New Multi-kinase Inhibitor, Regorafenib, Shows Strong First-Line Activity in Metastatic Renal Cell Carcinoma

In patients with metastatic renal cell carcinoma (RCC), the oral multikinase inhibitor regorafenib (BAY 73-4506) produced disease regression or stabilization in 81% of patients in a phase II study presented at the ECCO 15 - ESMO 34 Joint Congress. The results were reported by Tim Eisen, PhD, of Addenbrooke’s Hospital at the University of Cambridge, United Kingdom.

“This study suggests regorafenib has encouraging activity as a potential first-line treatment option for advanced RCC. I am excited about the potential of this compound,” Dr Eisen said.

The drug is an oral multi-kinase inhibitor that targets angiogenic, stromal, and oncogenic receptor tyrosine kinases. The distinct anti-angiogenic profile includes inhibition of both VEGF receptor 2 and TIE2 tyrosine kinase. “TIE2 is redundant with VEGF,” he explained, “and is an escape mechanism for the tumor that may well be worth inhibiting” in a number of tumor types.

The study included 49 patients with previously untreated, unresectable or metastatic RCC, predominantly clear cell histology. Treatment consisted of regorafenib 160 mg once daily for 3 weeks, followed by 1 week off, until progression. By MSKCC score at screening, 23 patients were deemed “low risk” and 26 “intermediate risk.” This was the final efficacy analysis, with data cut-off as of May 31, 2009. At that time, 25 of 49 patients were still on treatment.

Median PFS was 8.3 months in this open-label study. A confirmed partial response was observed in 15 (31%); two additional patients had a PR after the formal study cut-off, which would raise the PR rate to 35%. Twenty-four patients (50%) had stable disease, yielding a disease control rate of 81%. Only five (10%) patients progressed; four (8%) were not assessable, Dr Eisen reported.

A number of confirmed responders maintained their response for 5 to 9 months, “giving a hint that benefit is often prolonged in those who do respond,” he noted. He added that 80% of patients with a PR were maintaining their response at the time of this analysis. Some patients with stable disease also experienced control of their disease for more than 5 months. Tumor shrinkage of some degree occurred in 89% of patients.

Adverse events were typical of the drug class, and were manageable. Hand-foot skin reaction was observed in 65% of patients (grade 3 in 29%), which Dr Eisen noted was “more easily managed” than in patients receiving other TKIs. Fatigue, however, which was reported by 51%, may be somewhat worse than with other TKIs, he said.

Other common side effects were hypertension, mucositis, diarrhea and alopecia. An unexpected occurrence was the development of renal failure in four patients, which investigators attributed to dehydration from rotovirus infection among patients at one study site.

ECCO/ESMO Abstract O-7105