Brian I Rini1, Thomas Powles2, Michael B Atkins3, Bernard Escudier4, David F McDermott5, Cristina Suarez6, Sergio Bracarda7, Walter M Stadler8, Frede Donskov9, Jae Lyun Lee10, Robert Hawkins11, Alain Ravaud12, Boris Alekseev13, Michael Staehler14, Motohide Uemura15, Ugo De Giorgi16, Begoña Mellado17, Camillo Porta18, Bohuslav Melichar19, Howard Gurney20, Jens Bedke21, Toni K Choueiri22, Francis Parnis23, Tarik Khaznadar24, Alpa Thobhani25, Shi Li26, Elisabeth Piault-Louis26, Gretchen Frantz26, Mahrukh Huseni26, Christina Schiff26, Marjorie C Green26, Robert J Motzer27. 1. Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address: rinib2@ccf.org. 2. Barts Cancer Institute and the Royal Free Hospital, Queen Mary University of London, London, UK. 3. Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA. 4. Gustave Roussy, Villejuif, France. 5. Beth Israel Deaconess Medical Center, Boston, MA, USA. 6. Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. 7. Azienda Ospedaliera S Maria, Terni, Italy. 8. The University of Chicago Medicine, Chicago, IL, USA. 9. Department of Oncology, Aarhus University Hospital, Aarhus, Denmark. 10. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 11. The Christie NHS Foundation Trust, Manchester, UK. 12. CHU Hôpitaux de Bordeaux-Hôpital Saint-André, Bordeaux, France. 13. P Herzen Oncology Research Institute, Moscow, Russia. 14. Klinikum der Universität München, Campus Großhadern, München, Germany. 15. Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan. 16. Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS, Meldola, Italy. 17. Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain. 18. IRCCS San Matteo University Hospital Foundation, Pavia, Italy. 19. Lékařská Fakulta Univerzita Palackého a Fakultní Nemocnice Olomouc, Olomouc, Czech Republic. 20. Department of Clinical Medicine, Macquarie University, Sydney, NSW, Australia. 21. Department of Urology, University of Tübingen, Tübingen, Germany. 22. Dana-Farber Cancer Institute, Boston, MA, USA. 23. Ashford Cancer Centre Research, Kurralta Park, SA, Australia. 24. F Hoffmann-La Roche, Basel, Switzerland. 25. Roche Products Ltd, Welwyn Garden City, UK. 26. Genentech, Inc, South San Francisco, CA, USA. 27. Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Abstract
BACKGROUND: A phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma. METHODS: In this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821. FINDINGS: Of 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumabgroup and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11·2 months in the atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio [HR] 0·74 [95% CI 0·57-0·96]; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76-1·14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3-4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation. INTERPRETATION:Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma. FUNDING: F Hoffmann-La Roche Ltd and Genentech Inc.
RCT Entities:
BACKGROUND: A phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma. METHODS: In this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821. FINDINGS: Of 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11·2 months in the atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio [HR] 0·74 [95% CI 0·57-0·96]; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76-1·14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3-4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation. INTERPRETATION:Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma. FUNDING: F Hoffmann-La Roche Ltd and Genentech Inc.
Authors: Toni K Choueiri; Michael B Atkins; Ziad Bakouny; Maria I Carlo; Charles G Drake; Eric Jonasch; Payal Kapur; Bryan Lewis; W Marston Linehan; Michael J Mitchell; Sumanta K Pal; Kevin Pels; Susan Poteat; W Kimryn Rathmell; Brian I Rini; Sabina Signoretti; Nizar Tannir; Robert Uzzo; Christopher G Wood; Hans J Hammers Journal: J Natl Cancer Inst Date: 2021-03-01 Impact factor: 13.506
Authors: Shaan Dudani; Jeffrey Graham; J Connor Wells; Ziad Bakouny; Sumanta K Pal; Nazli Dizman; Frede Donskov; Camillo Porta; Guillermo de Velasco; Aaron Hansen; Marco Iafolla; Benoit Beuselinck; Ulka N Vaishampayan; Lori A Wood; Elizabeth Liow; Flora Yan; Takeshi Yuasa; Georg A Bjarnason; Toni K Choueiri; Daniel Y C Heng Journal: Eur Urol Date: 2019-08-22 Impact factor: 20.096