Targeting of the VEGF or mTOR molecular signalling pathways has been a strategy for treating advanced renal cell carcinoma. A new study has reported on the results of a clinical trial combining both forms of therapy, with promising results.
Renal Cell Carcinoma
Renal cell carcinoma is a cancer that originates in the kidney, making up approximately 85% of total cases of kidney cancers. Renal cell carcinoma occurs more frequently in men, and its incidence is on the rise. Renal cell carcinoma is usually diagnosed at later stages of progression, when cancer is more likely to progress despite treatment with chemotherapy or radiation.
Targeting the VEGF and mTOR Signalling Pathways
Investigation of the molecular components of renal cancer cell signalling and survival has revealed key pathways that can be used as therapeutic targets. The VEGF signalling pathway is one of these regulatory pathways, involved in renal cell carcinoma pathogenesis via promoting the formation of blood vessels, inducing cell division and migration, and promoting cell survival. More recent therapies, such as bevacizumab, have therefore aimed to block VEGF signalling by binding to and blocking the VEGF receptor. Other methods include blocking downstream signalling of the VEGF receptor with drugs such as sunitinib, sorafenib, and pazopanib. The mTOR signalling pathway has also been a target for renal cell cancer therapies. mTOR is a growth regulator that can be inhibited by the drugs everolimus and temsirolimus.
Targeting these pathways has proven to be a promising method of treating renal cell carcinoma. Currently, standard therapy for metastatic renal cell carcinoma is a sequence of drug treatments targeting both the VEGF or mTOR signalling pathways within cancer cells. First choices for treatment include sunitinib and pazopanib. If cancer progresses after treatment with these drugs, axitinib or everolimus are also available for use.
Lenvatinib is a drug that also targets VEGF signalling, by inhibiting the VEGFR1, VEGFR2, and VEGFR3 proteins. In addition, lenvatinib also inhibits several other proteins such as the FGFRs. Studies in mice have shown beneficial effects of combining lenvatinib and everolimus to kill renal cancer cells.
A phase 1 study of lenvatinib assessed safety and tolerability with everolimus in patients with metastatic renal cell carcinoma. Results from the phase 2 part of the study were reported this month in the Lancet. The study compared treatment with either lenvatinib or everolimus alone, or in combination, in patients with metastatic renal cell carcinoma who had progressed following treatment with another form of VEGF-targeted therapy. The study took place at over 37 study centres across five countries (Czech Republic, Poland, Spain, the UK, and the USA). Participants were included in the study if they were over the age of 18, with confirmed progression of renal cell carcinoma, with previous treatment having been stopped within 9 months.
The study reported that second-line treatment with lenvatinib resulted in better progression-free survival, either alone or in combination with everolimus, when compared with everolimus treatment alone. The best result, however, was seen with lenvatinib plus everolimus treatment, with an increase in overall survival in this treatment group. The side-effects noted included fatigue, hypertension, diarrhoea, and proteinuria.
The results of this trial are particularly important, since increases in overall survival are rarely seen in clinical trials of metastatic renal cell carcinoma. The authors suggest that future studies should evaluate the combination in terms of risk versus benefit, due to the high frequency of adverse events.
Another phase 1 clinical trial assessing the safety and tolerability of lenvatinib combined with everolimus in patients with unresectable advanced or metastatic renal cell carcinoma is currently recruiting participants. Results of this study will confirm and extend the results of the current study, providing further support for this combination of therapies in the treatment of advanced renal cell carcinoma.
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Motzer, RJ, Hutson, TE, Glen, H, Michaelson, MD, Molina, A, Elsen, T, Jassem, J, Zolnierek, J, Maroto, JP, Mellado, B, Melichar, B, Tomasek, J, Kremer, A, Kim, H-J, Wood, K, Dutcus, C, Larkin, J. “Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial” The Lancet Oncology, Volume 16 , Issue 15 , 1473 http://www.lancet.com/journals/lanonc/article/PIIS1470-2045(15)00290-9/fulltext
clinicaltrials.gov “Study of Lenvatinib in Combination With Everolimus in Patients With Unresectable Advanced or Metastatic Renal Cell Carcinoma (RCC)” Available from: https://www.clinicaltrials.gov/ct2/show/NCT02454478?term=lenvatinib&recr=Open&no_unk=Y&rank=2 Last Accessed: November 5, 2015.
Written by Deborah Tallarigo, PhD