ESGO 2013
Results from the TRINOVA 1 trial
Prof Bradley Monk - Creighton University School of Medicine, USA
Brad, you’ve got something completely new here, a new way of looking at ovarian cancer. What have you been doing with this new agent? First of all it’s called trebananib?
Trebananib is a new molecule that targets a new pathway. You’ve probably seen we have seven phase III positive trials of angiogenesis in ovarian cancer but they all target VEGF. VEGF, as you know, has been associated with hypertension, bowel perforation, bleeding, thrombosis, wound healing problems, proteinuria, CNS disturbances even. So this study called TRINOVA 1, trebananib in ovarian cancer, was to look at a new agent that binds angiopoietin 1/2.
And tell me about that.
Angiopoietin 1/2 is another angiogenesis pathway other than VEGF. So we did a randomised phase III trial in recurrent ovarian cancer and showed a prolongation in progression free survival with a hazard ratio of 0.66.
And what went before this? You had some earlier studies.
We had done a randomised phase II which showed a very interesting prolongation in PFS; even in the phase I programme it was well tolerated and showed single agent activity.
So you’ve got an extension of progression free survival, the big question, of course, is overall survival. I believe you had what you call a trend but that’s always a little difficult to estimate, isn’t it?
We thought that when we reported the PFS endpoint that it should be co-ordinated to at least half of the OS events. We wanted to tell you and the scientific community whether or not there was a decrement, maybe even a trend in improvement in OS. We have a hazard ratio of 0.86 for overall survival, again only half of the OS events, but such a trend is very provocative and I hope to share with you the OS next year.
So you’ve got positive results with progression free survival, what about, the big question, toxicities?
Of course. We do not see the classic VEGF associated toxicities but we do see oedema. Not only does angiopoietin 1/2 inhibit angiogenesis but lymph angiogenesis. So the incidence of oedema, generalised oedema, localised oedema, pleural effusion, [?? 2:20], weight gain is two to three times what we see in the placebo arm. Remember, this was combined with weekly paclitaxel so TRINOVA 1 – weekly paclitaxel, placebo, weekly paclitaxel plus trebananib. Oedema seems to be the real issue.
And what would you say to busy oncologists about managing that if this drug were to progress to licensing?
First of all, grade 3 and worse was only 2-4%, so not that serious. But grade 2 oedema can still be very troublesome to the patients so we used diuretics, we used compressions, elevation and we need to learn more about the factors that predict oedema and what the natural history of oedema are.
What would you sum up, then, about the clinical recommendations or the clinical implications, anyway, future ones, so far?
We need to combine it with other cytotoxics. We’re combining it with pegylated liposomal doxorubicin in a study called TRINOVA 2, remember ours was TRINOVA 1. TRINOVA 3 is adding it to frontline and I think because it works after anti-VEGF therapy failure we want to combine it with anti-VEGF. If these are distinct targets, angiopoietin1/2 and VEGF, and complementary and, in fact, even mechanistically related to resistance, I think we want to combine anti-VEGF and anti-angiopoietin therapy together.
So what’s the take home message for cancer doctors at this point?
The take home message is that angiogenesis is valid in ovarian cancer and it’s not all about VEGF, that we have a new target, angiopoietin 1/2, and a new agent, trebananib, in inhibiting that access.
And which particular patients can benefit potentially the most from this?
These were patients who had up to three prior lines of therapy with a platinum free interval of less than twelve months. So this is a large proportion of patients with recurrent ovarian cancer.
Brad, thanks very much.
My pleasure, thanks.
