ASCO 2018: Measurable Immunologic Changes and Improved Clinical Activity in mRCC with Nivolumab + Bevacizumab or Nivolumab + Ipilimumab

Chicago, IL ( Frontline therapy for metastatic renal cell carcinoma has changed dramatically over the past 25 years. The therapies exploit different biologic pathways which are dysregulated in RCC, including targeting vascular endothelial growth factor, fibroblast growth factor, stem-cell factor, and platelet-derived growth factor via tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors1. Immunotherapy was there at the very beginning with IL-2 – however, only a small portion of patients had a durable benefit2. More recently, Motzer et al reported on Checkmate 214, a phase III randomized controlled trial comparing nivolumab plus ipilimumab with sunitinib for previously untreated clear cell advanced RCC3. In this study, the combination of nivolumab plus ipilimumab had a significant overall survival benefit over sunitinib (12 month OS: 80% vs 72%) as well as improved median overall survival (not reached vs 26 months).The response rates were also greater in the ipi/nivo arm (42% vs 27%). 

This novel study expands the body of literature around combination checkpoint inhibition therapy prior to cytoreductive nephrectomy or metastasectomy by comparing nivolumab vs nivolumab + bevacizumab vs nivolumab + ipilimumab. In this open label randomized study, 90 patients with metastatic RCC have been evaluated this far and responses were assessed after 12 weeks. Patients were randomized in a 2:3:2 ratio to receive nivolumab, nivolumab + bevacizumab or nivolumab + ipilimumab, followed by surgery (CN or MS), or biopsy, and subsequently nivolumab maintenance therapy up to 2 years

In the nivolumab arm (n=26), 50% of patients have a complete response or partial response, vs 48% of patients in the nivolumab + bevacizumab arm (n=38), compared with 39% in the nivolumab + ipilimumab arm (n=26). There was no significant difference between progression free survival in between the three arms but the main goal of this study was to establish the safety of the therapy. Grade 3+ adverse events ranged from 24-30% between the in the three arms which was acceptable per Dr. Shuch. 

Given this trial design, Dr. Shuch noted that the authors now have a very rich supply of tissue which they can use to compare differences in immune environments between the responders and non-responders. Already, some data has signaling data has revealed increased interferon gamma signaling in the responders compared to non-responders as expected, as well as increased immune cell signals in both pre- and post-treatment tumor tissues. 

In conclusion, Shuch stated that pre-surgical therapy with nivolumab + bevacizumab or ipilimumab is safe with good clinical benefit and for those patients who are able to stay on therapy, they had excellent disease control with rates as high as 69-93% (CR/PR/SD). Further immune/molecular correlative studies are likely to be produced from this study which may highlight important biomarkers for mono and dual therapy checkpoint therapy in combination with anti-VEGF therapy. 

Presented by: Jianjun Gao, MD, Ph.D. The University of Texas MD Anderson Cancer Center
Discussion by: Brian Shuch, MD

1. Curti BD. Immunotherapy in Advanced Renal Cancer — Is Cure Possible? New England Journal of Medicine 2018;378:1344-5.
2. Dutcher JP, Atkins M, Fisher R, et al. Interleukin-2-based therapy for metastatic renal cell cancer: the Cytokine Working Group experience, 1989-1997. The cancer journal from Scientific American 1997;3:S73-8.
3. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2018;378:1277-90.

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA
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