Though quite curable when diagnosed early, kidney cancer in advanced stages can become a stubborn disease.
However, the outlook for patients with metastatic kidney cancer has brightened in the past several years. Oncologists have added to their arsenal a number of designer drugs that attack molecular targets – genetic abnormalities that drive tumors – with high specificity.
Prior to 2005, there was just one FDA-approved drug for kidney cancer, interleukin-2, and it was often ineffective. Since 2005, seven new targeted drugs have been approved and more are on the way, notes Toni Choueiri, MD, clinical director of the Kidney Center in Dana-Farber’s Lank Center for Genitourinary Oncology.
Many of the therapies are designed to curb tumor growth by blocking angiogenesis – the formation of new blood vessels in and around tumors that enables them to grow and spread. In time, however, cancer cells often learn to evade even these highly specific attacks by activating alternate growth pathways such as PI3K and the MET pathways. “We are currently doing studies of drugs with which we plan to attack these resistance mechanisms in kidney cancer cells,” says Choueiri.
Abnormally activated MET is an escape route kidney tumors use to resist the angiogenesis inhibitors pazopanib and sunitinib. Choueiri and colleagues led a clinical trial using cabozantinib, a drug that simultaneously blocks both MET and VEGF – a protein involved in angiogenesis. When cabozantinib was given to patients whose kidney cancers had progressed despite several rounds of treatment, “we found significant activity and a response rate of up to 30 percent in a small trial,” Choueiri says. This led to an international large phase 3 trial that Choueiri is leading.
Choueiri also led a study published in the New England Journal of Medicine in August 2013 that compared the efficacy and the side effects of pazopanib and sunitinib. The results favored pazopanib, and the researchers recommended that it be the preferred first choice, because it is better tolerated than is sunitinib.
Renewed excitement about cancer immunotherapy has been prompted by the success of new strategies for stirring the immune system to recognize and attack cancer cells in some cancers. Past efforts have focused on revving up the immune defenses, like pressing a car’s accelerator, with limited success. Newer approaches are aimed at releasing the molecular “brakes” that cancer cells use to suppress the immune forces; one of these braking mechanisms involves proteins called PD-1 and PD-L1.
Immunotherapies that counteract PD-1 and PD-L1 are having striking success in some cancers, chiefly melanoma, leading to trials in other types, including kidney cancer. “These PD-1 inhibitors seem to be well tolerated, and we are seeing activity in metastatic kidney cancer,” says Choueiri. “We have finished two large studies and are eagerly awaiting the results.”