Emerging therapeutic approaches in renal cell carcinoma

Abstract

In the past decade, targeted therapy with VEGF and mTOR inhibition has significantly improved the outcome of renal cell carcinoma. However, the management of metastatic renal cell carcinoma still remains challenging as most patients eventually progress on targeted therapy, and long-term survivors are still relatively uncommon. There has recently been a resurgence of interest in cancer immunotherapy with the development of checkpoint inhibitors. Here we discuss the best methods to optimize the current standard of care with targeted therapy, and describe select emerging targeted therapies and immunotherapies with anti programmed death-1 pathway inhibitors in the management of metastatic renal cell carcinoma.

Keywords:

• anti programmed death-1 therapies
• immunotherapy
• ipilimumab
• nivolumab
• renal cell carcinoma
• targeted therapy

Financial & competing interests disclosure

BI Rini has served as a consultant for Pfizer, Bristol-Myers Squibb and AstraZeneca. 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.

Key issues

• Immunotherapy has played a role in the management of the metastatic RCC (mRCC) patients and therapy with high-dose IL-2 results has potential of long-term complete remission in clear cell mRCC, but its use is limited due to severe toxicity.

• In last decade, new therapies including tyrosine kinase targeting VEGF and serine/threonine mTOR kinase inhibitors such as sunitinib, sorafenib, pazopanib, axitinib, temsirolimus and everolimus have been approved for the treatment of mRCC.

• Current areas of interest in management of mRCC focus on optimization of dose and schedule of tyrosine kinase inhibitors to minimize side effects, dose escalation and optimal sequence strategies (e.g., alternate sunitinib schedule, axitinib dose titration).

• Anti-programmed death-1 (PD-1) and anti-programmed death ligand 1 antibodies have shown promising results in monotherapy studies and in combination with VEGF-targeted therapy in Phase I and Phase II studies.

• Combined immunotherapy with anti-PD-1 pathway and anti-cytotoxic T lymphocyte antigen-4 pathway antibody is another area under investigation, and combination of nivolumab and ipilimumab has shown encouraging results in early phase studies.

• Although immunotherapy with anti-PD-1 agent has the potential to change outcome of mRCC, there still remains several answered questions, identifying predictive biomarkers, when to stop/restart therapy, sequential checkpoint inhibition and toxicity management.