ECC 2015

Cabozantinib improves advanced kidney cancer survival: METEOR trial results

Prof Toni Choueiri - Dana-Farber Cancer Institute, Boston, USA

Toni, now first of all tell us about yourself. You’re at the Dana, a big centre, and you’re now looking at renal cell carcinoma. But what’s your position there and what’s your lab doing?

I’m the Clinical Director of the Lank Center for Genitourinary Oncology and I’m a genitourinary medical oncologist focussing on kidney cancer and that’s where my clinical and my research work goes. I’ve been at Dana-Farber now for some time and Harvard Medical School actually too.

Now, this is a big issue, improving treatment in renal cell carcinoma, especially disease that has progressed. What did you do in the METEOR study?

We know now for some time, for five years or more, that actually treatment resistance with drugs that we use, VEGF inhibitors we call them, do actually develop and it’s really an unmet need. We haven’t had a drug approved for four or five years now in kidney cancer. So one of the most interesting strategies is to have drugs that target the mechanism of VEGF resistance. So cabozantinib is one of these that target the VEGF receptors still but that target other kinases such as MET and XL (?) and now there’s mounting evidence that MET and XL contribute to this mechanism of resistance to VEGF inhibitors.

One of your options in progressing disease would have been everolimus, wouldn’t it?

Correct, that’s a standard second line option based on a paper from 2009. The drug as approved was compared to placebo in patients that progressed after sunitinib. It showed a progression free survival benefit.

So now you’ve gone head to head with everolimus with cabozantinib. What did you do, in fact?

We conducted a randomised phase III trial, that being 658 patients, randomised to everolimus, the standard, versus the experimental agent cabozantinib, the inhibitor of the VEGF receptor, MET and XL. Before that we have evidence in a smaller study in heavily pre-treated kidney cancer that the drug works, it resulted in responses. So we went against everolimus and actually the primary endpoint of the study, being progression free survival, was met. Cabozantinib resulted in a median progression free survival of 7.4 months compared to 3.8 months with everolimus.

So practically a doubling.

Practically a doubling, a 42% decrease in the risk of death or progression.

What about other endpoints then?

We looked at response rate and it was four times more, 5%  versus 21%. We looked at adverse events, especially in terms of treatment discontinuation due to adverse events and it was around 9-10% in both arms. We also conducted an interim analysis for overall survival. It’s a bit early because we have only six months follow-up since the last patient was enrolled. Even with that we found a 33% decrease in the risk of death. So the next thing we’re going to do, hopefully early in 2016, is to see if we update overall survival analysis and hopefully we’ll reach that.

What should doctors be reading into this as an interim interpretation right now?

As doctors and patients, a great day for kidney cancer yesterday. This is another drug that in a phase III trial improves outcome. It doesn’t improve outcomes in a statistically significant way only but this is a clinically meaningful way by doubling of progression free survival almost. So look out for the drug cabozantinib, hopefully it will be in your hands soon to be used for patients with kidney cancer.

And if licensed in this indication what are your recommendations? Is this going to be practice changing?

This will be practice changing.

What are your plans now though? You’ve done progressing disease, can this drug be used elsewhere?

We do have a small study against sunitinib that finished accrual that compared cabozantinib with sunitinib. It’s a randomised phase II so it’s a smaller study. We’re going to look at that. I think one of the important things in oncology we always do is when we find drugs with different classes that work we try to combine them. So hopefully we’ll be able to combine cabozantinib, perhaps with a checkpoint inhibitor, as a frontline strategy. That’s something we’re thinking about seriously.

What is this telling us about renal cell carcinoma and how to treat it?

So patients are living longer. I don’t think we’re having a lot of complete responses that are durable and curing disease but patients are living longer. We are finding agents now that are slowing the pace of the disease.

So could you summarise the clinical messages for doctors coming out of this new research?

Cabozantinib is a drug that is a VEGF receptor inhibitor but also targets other receptors involved in VEGF resistance. The drug doubled the progression free survival and quadrupled the response rate versus everolimus and the interim and preliminary overall survival seem to be promising. The overall side effects seem to be also manageable.

Very interesting. Toni, thank you very much.

Thank you, Peter.