2010 San Antonio Breast Cancer Symposium, 8-12th December, USA
Interview with Professor John Robertson (University of Nottingham, UK)
FIRST trial follow-up results
The FIRST trial is a trial in post-menopausal patients with advanced breast cancer giving one of two drugs in the first line setting. It compares Fulvestrant 500mg, which is often called high dose, versus Anastrozole 1mg. It was a phase II trial of 102 patients, open label study, and the primary endpoint was clinical benefit rate with a secondary endpoint being time to progression.
What was found?
The primary endpoint was reported two years ago, here at San Antonio, and it showed that in the initial response rate and clinical benefit rate there was a numerical but not statistically significant difference in favour of the 500 dose and people had interpreted that at the time to mean that in de novo resistant patients it didn’t have any additional effect, maybe a small effect – the hazard ratio was 1.3 but it wasn’t statistically significant.
What it also showed in that primary analysis was that the time to progression was prolonged in the 500 dose, in other words it appeared to be more affecting acquired resistance and delaying the onset of acquired resistance. Now the point that was made two years ago was that first of all the data was short follow-up for time to progression. The second thing was at that time it was a phase II open label study, as I said, and there was no phase III randomised data on the 500 high dose regime. In the intervening period confirm a study of 500 versus 250 Fulvestrant was reported last year at San Antonio and showed again that the 500mg dose was superior in the time to progression which was the primary endpoint in that study.
This study now was looking at an updated analysis of the first trial showing extended time to progression to see if that difference could be shown to be sustained. What we did show was that in fact the time to progression curve did show a benefit in favour of Fulvestrant and in fact the median time to progression on the EI Anastrozole was thirteen months but for Fulvestrant was 24 months, not quite but almost double that.
What impact could this have in the clinic?
That’s an interesting question. We said two years ago when FIRST was reported and there was no phase III, no confirmed data, we said then that although it was statistically significant that it shouldn’t be practice changing. Today you have to acknowledge that there are one or two things about the study, as I said it’s an open label study, it’s a phase II study, and therefore it doesn’t have perhaps the robustness of a phase III trial. On the other hand it now falls on CONFIRM, supporter of that data and it has extended follow up. So I think while it is not a phase III trial, individual clinicians will look at that data and make their own decision as to which drug they may want to use in a situation. But I don’t think, as it’s not a phase III trial, I don’t think that it’s something that you’d say this should now change practice for every person.
What about side effects?
Yes, the side effects of the 500 dose are very good. I know in the confirmed data that in fact you saw no difference in the side effects for doubling the dose; you saw improved efficacy but no difference in side effects. In fact I don’t really know of any other anti-cancer drug where you can double the dose, improve the efficacy and get no increase in side effects, same tolerability. In this study we found that the side effects were exactly the same as in EI. These were predefined adverse events, predefined side effects, and no statistically significant difference. So again a well-tolerated regime even at a higher dose.
What about the future?
If you were looking at these data there are two ways in which you might want to develop this by further studies. One would be a phase III trial in first line therapy to confirm the data; the other opportunity would be to move directly into the adjuvant setting and personally I think that a much more exciting development would be to try and move the 500 dose into some sort of adjuvant programme in the sense that the hazard ratio we’ve seen is so big, it’s 0.6, and it is bigger than we’ve seen before with EIs and Tamoxifen. So I think that would be a new and exciting development. Then the question would be what would be the most appropriate design – an up-front study or BIG 198 type attack, or would it be something like a switch study – two years after an EI you switch to Fulvestrant or continue in EI. Personally if you were only going to do one of those studies I think I would do the second, one, because I think it will bring Fulvestrant 500 to the adjuvant setting much quicker, and secondly what we’ve seen in the advance disease setting is that most of the effect of the 500 dose, as I said, was in time to progression and particularly in delaying acquired resistance. Therefore I think that crossover study is likely to show a bigger effect because you are further out from treatment, you’re looking for more of an effect on acquired resistance and also too because you don’t have to wait the five years from starting therapy to see your outcome measures. I think if I choose between the two, that would be the adjuvant therapy that I would choose. Because I think those are the potential developments which one would like to see following on from the FIRST study.
