ASCO 2015

Lenvatinib increases progression free survival when used with everolimus in metastatic renal cell carcinoma

Dr James Larkin - Royal Marsden Hospital, London, UK

You’ve been looking at renal clear cell… metastatic renal cell cancer, what was the issue that you were trying to resolve with this study?

The issue with this study is that patients who have progressed on first line treatment, say with sunitinib or pazopanib, in the second line situation everolimus is a standard treatment. But the level of benefit is relatively modest, you’re talking about median progression free survival of about five months. So this study was actually looking at a new drug, lenvatinib, in comparison with everolimus in that setting, basically.

Can you tell me what lenvatinib does and what you hoped it would do for your patients?

Lenvatinib is a multi-targeted kinase inhibitor which targets the VEGF receptor and also fibroblast growth factor receptor, or receptors because there’s more than one. They have been implicated in resistance, the FGFR receptors or that pathway, to anti-VEGF treatment. So the idea of this treatment would be that there is increased activity in the patients who are resistant to anti-VEGF treatment. In the trial what we saw is that the everolimus arm performed as expected, so a median progression free survival of about five months; lenvatinib on its own was better, a median progression free survival of about seven months. But the real take home message here is that the two drugs combined, and that was the third arm of the study, the median progression free survival was fourteen months. So that’s unprecedented actually.

Could you put this into focus of the size of the study and what you actually did to get those interesting results?

Yes, so this was a randomised phase II study, 150 patients, three arms, so about 50 patients in each arm. Patients were allocated at random into those three arms and they were treated in a standard way on trial as long as the disease was controlled and side effects were manageable. That’s actually an important point, the side effects of the two drugs together, the experience in this disease in the last ten years is that combining these drugs actually causes lots of side effects. In this trial actually what we saw, we did see side effects but they were manageable side effects, things like diarrhoea, hypertension, the kinds of things, actually, we’re used to managing as kidney cancer doctors. So we didn’t see anything new.

Can you tell me the size of the benefit in progression free survival and overall response rate, how big was that?

So for response rate, again it’s important to see the bench mark of everolimus which the response rate was about 5-6%. Lenvatinib alone the response rate was just between 25-30% and the two together was actually over 40%. So, again, that’s something we haven’t really seen before in this situation.

And in terms of progression free survival the numbers were what?

Five, seven and fourteen months for everolimus, lenvatinib and the combination respectively.

You also had a statistically significant signal in overall survival.

That’s right. So there was an analysis for overall survival and again that showed that the combination treatment seemed to provide benefit in terms of overall survival. So it’s all very encouraging but a randomised phase II study nevertheless.

OK, phase II, you’d like to take it further, I’m sure. But the interim message in terms of potential clinical implications would be what?

This is very encouraging data, I think is the first thing to say. We have some evidence actually at last that you can combine targeted drugs in kidney cancer with acceptable side effects with an increase in efficacy.

So do you see this as potentially paradigm changing?

I’d like to see confirmatory data, I’d like to see larger numbers of patients treated. But I hope that the benefit we’ve seen in this randomised phase II study will be borne out in the future.

And what brief message would you like doctors to take home from what you’ve been saying here at ASCO?

It’s a new drug and it’s got clear efficacy in this disease and it seems to have combinability in a way that we haven’t seen before. So I think there’s a promising future but it requires further study.