Combination targeted therapy in advanced renal cell carcinoma

Abstract

Several novel therapies have been approved recently in advanced renal cell carcinoma (RCC). These agents inhibit pathways downstream of loss of the von Hippel‐Lindau gene VHL. They target the vascular endothelial growth factor (VEGF) ligand, VEGF receptor (VEGFR), mammalian target of rapamycin (mTOR), and other potentially important pathways. Even with improvements in survival, disease progresses in all patients. There is a critical need to increase complete responses (now rare). One such strategy is combining several agents to block different levels of the VEGF‐VEGFR axis (vertical blockade). Alternatively, combination of a VEGF‐VEGFR inhibitor with an mTOR inhibitor is attractive. Finally, horizontal blockade of VEGFR with epidermal growth factor receptor and/or platelet‐derived growth factor receptor, all signaling pathways activated by hypoxia‐inducible factor, is another approach. Already trials have revealed difficulties with combination therapy. By combining agents, the toxicity of 1 or both can be enhanced. The authors of this article report their experience with sorafenib plus bevacizumab, which produced increases in hand‐foot syndrome, hypertension, and proteinuria, all known toxic effects. Clinical activity was impressive with 25 responses in 48 patients (52% response rate). Other combinations also required dose reductions (sorafenib with temsirolimus) or were intolerable (sunitinib with temsirolimus or sunitinib with bevacizumab). Unexpected toxicity characterized by microangiopathic hemolytic anemia occurred late in treatment with sunitinib and bevacizumab. Toxicity may be more severe in patients with RCC, who frequently have 1 kidney and poor renal function. Once tolerability for combination regimens has been established, it will be critical to design informative phase 2 trials and address the benefit of combination versus sequential therapy. Cancer 2009;115(10 suppl):2368‐75. © 2009 American Cancer Society.

Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity

“…Objective response (21%) and SD (69%) were observed in 42 evaluable patients. Sosman and Puzanov (2009) evaluated the combination of sorafenib and bevacizumab in a phase I/II trial in mRCC yielding PRs in 4 of 14 patients. Hand -foot skin reaction, hypertension, and stomatitis were dose limiting.…”

Combination of Temsirolimus and tyrosine kinase inhibitors in renal carcinoma and endothelial cell lines

“…Combinations of Sunitinib with Temsirolimus were considered toxic in various early phase 1 trials, but all these trials were conducted at the same doses as used in monotherapy Sosman and Puzanov 2009;Patel et al 2009;Patnaik 2007;Soria et al 2009;Négrier et al 2011). A combination of Sorafenib and Everolimus was recently studied and proven acceptable in terms of toxicity with encouraging evidence of eYcacy (Harzstark et al 2011).…”

A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma

“…Patients with advanced disease are currently treated with antiangiogenesis agents, such as multitargeted tyrosine kinase inhibitors and specific VEGF antagonists, inhibitors of mTOR, and immunomodulatory agents, such as inhibitors of PD-1. Few patients experience a complete response to these agents, and nearly all tumors progress during treatment (2). For patients with advanced or metastatic ccRCC, the 5-year survival rate is only 8% (1).…”