RCC clinical trials: positive results and new phase III clinical study

Renal cell carcinoma (RCC) is by far the most common type of kidney cancer and it can be caused by genetic conditions such as BHD (Randall et al., 2014). BHD patients can develop multiple kidney tumours.  In most cases these tumours can be surgically removed.  However, surgery and traditional chemotherapies can leave patients with reduced renal function and at risk of relapse. In addition, advanced or metastatic RCC is difficult to treat with surgery. Therefore, the development and improvement of molecular targeted drug treatments is becoming a very active field. The standard first-line treatment for RCC is an anti-angiogenic and anti-proliferative tyrosine kinase inhibitor (TKI) such as sunitinib or sorafenib. This blog summarises recent results from a clinical trial assessing a new RCC drug treatment and the initiation of a new study.

  • The biopharmaceutical company Exelixis recently announced promising results from the CABOSUN randomized phase 2 trial of the TKI cabozantinib in patients with previously untreated advanced RCC with intermediate- or poor-risk disease.. CABOSUN enrolled 157 patients. In this study with a median follow-up of 20.8 months, cabozantinib demonstrated a 31% reduction in the rate of disease progression or death. The median progression-free survival (PFS) for cabozantinib was 8.2 months versus 5.6 months for the standard drug sunitinib, corresponding to a 46% improvement. Objective response rate was also significantly improved, at 46% for cabozantinib versus 18% for sunitinib. With a median follow up of 22.8 months, median overall survival was 30.3 months for cabozantinib versus 21.8 months for sunitinib. Discontinuation rate due to adverse effects was 20% with cabozantinib and 21% with sunitinib. This study successfully demonstrated that cabozantinib has the potential to benefit patients with advanced renal cell carcinoma as a first-line therapy.  Based on these results, Exelixis plans to submit a Supplemental New Drug Application for cabozantinib as a treatment of advanced RCC.
  • The company Eisai very recently announced the initiation of a global Phase III Clinical Study (CLEAR Study) of the multiple receptor TKI lenvatinib in combination with the mTOR inhibitor everolimus or the anti-PD-1 antibody pembrolizumab as a potential first-line treatment for advanced RCC. The CLEAR study aims to compare the efficacy and safety of lenvatinib/everolimus and lenvatinib/pembrolizumab versus sunitinib alone. Basic research into the combination of lenvatinib and everolimus suggested a synergistic effect with higher anti-angiogenic activity and a stronger anti-tumour effect than each single therapy in RCC models (Mitsuhashi et al., 2016; Adachi et al., 2016). Basic research into the combination of lenvatinib and anti-PD-1 suggested that lenvatinib enhances the antitumor activity of the anti-PD-1 antibody by reducing the percentage of tumour associated macrophages (Kato et al., 2015). In May 2016, lenvatinib was approved in combination with everolimus for the treatment of patients with advanced RCC following one prior anti-angiogenic therapy by the FDA (see previous blog). In addition, lenvatinib was also approved in combination with everolimus for the treatment of advanced RCC following one prior vascular endothelial growth factor (VEGF) targeted therapy in Europe. The CLEAR study will be initially conducted in the United States and Europe. Approximately 735 patients with confirmed advanced RCC will be randomized 1:1:1 to one of three treatment arms to receive either lenvatinib plus everolimus, lenvatinib plus pembrolizumab, or sunitinib alone on a schedule of four weeks on treatment followed by two weeks off. The primary outcome is to compare PFS. Secondary outcomes are objective response rate, overall survival, and safety.

In the past years, the rate of progress in the treatment of kidney cancer has rapidly increased. However, with low survival rates, RCC remains a disease with a high unmet medical need.

  • Randall, J., Millard, F., & Kurzrock, R. (2014). Molecular aberrations, targeted therapy, and renal cell carcinoma: current state-of-the-art Cancer and Metastasis Reviews, 33 (4), 1109-1124 DOI: 10.1007/s10555-014-9533-1

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