Immunomodulatory Activity of Nivolumab in Previously Treated and Untreated Metastatic Renal Cell Carcinoma (Mrcc): Biomarker-Based Results from a Randomized Clinical Trial

Abstract

ABSTRACT Aim: Nivolumab, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has shown encouraging activity in mRCC. This trial assessed immunomodulatory activity, antitumor response, and safety of nivolumab in patients (pts) with mRCC. Methods: 91 pts received nivolumab IV Q3W: previously treated pts (1-3 prior therapies; ≥1 anti-angiogenic agent) received 0.3 (n = 22), 2 (n = 22), or 10 mg/kg (n = 23); untreated pts received 10 mg/kg (n = 24). Fresh biopsies and serum were obtained at baseline (BL) and at nivolumab cycle 2 day 8 (C2D8; biopsy) and cycle 4 day 1 (C4D1; serum). The primary objective assessed immunomodulatory activity of nivolumab on serum chemokines (CXCL9, CXCL10) and tumor T cell infiltrates from BL to posttreatment. Secondary/exploratory objectives included safety, antitumor activity (ORR, RECIST 1.1; PFS), BL and treatment-induced changes in PD-1 ligand (PD-L1) expression (Dako immunohistochemistry assay; PD-L1 positivity: >5% tumor membrane staining at any intensity) and association of clinical activity with BL PD-L1 expression. Results: T cell infiltrates increased by a median of 70% (CD3 + ; range 53-220%) and 88% (CD8 + ; 61-257%) from BL to C2D8. Mean increase from BL to C4D1 was 180% for CXCL9 and 79% for CXCL10. In evaluable pts ORR was 17% (15/90); 18% previously treated, 13% untreated pts. Median duration of response was 64 weeks; 6 (43%) responses are ongoing. PFS rate at 48 wks was 18% (16/90). Grade 3-4 AEs occurred in 15% (14/91): colitis and elevated AST (n = 2 each), diarrhea, elevated ALT and pneumonitis (n = 1 each). Of 56 evaluable pretreatment biopsies, 18 (32%) were PD-L1+. ORR was 22% (4/18) for PD-L1+ pts vs 8% (3/38) for PD-L1–. In 5/27 (19%) matched biopsy pairs PD-L1 expression increased >5% by C2D8. Conclusions: In this prospective study, changes in biomarkers were consistent with PD-1 inhibition, evidence of nivolumab's immunomodulatory effects in serum and the tumor microenvironment. Nivolumab demonstrated antitumor activity and manageable safety in pts with previously treated or untreated mRCC. Responses were numerically higher in PD-L1+ pts, but also present in PD-L1– pts. Disclosure: T. Choueiri: Ad Board: Pfizer, Novartis, GSK, Bayer, Aveo Research: Pfizer; M.N. Fishman: I have received funding for research trials from Bristol Myers Squibb; B. Escudier: I have received compensation for consultation/ advisory position to the following: Bayer, Pfizer, Novartis I have received honoraria from the following: Bayer, Roche, Pfizer, Genentech, Novartis, AVEO, GSK; W.M. Stadler: University of Chicago/I has received funding for research from Bristol Myers-Squibb; J.L. Perez-Garcia: I have received funding for research from Bristol Myers Squibb; M.R. Harrison: I have consulted/worked in advisory role to: Novartis, AVEO, Exelixis, Bayer; I have received honoraria from: Novartis, Prometheus; I have received funding for research from: BMS, Argos, Exelixis, Pfizer, Exelixis; E.R. Plimack: Has received grants and/or personal fees from: BMS, GSK, Dendreon, Astellas, Pfizer, Amgen, Acceleron, MedImmune, Merck, Lilly, AZ; L. Appleman: I have received funding from Bristol Myers-Squibb; L. Fong: I have received funding for research from Bristol Myers-Squibb; C.G. Drake: Sponsored Research: Aduro Biotech, BMS, Janssen, I have consulted to: BMS, Compugen, Dendreon, Pfizer, Roche/ Genentech, NexImmune; L. Cohen: I am an employee of Bristol Myers Squibb; S. Srivastava: I am an employee of Bristol Myers Squibb; M. Jure-Kunkel: I am an employee of and have stock or other ownership interest in BMS; Q. Hong: I am an employee of and have stock or other ownership interest in BMS; J. Kurland: I am an employee of and have stock or other ownership interest in BMS; M. Sznol: I have received personal Fees from BMS, Amgen, Medimmune, Genentech, Symphogen, Nektar, Anaeropharma, Immune Design, Merus, Lion Biotechnologies, Kyowa-Kirin, Astra-Zeneca-Medimmune. All other authors have declared no conflicts of interest.