You’ve been looking at what’s categorised as unfavourable renal cell carcinoma and using a VEGF compound. What were you doing in the ASSURE trial, what was your basic issue you were trying to resolve here?

The VEGF tyrosine kinase inhibitors are widely used in advanced kidney cancer, so kidney cancer that has spread to other parts of the body. Thousands of patients have benefitted from the use of the drugs in that setting. The current standard of care, however, for completely resected local kidney cancer is close observation. So we asked the question could sunitinib or sorafenib decrease the risk of recurrence in this patient population.

So how did you set this up? First of all you chose your patients.

We selected patients based on risk grouping and we used a risk grouping called UISS which categorises patients as far as their energy level, whether they’re having any symptoms, the size of their kidney cancer, whether they have lymph node involvement. We used the groupings that predicted that patients would have roughly a 50% chance of relapsing. Some people might have a 70% chance of relapsing and some people might have a 40% chance of relapsing but in general we were going after a group of people that was high risk for relapsing from their kidney cancer.

And your anti-VEGF TKI was either sorafenib or sunitinib. Was that relevant which one?

What do you mean by was it relevant?

Did it matter whether you used sorafenib or sunitinib?

Interestingly we approached this historically as one drug versus placebo and we were basically talking with two different companies and both were interested. So the way it turned out we ended up testing both. At the time of the study design they were both very promising agents in kidney cancer and so the set-up of the design actually compares each drug to placebo, the drugs are not statistically compared to one another. That’s the way. And patients are treated with one year of therapy and then followed thereafter with scan assessments and physical exam.

So what did you find?

What we found was that the disease free survival in this patient population was about 5.8 years and we saw the same result in the patients treated with sunitinib as sorafenib as placebo. So there was essentially no difference in how well people did receiving the drugs versus receiving placebo.

I need to ask then about tolerability. What sort of impact did these agents have on quality of life?

We did collect quality of life information, that won’t be the context of the presentation tomorrow but we did record toxicity. Two things we found, one was about when about two-thirds of the patients were accrued we noticed that quite a few patients were dropping out of the study because of side effects that were either severe enough that we labelled them as toxicity or there were intolerability issues - people just didn’t want to stay on the drugs because they just didn’t feel well. So we had to make some adjustments in the design of the trial which other adjuvant trials have done as well which is that we reduced the dose of the drugs slightly and patients then started on the lower dose of treatment and if they felt well they had a mandatory escalation to the full dose after they’d been on the lower dose for two months. That seemed to well address the dropout rate but the redesign required that we added another 600 patients onto the study. So what originally was a 1300 patient study became a roughly 1900 patient study.

So you got nearly 2000 patients, you’ve given it a good try to see whether adjuvant therapy with an anti-VEGF TKI works, what are your conclusions?

One of the conclusions about the side effects, there were a large number of patients in very small numbers with a whole bunch of different side effects. The most common side effects that we saw were hypertension, high blood pressure, which was an expected side effect on these agents because they come and they cause high blood pressure and it was quite easy to manage. The other side effects that we saw in a higher proportion were also expected – things like hand-foot syndrome and tiredness. There were enough patients that got those side effects that we feel that the patients got adequate dosing. Then there were a whole bunch of other little, less than 1%, side effects that people reported.

So coming out of this, what do you conclude?

I conclude that sunitinib or sorafenib should not be used in the adjuvant setting. We’re obviously still analysing subsets of patients; we’re looking at the numbers of cycles people got and high risk versus low risk disease and females versus males and minorities versus Caucasian population. We’ll be digging deep into those analyses to see if there are small subgroups that perhaps would benefit or where it would actually be more harmful. But that data is still being analysed.

This is a big study, the assure study, what is your interim message for doctors coming out of this about adjuvant therapy using a TKI targeting VEGF?

My main message is that most of the trials have completed enrolment and we need to see what the other trials show. My own sense is that the antiangiogenic agents in this scenario their interaction with micrometastases is probably different than with established metastatic disease or primary tumours. This has been borne out in other solid tumours like colon cancer and breast cancer where you see a lot of activity in the metastatic setting and you don’t see activity in the adjuvant setting. There are two trials that are still continuing to enrol, one of them is the EVEREST trial which is a completely different class of drugs, an mTOR inhibitor everolimus, and the other one is axitinib in the ATLAS trial. That is also answering an important question about duration of therapy in that those patients get to have at least one year but up to three years of treatment. So I think that those are still very valuable questions that we need to continue to support those two trials but I suspect that there won’t be any further designs in tyrosine kinase inhibitor adjuvant trials, at least in this kind of design.