Targeted Therapies for the Treatment of Metastatic Renal Cell Carcinoma: Clinical Evidence

Abstract

Although systemic therapy for patients with metastatic renal cell carcinoma (mRCC) was once limited to the cytokines interleukin-2 and interferon (IFN)-␣, in recent years several targeted therapies have become available for first-and second-line use. These include sorafenib, sunitinib, bevacizumab (plus IFN-␣), temsirolimus, everolimus, and, most recently, pazopanib. This expanded list of treatment options arose from molecular biological research that revealed aberrant signal transduction activities in RCC, enabling the identification of specific molecular targets for therapy. Molecular-targeted therapies have better efficacy and tolerability than cytokine therapy, and many are administered orally. The superior outcomes achieved with molecular-targeted agents are prompting investigators to reconsider overall survival as a primary endpoint in clinical trials, given the inherent complications of a required long duration of follow-up, a required large population, and confounding caused by crossover trial designs or effects of subsequent therapy after progression on the agent of interest. In mRCC trials, progression-free survival has become a popular primary endpoint and has served as the basis of approval for several targeted therapies. In addition to the identification of new agents, current research is focused on the evaluation of combination therapy with targeted agents. As more information regarding mechanisms of disease and drug resistance becomes available, new targets, new targeted agents, and new combinations will be studied with the goal of providing maximal efficacy with minimal toxicity. This article reviews the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in their pivotal clinical trials, and outlines future research directions. The Oncologist 2011;16(suppl 2):14 -22

Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy

“…OS-RC-2 cells (1 × 10 6 cells) in 70 L PBS were s.c. inoculated into their back, and then grown until the tumor volume was 80-150 mm 3 . Tumor volume was calculated using the formula: 1/2 × a × b 2 , where a and b represent the largest and smallest tumor diameters, respectively.…”

“…This poor or complete lack of response to chemotherapy in RCC can be mainly attributed to acquired drug resistance, including up-regulated P-glycoprotein (P-gp) which functions as an efflux pump for chemotherapeutic drugs [2]. Although interleukin (IL)-2 or interferon (IFN)- based immunotherapy is approved for use, RCC is also resistant to this type of chemotherapy [3]. As a result, the resistance of cancer cells to chemotherapeutic treatment remains a major obstacle to the successful treatment of kidney cancer.…”

“…As a result, the resistance of cancer cells to chemotherapeutic treatment remains a major obstacle to the successful treatment of kidney cancer. Recently, new classes of drugs, sunitinib, sorafenib or bevacizumab, which target specific molecules that are related to the angiogenesis process, such as vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) have been approved for the treatment of RCC [3,4]. Although RCC patients suffer from side effects, the new class drugs appear to have improved clinical benefits [3,4].…”

Beyond Traditional Outcomes: Improving Quality of Life in Patients with Renal Cell Carcinoma

“…As discussed in detail in the article in this supplement by Hutson [20], six molecular targeted agents are currently approved for the treatment of mRCC, including three multitargeted tyrosine kinase inhibitors (TKIs; sunitinib, sorafenib, and pazopanib), two mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus), and one monoclonal antibody against vascular endothelial growth factor (VEGF) in combination with IFN-␣ (bevacizumab plus IFN-␣). Available tolerability and HRQOL data for these agents are summarized below and in Tables 2-5; to date, no HRQOL data have been published for bevacizumab plus IFN-␣ in patients with mRCC.…”

Activity and safety of sunitinib in poor risk metastatic renal cell carcinoma patients

“…These agents include inhibitors of the vascular endothelial growth factor (VEGF) pathway (sunitinib, pazopanib, bevacizumab) and inhibitors of the mammalian target of rapamycin (mTOR) pathway (temsirolimus) (1).…”