Abstract
Insights into the biology of advanced renal cell carcinoma (aRCC) and the development of agents targeting the vascular endothelial growth factor (VEGF) pathway have positively impacted the outcomes for patients with aRCC. With the recent approval of the dual immune checkpoint inhibitors (ICIs), nivolumab and ipilimumab, by the U.S. Food and Drug Administration (USFDA), and the European Medicines Agency (EMA), the era of VEGF monotherapy for untreated aRCC appears to be coming to an end for patients with access to the combination therapy. The frontline treatment options for renal cell carcinoma are evolving rapidly and will lead to the approval of other combination immunotherapies—especially those with VEGF inhibitors. Here we review the clinical data for dual immune checkpoint inhibition with nivolumab plus ipilimumab as well as the emerging data for ICI plus VEGF inhibitor combinations and discuss the challenges these will pose for the clinical practitioner.
Highlights
Historical PerspectiveImmunotherapy with high-dose interleukin-2 (HD IL-2) [1, 2] had been the mainstay for treatment of advanced renal cell carcinoma in the United States until agents targeting the vascular endothelial growth factor (VEGF) pathway became available in 2005
The approval of combination immunotherapy with nivolumab plus ipilimumab marks the beginning of a new era in the therapeutic landscape for patients with advanced renal cell carcinoma
While pazopanib was shown to have adequate VEGF inhibition and immunomodulatory activity, the tolerability has been marginal in combination with immune checkpoint inhibitors (ICIs)
Summary
Immunotherapy with high-dose interleukin-2 (HD IL-2) [1, 2] had been the mainstay for treatment of advanced renal cell carcinoma (aRCC) in the United States until agents targeting the VEGF pathway became available in 2005. PRoleukin Observational Study to Evaluate the Treatment Patterns and CLinical Response in Malignancy (PROCLAIM), a US-based multicenter study designed to capture real-world clinical data for interleukin-2 in patients with metastatic melanoma, aRCC, or other malignancies showed that response after treatment with HD IL-2 was durable. The advent of multi-tyrosine kinase inhibitors (TKIs) or antibodies targeting the VEGF axis clearly had a significant and broad impact on the natural history of advanced renal cell carcinoma; durable response is rare [5,6,7,8,9,10,11,12,13,14], and the development of new options that are tolerable and have the potential for durable responses remains an area of active investigation
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