ESMO 2012

Advances in advanced renal cell carcinoma from ESMO 2012: Part 2

Professor Tim Eisen – Addenbrooke’s Oncology Centre, UK
Professor Bernard Escudier - Institut Gustave Roussy, France
Dr Thomas Powles – St Bartholomew Hospital, UK
Dr Thomas Hutson – Baylor Sammons Cancer Center, USA


Post first line TKI therapy

TE:    Tivozanib and axitinib, these drugs are highly specific and highly potent, is that as good as it gets in anti-angiogenic TKI drugs rather than the way we use them but just the drugs themselves?

BE:    I think it’s an important question; I think they are more potent, they are probably certainly more selective. My main concern is that axitinib, at least in second line, was not able to improve OS. Somewhere I am still a little concerned that even in the post-Cytoxan group where the PFS was more than doubled still OS was not improved. So I still want to see the overall survival data for the first line study before being as convinced as I am actually because the PFS is really good.

TE:    OK, thank you very much. Tom, you’ve presented data comparing sorafenib with temsirolimus in the second line setting, can you tell us what you think is the bottom line of that study?

TH:    Yes, so the INTORSECT trial, which was a trial comparing temsirolimus versus sorafenib in patients who had progression on front line sunitinib was reported earlier today. It was an international trial of over 500 patients where they were randomised one to one to either of those two treatment arms. The primary endpoint was progression free survival and, as you know from the report, there was no statistical significant difference between arms. The secondary endpoints of the trial, which included the traditional overall survival, response rate and safety and tolerability measures, showed us something very shocking, it showed us an overall  survival difference that  was statistically significantly in favour of  the sorafenib or the VEGF inhibitor arm of over four months. So with that degree and magnitude of survival difference it brings up several questions to an oncologist. First and foremost is progression free survival an appropriate surrogate for overall survival? This trial would suggest maybe we need to re-examine that. The second would be a more taxing and more probably controversial area, would be is there some detrimental long-term effect of using mTOR inhibition that we don’t understand yet that would allow another agent such as sorafenib to have a longer survival advantage? Or third, is this all just a fluke, it just happens to be related to confounding and other biases? So I think we won’t have an exact answer to that question right now but hopefully in the future as we look at other trials that come forward that we will be able to answer that more definitively.

TE:    So do you have a favourite one of those three possible explanations?

TH:    I think clinically and I think when we use the data from this trial, and with other trials that have been reported, I think there is a building evidence that going sequentially with VEGF inhibitors in  the first and second line setting, moving into mTOR inhibitor potentially in the third line setting makes rational sense. Again, that’s just compiling data across trials, there’s not a definitive de facto trial that’s going to establish it but it’s just that there is certainly a movement towards that with this data.

TE:    So you don’t feel that the mTOR field in the advanced disease setting is dead?

TH:    Not at all. I think the drugs are active and what we need to do as a field in oncology is to try to understand how the sequences should play out, if they’re important at all. Maybe it will be like other cancers, like colon cancer, where just exposure to all the agents is what drives survival at the end of the day.

TE:    And in the US you use quite a lot of temsirolimus which we tend to use much less in Europe, do you think that these data will have an impact on that use?

TH:    I don’t think so. I think right now, when I personally look at temsirolimus use, that really I have it pigeon-holed primarily in the  poor risk front line, in which case that’s an easier setting. I rarely will substitute temsirolimus for everolimus in later line of therapy and when I do so I think most of us would feel it would be appropriate to do so in certain situations and patients. So there are some patients who coming in weekly for a visit is very important,  just based upon comorbidities and other things; sometimes I find that patients tolerate the IV version easier than the oral version so that would be another situation. But the majority of use of IV temsirolimus, that I’m aware of in the States, is predominantly frontline and this data in the second line should not support that. I’ll remind you that it wasn’t that temsirolimus and sorafenib did not have activity, in fact they had activity, it was approximately four months PFS which is not outside the ballpark of anything else that we’ve seen in the second line, including axitinib and including everolimus.

TE:    OK, thank you. Tom, I think most people would accept that mTOR inhibitors do work well but for a relatively small proportion of patients. Do you think we’ll ever be able to identify in a predictive way which patients those are?

TP:    I hope so. I think it’s the next big goal. I think Tom’s data, the 404 data he’s just described, the survival difference is very significant and it does trouble me a little. I agree with Tom at the moment that when choosing these drugs it does seem that sequential VEGF targeted therapy in the entire population seems wise at the moment. The disadvantage associated with  the mTOR  inhibitors is concerning and it probably would change the way I perceive the field at the moment and I probably would be keener to go into sequential VEGF targeted therapy and using mTOR third line than going second line at the moment.

TE:    Would you need more data to do that or do you think you have enough?

TP:    I think at the moment we probably have enough data, I think there are not many renal cancer studies with a survival difference, in fact there are  very few  VEGF targeted studies with a survival  difference, in fact I might say sorafenib, this  is the most significant survival difference we’ve had. Bernard is absolutely right, the axitinib sorafenib study showed no survival difference so these goals are difficult to achieve and very significant results have been achieved. So unless we can identify subgroups of patients who specifically benefit from mTOR, and we all have anecdotal experience that those exist, then I think it’s very difficult to pursue a one size fits all policy using mTOR in this population, second line at the moment.