Robert J Motzer1, Thomas Powles2, Michael B Atkins3, Bernard Escudier4, David F McDermott5, Boris Y Alekseev6, Jae-Lyun Lee7, Cristina Suarez8, Daniil Stroyakovskiy9, Ugo De Giorgi10, Frede Donskov11, Begoña Mellado12, Romain Banchereau13, Habib Hamidi13, Omara Khan14, Veronica Craine14, Mahrukh Huseni13, Nick Flinn14, Sarita Dubey13, Brian I Rini15. 1. Memorial Sloan Kettering Cancer Center, New York, New York. 2. Barts Cancer Institute and the Royal Free Hospital, Queen Mary University of London, London, UK. 3. Georgetown Lombardi Comprehensive Cancer Center, Washington, DC. 4. Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. 5. Biologic Therapy and Cutaneous Oncology Programs, Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts. 6. P. Herzen Oncology Research Institute, Moscow, Russia. 7. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 8. Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain. 9. Moscow City Oncology Hospital, Moscow, Russia. 10. IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori, Meldola, Italy. 11. Department of Oncology, Aarhus University Hospital, Aarhus, Denmark. 12. Hospital Clínic of Barcelona, Medical Oncology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain. 13. Genentech Inc, South San Francisco, California. 14. F. Hoffmann-La Roche Ltd, Basel, Switzerland. 15. Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
Abstract
IMPORTANCE: Interim analyses of the IMmotion151 trial (A Study of Atezolizumab in Combination With Bevacizumab Versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma) reported improved progression-free survival (PFS) for patients with programmed death ligand 1-positive (PD-L1+) metastatic renal cell carcinoma (mRCC) receiving the PD-L1 inhibitor atezolizumab plus the vascular endothelial growth factor (VEGF) inhibitor bevacizumab vs the receptor tyrosine kinase inhibitor sunitinib. Overall survival (OS) results were immature at interim analyses. OBJECTIVE: To report the final OS results, safety, and exploratory biomarker analyses of the association of transcriptomic subgroups with OS in the IMmotion151 trial. DESIGN, SETTING, AND PARTICIPANTS: IMmotion151 was a multicenter, open-label, phase 3 randomized clinical trial that compared the efficacy and safety of atezolizumab plus bevacizumab vs sunitinib in patients with untreated mRCC. IMmotion151 included patients from 152 academic medical centers and community oncology practices in 21 countries. Adult patients with mRCC with components of clear cell or sarcomatoid histologic features, measurable disease (according to Response Evaluation Criteria in Solid Tumors, version 1.1), adequate performance status, hematologic and end organ function, and tumor tissue available for PD-L1 testing were included. IMmotion151 was initiated on May 20, 2015, and the study is ongoing. This final analysis was performed from May 20, 2015, to February 14, 2020. INTERVENTIONS: Receipt of 1200 mg of intravenous (IV) atezolizumab every 3 weeks and 15 mg/kg of IV bevacizumab every 3 weeks or 50 mg orally once daily of sunitinib (4 weeks on and 2 weeks off). MAIN OUTCOMES AND MEASURES: The coprimary end points were PFS (previously reported) in patients with PD-L1+ disease and OS in the intention-to-treat population. Additional exploratory outcomes included OS in the PD-L1+ population, association with transcriptomic subgroups, and safety. RESULTS: The IMmotion151 trial assessed 915 patients with metastatic renal cell carcinoma. Mean (IQR) age was 62 (56-69) years for patients receiving atezolizumab plus bevacizumab and 60 (54-66) years for patients receiving sunitinib; 669 (73.1%) were male and 246 (26.9%) were female. The final analysis showed similar median OS in patients receiving atezolizumab plus bevacizumab vs sunitinib in the intention-to-treat (36.1 vs 35.3 months) and PD-L1+ (38.7 vs 31.6 months) populations. No new safety signals were reported. The additional exploratory outcome of atezolizumab plus bevacizumab vs sunitinib showed improved median OS trends in patients whose tumors were characterized by T-effector/proliferative, proliferative, or small nucleolar RNA transcriptomic profiles (35.4 vs 21.2 months; hazard ratio, 0.70; 95% CI, 0.50-0.98). CONCLUSIONS AND RELEVANCE: The primary end point of PFS was met at interim analyses, although no improvement in OS was observed with atezolizumab plus bevacizumab at the final analysis. Biomarker analyses provided insight into which patients with mRCC may benefit from combined anti-PD-L1 and anti-VEGF therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02420821.
IMPORTANCE: Interim analyses of the IMmotion151 trial (A Study of Atezolizumab in Combination With Bevacizumab Versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma) reported improved progression-free survival (PFS) for patients with programmed death ligand 1-positive (PD-L1+) metastatic renal cell carcinoma (mRCC) receiving the PD-L1 inhibitor atezolizumab plus the vascular endothelial growth factor (VEGF) inhibitor bevacizumab vs the receptor tyrosine kinase inhibitor sunitinib. Overall survival (OS) results were immature at interim analyses. OBJECTIVE: To report the final OS results, safety, and exploratory biomarker analyses of the association of transcriptomic subgroups with OS in the IMmotion151 trial. DESIGN, SETTING, AND PARTICIPANTS: IMmotion151 was a multicenter, open-label, phase 3 randomized clinical trial that compared the efficacy and safety of atezolizumab plus bevacizumab vs sunitinib in patients with untreated mRCC. IMmotion151 included patients from 152 academic medical centers and community oncology practices in 21 countries. Adult patients with mRCC with components of clear cell or sarcomatoid histologic features, measurable disease (according to Response Evaluation Criteria in Solid Tumors, version 1.1), adequate performance status, hematologic and end organ function, and tumor tissue available for PD-L1 testing were included. IMmotion151 was initiated on May 20, 2015, and the study is ongoing. This final analysis was performed from May 20, 2015, to February 14, 2020. INTERVENTIONS: Receipt of 1200 mg of intravenous (IV) atezolizumab every 3 weeks and 15 mg/kg of IV bevacizumab every 3 weeks or 50 mg orally once daily of sunitinib (4 weeks on and 2 weeks off). MAIN OUTCOMES AND MEASURES: The coprimary end points were PFS (previously reported) in patients with PD-L1+ disease and OS in the intention-to-treat population. Additional exploratory outcomes included OS in the PD-L1+ population, association with transcriptomic subgroups, and safety. RESULTS: The IMmotion151 trial assessed 915 patients with metastatic renal cell carcinoma. Mean (IQR) age was 62 (56-69) years for patients receiving atezolizumab plus bevacizumab and 60 (54-66) years for patients receiving sunitinib; 669 (73.1%) were male and 246 (26.9%) were female. The final analysis showed similar median OS in patients receiving atezolizumab plus bevacizumab vs sunitinib in the intention-to-treat (36.1 vs 35.3 months) and PD-L1+ (38.7 vs 31.6 months) populations. No new safety signals were reported. The additional exploratory outcome of atezolizumab plus bevacizumab vs sunitinib showed improved median OS trends in patients whose tumors were characterized by T-effector/proliferative, proliferative, or small nucleolar RNA transcriptomic profiles (35.4 vs 21.2 months; hazard ratio, 0.70; 95% CI, 0.50-0.98). CONCLUSIONS AND RELEVANCE: The primary end point of PFS was met at interim analyses, although no improvement in OS was observed with atezolizumab plus bevacizumab at the final analysis. Biomarker analyses provided insight into which patients with mRCC may benefit from combined anti-PD-L1 and anti-VEGF therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02420821.
Authors: Thomas Powles; Elizabeth R Plimack; Denis Soulières; Tom Waddell; Viktor Stus; Rustem Gafanov; Dmitry Nosov; Frédéric Pouliot; Bohuslav Melichar; Ihor Vynnychenko; Sergio J Azevedo; Delphine Borchiellini; Raymond S McDermott; Jens Bedke; Satoshi Tamada; Lina Yin; Mei Chen; L Rhoda Molife; Michael B Atkins; Brian I Rini Journal: Lancet Oncol Date: 2020-10-23 Impact factor: 41.316
Authors: Brian I Rini; Thomas Powles; Michael B Atkins; Bernard Escudier; David F McDermott; Cristina Suarez; Sergio Bracarda; Walter M Stadler; Frede Donskov; Jae Lyun Lee; Robert Hawkins; Alain Ravaud; Boris Alekseev; Michael Staehler; Motohide Uemura; Ugo De Giorgi; Begoña Mellado; Camillo Porta; Bohuslav Melichar; Howard Gurney; Jens Bedke; Toni K Choueiri; Francis Parnis; Tarik Khaznadar; Alpa Thobhani; Shi Li; Elisabeth Piault-Louis; Gretchen Frantz; Mahrukh Huseni; Christina Schiff; Marjorie C Green; Robert J Motzer Journal: Lancet Date: 2019-05-09 Impact factor: 79.321
Authors: Toni K Choueiri; Thomas Powles; Mauricio Burotto; Bernard Escudier; Maria T Bourlon; Bogdan Zurawski; Victor M Oyervides Juárez; James J Hsieh; Umberto Basso; Amishi Y Shah; Cristina Suárez; Alketa Hamzaj; Jeffrey C Goh; Carlos Barrios; Martin Richardet; Camillo Porta; Rubén Kowalyszyn; Juan P Feregrino; Jakub Żołnierek; David Pook; Elizabeth R Kessler; Yoshihiko Tomita; Ryuichi Mizuno; Jens Bedke; Joshua Zhang; Matthew A Maurer; Burcin Simsek; Flavia Ejzykowicz; Gisela M Schwab; Andrea B Apolo; Robert J Motzer Journal: N Engl J Med Date: 2021-03-04 Impact factor: 91.245
Authors: Robert J Motzer; Romain Banchereau; Habib Hamidi; Thomas Powles; David McDermott; Michael B Atkins; Bernard Escudier; Li-Fen Liu; Ning Leng; Alexander R Abbas; Jinzhen Fan; Hartmut Koeppen; Jennifer Lin; Susheela Carroll; Kenji Hashimoto; Sanjeev Mariathasan; Marjorie Green; Darren Tayama; Priti S Hegde; Christina Schiff; Mahrukh A Huseni; Brian Rini Journal: Cancer Cell Date: 2020-11-05 Impact factor: 31.743
Authors: Robert Motzer; Boris Alekseev; Sun-Young Rha; Camillo Porta; Masatoshi Eto; Thomas Powles; Viktor Grünwald; Thomas E Hutson; Evgeny Kopyltsov; María J Méndez-Vidal; Vadim Kozlov; Anna Alyasova; Sung-Hoo Hong; Anil Kapoor; Teresa Alonso Gordoa; Jaime R Merchan; Eric Winquist; Pablo Maroto; Jeffrey C Goh; Miso Kim; Howard Gurney; Vijay Patel; Avivit Peer; Giuseppe Procopio; Toshio Takagi; Bohuslav Melichar; Frederic Rolland; Ugo De Giorgi; Shirley Wong; Jens Bedke; Manuela Schmidinger; Corina E Dutcus; Alan D Smith; Lea Dutta; Kalgi Mody; Rodolfo F Perini; Dongyuan Xing; Toni K Choueiri Journal: N Engl J Med Date: 2021-02-13 Impact factor: 91.245
Authors: T K Choueiri; R J Motzer; B I Rini; J Haanen; M T Campbell; B Venugopal; C Kollmannsberger; G Gravis-Mescam; M Uemura; J L Lee; M-O Grimm; H Gurney; M Schmidinger; J Larkin; M B Atkins; S K Pal; J Wang; M Mariani; S Krishnaswami; P Cislo; A Chudnovsky; C Fowst; B Huang; A di Pietro; L Albiges Journal: Ann Oncol Date: 2020-04-25 Impact factor: 32.976
Authors: Aly-Khan A Lalani; Daniel Y C Heng; Naveen S Basappa; Lori Wood; Nayyer Iqbal; Deanna McLeod; Denis Soulières; Christian Kollmannsberger Journal: Ther Adv Med Oncol Date: 2022-06-28 Impact factor: 5.485