The results of the study comparing Aveo’s tivozanib to sorafenib for the treatment of metastatic renal cell carcinoma showed no improvement in overall survival, the basis for the FDA’s rejection of the company’s new drug application earlier this year.
The results of the phase III study comparing Aveo’s tivozanib to sorafenib for the treatment of metastatic renal cell carcinoma, which were the basis for the US Food and Drug Administration’s (FDA) rejection of the company’s new drug application earlier this year, were published recently in the Journal of Clinical Oncology.
Although the results indicated that tivozanib improved progression-free survival compared to sorafenib, it failed to show an improvement in overall survival.
Robert J. Motzer, MD, of the Memorial Sloan-Kettering Cancer Center, and colleagues conducted a study of the potent and selective tyrosine kinase inhibitor of VEGF receptor 1, 2 and 3 in comparison to the drug sorafenib. They enrolled 517 patients and randomly assigned them to tivozanib (n = 260) or sorafenib (n = 257).
Patients assigned to sorafenib were given the option to cross-over to receive tivozanib at progression; of the 162 patients in this arm who elected to receive a second targeted-agent at progression, 156 received tivozanib (61%).
The median progression-free survival was 11.9 months with tivozanib compared with 9.1 months with sorafenib (P = .042). In addition, patients on tivozanib had an improved overall response rate (33.1%) compared with sorafenib (23.3%; P = .014).
However, the tivozanib only showed a trend towards improved overall survival compared with sorafenib. Forty-two percent of patients in the intention-to-treat population died. The median overall survival was 29.3 months for tivozanib compared with 28.8 months for sorafenib (P = .105).
Adverse events, although different with each of the study drugs, were comparable.
In an editorial that accompanied the trial results, Marc B. Garnick, MD, of Beth Israel Deaconess Medical Center, Boston, wrote that based on the results of this study many projected that tivozanib would be approved for the treatment of metastatic RCC; however, according to Garnick the study design compromised the “sanctity of overall survival” with its allowing patients on the sorafenib arm to cross-over to tivozanib at progression.
“In particular, differences in overall survival in favor of the sorafenib arm could not be adequately assessed because this study represents, in essence, a sequential trial of two agents (sorafenib [then] tivozanib) compared with one agent (tivozanib),” Garnick wrote. “Although the overall survival results might be attributed to a design that compares sequential therapy with monotherapy, other equally plausible explanations were put forth by the FDA review team, including that sorafenib may be more effective than tivozanib in improving overall survival, that tivozanib has greater delayed toxicity, or that tivozanib has unrecognized toxicity that contributed to the lower survival in ways that are difficult to appreciate.”
And, in fact, Garnick wrote that researchers may never know. Instead, he suggested that researchers learn a lesson from this situation mainly that any approval based on a trial with a primary endpoint of progression-free survival must not have any study design weaknesses.