It’s been a while since I’ve posted to the Cancer Grace website, but that’s not for a lack of very exciting studies in the area of metastatic kidney cancer. We’ve seen a number of small studies this year reported for promising targeted drugs, such as the PD-1 inhibitors and the agents targeting MET. However, I wanted to discuss on this post data related to the agent tivozanib. Tivozanib is a drug that has a mechanism of action that is very similar to sunitinib or pazopanib, but it differs in that it binds more tightly to the same receptors that sunitinib or pazpnanib does. Presumably, this may actually make tivozanib a clinically more effective agent and that was the rationale behind the large Tivo-1 trial. This was a phase III study in which tivozanib was compared to sorafenib. Patients that were enrolled in this study had to have clear cell disease and in addition, they had to have prior nephrectomy or removal of their kidney. Patients may have received up to one prior therapy, but many patients in this trial have received no prior treatments. Tivozanib was given in an oral formulation three weeks on and one week off, while sorafenib was given at the standard schedule, which is a total of 400 mg twice daily. If patients were randomized to sorafenib they had the option to receive tivozanib if their disease worsened.
We saw some data presented at the American Society of Clinical Oncology meeting this year that clarified the delay in cancer growth in both the overall study and specifically in those patients that had received no prior treatment. What we saw is that in the overall study population there is a pretty modest difference in terms of progression-free survival or delay in cancer growth. Specifically, progression-free survival was 11.9 months with tivozanib versus 9.1 months with sorafenib, and this was a significant difference by the statistical methods used in this analysis. In the population of patients that had received no prior therapy, we saw a slightly more pronounced difference in terms of median progression-free survival, 9.1 months versus 12.7 months. One thing that I will point out is that all this data was called into question on the basis of the overall survival that was determined in this study. Specifically with tivozanib, the overall survival noted was 28.8 months versus 29.3 months with sorafenib. Now, this is a very slight difference, but nonetheless this change in favor of sorafenib really did cause some concern when this data was reviewed by the Oncology Drug Advisory Committee to the Food and Drug Administration.
Now, there are a number of reasons that account for the finding of sorafenib having a longer survival than tivozanib. First and foremost, a lot of patients in this trial were accrued in central and eastern Europe where treatment options are very limited. Here in the United States we have the benefit of having multiple lines of therapy available to us so if a patient progresses on tivozanib or sorafenib, they may have one of a number of different agents available to them, for instance axitinib, everolimus, and so on. However, in many countries there may not be such availability. As such, only about 10% of patients who receive tivozanib in the first-line setting went on to get another VEGF-directed therapy. In contrast, about 70% of patients went on to receive tivozanib or another VEGF-directed therapy amongst those who got sorafenib upfront. This may certainly account for the difference of survival that was seen in the study, but the Oncology Drug Advisory Committee nonetheless did not recommend tivozanib for approval in spite of this caveat.