Update on clinical trials and treatments for RCC

Renal cell carcinoma (RCC) is the most common type of kidney cancer and although the majority of cases are sporadic approximately 3% of cases are caused by genetic conditions such as BHDVHLHLRCC and TSC (Randall et al., 2014). These inherited forms of RCC have provided great insights into sporadic cancer genetics. BHD patients can develop multiple kidney tumours.  In most cases these tumours are small local RCCs that can be surgically removed.  However, these treatments are not without risk, and sometimes complete nephrectomies are carried out which leave patients with severely reduced kidney function and at risk of recurrence. The development of selective drug treatments that target only cancer cells can therefore improve disease outcome and increase patient quality of life. Even though significant advances have been made in the treatment of kidney cancer, there is a need for effective and more tolerable treatments, both for single agent and combination use. This blog summarises recent results from clinical trials assessing new treatments.

  • The U.S. Food and Drug Administration (FDA) very recently approved Lenvima (lenvatinib), a multiple receptor tyrosine kinase inhibitor (TKI), in combination with Everolimus for the treatment of patients with advanced renal cell carcinoma (aRCC) who were previously treated with an anti-angiogenic therapy. This approval was based on the impressive results of aphase II study with 153 patients (Motzer et al., 2015), in which the combination of Lenvima and Everolimus significantly prolonged progression-free survival and median overall survival when compared with Everolimus alone, the standard of care for patients with aRCC following prior anti-angiogenic therapy.
  • AVEO Oncology have announced that the first patient has been dose in the TIVO-3 trial, a randomized study created to compare the vascular endothelial growth factor (VEGF) TKI tivozanib hydrochloride to sorafenib in patients with refractory advanced RCC. The Phase III trial is expected to enrol approximately 322 patients with recurrent or metastatic RCC who have failed at least two prior treatments, including other VEGFR-TKI therapies. The primary endpoint of the study is progression free survival. Secondary endpoints include overall survival, overall response rate, safety and tolerability. Top line readout of the study is currently projected for the first quarter of 2018 and depending on the results the study completion date is currently projected for June 2019.
  • A small phase II study (Muselaers et al., 2016) with only 14 patients highlights modest efficacy and a concerning safety profile associated with the 177Lu-labelled girentuximab compound in patients with metastatic RCC. Carbonic anhydrase IX (CAIX) expression has been investigated as a prognostic biomarker in RCC and as a consequence CAIX-directed treatments have emerged, including 177Lu-labelled girentuximab. However, the questionable efficacy and concerning safety profile of the study might limit research to develop this agent further.
  • Very recently, Pfizer announced positive results from the phase III S-TRAC trial of SUTENT (sunitinib), an oral TKI, as adjuvant therapy in patients with RCC at high risk for recurrence after surgery. The study that includes more than 670 patients met its primary endpoint of improving disease-free survival (DFS) becoming the first RCC trial of a TKI to prolong DFS in the adjuvant setting. The concept of adjuvant therapy is to help lower the risk of cancer recurrence in patients with early-stage cancer. The adverse events observed for the compound in the trial were consistent with its known safety profile. Full efficacy and safety data will be submitted for presentation at the ESMO 2016 Congress in Copenhagen, October 2016 and study completion date is currently projected for August 2017.

The development of new and more efficient drug treatments for RCC is a very active field. Ongoing basic research into the biology of kidney tumorigenesis and the identification of biomarkers, a topic discussed in a past blog post, will enable a more efficient selection of patient cohorts more likely to respond to treatment and the design of more specific and targeted single or combination drugs.

 

Randall JM, Millard F, & Kurzrock R (2014). Molecular aberrations, targeted therapy, and renal cell carcinoma: current state-of-the-art. Cancer metastasis reviews, 33 (4), 1109-24 PMID: 25365943

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