Matthew J Matasar1, Marcelo Capra2, Muhit Özcan3, Fangfang Lv4, Wei Li5, Eduardo Yañez6, Katya Sapunarova7, Tongyu Lin8, Jie Jin9, Wojciech Jurczak10, Aryan Hamed11, Ming-Chung Wang12, Ross Baker13, Igor Bondarenko14, Qingyuan Zhang15, Jifeng Feng16, Klaus Geissler17, Mihaela Lazaroiu18, Guray Saydam19, Árpád Szomor20, Krimo Bouabdallah21, Rinat Galiulin22, Toshiki Uchida23, Lidia Mongay Soler24, Anjun Cao24, Florian Hiemeyer25, Aruna Mehra24, Barrett H Childs24, Yuankai Shi26, Pier Luigi Zinzani27. 1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: matasarm@mskcc.org. 2. Centro de Hematologia e Oncologia, Hospital Mãe de Deus, Porto Alegre, Brazil. 3. Ankara University School of Medicine, Ankara, Turkey. 4. Fudan University Shanghai Cancer Center, Shanghai, China. 5. The First Hospital of Jilin University, Changchun, China. 6. Oncology-Hematology Unit, Department of Internal Medicine, School of Medicine, University of La Frontera, Temuco, Chile. 7. Medical University, Plovdiv, Bulgaria. 8. Sun Yat-sen University Cancer Center, Guangzhou, China. 9. The First Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, China. 10. Maria Skłodowska-Curie National Research Institute of Oncology, Krakow, Poland. 11. Petz Aladár Megyei Oktató Kórház, Győr, Hungary. 12. Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. 13. Hollywood Private Hospital, Nedlands, WA, Australia. 14. Chemotherapy Department, City Dnipropetrovsk Multi-field Clinical Hospital, 4 DSMA, Dnipro, Ukraine. 15. Harbin Medical University Cancer Hospital, Harbin, China. 16. Jiangsu Cancer Hospital, Nanjing, China. 17. Sigmund Freud University, Vienna, Austria. 18. SC Policlinica de Diagnostic Rapid SA, Brasov, Romania. 19. Ege Üniversitesi Tıp Fakültesi, Izmir, Turkey. 20. Pécsi Tudományegyetem Klinikai Központ, Pécs, Hungary. 21. Hematology and Cellular Therapy Department, University Hospital of Bordeaux, Bordeaux, France. 22. Department of Chemotherapy for Children and Adults, Clinical Oncological Dispensary of Omsk Region, Omsk, Russian Federation. 23. Hematology and Oncology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan. 24. Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA. 25. Pharmaceuticals Division, Bayer, Berlin, Germany. 26. Department of Medical Oncology, National Cancer Center-National Clinical Research Center for Cancer-Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: syuankai@cicams.ac.cn. 27. IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", and Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy.
Abstract
BACKGROUND: Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma. METHODS: CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receivechemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m2 given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT02367040 and is ongoing. FINDINGS:Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximaband 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19·2 months (IQR 7·4-28·8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21·5 months (95% CI 17·8-33·0) versus 13·8 months (10·2-17·5; hazard ratio 0·52 [95% CI 0·39-0·69]; p<0·0001). The most common grade 3-4 adverse events were hyperglycaemia (173 [56%] of 307 patients in the copanlisib plus rituximab group vs 12 [8%] of 146 in the placebo plus rituximab group) and hypertension (122 [40%] vs 13 [9%]). Serious treatment-emergent adverse events were reported in 145 (47%) of 307 patients receivingcopanlisib plus rituximab and 27 (18%) of 146 patients receiving placebo plus rituximab. One (<1%) drug-related death (pneumonitis) occurred in the copanlisib plus rituximab group and none occurred in the placebo plus rituximab group. INTERPRETATION:Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma. FUNDING: Bayer.
RCT Entities:
BACKGROUND:Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma. METHODS: CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m2 given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT02367040 and is ongoing. FINDINGS: Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19·2 months (IQR 7·4-28·8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21·5 months (95% CI 17·8-33·0) versus 13·8 months (10·2-17·5; hazard ratio 0·52 [95% CI 0·39-0·69]; p<0·0001). The most common grade 3-4 adverse events were hyperglycaemia (173 [56%] of 307 patients in the copanlisib plus rituximab group vs 12 [8%] of 146 in the placebo plus rituximab group) and hypertension (122 [40%] vs 13 [9%]). Serious treatment-emergent adverse events were reported in 145 (47%) of 307 patients receiving copanlisib plus rituximab and 27 (18%) of 146 patients receiving placebo plus rituximab. One (<1%) drug-related death (pneumonitis) occurred in the copanlisib plus rituximab group and none occurred in the placebo plus rituximab group. INTERPRETATION:Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma. FUNDING: Bayer.
Authors: Juan Pablo Alderuccio; Thomas Habermann; Russ Kuker; Craig H Moskowitz; Andrew D Zelenetz; Izidore S Lossos Journal: Am J Hematol Date: 2022-09-12 Impact factor: 13.265