WASHINGTON — In the last decade, the development of multiple molecular-targeted therapies has dramatically altered the treatment landscape for advanced renal cell carcinoma (RCC).

The rate of new drug approvals has outpaced the ability of most guidelines to keep up, with four therapies receiving approval or breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) in just the last year.

The following are approved targeted therapies for metastatic RCC with approval dates:

  • Sorafenib (2005)
  • Sunitinib (2006 for first-line use and in 2017 for adjuvant therapy)
  • Temsirolimus (2007)
  • Pazopanib (2009)
  • Everolimus (2009)
  • Bevacizumab + interferon alfa-2b (2010)
  • Axintinib (2012)
  • Nivolumab (2015)
  • Lenvatinib + everolimus (2016)
  • Cabozantinib (2017)
  • Nivolumab+ ipilimumab (2018), for patients with intermediate or poor risk

In addition, pembrolizumab plus lenvatinib and axitinib plus avelumab have received breakthrough therapy designation in the last year.

The targeted therapies fall into two main classes, vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin (mTOR) inhibitors. The National Comprehensive Cancer Network (NCCN) recommends the VEGF inhibitors sunitinib, pazopanib, bevacizumab plus interferon alpha, and cabozantinib in the first-line setting for primarily clear cell renal cell carcinoma. Sorafenib, axitinib and lenvatinib plus everolimus are NCCN recommended second-line therapies.

Of the mTOR inhibitors, NCCN recommends temsirolimus as a first-line therapy for poor-prognosis patients. Everolimus is recommended as a second-line option.

The newest approved agent, nivolumab plus ipilimumab, combines two immune checkpoint inhibitors. Nivolumab targets the programmed death 1 (PD-1) checkpoint protein, while the monoclonal antibody ipilimumab inhibits the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) protein. The combination received FDA approval subsequent to publication of the 2018 NCCN guidelines.

In the phase 3 CheckMate-214 trial on which the FDA based its decision, the nivolumab/ipilimumab combination demonstrated a survival benefit as well as both higher response rates and more durable responses compared to sunitinib in patients with intermediate to poor risk. With a median follow-up of 25.2 months, patients on the combination drug had an 18-month overall survival of 75% and median overall survival was not reached, while those receiving sunitinib had a 60% 18-month overall survival and a median overall survival of 26 months. The combination reduced the risk of progression or death by 28% compared to the standard therapy.1

1Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, et. Al.
CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. doi:10.1056/NEJMoa1712126. Epub 2018 Mar 21. PubMed PMID: 29562145.