John Kuruvilla1, Radhakrishnan Ramchandren2, Armando Santoro3, Ewa Paszkiewicz-Kozik4, Robin Gasiorowski5, Nathalie A Johnson6, Laura Maria Fogliatto7, Iara Goncalves8, Jose S R de Oliveira9, Valeria Buccheri10, Guilherme F Perini11, Neta Goldschmidt12, Iryna Kriachok13, Michael Dickinson14, Mieczyslaw Komarnicki15, Andrew McDonald16, Muhit Ozcan17, Naohiro Sekiguchi18, Ying Zhu19, Akash Nahar19, Patricia Marinello19, Pier Luigi Zinzani20. 1. Princess Margaret Cancer Centre, Toronto, ON, Canada. Electronic address: john.kuruvilla@uhn.ca. 2. Department of Medicine, University of Tennessee, Knoxville, TN, USA. 3. Humanitas University, Department of Biomedical Sciences, Milan, Italy. 4. Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland. 5. Concord Hospital, University of Sydney, Sydney, NSW, Australia. 6. Jewish General Hospital Montreal, Montreal, QC, Canada. 7. Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil. 8. Fundação Pio XII-Hospital de Câncer de Barretos, São Paulo, Brazil. 9. Casa de Saude Santa Marcelina, São Paulo, Brazil. 10. Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. 11. Hospital Israelita Albert Einstein, São Paulo, Brazil. 12. Hadassah Medical Center, Jerusalem, Israel. 13. National Cancer Institute, Kiev, Ukraine. 14. Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia. 15. Szpital Kliniczny im Przemienienia, Poznań, Poland. 16. Pretoria East Hospital, Pretoria, South Africa. 17. Ankara University School of Medicine, Ankara, Turkey. 18. Department of Hematology, National Hospital Organization Disaster Medical Center, Tokyo, Japan. 19. Concord Hospital, Merck & Co, Kenilworth, NJ, USA. 20. IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy.
Abstract
BACKGROUND: PD-1 blockade via pembrolizumab monotherapy has shown antitumour activity and toxicity in patients with relapsed or refractory classical Hodgkin lymphoma. Here, we present interim analyses from the KEYNOTE-204 study evaluating pembrolizumab versus brentuximab vedotinfor relapsed or refractory classical Hodgkin lymphoma. METHODS: In this randomised, open-label, phase 3 study, patients aged 18 years or older with relapsed or refractory classical Hodgkin lymphoma with measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 who were ineligible for or had relapsed after autologous haematopoietic stem-cell transplantation (HSCT) were enrolled at 78 hospitals and cancer centres in 20 countries and territories. Patients were randomly assigned (1:1) with an interactive voice response system to pembrolizumab 200 mg intravenously every 3 weeks or brentuximab vedotin 1·8 mg/kg intravenously every 3 weeks. Randomisation was stratified by previous autologous HSCT and status after front-line therapy. Results from the second interim analysis are presented here, with a database cutoff of Jan 16, 2020. The dual primary endpoints assessed in the intention-to-treat population were progression-free survival as assessed by blinded independent central review, and overall survival (not analysed at this interim analysis). Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT02684292. Recruitment for this trial is closed. FINDINGS:Between July 8, 2016, and July 13, 2018, 151 patients were randomly assigned to pembrolizumab and 153 to brentuximab vedotin. After a median time from randomisation to data cutoff of 25·7 months (IQR 23·4-33·0), median progression-free survival was 13·2 months (95% CI 10·9-19·4) for pembrolizumab versus 8·3 months (5·7-8·8) for brentuximab vedotin (hazard ratio 0·65 [95% CI 0·48-0·88]; p=0·0027). The most common grade 3-5 treatment-related adverse events were pneumonitis (six [4%] of 148 patients in the pembrolizumab group vs one [1%] of 152 patients in the brentuximab vedotin group), neutropenia (three [2%] vs 11 [7%]), decreased neutrophil count (one [1%] vs seven [5%]), and peripheral neuropathy (one [1%] vs five [3%]). Serious treatment-related adverse events occurred in 24 (16%) of 148 patients receivingpembrolizumab and 16 (11%) of 152 patients receiving brentuximab vedotin. One treatment-related death due to pneumonia occurred in the pembrolizumab group. INTERPRETATION:Pembrolizumab showed statistically significant and clinically meaningful improvement in progression-free survival compared with brentuximab vedotin, with safety consistent with previous reports. These data support pembrolizumab as the preferred treatment option for patients with relapsed or refractory classical Hodgkin lymphoma who have relapsed post-autologous HSCT or are ineligible for autologous HSCT. FUNDING: Merck Sharp & Dohme Corp (a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA).
RCT Entities:
BACKGROUND:PD-1 blockade via pembrolizumab monotherapy has shown antitumour activity and toxicity in patients with relapsed or refractory classical Hodgkin lymphoma. Here, we present interim analyses from the KEYNOTE-204 study evaluating pembrolizumab versus brentuximabvedotin for relapsed or refractory classical Hodgkin lymphoma. METHODS: In this randomised, open-label, phase 3 study, patients aged 18 years or older with relapsed or refractory classical Hodgkin lymphoma with measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 who were ineligible for or had relapsed after autologous haematopoietic stem-cell transplantation (HSCT) were enrolled at 78 hospitals and cancer centres in 20 countries and territories. Patients were randomly assigned (1:1) with an interactive voice response system to pembrolizumab 200 mg intravenously every 3 weeks or brentuximabvedotin 1·8 mg/kg intravenously every 3 weeks. Randomisation was stratified by previous autologous HSCT and status after front-line therapy. Results from the second interim analysis are presented here, with a database cutoff of Jan 16, 2020. The dual primary endpoints assessed in the intention-to-treat population were progression-free survival as assessed by blinded independent central review, and overall survival (not analysed at this interim analysis). Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT02684292. Recruitment for this trial is closed. FINDINGS: Between July 8, 2016, and July 13, 2018, 151 patients were randomly assigned to pembrolizumab and 153 to brentuximabvedotin. After a median time from randomisation to data cutoff of 25·7 months (IQR 23·4-33·0), median progression-free survival was 13·2 months (95% CI 10·9-19·4) for pembrolizumab versus 8·3 months (5·7-8·8) for brentuximabvedotin (hazard ratio 0·65 [95% CI 0·48-0·88]; p=0·0027). The most common grade 3-5 treatment-related adverse events were pneumonitis (six [4%] of 148 patients in the pembrolizumab group vs one [1%] of 152 patients in the brentuximabvedotin group), neutropenia (three [2%] vs 11 [7%]), decreased neutrophil count (one [1%] vs seven [5%]), and peripheral neuropathy (one [1%] vs five [3%]). Serious treatment-related adverse events occurred in 24 (16%) of 148 patients receiving pembrolizumab and 16 (11%) of 152 patients receiving brentuximabvedotin. One treatment-related death due to pneumonia occurred in the pembrolizumab group. INTERPRETATION:Pembrolizumab showed statistically significant and clinically meaningful improvement in progression-free survival compared with brentuximabvedotin, with safety consistent with previous reports. These data support pembrolizumab as the preferred treatment option for patients with relapsed or refractory classical Hodgkin lymphoma who have relapsed post-autologous HSCT or are ineligible for autologous HSCT. FUNDING: Merck Sharp & Dohme Corp (a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA).
Authors: Florian Lüke; Dennis C Harrer; Karin Menhart; Daniel Wolff; Ernst Holler; Dirk Hellwig; Wolfgang Herr; Matthias Grube; Martin Vogelhuber; Albrecht Reichle; Daniel Heudobler Journal: Front Pharmacol Date: 2021-06-18 Impact factor: 5.810