Combination therapy regimens in the treatment of metastatic renal cell carcinoma: A review

Renal cell carcinoma (RCC) is one of the most common tumor types in urologic oncology practice. Despite the improvement of diagnostics methods, about 1/3 of patients with renal cell carcinoma have distant metastases at presentation resulting in an extremely high death rate. For many years, treatment of advanced forms of RCC was utterly ineffective. Standard chemotherapy regimens with fluoropyrimidines and antitumor antibiotics, cytokine therapy with interleukin-2, and interferon-α only slightly prolonged the life of patients while causing severe toxic side effects and anemia. Attempts to treat the tumor with radiation therapy have also failed and have been used only for symptomatic treatment of distant metastases. The introduction of tyrosine kinase inhibitors (TKIs) in the treatment of metastatic RCC (mRCC) has enabled much more significant results. Thus, a landmark event was the approval of TKIs sunitinib and then sorafenib, pazopanib, axitinib, lenvatinib, cabozantinib, and mammalian target of rapamycin (mTOR) inhibitors: everolimus and temsirolimus. Subsequent combined therapy using bevacizumab with low-dose interferon-α and lenvatinib with everolimus improved recurrence-free survival and objective response rates but contributed to increased toxicity of therapy. The next step in RCC therapy was the approval of the combination of the immuno-oncology agents ipilimumab and nivolumab for the treatment of mRCC by the U.S. Food and Drug Administration in April 2018. Later, combinations of immune checkpoint inhibitors with targeted agents were approved, which increased the life expectancy of patients and reduced the toxicity of antitumor therapy. One of the most effective regimens is the combination of a TKI axitinib or lenvatinib with the PD-1 inhibitor pembrolizumab. This article addresses the current progress in the treatment of patients with mRCC, reviewing the results of completed clinical trials on the use of combination therapy with targeted and immuno-oncology agents.