Abstract CT083: Clinical activity, immune and molecular correlates of nivolumab vs. nivolumab plus bevacizumab vs nivolumab plus ipilimumab in metastatic renal cell carcinoma
Authors: Gao Jianjun , Karam Jose A. , Wood Christopher G. , Matin Surena , Ahrar Kamran , Jonasch Eric , Tannir Nizar , Campell Matthew , Ng Chaan S. , Slack Rebecca S. , Rao Priya , Allison James P. , Blando Jorge M. , Vence Luis M. , Basu Sreyashi , Zhao Hao , Chen Tenghui , Chen Hong , Sharma Padmanee 
Published: July 2017

Abstract
Background: Immune checkpoint blockade including anti-CTLA-4 (ipilimumab, BMS) and anti-PD1 (nivolumab, BMS) as monotherapies have been known to have clinical activity against metastatic renal cell carcinoma (MRCC), but with relatively low clinical response rate (10-25%). Anti-VEGF antibody bevacizumab is a standard therapy for MRCC also with a low response rate (&lt;20%). Since anti-PD1 and anti-CTLA-4 use distinct mechanisms for T cell activation and bevacizumab can promote the function of antigen presenting cells, we hypothesize that combination therapy with nivolumab + bevacizumab or nivolumab + ipilimumab will lead to measurable immunological changes and improved clinical activity.
Methods: In this open-label, pilot, pre-surgical/pre-biopsy trial (NCT02210117), adults with MRCC without prior immune checkpoint therapy and anti-VGEF therapy were enrolled, stratified by planned surgical procedure, and randomized 1:2:1 to receive nivolumab monotherapy, nivolumab + bevacizumab or nivolumab + ipilimumab, followed by cytoreductive nephrectomy, metastasectomy, or post-treatment biopsy, and subsequent maintenance therapy with nivolumab for up to 2 years until disease progression and intolerable toxicity. Pre- and post-treatment blood and tumor samples were obtained for dynamic monitoring of immune and molecular correlates to clinical activity.
Results: Sixty patients were treated (median duration 17.1 weeks, range 2.74 to 85.1 weeks as of 12/6/16). Fourty-four were evaluable for clinical responses post-procedures. Five of 12 (42%) nivolumab monotherapy treated patients had partial response (PR), 4 (33%) had stable disease (SD), and 3 (25%) had progression of disease (PD) and 0 withdrew early (W). In the nivolumab + bevacizumab arm, 1 of 19 (5%) had complete response and 9 (47%) patients had PR, for a response rate of 53%, 3 (16%) had SD, 3 (16%) with PD and 3 (16%) W. In the nivolumab + ipilimumab arm, 5 of 13 (38%) patients had PR, 1 (8%) had SD and 5 (38%) had PD and 2 (15%) W. Treatment was generally well tolerated with mostly grade 1 or 2 adverse events. Grade 3 or higher toxicities were 19% in the nivolumab arm, 41% in the nivolumab + bevacizumab arm (including 17% bevacizumab-specific hypertension that was well controlled by anti-hypertensive medications), and 27% in the nivolumab + ipilimumab arm. Correlative laboratory studies including flow cytometry, IHC, and gene profiling analysis identified a number of immune gene signatures including an IFN-γ gene signature that we will report in more details.
Conclusions: Combination therapy with nivolumab + bevacizumab and nivolumab + ipilimumab showed promising clinical activities in patients with MRCC. Immune and molecular correlative studies may allow us to identify novel biomarkers that can be used for correlation with clinical outcomes in patients with MRCC.
Citation Format: Jianjun Gao, Jose A. Karam, Christopher G. Wood, Surena Matin, Kamran Ahrar, Eric Jonasch, Nizar Tannir, Matthew Campell, Chaan S. Ng, Rebecca S. Slack, Priya Rao, James P. Allison, Jorge M. Blando, Luis M. Vence, Sreyashi Basu, Hao Zhao, Tenghui Chen, Hong Chen, Padmanee Sharma. Clinical activity, immune and molecular correlates of nivolumab vs. nivolumab plus bevacizumab vs nivolumab plus ipilimumab in metastatic renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT083. doi:10.1158/1538-7445.AM2017-CT083