CHRONOS-3: RANDOMIZED PHASE III STUDY OF COPANLISIB PLUS RITUXIMAB VS RITUXIMAB/PLACEBO IN RELAPSED INDOLENT NON-HODGKIN LYMPHOMA
Author(s): ,
Pier Luigi Zinzani
Affiliations:
IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia 'Seràgnoli' and Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna,Bologna,Italy
,
Marcelo Capra
Affiliations:
Centro de Hematologia e Oncologia, Hospital Mãe de Deus,Porto Alegre,Brazil
,
Muhit Özcan
Affiliations:
Ankara University School of Medicine,Ankara,Turkey
,
Fangfang Lv
Affiliations:
Fudan University Shanghai Cancer Center,Shanghai,China
,
Wei Li
Affiliations:
The First Hospital of Jilin University,Changchun,China
,
Eduardo Yañez
Affiliations:
Department of Internal Medicine, Oncology-Hematology Unit, University of La Frontera,Temuco,Chile
,
Katya Sapunarova
Affiliations:
Medical University,Plovdiv,Bulgaria
,
Tongyu Lin
Affiliations:
Sun Yat-sen University Cancer Center,Guangzhou,China
,
Jie Jin
Affiliations:
The First Affiliated Hospital of Zhejiang University College of Medicine,Hangzhou,China
,
Wojciech Jurczak
Affiliations:
Maria Skłodowska Curie National Research Institute of Oncology,Krakow,Poland
,
Aryan Hamed
Affiliations:
Petz Aladár Megyei Oktató Kórház,Gyor,Hungary
,
Ming-Chung Wang
Affiliations:
Chang Gung Memorial Hospital Kaohsiung,Kaohsiung,Taiwan, Province of China
,
Ross Baker
Affiliations:
Perth Blood Institute, Murdoch University,Perth,Australia
,
Igor Bondarenko
Affiliations:
Chemotherapy Department, City Dnipropetrovsk Multi-field Clinical Hospital, 4 DSMA,Dnipro,Ukraine
,
Qingyuan Zhang
Affiliations:
Harbin Medical University Cancer Hospital,Harbin,China
,
Jifeng Feng
Affiliations:
Jiangsu Cancer Hospital,Nanjing,China
,
Klaus Geissler
Affiliations:
Sigmund Freud University,Vienna,Austria
,
Mihaela Lazaroiu
Affiliations:
S.C. Policlinica de Diagnostic Rapid S.A.,Brasov,Romania
,
Guray Saydam
Affiliations:
Ege Üniversitesi Tıp Fakültesi,Izmir,Turkey
,
Árpád Szomor
Affiliations:
Pécsi Tudományegyetem Klinikai Központ,Pécs,Hungary
,
Krimo Bouabdallah
Affiliations:
Hematology and Cellular Therapy Department, University Hospital of Bordeaux,Bordeaux,France
,
Rinat Galiulin
Affiliations:
Department of Chemotherapy for Children and Adults, Clinical Oncological Dispensary of Omsk Region,Omsk,Russian Federation
,
Toshiki Uchida
Affiliations:
Hematology and Oncology, Japanese Red Cross Nagoya Daini Hospital,Nagoya,Japan
,
Lidia Mongay Soler
Affiliations:
Bayer HealthCare Pharmaceuticals, Inc.,Whippany,United States
,
Anjun Cao
Affiliations:
Bayer HealthCare Pharmaceuticals, Inc.,Whippany,United States
,
Florian Hiemeyer
Affiliations:
Pharmaceuticals Division, Bayer AG,Berlin,Germany
,
Aruna Mehra
Affiliations:
Bayer HealthCare Pharmaceuticals, Inc.,Whippany,United States
,
Barrett H Childs
Affiliations:
Bayer HealthCare Pharmaceuticals, Inc.,Whippany,United States
,
Yuankai Shi
Affiliations:
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College,Beijing,China
Matthew J Matasar
Affiliations:
Department of Medicine, Memorial Sloan Kettering Cancer Center,New York,United States
EHA Library. Bishton M. 06/09/21; 324619; S211
Prof. Dr. Mark Bishton
Prof. Dr. Mark Bishton
Contributions
Abstract
Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S211

Type: Oral Presentation

Session title: Indolent & mantle cell lymphoma - Clinical

Background
Rituximab (R)-based therapies are standard for patients (pts) with relapsed advanced indolent non-Hodgkin lymphoma (iNHL). Copanlisib (C) is a PI3K inhibitor approved as monotherapy for relapsed follicular lymphoma (FL) in pts who have had ≥2 prior systemic therapies.

Aims
We report primary data from the Phase III CHRONOS-3 study of treatment with C+R vs placebo (P)+R in relapsed iNHL (NCT02367040).

Methods
Pts with relapsed iNHL who were progression-free and treatment-free for ≥12 months (mo) after last R-based therapy or unwilling/unfit to receive chemotherapy were randomized 2:1 to receive C+R or P+R. C 60 mg/P was given i.v. on days 1, 8, and 15 (28-day cycle); R 375 mg/m2 was given i.v. on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint: centrally assessed progression-free survival (PFS). Secondary endpoints: objective response rate (ORR), duration of response, complete response rate (CRR), overall survival (OS), and treatment-emergent adverse events (TEAEs). The data cut-off date was August 31, 2020. All pts provided informed consent.

Results
307 pts were randomized to C+R and 151 to P+R. FL was the most common lymphoma histology subtype (60.0%), followed by marginal zone (MZL, 20.7%), small lymphocytic (SLL, 10.9%), and lymphoplasmacytic/Waldenström macroglobulinemia (LPL/WM, 8.3%). Median age was 63 years (range 28-91). With a median follow-up of 19.2 mo, the primary study endpoint was met: C+R significantly reduced the risk of disease progression/death vs P+R (hazard ratio [HR] 0.52 [95% CI 0.39, 0.69]; 1-sided p=0.000002); median PFS was 21.5 mo (95% CI 17.8, 33.0) vs 13.8 mo (95% CI 10.2, 17.5), respectively. Reductions in risk of progression/death were seen across all histology subtypes (HR [95% CI]): FL 0.580 [0.404, 0.833]; MZL 0.475 [0.245, 0.923]; SLL 0.243 [0.111, 0.530]; LPL/WM 0.443 [0.160, 1.231]. ORRs were 80.8% (CRR 33.9%) for C+R and 47.7% (CRR 14.6%) for P+R. Higher ORRs and CRRs were seen across all iNHL subtypes with C+R treatment. Median OS was not estimable. Most common TEAEs (all grades [G]/G3+) in pts receiving C+R were hyperglycemia (69.4%/56.4%), hypertension (49.2%/39.7% [all G3]), and diarrhea (33.6%/4.9% [all G3]). For pts receiving P+R, hyperglycemia (23.3%/8.2% [all G3]), hypertension (19.2%/8.9% [all G3]), neutropenia (16.4%/12.3%), and upper respiratory tract infection (16.4%/0%) were the most common TEAEs. Serious adverse events were higher with C+R (47.2%) vs P+R (18.5%). G5 TEAEs occurred in 6 pts (2.0%) receiving C+R (1 [0.3%] deemed treatment-related; pneumonitis) and 1 (0.7%) receiving P+R.

Conclusion
C+R demonstrated broad and superior efficacy vs P+R in pts with relapsed iNHL. The safety profile of C+R was manageable and consistent with C and R as monotherapy. Copanlisib is the first PI3K inhibitor to be safely combined with R in relapsed iNHL, representing a potential new therapy option for relapsed iNHL across all subtypes.

Keyword(s): Indolent non-Hodgkin's lymphoma, Phase III, PI3K, Rituximab

Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S211

Type: Oral Presentation

Session title: Indolent & mantle cell lymphoma - Clinical

Background
Rituximab (R)-based therapies are standard for patients (pts) with relapsed advanced indolent non-Hodgkin lymphoma (iNHL). Copanlisib (C) is a PI3K inhibitor approved as monotherapy for relapsed follicular lymphoma (FL) in pts who have had ≥2 prior systemic therapies.

Aims
We report primary data from the Phase III CHRONOS-3 study of treatment with C+R vs placebo (P)+R in relapsed iNHL (NCT02367040).

Methods
Pts with relapsed iNHL who were progression-free and treatment-free for ≥12 months (mo) after last R-based therapy or unwilling/unfit to receive chemotherapy were randomized 2:1 to receive C+R or P+R. C 60 mg/P was given i.v. on days 1, 8, and 15 (28-day cycle); R 375 mg/m2 was given i.v. on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint: centrally assessed progression-free survival (PFS). Secondary endpoints: objective response rate (ORR), duration of response, complete response rate (CRR), overall survival (OS), and treatment-emergent adverse events (TEAEs). The data cut-off date was August 31, 2020. All pts provided informed consent.

Results
307 pts were randomized to C+R and 151 to P+R. FL was the most common lymphoma histology subtype (60.0%), followed by marginal zone (MZL, 20.7%), small lymphocytic (SLL, 10.9%), and lymphoplasmacytic/Waldenström macroglobulinemia (LPL/WM, 8.3%). Median age was 63 years (range 28-91). With a median follow-up of 19.2 mo, the primary study endpoint was met: C+R significantly reduced the risk of disease progression/death vs P+R (hazard ratio [HR] 0.52 [95% CI 0.39, 0.69]; 1-sided p=0.000002); median PFS was 21.5 mo (95% CI 17.8, 33.0) vs 13.8 mo (95% CI 10.2, 17.5), respectively. Reductions in risk of progression/death were seen across all histology subtypes (HR [95% CI]): FL 0.580 [0.404, 0.833]; MZL 0.475 [0.245, 0.923]; SLL 0.243 [0.111, 0.530]; LPL/WM 0.443 [0.160, 1.231]. ORRs were 80.8% (CRR 33.9%) for C+R and 47.7% (CRR 14.6%) for P+R. Higher ORRs and CRRs were seen across all iNHL subtypes with C+R treatment. Median OS was not estimable. Most common TEAEs (all grades [G]/G3+) in pts receiving C+R were hyperglycemia (69.4%/56.4%), hypertension (49.2%/39.7% [all G3]), and diarrhea (33.6%/4.9% [all G3]). For pts receiving P+R, hyperglycemia (23.3%/8.2% [all G3]), hypertension (19.2%/8.9% [all G3]), neutropenia (16.4%/12.3%), and upper respiratory tract infection (16.4%/0%) were the most common TEAEs. Serious adverse events were higher with C+R (47.2%) vs P+R (18.5%). G5 TEAEs occurred in 6 pts (2.0%) receiving C+R (1 [0.3%] deemed treatment-related; pneumonitis) and 1 (0.7%) receiving P+R.

Conclusion
C+R demonstrated broad and superior efficacy vs P+R in pts with relapsed iNHL. The safety profile of C+R was manageable and consistent with C and R as monotherapy. Copanlisib is the first PI3K inhibitor to be safely combined with R in relapsed iNHL, representing a potential new therapy option for relapsed iNHL across all subtypes.

Keyword(s): Indolent non-Hodgkin's lymphoma, Phase III, PI3K, Rituximab

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