Kidney tumours, if detected early enough, can often be removed surgically without the need for further drug treatments. However, if the primary tumour metastasises traditional chemotherapies and radiotherapies become ineffective and patient survival is limited. In recent years there have been great advances in treatments for metastatic renal cell carcinoma (mRCC) with several targeted treatments now available. However, these targeted treatments show variable response rates and efficacy. This blog summarises recent results from clinical trials assessing new treatments.
The standard first-line treatment for mRCC is an anti-angiogenic and anti-proliferative tyrosine kinase inhibitor (TKI) such as sunitinib or sorafenib. In a recent phase II trial sunitinib was used in combination with trebananib – a peptide-Fc fusion protein that acts on additional pathways to further limit angiogenesis. The combination treatment of trebananib and sunitinib showed an increased response rate and longer progression free survival (PFS) (Atkins et al., 2015).However, it also showed increased toxicity compared to sunitinib alone, with a higher percentage of severe adverse events.
In patients where tumours become resistant to the first-line TKI treatment it is common to use an mTOR inhibitor such as everolimus for the second-line treatment. Recently two trials have suggested that novel TKIs Cabozantinib and Lenvatinib could be provide more effective treatments. Patients on cabozantinib – which acts on VEGFR, MET, RET, KIT and AXL signalling – showed a 42% reduction in progression, extended PFS, and a greater rate of tumour reduction (Choueiri et al., 2015). It is also being trialled as a first line treatment and in combination with other treatments. Lenvatinib – which acts on VEGFR, FGFR, RET, KIT and PDGFR signalling – also enhanced PFS and overall survival (OS) in combination with everolimus compared to everolimus treatment alone (Motzer et al., 2015).
An alternative treatment strategy is immunotherapy which enables the body’s own immune system to more efficiently target tumour cells. Nivolumab is a PD-1 inhibitor that restores T-cell immune activity. In comparison to everolimus as a second line treatment, nivolumab was recently reported to increase overall survival and have a greater impact on tumour shrinkage. Patients receiving nivolumab also had a lower rate of severe adverse events (Motzer et al., 2015b).
Finally it was recently announced that Dr W. Marston Linehan is leading a phase II trial of Berg’s drug BPM 31510 at the NIH. BPM 31510 modulates mitochondrial metabolic networks to reverse the Warburg effect characteristic of tumour cells. Preclinical and early trials results show solid tumour reduction and stable disease with no reported severe adverse events.
The development of new and more efficient treatments for kidney cancer is an active field. Ongoing basic research into the biology of tumourigenesis will enable more specific and targeted drugs to be produced. Being able to select patient cohorts that are more likely to respond to a particular treatment would reduce unnecessary and ineffective treatments which can have severe side effects. This relies on the identification of biomarkers which will be discussed in a further blog post.
- Atkins MB, Gravis G, Drosik K, Demkow T, Tomczak P, Wong SS, Michaelson MD, Choueiri TK, Wu B, Navale L, Warner D, Ravaud A (2015). Trebananib (AMG 386) in Combination With Sunitinib in Patients With Metastatic Renal Cell Cancer: An Open-Label, Multicenter, Phase II Study. J Clin Oncol. 20;33(30):3431-8. PMID: 26304872
- Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ; METEOR Investigators (2015). Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 5;373(19):1814-23. PMID: 26406150
- Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim HJ, Wood K, Dutcus C, Larkin J (2015). Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 16(15):1473-82. PMID: 26482279
- Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P, & CheckMate 025 Investigators (2015). Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. The New England journal of medicine, 373 (19), 1803-13 PMID: 26406148