Ipilimumab and Nivolumab as First-Line Treatment of Patients with Renal Cell Carcinoma: The Evidence to Date

Abstract: Immunotherapy has revolutionized the management of metastatic renal cell carcinoma with four checkpoint inhibitors (nivolumab, ipilimumab, avelumab, and pembrolizumab) approved either as monotherapy or as combination therapy. The use of ipilimumab and nivolumab for treatment-naïve, intermediate to poor risk, metastatic renal cell carcinoma was the first checkpoint inhibitor-based combination therapy and remains the only dual checkpoint inhibitor combination approved in mRCC. In this article, we review the trials that led to the approval of ipilimumab and nivolumab in this setting. We also highlight the ongoing trials using this combination, its use in special populations, and clinically relevant unanswered questions.

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Keywords: ipilimumab, nivolumab, metastatic renal cell carcinoma, immunotherapy, kidney cancer, checkpoint inhibitors

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INTRODUCTION

Kidney cancer is one of the top ten most common cancers, with an estimated 73,820 new cases in 2019.¹ At presentation, 16–25% of patients will have de novo metastatic disease,² and an estimated 10–28% of patients with early stage disease will progress to metastatic disease despite local treatment. The difference in outcome between localized disease and metastatic disease is drastic with 5 year survival rates of 92.5% to 12.0%, respectively.³

The most common form of kidney cancer is renal cell carcinoma (RCC) which is known to be highly immunosensitive. The immunogenic nature of metastatic RCC (mRCC) was the rationale for the use of high dose interleukin-2 (IL-2) in these patients, though response rates were poor (objective response rates of 14–25% with complete response rates of 2–7%), and treatment related side effects were fairly toxic.^4–7

Subsequently, agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways, as well as checkpoint inhibitor (CPI) immunotherapy have become the primary treatment option for mRCC patients. Notably, in April 2018 the FDA approved the combination of ipilimumab (CTLA-4 antibody) and nivolumab (PD-1 antibody) for treatment-naïve intermediate and poor risk mRCC. This combination was the first CPI-based combination therapy approved and remains the only dual checkpoint blockade approved in mRCC. In this review, we address the evolution of the combination of ipilimumab and nivolumab in the treatment of mRCC. We also highlight ongoing trials with this combination, its use in special populations, and clinically relevant unanswered questions.

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