What Combinations Should Be Tested? 

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If the therapy combinations tested in the BeST trial don’t deserve to move on to phase III trials, what other combinations do show enough promise against renal cell carcinoma to merit being tested in phase III trials?

“None at the present time,” maintained Bernard Escudier, MD, of the Institut Gustave Roussy, Villejuif, France, at the 11th International Kidney Cancer Symposium.

Before conducting a phase III trial of combination therapy against renal cancer, “we need to have a good scientific rationale based on mechanism of action; we need good in vitro data; and moreover, we need convincing clinical data, both in terms of efficacy and in terms of toxicity,” Dr. Escudier said. These criteria have not been met, however, by combinations tested in phase I or II trials so far, he stated.

Toxic Combinations

Phase I trials with various combinations of sunitinib (Sutent), temsirolimus (Torisel), everolimus (Afinitor), and sorafenib (Nexavar) have shown that the combined use of mTOR inhibitors and tyrosine kinase inhibitors is very toxic, Dr. Escudier said. Based on these results, it is not necessary to test every new tyrosine kinase inhibitor with an mTOR inhibitor, he added. Other trials have shown that combining bevacizumab (Avastin) and tyrosine kinase inhibitors is also toxic, in addition to not being particularly effective, he said.

A phase I trial with bevacizumab and an mTOR inhibitor found the combination was “feasible” at full dose, with promising efficacy, but that was based on just 8 of 12 patients achieving partial responses, Dr. Escudier noted. “Progression-free survival has never been reported [for this combination]. There were no complete responses in this group of patients. And based on that, it has been recommended for further testing,” he said.

That recommendation triggered two randomized phase II studies—the BeST study, with 360 patients, and the TORAVA trial, with 160 patients—as well as a phase III study, the INTORACT trial, with 822 patients, for a total of 1,342 patients. Dr. Escudier noted that patients receiving the bevacizumab/mTOR inhibitor combination in these trials did not show an increase in progression-free survival.

Ideal Combinations

“Ideal combinations are combinations that could induce complete responses, and so far we have not seen any combinations that could induce complete responses,” Dr. Escudier continued. He proposed that before testing drugs in combination, they first be tested sequentially. Doing sequential testing “before embarking on a large phase III trial would avoid a lot of problems,” he said. “That might be an ideal way to test in a randomized phase II study, a combination that could lead to a positive phase III study.”

Dr. Escudier also pointed out that “drug company requests to speed up are dangerous” and not a good reason to go to phase III trials. “Analyzing preliminary data is critical,” he said.

While Dr. Escudier said that no combinations are currently suitable for phase III testing, “there is one just to think about,” he noted. That combination is bevacizumab plus low-dose interferon, which he called “quite attractive.” In a phase II trial involving 147 patients, he noted that progression-free survival was 15.6 months and overall survival, 30.7 months.1 “So maybe that would be a good combination to test,” he concluded. ■

Disclosure: Dr. Escudier reported no potential conflicts of interest.


1. Melichar B, Bracarda S, Matveev V, el al: BEVLiN: Prospective study of the safety and efficacy of first-line bevacizumab (BEV) plus low-dose interferon-α2a (IFN) in patients (pts) with metastatic renal cell carcinoma (mRCC). 2011 ASCO Annual Meeting. Abstract 4546. Presented June 7, 2011. 

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