched pt analyses were conducted using data on mIDH1 R/R AML pts from the AML Study Group (AMLSG) registry (NCT01252485) and a real-world chart review study (RWD) from France, Germany, the UK, and Spain.

Methods
Individual pt data from Arm 1+ of the AG120-C-001 study (n=159) was compared to a historical control (HC), combining individual pt data from the AMLSG registry (n=127) and the RWD (n=148). Treatment with IVO was compared to the most recent therapy received for the HC. Four propensity score–based matching/weighting methods were used (optimal full matching, optimal 1:1 matching, greedy nearest-neighbor 1:1 matching, and inverse probability of treatment weighting [IPTW]). A literature review and data availability led to the inclusion of 8 baseline prognostic factors for estimation of propensity scores (prior hematopoietic stem cell transplant, age, number of prior regimens, de novo vs secondary AML, cytogenetic risk, primary refractory status, relapse-free survival after initial induction chemotherapy, and receipt of prior induction chemotherapy); Eastern Cooperative Oncology Group (ECOG) performance status was included in sensitivity analyses. Balance between populations was assessed pre- and postmatch via comparison of (weighted) standardized differences for each covariate. Time-to-event data were summarized via Kaplan-Meier estimators with 2-sided 95% CIs. Cox regression analysis, using the key prognostic factors as covariates, was applied to estimate hazard ratios (HRs) of overall survival (OS), and the corresponding 95% CI was estimated using the sandwich estimator. Subgroup analyses were also conducted on OS and complete remission (CR) rate, comparing IVO pts, none of whom were eligible for intensive salvage therapies (IC), to the subsets of RWD pts who received IC and nonintensive salvage therapies (non-IC). Updated analyses by IC/non-IC on the full combined cohort (AMLSG registry and RWD pts) are planned.

Results
Before matching/weighting, IVO pts (n=159) had numerically longer OS than HCs (n=275) (median, 8.8 vs 5.4 mo), despite an increased proportion of pts with adverse prognostic factors. In matched/weighted analyses, IVO pts had longer survival than HCs, with HRs ranging from 0.43–0.73 (Figure). The 95% CI upper bounds were all <1, except for one sensitivity analysis. When compared to non-IC RWD pts (n=65), the survival benefit of IVO was more pronounced, with significantly prolonged survival in the unmatched IVO population (n=157) (median 8.8 vs 3.8 mo; unadjusted HR 0.55). Matched results showed a consistent benefit with HRs of 0.26–0.57, and all analyses except one sensitivity analysis had a 95% CI upper bound of <1. IVO OS was slightly worse when compared to IC RWD pts (n=61) (unadjusted median 8.8 vs 10.8 mo; unadjusted HR 1.69). IVO was also associated with an increased likelihood of CR compared to non-IC RWD pts (n=65) (21.7% vs 7.7%; unadjusted odds ratio [OR] 3.32) and a lower likelihood of CR compared to IC RWD pts (n=61) (21.7% vs 47.5%; unadjusted OR 0.31).

Conclusion
IVO monotherapy may prolong survival vs standard-of-care therapies in mIDH1 R/R AML, particularly in pts unable to receive intensive therapy.

Session topic: 04. Acute myeloid leukemia - Clinical

Keyword(s): Ivosidenib, Relapsed acute myeloid leukemia, Survival

Abstract: EP540

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background
Ivosidenib (IVO) monotherapy was approved by the FDA for the treatment of mutant isocitrate dehydrogenase 1 (mIDH1) relapsed/refractory (R/R) acute myeloid leukemia (AML) in 2018, and in newly diagnosed patients (pts) ≥75 y of age or pts ineligible for intensive therapies in 2019, based on the results of the open-label AG120-C-001 (NCT02074839) study.

Aims
To evaluate the comparative benefit of IVO, matched pt analyses were conducted using data on mIDH1 R/R AML pts from the AML Study Group (AMLSG) registry (NCT01252485) and a real-world chart review study (RWD) from France, Germany, the UK, and Spain.

Methods
Individual pt data from Arm 1+ of the AG120-C-001 study (n=159) was compared to a historical control (HC), combining individual pt data from the AMLSG registry (n=127) and the RWD (n=148). Treatment with IVO was compared to the most recent therapy received for the HC. Four propensity score–based matching/weighting methods were used (optimal full matching, optimal 1:1 matching, greedy nearest-neighbor 1:1 matching, and inverse probability of treatment weighting [IPTW]). A literature review and data availability led to the inclusion of 8 baseline prognostic factors for estimation of propensity scores (prior hematopoietic stem cell transplant, age, number of prior regimens, de novo vs secondary AML, cytogenetic risk, primary refractory status, relapse-free survival after initial induction chemotherapy, and receipt of prior induction chemotherapy); Eastern Cooperative Oncology Group (ECOG) performance status was included in sensitivity analyses. Balance between populations was assessed pre- and postmatch via comparison of (weighted) standardized differences for each covariate. Time-to-event data were summarized via Kaplan-Meier estimators with 2-sided 95% CIs. Cox regression analysis, using the key prognostic factors as covariates, was applied to estimate hazard ratios (HRs) of overall survival (OS), and the corresponding 95% CI was estimated using the sandwich estimator. Subgroup analyses were also conducted on OS and complete remission (CR) rate, comparing IVO pts, none of whom were eligible for intensive salvage therapies (IC), to the subsets of RWD pts who received IC and nonintensive salvage therapies (non-IC). Updated analyses by IC/non-IC on the full combined cohort (AMLSG registry and RWD pts) are planned.

Results
Before matching/weighting, IVO pts (n=159) had numerically longer OS than HCs (n=275) (median, 8.8 vs 5.4 mo), despite an increased proportion of pts with adverse prognostic factors. In matched/weighted analyses, IVO pts had longer survival than HCs, with HRs ranging from 0.43–0.73 (Figure). The 95% CI upper bounds were all <1, except for one sensitivity analysis. When compared to non-IC RWD pts (n=65), the survival benefit of IVO was more pronounced, with significantly prolonged survival in the unmatched IVO population (n=157) (median 8.8 vs 3.8 mo; unadjusted HR 0.55). Matched results showed a consistent benefit with HRs of 0.26–0.57, and all analyses except one sensitivity analysis had a 95% CI upper bound of <1. IVO OS was slightly worse when compared to IC RWD pts (n=61) (unadjusted median 8.8 vs 10.8 mo; unadjusted HR 1.69). IVO was also associated with an increased likelihood of CR compared to non-IC RWD pts (n=65) (21.7% vs 7.7%; unadjusted odds ratio [OR] 3.32) and a lower likelihood of CR compared to IC RWD pts (n=61) (21.7% vs 47.5%; unadjusted OR 0.31).

Conclusion
IVO monotherapy may prolong survival vs standard-of-care therapies in mIDH1 R/R AML, particularly in pts unable to receive intensive therapy.

Session topic: 04. Acute myeloid leukemia - Clinical

Keyword(s): Ivosidenib, Relapsed acute myeloid leukemia, Survival

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