Editing Metastatic Kidney Cancer (section)

== Targeted molecular agents in ccRCC ==

* '''Vascular endothelial growth factor (VEGF) antagonists''' '''(-nib + bevacizumab)'''
** '''Bevacizumab'''
*** Humanized '''monoclonal antibody against VEGF-A'''
*** The first VEGF pathway antagonist used in clinical trials
*** Not widely used as a single agent in the initial therapy for metastatic ccRCC but may have a role in patients who have failed standard therapy with first-line VEGFR antagonists, either alone or in combination with other agents, particularly IFN-α
** '''Sunitnib (Sutent)'''
*** An '''oral''' receptor '''kinase inhibitor''' with activity against VEGFR-2, PDGFR-β, c-Kit, and fms-like tyrosine kinase 3 (Flt3)
*** '''Widely used in the initial treatment of metastatic ccRCC'''
*** '''In an RCT comparing sunitinib vs. IFN-α in patients with metastatic clear cell RCC, sunitinib improved OS, PFS, RECIST response rates (30-40%), and quality of life'''
**** Motzer, Robert J., et al."Sunitinib versus interferon alfa in metastatic renal-cell carcinoma." New England Journal of Medicine 356.2 (2007): 115-124.  
*** The dose and schedule of sunitinib should be optimized for each patient in order to derive the most benefit. '''Recommended to start with the monograph standard of 4-week-on/2-week-off dosing schedule'''. After evaluation of type and timing of toxicities, patients may require adjustments to the schedule and/or dose
*** '''Potential adverse effects'''
***# '''Diarrhea'''
***# '''Hand-foot syndrome'''
***# '''Hypothyroidism'''
***#* '''Patients should be monitored with TSH and T4 measurements'''
***# '''Hypertension'''
***# '''Rash'''
***# '''Fatigue'''
***# '''Asthenia'''
***# '''Bone marrow suppression'''
** '''Sorafenib''' (Nexavar)
*** An oral receptor '''kinase inhibitor''' with activity against VEGFR-2, PDGF receptor-β (PDGFR-β), and raf-1.
*** '''Side effect profile comparable to that of other agents in this class and includes hypertension, fatigue, rash, hand-foot syndrome, and diarrhea.'''
*** In a randomized phase 2 study, '''sorafenib was not superior to IFN-α in previously untreated patients with metastatic clear cell RCC'''
*** Currently, '''infrequently used in the first-line setting.'''
*** Anecdotal evidence and small case series suggest that patients whose disease has progressed on other VEGFR inhibitors may respond favorably to sorafenib, and the agent is commonly used in patients whose disease has progressed on sunitinib or similar agents.
** '''Pazopanib'''
*** '''Agents such as sunitinib and sorafenib have activity against a wide array of target molecules, some of which may not be relevant in ccRCC.''' '''A variety of newer agents with''' '''selective activity against the VEGFR''' family have recently gained attention as a possible means of diminishing the side effects associated with therapy without compromising efficacy
*** '''COMPARZ'''
**** '''Randomized 1110 patients with metastatic ccRCC to pazopanib vs. sunitnib'''
**** '''OS similar between groups''', with a median OS of 28.4 months in the pazopanib group versus 29.3 months in the sunitinib group; PFS with pazopanib was noninferior to sunitinib
**** '''Different adverse event profile''':
***** '''Sunitinib associated with increased incidence of fatigue, thrombocytopenia, and hand-foot syndrome'''
***** '''Pazopanib associated with increased levels of alanine aminotransferase'''
*** Pazopanib is a reasonable first-line option for patients with advanced clear cell RCC. Although pazopanib appears to be better tolerated than sunitinib by the majority of patients, it appears to be associated with an '''increased incidence of''' '''hepatotoxicity''' and must be used with caution in patients at risk for this complication
** '''Axitinib'''
*** Highly selective oral small molecule tyrosine '''kinase inhibitor''' of VEGFR-1, VEGFR-2, and VEGFR-3
*** '''AXIS'''
**** Based on the improved PFS compared to sorafenib in the AXIS trial, axitinib was approved by the FDA for use in the second-line setting in patients with advanced RCC.
** Other agents targeting the VEGF pathway: tivozanib, nintedanib, and dovitinib
** '''Cabozantinib'''
*** Dual VEGFr/MET and AXL inhibitor
*** Not yet approved for patients with metastatic RCC or any other tumour site in Canada, and so it is not considered an option for Canadian patients

* '''Mammalian target of rapamycin (mTOR) inhibitors''' ('''-limus)'''
** mTOR inhibition correlates with a block in HIF-1α translation
** 2 analogues of sirolimus, '''temsirolimus and everolimus''', have been clinically evaluated with demonstrable activity in RCC
** '''Temsirolimus'''
*** '''ARCC'''
**** In poorer-risk patients, IV temsirolimus produces an improvement in PFS and OS compared to IFN-α alone, and the combination of temsirolimus and IFN-α does improve OS over IFN-α alone
* '''Combination and sequential therapy with agents targeting the von Hippel-Lindau pathway'''
** '''RECORD-3'''
*** A non-inferiority trial that examined oral sunitinib followed by oral everolimus at progression or the alternate order of drug administration in all risk groups of patients with metastatic RCC. Non-inferiority of first-line everolimus was rejected i.e. first-line everolimus inferior. Thus, '''data for first-line mTOR inhibitors only supports the use of temsirolimus, and only in poorer-risk patients'''
** '''First-line VEGFR–tyrosine kinase inhibitor followed by mTOR agent upon disease progression results in better outcomes than using an mTOR agent first'''
* '''Other treatment options in patients with clear cell RCC'''
** '''Conventional cytotoxic chemotherapy has been largely ineffective in the management of ccRCC'''
** Progestational and other hormonal agents have no role in the current management of RCC.