Emerging therapeutics in refractory renal cell carcinoma

ABSTRACT

Introduction: Metastatic renal cell carcinoma (mRCC) has seen the introduction of numerous new treatments over the past decade. However, the efficacy of these therapies has plateaued, and new treatment options are needed for the majority of patients with mRCC whose disease inevitably progresses through one or more standard therapies (‘refractory’ mRCC). Recently approved agents in this space have shown great promise.

Areas covered: This article reviews the evidence behind current management strategies for mRCC. After reviewing clinical trials that established current first-line therapies and agents used in the refractory setting, we address new ideas for the treatment of refractory disease including combination therapies and novel targeted agents. In particular, we focus on targeted immunotherapy in refractory mRCC. We conclude by considering future directions in combination treatments utilizing these novel agents.

Expert opinion: Numerous approaches have produced tangible benefits for the treatment of patients with mRCC. These include development of next generation VEGFR/TKIs, targeted immunotherapy agents, and the development of combined regimens. In particular, immunotherapy agents targeting the PD1/PD-L1 pathway have shown great promise with a robust survival advantage seen in patients treated with nivolumab. A tolerable side effect profile of immunotherapy agents makes them amenable for use in combination therapies and ongoing trials are addressing this question.

KEYWORDS:

• Immunotherapy
• checkpoint inhibitor
• metastatic renal cell carcinoma
• targeted therapy
• nivolumab
• cabozantinib
• VEGFR/TKI
• PD-1/PD-L1 pathway

Article highlights

• The past decade has seen the introduction of numerous new therapies for metastatic RCC (mRCC) targeting VEGF and mTOR pathways including: sunitinib, pazopanib, axitinib, sorafenib, bevacizumab, temsirolimus and everolimus, but despite good initial response to these targeted agents most patients inevitably progress.

• Renal cell carcinoma has long been known to be an immunologically affected tumor and recent advances in immunotherapies targeting the programmed death (PD-1/PD-L1) pathway have shown efficacy in refractory disease.

• Nivolumab, an antibody against programmed death receptor-1 (PD-1), was shown in a randomized phase III trial to have an overall survival advantage and a tolerable side effect profile leading to its recent FDA approval for refractory mRCC.

• Cabozantinib, a second generation VEGFR/TKI, has shown promising results in refractory mRCC and ongoing clinical trials are assessing its efficacy in the first line setting as well as part of a combination regimen.

• The efficacy and tolerable side effect profile of targeted immunotherapy make it amenable for use in combination regimens, with several agents currently being assessed in clinical trials. Although numerous questions remain to be answered regarding patient selection and duration of therapy, targeted immunotherapy will likely become the backbone of therapy for refractory mRCC.

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Declaration of interests

B.I. Rini has acted as a consultant for Pfizer, Bristol-Myers Squibb, Novartis and Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.