A phase II trial of savolitinib, a MET inhibitor, found that the drug induced partial responses in some patients with papillary renal cell carcinoma and was well tolerated, prompting drug makers Chi-Med and AstraZeneca to launch a phase III study.

A phase II trial of savolitinib yielded partial responses in several patients with locally advanced or metastatic papillary renal cell carcinoma (PRCC), results promising enough to prompt drug makers Chi-Med and AstraZeneca to initiate a phase III study of the MET inhibitor.

PRCC accounts for about 10% of all renal cell carcinomas, affecting about 6,400 people a year in the United States. The prognosis is poor for people with advanced disease, and the overall response rate (ORR) to sunitinib (Sutent; Pfizer)—a therapy that elicits an ORR of about 25% to 30% in other types of renal cell carcinoma—hovers around 10% for PRCC.

Patients with PRCC often display aberrant expression of MET, a receptor tyrosine kinase, which can spur tumor growth, angiogenesis, and metastasis. Savolitinib is a potent and selective inhibitor of MET that binds and inhibits its kinase activity, making it a potential therapy for PRCC.

In the phase II trial, Toni Choueiri, MD, of Dana-Farber Cancer Institute in Boston, MA, and his team administered savolitinib to 109 patients with PRCC: Forty-four had MET-dependent disease—defined as chromosome 7 copy gain, focal MET or HGF amplification, or MET kinase domain mutations—and 46 had MET-independent disease; MET status was unknown in 19. Among all of the patients, the ORR was just 7%. However, among the patients with MET-driven PRCC, eight (18%) experienced confirmed partial responses, whereas none of the patients with MET-independent PRCC did. Median survival was also higher in the MET-driven group than the MET-independent patients—6.2 months versus 1.4 months, respectively.

The adverse effects, the most common of which were nausea, fatigue, vomiting, and abnormal liver function, were generally mild. Nine patients discontinued the drug due to adverse events.

Savolitinib is “a well-tolerated drug that appears to have activity in papillary kidney cancer, and we may have an ability to predict which patients are going to have the better response to therapy,” said Brian Shuch, MD, an assistant professor of urology at the Yale School of Medicine in New Haven, CT, who was not involved in the study.

The results were encouraging enough that Chi-Med and AstraZeneca have launched a phase III follow-up study. Called SAVOIR, it will be a randomized, controlled trial that compares savolitinib to sunitinib in about 180 patients with confirmed MET-driven PRCC. In addition to SAVOIR, further randomized phase II trials are comparing three MET inhibitors—savolitinib, crizotinib (Xalkori; Pfizer), and cabozantinib (Cabometyx; Ipsen)—to sunitinib.

Although savolitinib is not the only MET inhibitor in development, it may be the most specific to the pathway. For example, cabozantinib also acts on VEGFR2, which could be beneficial. However, broader specificity may also increase the chances for off-target effects. “Savolitinib is a pure, pure MET inhibitor,” says Choueiri. “I like the fact that with this compound you practice precision medicine at its best.” –David Shultz