CHICAGO (EGMN) – The combination of two standard treatments, temsirolimus and bevacizumab, dramatically increased toxicity without any signal of increased efficacy in the first-line treatment of metastatic kidney cancer in the phase II TORAVA trial.

Among 88 patients randomized to temsirolimus (Torisel) and bevacizumab (Avastin), 41% stopped treatment early due to toxicity. The serious adverse event rates were striking, with 26% of patients experiencing a grade 3 event, 12.5% a grade 4 event and three deaths (3.4%) occurring.

“Based on this phase II, such combination can not be recommended for first-line metastatic kidney cancer patients,” Dr. Bernard Escudier reported on behalf of the French Group on Renal Cancer at the annual meeting of the American Society of Clinical Oncology. “There is a large phase III ongoing that might change our feeling.”

When asked whether the phase III trial should be shut down, Dr. Escudier told the audience that the study is almost complete and would be designed differently if started today. He added that the phase III data may be different from the phase II data, but that the chance of the trial being positive is “obviously low.”

The researchers evaluated temsirolimus and bevacizumab after the combination proved feasible at full doses of each agent in a phase I study with a promising response rate. Both drugs are approved for the first-line treatment of kidney cancer – bevacizumab in combination with interferon and temsirolimus in poor-risk patients.

The three-armed phase II TORAVA trial involved 171 patients with metastatic renal cell carcinoma and a performance status of 0-2 who were randomized on a 2:1:1 basis: 88 patients to temsirolimus 25 mg IV weekly plus bevacizumab 10 mg/kg every 2 weeks; 42 patients to oral sunitinib (Sutent) 50 mg daily for 4 weeks with 2 weeks off; and 41 patients to bevacizumab at the same dose plus interferon 9 MU subcutaneously 3 times a week.

Dose adjustments were not allowed in the experimental arm for bevacizumab, but reductions to 20 mg and 15 mg were possible for temsirolimus. The study excluded patients with papillary renal cancer. Median follow-up was 14.7 months.

The study’s primary end point of nonprogression rates at 48 weeks showed only 31% for bevacizumab plus temsirolimus compared with 40.5% for sunitinib, and 66% for bevacizumab plus interferon, reported Dr. Escudier of the Institut Gustave Roussy in Villejuif, France. Median progression-free survival was 8.2 months, 8.2 months, and 16.8 months, respectively.

The best overall response rate for temsirolimus plus bevacizumab was 27% (2% complete responses and 25% partial responses), 24% for sunitinib (partial responses only) and 39% for bevacizumab plus interferon (2% CR, 37% PR), he said.

Despite the small numbers and noncomparative design of the study, there is little chance that the numbers in the experimental arm will exceed those in the control arms or the median progression-free survival of 11 months reported in previous trials of monotherapy with sunitinib or pazopanib (Votrient), said Dr. Marc Dror Michaelson of Massachusetts General Hospital, Boston, who was invited to discuss the findings.

He commented that the toxicities seen in the experimental arm were far higher than one would expect with either agent alone. “Toxicity certainly seemed to be synergistic rather than just additive,” he said.

In the control arms, grade 3 events were reported in 12% of patients in the sunitinib arm and in 20% of patients in the bevacizumab-plus-interferon arm. Grade 4 events occurred in 2.4% and 7.5%, respectively, with no deaths occurring.

Several other studies have attempted to combine different classes of targeted agents in the treatment of renal cell carcinoma. In many cases, the combination resulted in intolerable toxicity, as with sunitinib plus temsirolimus or sunitinib plus bevacizumab, or required significant dose modifications, he said.

A phase II Cytokine Work Group Study reported during the same session suggests it is feasible, however, to combine bevacizumab with immunotherapy using high-dose aldesleukin (Proleukin or IL-2) in untreated metastatic renal cell carcinoma. There were many grade 3 and 4 toxicities among the 49 evaluable patients, but they were as expected when either drug is used alone, said Dr. Uday Dandamudi of Dartmouth-Hitchcock Medical Center, Lebanon, N.H. One death occurred from pulmonary embolism and one hospitalization from GI perforation.

Four patients achieved a complete response and 10 a partial response. Median progression-free survival was 9 months and median overall survival 24.6 months, he said.

While the combination is feasible and the toxicity does not appear synergistic, the efficacy results do not appear to be superior to those with some of the currently available monotherapies such as sunitinib, Dr. Michaelson commented.

TORAVA was supported by the French Ministry of Health, Wyeth, and Roche. The authors have financial ties with these and five other companies. Dr. Dandamudi has ties with seven companies. Dr. Michaelson serves on the advisory boards of Pfizer, Novartis, Genentech, Eisai, Aveo, and Wyeth.