Biologic Combo Boosts Response in Metastatic Renal Cell Carcinoma

DURHAM, N.C., July 30 -- The response rate in renal cell carcinoma more than tripled with both an immunomodulator and an angiogenesis inhibitor compared with typical results with either drug alone, investigators here found.

A third of patients with metastatic renal cell cancer had major responses with the combination of interferon-?-2b and sorafenib, according to a report in the Aug. 1 issue of the Journal of Clinical Oncology.

By comparison, monotherapy with either agent typically produces response rates of just 5% to 10%, said Jared A. Gollob, M.D., of Duke University, and colleagues.

"Most tumors that respond to either therapy alone begin growing again after about five or six months," said Dr. Gollob. "By using interferon-alpha and sorafenib in combination, we not only increased the response rate but found we could double the amount of time that these patients could survive without their tumors growing."

The combination was more toxic than either drug by itself, but dose reductions and breaks between treatment cycles allowed chronic therapy, they investigators stated.

In recent years treatment of metastatic renal cell carcinoma has moved away from emphasis on cytokine therapy and toward signaling pathways involved in clear cell tumors with loss of von Heppel-Lindau protein.

Sorafenib, an inhibitor of vascular endothelial growth factor receptors, has produced response rates as high as 10% and has modestly improved progression-free survival in patients with metastatic disease.

Interferon-? also induces response rates that peak at about 10% and is one of only two drugs (temsirolimus is the other) shown to improve overall survival in renal cell carcinoma.

In previous studies, combining interferon-? with biologic or chemotherapeutic agents has failed to produce consistent results. However, interferon-? has antiangiogenic as well as immunomodulatory properties, providing a rationale for combining it with another antiangiogenic agent.

Dr. Gollob and colleagues evaluated the combination of interferon-?-2b and sorafenib in 40 patients with metastatic renal cell carcinoma. The combination was the initial systemic therapy for 25 of the patients.

Patients were evaluated for response after an initial eight-week cycle of therapy, and those who had objective responses or stable disease continued treatment until disease progression.

The treatment led to partial response in 28% of the patients and complete response in 5%. Additionally, 45% of patients had stable disease for at least one cycle of therapy. All the responses occurred in patients with clear cell disease or the sarcomatoid variant.

"Responses occurred quickly, with the majority of tumor regression observed after the first one to two cycles," the authors stated.

Median progression-free survival was 10 months, and the one-year progression-free survival was 48%, the researchers said. Overall survival had not been reached at the time of publication, and 73% of patients remained alive at one year.

Patients received a median of three cycles of therapy, and all patients elected to take a two-week break between cycles. Additionally, 65% of patients required dose reductions of one or both drugs.

Toxicity, both hematologic and nonhematologic, was common, but severe toxicity (grade 3-4) was not, the researchers said. The most common severe adverse events were hypophosphatemia (N=15, 37%), neutropenia (N=10, 25%), fatigue and rash (N=5, 13%), and hand-foot reaction (N=4, 10%). Dose reductions were required in 65% of patients.

The only unexpected toxicity was a minor stroke in one patient.

The authors concluded that larger controlled, randomized trials are needed to determine whether the combination regimen has a significant role in the treatment of renal cell carcinoma. Modifications to reduce toxicity also should be examined, they added.