He said future trials should combine agents with multiple mechanisms, and that vertical blockade of a single signaling pathway, in this case the vascular endothelial growth factor (VEGF) pathway, "is certainly not the way to go" with currently available agents because it is either too toxic or lacks convincing efficacy.
INTORSECT: Striking Finding
INTORSECT, the first head-to-head phase III trial comparing an mTOR inhibitor and a VEGF receptor inhibitor in second-line RCC, provided no easy answers regarding the optimal treatment sequence after sunitinib in advanced RCC.
The trial randomly assigned 512 patients to temsirolimus 25 mg weekly or sorafenib 400 mg twice daily until progressive disease or unacceptable toxicity. All patients had received first-line sunitinib, and about 82% had clear cell histology.
The confirmed objective response rates were 8% for both the temsirolimus and sorafenib groups, with stable disease reported in 61% of all patients.
Although patients receiving temsirolimus had a numerically longer progression-free survival by independent assessment (median 4.2 months vs. 3.9; HR 0.87; P = .193), those given sorafenib lived a median of four months longer (16.64 months vs. 12.27 months; HR 1.31, P = .014), reported Dr. Thomas Hutson, Pharm.D., of the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas.
Dr. Kollmannsberger described this as the most striking finding of the trial, and said it is likely the longest survival time observed in a randomized trial. The difference in survival is unlikely to be explained by patient characteristics, discontinuations because of adverse events with temsirolimus and sorafenib (17% vs. 14%), or subsequent therapies, since few patients had third-line therapy.
One possible explanation may be that prior VEGF therapy alters the biology of the disease. This hypothesis is supported by a recent analysis of sequential tissue samples suggesting that the protein expression in metastatic cell RCC changes with sunitinib therapy, Dr. Kollmannsberger said.
"I think in the end, the significant survival difference remains to be conclusively explained, but it at least gives rise to the hypothesis that the sequence of drugs does actually matter and matters more than we may think at the present time," he said.
INTORACT was sponsored by Pfizer Inc., which also provided funding for editorial support by Peloton Advantage. Dr. Rini reported research funding from and consulting for Pfizer. RECORD-2 was sponsored by Novartis. Dr. Ravaud reported financial ties with several firms including Pfizer and Novartis. Dr. Hutson reported serving as an adviser and investigator for Aveo, Bayer, GlaxoSmithKline, Novartis, and Pfizer, which sponsored INTORSECT. Dr. Kollmannsberger reported being an investigator on the INTORSECT study, and serving as an advisor for and travel support from Pfizer, Novartis and GSK.