Promising Treatments on the Horizon for Advanced RCC

Angiogenic escape drives resistance to frontline VEGF inhibition for many patients with advanced renal cell carcinoma (RCC), representing a major area of focus for the development of new therapies, states David F. McDermott, MD. When a tumor is forced into a state of hypoxia by current therapies, the tumor struggles to seek ways to survive, explains McDermott. Pathways that allow it to survive and proliferate in the hypoxic state include those that involve c-MET and fibroblast growth factor (FGF).

Cabozantinib is a small molecule inhibitor that targets multiple tyrosine kinases, including c-MET and VEGF, explains Thomas E. Hutson, DO, PharmD. In the open-label phase III METEOR trial, cabozantinib reduced the risk of progression or death by 42% versus everolimus (HR, 0.58; P <.0001), which was the primary endpoint of the study. Overall survival with cabozantinib was improved by 33% versus everolimus, with data continuing to mature (HR, 0.67; P = .005).

Another investigational agent, lenvatinib, a multi-kinase inhibitor of VEGF and FGF, was evaluated in combination with everolimus in a 3-arm phase II trial. Individuals were randomized in the second or third-line setting to receive lenvatinib with everolimus, lenvatinib monotherapy, or everolimus monotherapy. In this study, the median progression-free survival (PFS) was 14.6 months for lenvatinib plus everolimus, 7.4 months for lenvatinib alone, and 5.5 months for everolimus.

The PFS seen with the combination in this phase II study is greater than what has been reported with single-agent axitinib in patients with pretreated advanced RCC, adds Hutson. Based on findings from this study, the FDA granted lenvatinib a breakthrough therapy designation as a potential treatment for patients with advanced RCC.

CRLX101 is a novel formulation of camptothecin, a cytotoxic chemotherapy that may be involved in hypoxia inducible factor (HIF) production. It is currently being studied in combination with bevacizumab versus standard of care in the third and fourth-line setting, and results are promising, says Hutson. Preliminary top-line findings from a phase Ib/II study demonstrated a median PFS of 9.9 months compared with 3.5 months with the current standard of care.

Dalantercept is an investigational ALK1 receptor-fusion protein that has demonstrated promise as monotherapy. This agent inhibits signaling that is thought to be important in the maturation of tumor vasculature, describes McDermott. The ongoing DART study is comparing dalantercept plus axitinib with placebo plus axitinib in pretreated patients with advanced disease.

In findings from the first part of the DART study, the combination of dalantercept and axitinib was found to be well tolerated and associated with encouraging activity for patients with advanced RCC treated with prior VEGF, mTOR, and immune therapies. In patients who received ≥2 therapies, the objective response rate was 25% and a preliminary PFS of 8.3 months.