A Review of Data on Optimal Sequencing and Combinations of Current Therapies in Renal Cell

Robert Dreicer, MD, MS
Published: Friday, Mar 04, 2011
The past 2 to 3 decades saw a palpable therapeutic nihilism associated with the management of patients with advanced renal cell carcinoma (RCC), interrupted briefly by the initial excitement regarding high-dose interleukin-2.1 Over the past several years, phase I/II clinical trials of tyrosine kinase inhibitors (TKIs), vascular endothelial growth factor (VEGF) inhibitors, and mammalian target of rapamycin (mTOR) inhibitors in advanced RCC (primarily of clear cell histology) demonstrated intriguing, paradigm-shifting activity. This led to a series of phase III trials that culminated with the FDA’s approval of 6 new drugs in a 5-year span for the management of advanced RCC.

As we reach the midway point of the first decade of targeted therapeutics in RCC, some high-level observations can be made. Despite unequivocal progress, none of the currently available agents cure patients with metastatic RCC and few complete responses are seen with any of them. Although clinical studies with the mTOR inhibitor temsirolimus (Torisel) provided evidence of an improvement in overall survival (OS) in patients with poor risk (per Memorial Sloan-Kettering criteria) disease, demonstrating improvement in survival with other agents has been problematic. This is likely because studies for most of these drugs allowed crossover by large numbers of patients.2 From a patient management perspective, these agents are generally associated with significant toxicity, negatively affecting the quality of life for many patients. Although published data on sequential therapy are limited, it has become a de facto standard of care. Using these agents in combination is more than a little challenging, pending results from additional studies.


It was the significant progress in our understanding of the molecular pathogenesis of RCC during the past decade that led to the development of therapies targeting the VEGF and mTOR pathways.3 Results from a series of phase III studies provide compelling evidence that sunitinib (Sutent), pazopanib (Votrient), temsirolimus, and the combination of bevacizumab (Avastin) and interferon-alpha are clinically active in patients with metastatic RCC as initial therapies or following initial cytokine therapy. The objective response rate (ORR) ranged from 7% to 31% with these agents, and progression-free survival (PFS) ranged from 4 to 11 months.4-8

In chronic myeloid leukemia, another malignant disease commonly treated with targeted agents (eg, imatinib [Gleevec] and nilotinib [Tasigna]), the mechanism of drug resistance is presumed to be mutation of a gene that encodes a key tyrosine kinase receptor targeted by the drug. In contrast, investigators exploring resistance mechanisms in RCC note that because the main target for VEGF receptor (VEGFR) inhibitors resides on the surface of endothelial cells,9 a mutation conferring treatment resistance would most likely have to occur in the tumor endothelium, but it is highly improbable that such a mutation would occur simultaneously in the endothelium of each individual tumor metastasis.10 Other proposed mechanisms for acquired resistance include reemergence of VEGF-driven vasculature, upregulation of alternative proteins in the setting of persistent VEGF or mTOR blockade, and novel mechanisms that are not antiangiogenic in nature.10-13


Following FDA approval of sunitinib, many clinicians managing RCC patients with disease progression on sorafenib (Nexavar) empirically used sunitinib as a salvage option. Retrospective series soon appeared in the literature documenting responses to both agents when used in sequence and reporting clinical activity in patients with disease progression following other VEGFtargeting agents, such as bevacizumab.14-17

More recently, prospectively designed phase II trials have addressed the issue of cross-resistance when using VEGFtargeted therapeutics in sequence. Rini and associates conducted a prospective multicenter phase II trial of sunitinib in 61 patients with metastatic clear cell RCC that had evidence of progression following a bevacizumab-based therapy regimen. Patients received 50 mg of sunitinib daily in 6-week cycles, comprising 4 weeks on therapy followed by 2 weeks off therapy. The researchers observed an ORR of 23% with a median PFS of 30 weeks and a median OS of 47 weeks. Observed treatment-related toxicity was typical of sunitinib in other settings.16

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