**8. Mammalian Target of Rapamycin (mTOR) inhibitors**

Temsirolimus is an inhibitor of mammalian target of rapamycin (mTOR), a molecule impli‐ cated in multiple tumor-promoting intracellular signaling pathways.

Activation of the mTOR protein, through cellular stimuli-triggered activation of the PI3K/Akt pathway, can also result in HIF accumulation. mTOR phosphorylates and activates p70S6K, which results in enhanced translation of certain proteins, including HIF. Activated HIF translocates into the nucleus, where it triggers the transcription of a large number of hypoxiainducible genes; among these are the growth factors vascular endothelial growth factor (VEGF) and PDGF. These growth factors interact with their respective cell-surface receptors, leading to cell migration, proliferation, and permeability. Temsirolimus and everolimus bind to the FK506-binding protein; this resultant protein-drug complex inhibits the kinase activity of mTOR within the mTORC1 complex.

**9. Axitinib (AG013736)**

**10. Pazopanib (GW786034)**

**11. BAY 73-4506**

AG013736 is another orally bioavailable small-molecule TKI of VEGFR-2 and PDGFR-B that has shown activity in metastatic RCC. Preclinical data from Inai and colleagues suggested that AG013736 inhibited angiogenesis and caused regression of existing tumor vessels.A phase II trial enrolled 62 treatment-refractory patients with RCC that had progressed on sorafenib [24]. They were treated with oral axitinib 5mg twice daily. Of 62 patients, 13 (21%) patients exhibited a partial response and the median PFS was 7.4 months. Another phase II trial with axitinib enrolled cytokine-refractory, nephrectomized patients and demonstrated a response rate of 44.2% and a median time to progression of 15.7 months (25]. Grade 1/2 toxicity included hypertension (33%), fatigue (29%), nausea (29%), diarrhea (27%), hoarseness (19%), anorexia (17%), and weight loss (15%). Grade 3/4 toxicity included hypertension (18%), diarrhea (6%), fatigue (6%), blister (4%), and limb pain (4%). These studies confirm that AG-013736 produces

Current Perspectives in Metastatic Renal Cell Carcinoma Treatment: The Role of Targeted Therapies

http://dx.doi.org/10.5772/54856

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Pazopanib hydrochloride is an oral, angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-kit. In October 2009, the US Food and Drug Administration–approved pazopanib for the treatment of patients with advanced renal cell carcinoma. In the international, multicenter, randomized, double-blind trial, 435 patients were randomly assigned (2:1) to receive pazopanib (n = 290) or placebo (n = 145), [26]. The study demonstrated a median progression-free survival (the primary endpoint) of 9.2 months in the pazopanib arm vs 4.2 months in the placebo arm (hazard ratio [HR]: 0.46; P <.001). This effect was observed both in patients who had not received previous treatment (HR: 0.40) as well as patients pretreated with cytokine therapy (HR: 0.54). The median duration of responses was 13.5 months. The overall survival results were not mature yet and 40% of patients died by the time of final data cut-off. Based on this study, the recommended dose of pazopanib for the treatment of advanced renal cell carcinoma is 800 mg administered orally

BAY 73-4506 is an orally active, potent multikinase inhibitor targeting both tumor cell proliferation and tumor vasculature through inhibition of receptors of tyrosine kinases (VEGFR, KIT, RET, FGFR, and PDGFR) and serine/threonine kinases (RAF and p38MAPK). Previously untreated patients with predominantly clear cell RCC and measurable disease according to RECIST were enrolled in this multicenter, open-label, phase II study. Eligibility criteria included ECOG performance status 0–1, low or intermediate risk MSKCCC prognostic profiles, and adequate bone marrow and organ function. Treatment consisted of BAY 73-4506

a substantial objective response rate in cytokine-refractory, metastatic RCC.

once daily without food (at least 1 hour before or 2 hours after a meal).

Temsirolimus was initially evaluated for patients with mRCC in a randomized phase II study of three different dose levels [21]. When patients were retrospectively stratified into MSKCC prognostic risk groups, the poor risk group appeared to have a better than expected OS, leading to further evaluation in this population.

The subsequent phase III trial with temsirolimus had a primary endpoint of OS. Six hundred and twenty-six previously untreated patients with poor prognostic criteria were randomized to temsirolimus 25mg IV weekly, IFN alpha 18 million units (MU) three times a week or temsirolimus 15 mg IV weekly plus IFN 6 MU three times a week [22]. To be considered poor risk, patients were required to have three or more of the following adverse risk features: Karnofsky performance status less than 80%, lactate dehydrogenase over 1.5 times the upper limit of normal, hemoglobin below the lower limit of normal, serum corrected calcium more than 10 mg/dl, time from first diagnosis of RCC to start of therapy of less than a year and three or more metastatic sites. Of patients included in this trial, 19% had nonclear cell or unknown histology. Temsirolimus monotherapy demonstrated an OS advantage compared to IFN alpha (10.9 months versus 7.3 months, log rank p<0.008). The objective response rates were 8.6% for temsirolimus and 4.8% for IFN, which was not statistically significant. The median PFS for the temsirolimus monotherapy arm and interferon arm was 3.8 months (95% confidence interval (CI): 1.9–2.2) and 1.9 months (95% CI: 3.6–5.2), respectively. Common side effects include fatigue, hypercholesteremia and hyperglycemia. Temsirolimus has become a first-line option for patients with metastatic RCC of any histologic subtype, appropriately applied to patients with poor prognostic criteria.

Another mTOR inhibitor, everolimus (RAD001) has recently been reported to improve progression-free survival in a phase III trial of patients with mRCC who had progressed on sunitinib, sorafenib or both [23]. These patients were randomized to receive either ev‐ erolimus 10mg orally daily or placebo and were stratified by the number of previous ty‐ rosine kinase inhibitors (TKI) and MSKCC 'previously treated' risk groups (one point each for anemia, hypercalcemia, and Karnofsky performance status <80; 0 points=favora‐ ble, 1 point=intermediate, 2 +points=poor risk group). The primary endpoint was PFS and in the everolimus and placebo groups it was 4.9 months and 1.87 months (p<0.0001), re‐ spectively. The PFS benefit was seen in all three MSKCC risk groups. Common side ef‐ fects included asthenia, anemia and stomatitis. Up to 14% of patients experienced some form of pneumonitis. OS was 14.79 and 14.39 months (p=0.117) respectively, however crossover to everolimus was permitted in this study. One hundred and six patients randomized to placebo crossed over to receive everolimus after initial progression. For this group, the median PFS was 5.09 months, which is similar to the PFS of the original everolimus group. This is the first agent tested in a second-line trial after initial TKI fail‐ ure to demonstrate benefit. US FDA approval has recently been granted.
