Bempegaldesleukin Plus Nivolumab Versus Sunitinib or Cabozantinib in Previously Untreated Advanced Clear Cell Renal Cell Carcinoma: A Phase III Randomized Study (PIVOT-09)
Authors: Tannir Nizar M. , Formiga Maria Nirvana , Penkov Konstantin , Kislov Nikolay , Vasiliev Aleksandr , Gunnar Skare Nils , Hong Walter , Dai Stanley , Tang Lily , Qureshi Anila , Zalevsky Jonathan , Tagliaferri Mary A. , George Daniel , Agarwal Neeraj , Pal Sumanta , Marathe Omkar , Curti Brendan , Hussain Arif , Bilen Mehmet Asim , Pal Sumanta Kumar , Tannir Nizar M. , Uchio Edward , Nair Seresh , Zuniga Richard , Clark William , Agarwal Neeraj , Tester William , Franks Emily , Patel Kamal , Barata Pedro C. , Sharma Janaki Neela , Radhi Saba , Joshi Monika , Parnis Francis , Gurney Howard , Zielinski Robert , Guminski Alexander , Campbell David , Fu Simon , Vasiliev Alexandr , Kopyltsov Evgeniy , Penkov Konstantin , Gladkov Oleg , Perlin Dmitry , Nosov Dmitry , Kheifets Vladimir , Lifirenko Igor , Varlamov Sergey , Kislov Nikolay , Karyakin Oleg , Zhiltsova Elena , Fadeeva Natalia , Kahl Susana , Kowalyszyn Rubén , Pilnik Norma , Amuchastegui Valeria Agostinetti , Pastor Andrea , Vázquez Rocío , Lucas Kaen Diego , Brown Arnold Mario Alfredo , Palazzo Felipe Salvador , Jarchum Gustavo , Pfluger Yanina , Salinas Jorge , Re Juan Pablo , Jobim de Azevedo Sergio , Fay Andre Poisi , Kussumoto Celio , Rocha Roberto Odebrecht , Ferreira Ubirajara , Jose da Fonseca Vinholes Jeferson , Girotto Gustavo Colagiovanni , Lopes dos Santos Victor Marcondes , Nirvana da Cruz Formiga Maria , Zereu Manuela , de Cassia Costamilan Rita , D'Almeida Preto Daniel , Holanda Soares Joao Paulo , Skare Nils Gunnar , Kann Ariel Galapo , Guimaraes Rodrigo Cunha , Patricia dos Santos Martins Suelen , Azambuja Alan Arrieira , Lopes Nogueira Jose Alberto , Brust Leandro , Martins Segalla Jose Getulio , de Liz Vassen Schurmann Maite , Franke Fabio Andre , Sales Silvio Correia , de Castro Monteiro Daniel , Marinho dos Santos Gisele , Cesar de Andrade Mota Augusto , Martinez Lira Jose Luis , Bernal Eduardo Tellez , Bailon Denisse Anorve , Alvarez Ivan Martinez , Soto Francisco Medina , Acevedo Zanabria Carmen Laura , Torrejon Alejandro Figueroa , Zorrilla Silvera Jose David , Salas Rojas Renzo Mauricio , Panay Sergio , Acevedo Gaete Alejandro Andres , Gorena Palominos Mario Alberto , Salman Boghikian Pamela Victoria , de las Nieves Loredo Fort Eugenia , Orellana Ulunque Eric Armando , Hornig Epple Valentina Isabel , Elqueta Pinochet Sergio Fabian , Peng Thomas Soh I. , Sing Ng Quan , Crilley Pamela , Ghani Muhammad 
Published: June 2024

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.