Bempegaldesleukin Plus Nivolumab Versus Sunitinib or Cabozantinib in Previously Untreated Advanced Clear Cell Renal Cell Carcinoma: A Phase III Randomized Study (PIVOT-09)
Nizar M. Tannir, Maria Nirvana Formiga, Konstantin Penkov, Nikolay Kislov, Aleksandr Vasiliev, Nils Gunnar Skare, Walter Hong, Stanley Dai, Lily Tang, Anila Qureshi, Jonathan Zalevsky, Mary Tagliaferri, Daniel J. George, Neeraj Agarwal, Sumanta K. Pal, Omkar Marathe, Brendan D. Curti, Arif Hussain, Mehmet Asım Bilen, Sumanta K. Pal, Nizar M. Tannir, Edward Uchio, Seresh Nair, Richard Zuniga, William R. Clark, Neeraj Agarwal, William Tester, Emily Franks, Kamal Patel, Pedro C. Barata, Janaki Sharma, Saba Radhi, Monika Joshi, Francis Parnis, Howard Gurney, Robert Zielinski, Alexander Guminski, David Campbell, Simon Fu, Alexandr Vasiliev, Evgeniy Kopyltsov, Konstantin Penkov, Oleg Gladkov, Dmitry Perlin, Dmitry Nosov, Vladimir Kheifets, Igor Lifirenko, Sergey Varlamov, Nikolay Kislov, Oleg Karyakin, E. K. Zhiltsova, Natalia Fadeeva, Susana Kahl, Rubén Dario Kowalyszyn, N. Pilnik, Valeria Agostinetti Amuchastegui, Andrea Pastor, Rocío Vázquez, Diego Kaen, Mario Alfredo Brown Arnold, Felipe Salvador Palazzo, Gustavo Jarchum, Yanina Pflüger, Jorge Salinas, Juan Pablo Re, Sérgio Jobim Azevedo, Andre Poisi Fay, Celio Kussumoto, Roberto Odebrecht Rocha, Ubirajara Ferreira, Jeferson Jose da Fonseca Vinholes, Gustavo Girotto, Victor Marcondes Lopes dos Santos, Maria Nirvana Formiga, Manuela Zereu, Rita de Cássia Costamilan, Daniel D’Almeida Preto, João Paulo Holanda Soares, Nils Gunnar Skare, Ariel Galapo Kann, Rodrigo Cunha Guimaraes, Suelen Patrícia dos Santos Martins, Alan A. Azambuja, Jose Alberto Lopes Nogueira, Leandro Brust, J. G. M. Segalla, Maite de Liz Vassen Schurmann, Fábio Franke, Silvio Correia Sales, Daniel de Castro Monteiro, Gisele Marinho dos Santos, Augusto César de Andrade Mota, Jose Luis Martinez Lira, Eduardo Téllez Bernal, Denisse Anorve Bailon, I. Alvarez, Francisco Soto, Carmen Laura Acevedo Zanabria, Alejandro Figueroa Torrejon, Jose David Zorrilla Silvera
Abstract
PURPOSE Bempegaldesleukin (BEMPEG) is a pegylated interleukin (IL)-2 cytokine prodrug engineered to provide controlled and sustained activation of the clinically validated IL-2 pathway, with the goal of preferentially activating and expanding effector CD8 + T cells and natural killer cells over immunosuppressive regulator T cells in the tumor microenvironment. The open-label, phase III randomized controlled PIVOT-09 trial investigated the efficacy and safety of BEMPEG plus nivolumab (NIVO) as first-line treatment for advanced/metastatic clear cell renal cell carcinoma (ccRCC) with intermediate-/poor-risk disease. METHODS Patients with previously untreated advanced/metastatic ccRCC were randomly assigned (1:1) to BEMPEG plus NIVO, or investigator's choice of tyrosine kinase inhibitor (TKI; sunitinib or cabozantinib). Coprimary end points were objective response rate (ORR) by blinded independent central review and overall survival (OS) in patients with International Metastatic RCC Database Consortium (IMDC) intermediate-/poor-risk disease. RESULTS Overall, 623 patients were randomly assigned to BEMPEG plus NIVO (n = 311) or TKI (n = 312; sunitinib n = 225, cabozantinib n = 87), of whom 514 (82.5%) had IMDC intermediate-/poor-risk disease. In patients with IMDC intermediate-/poor-risk disease, ORR with BEMPEG plus NIVO versus TKI was 23.0% (95% CI, 18.0 to 28.7) versus 30.6% (95% CI, 25.1 to 36.6; difference, –7.7 [95% CI, –15.2 to –0.2]; P = .0489), and median OS was 29.0 months versus not estimable (hazard ratio, 0.82 [95% CI, 0.61 to 1.10]; P = .192), respectively. More frequent all-grade treatment-related adverse events (TRAEs) with BEMPEG plus NIVO versus TKI included pyrexia (32.6% v 2.0%) and pruritus (31.3% v 8.8%). Grade 3/4 TRAEs were less frequent with BEMPEG plus NIVO (25.8%) versus TKI (56.5%). CONCLUSION First-line BEMPEG plus NIVO for advanced/metastatic ccRCC did not improve efficacy in patients with intermediate-/poor-risk disease but led to fewer grade 3/4 TRAEs versus TKI.