BOLERO2 data in breast cancer impresses at ECCO 2011
This year I decided to write some longer posts from the ECCO/EMCC meeting owing to the amount of potentially paradigm changing data coming out. These in depth op eds will roll out over the next few days.
Quite a few people have been asking what my picks of the conference are, so here goes, in order of Wow factor (purely from my perspective):
- Everolimus BOLERO-2 data in ER/PR+ HER2- breast cancer
- Alpharadin in advanced prostate cancer
- T-DM1 in HER2+ breast cancer
- Vismodegib phase III data in basal cell carcinoma
You can read more about the Alpharadin data on the companion Biotech Strategy Blog, but I will put up a post in the pros and cons of this therapeutic later in the week. It’s going to be very interesting indeed to see how this pans out.
Why did I pick the everolimus (Afinitor) data first over the others?
Well, regular readers here on PSB will know that I’m a great believer in
a) targeted therapies and
b) identifying mechanisms of resistance to determine logical combinations
We know that the PI3K-mTOR pathway is dysregulated in hormonal sensitive breast cancer leading to resistance, so a logical approach would be to treat women whose initial AI therapy has failed with another, but add in an mTOR or PI3K inhibitor. That’s exactly the case here.
The results? Simply stunning!
Jose Baselga presented the BOLERO-2 data to a packed audience. When he showed the slide for PFS, there were gasps in the audience around me – a shift in favour of the treatment arm (everolimus plus exemestane) over control (placebo + exemestane) not of the usual 1-2 months, but 6.5 months:
The side effect profile was consistent with what we know about mTOR and Aromatase inhibitors. One thing I would very much like to see is some subset analysis to see what factors separated the super responders from the average responders. This trial tested the combination in a general unselected population, but it would be nice to see if any factors can be derived from the data that suggests what might be predictive of response.
While these results are a major paradigm shift in women with hormonally sensitive breast cancer, the big question is can we do even better?
We also know from basic science that mTOR upregulates AKT, so eventually adaptive resistance will occur through that route too, but you can see where the next round of logical therapies might emerge in future. The current batch of AKT inhibitor have some challenging side effects when used in combination, but next generation of inhibitors might have a more tolerable and improved side effect profile.
All in all, I thought the BOLERO-2 data were my pick of the conference for major practice changing data and I hope to see this data submitted for approval to the Health Authorities very soon. This development is very good news indeed for women with ER/PR+ breast cancer.
5 Responses to “BOLERO2 data in breast cancer impresses at ECCO 2011”
Sally,
Great post with very rich analysis and insights.
Its very encouraging to see drug companies and physicians coming up with
smart logical combinations after understanding the molecular drivers of cancer.
Combining two targets together – hormonal (targeting ER, PR) and mutational
(with over-active Pi3k-akt-mtor) pathways in such cancers that harbors these
molecular defects made a lot of sense.
A few observations and would welcome your thoughts:
1. I understand there are clinical trials evaluating a combination of an
aromatase inhibitor and a dual pi3k/mtor inhibitor; which could potentially
mitigate adapative resistance that you talked about; thereby potentially
offering better results (offcourse toxicity could be more as well). Would be
great to see any emerging trends / results on such trials.
2. Cancers like Endometrial /Uterine (endometrioid variety) also are hormonal
in nature; and many (upto ~ 30-60 %) harbor defects in the pi3k-akt-mtor
pathways. As such, for relapsed, metastatic uterine cancers; there are not too
many fda-approved therapies and such treatment strategies could be of value. Not
sure if you came across this study presented at the recent ESGO ( http://www.medpagetoday.com/MeetingCoverage/ESGO/28598 )
with some promising results.
3. I was wondering if the BOLERO2 study analysed mutational status of
patients (Either pi3k mutation / amplification) and whether it predicted
response ? If such predictive bio-markers are developed, it could help match
therapies benefiting patients and drug companies equally.
I write as a patient’s care-giver (my family member has an endometrioid ER+ve
cancer that arose from endometriosis) and have followed your posts with great
interest.They have been very educative and insightful and have greatly benefited
us. Would love to bounce a few thoughts with you on email (apart from sharing a
patient’s perspective on targeted therapies); so if you could leave me your
email my email id on your post ; would greatly appreciate it.
thanks much
Andy
Hi Andy, good to hear from you. In answer to your questions….
1. Yes, there are trials ongoing in breast cancer with a dual PI3K/mTOR and an AI, but we don’t know whether that strategy will be any better than an mTOR alone yet. There will likely be different adverse adverse with the dual inhibitors and the adaptive resistance pathways will be different. I think it’s a nice idea, and look forward to seeing the results when they mature.
2. Yes, I saw the promising ESGO data and have long argued that targeting mTOR and/or PI3K with an AI or other targeted combinations would be a useful strategy in endometrial cancer. There is a phase II ongoing with Merck/Ariad’s ridaforolimus, for example, (see: http://clinicaltrials.gov/ct2/show/NCT00739830) and also one with everolimus (see: http://clinicaltrials.gov/ct2/show/NCT01068249), both in combination with aromatase inhibitors.
3. I have no idea if Novartis collected biomarker data (though I suspect they did) and stratified the BOLERO2 patients by mutations and amplifications, but no doubt that analysis will appear at some point if they did. Certainly it will be interesting to see if there is any new data at SABCS in December.
You can email me directly anytime by clicking on the mail icon at the top of the right hand column (you may need to click on the Blog button at the top to see it) 🙂
[…] previously wrote about the exciting BOLERO2 results that were presented at the European Multidisciplinary Cancer Conference… in September. More data is expected at SABCS to coincide with a publication in the New England […]
[…] Symposium (SABCS), although it should be noted that the NEJM article is based on the phase III ECCO data previously presented by Jose Baselga in […]
[…] breast cancer. Recall that one mechanism of resistance to AI treatment is mTOR, which is why the BOLERO2 trial with an AI (exemestane) plus an mTOR (everolimus) in the relapsed setting did so well in ER+ women. Not all of the women in the trial responded to […]
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