ASCO 2012, Chicago, USA

Insight into the EMILIA trial and systemic challenges with neoadjuvant therapy

Dr Erica Mayer – Dana-Farber Cancer Institute, Boston, MA, USA

Erica Mayer, lovely to get you here. You’ve been talking about a whole lot of things here at this year’s ASCO but, of course, I want to ask you first of all about EMILIA – very important to look at a conjugate, an immunoconjugate, to see just how helpful that might be in HER2 positive metastatic breast cancer. So first off, tell us what’s your take on this?

The EMILIA study is probably the most important abstract at ASCO this year. EMILIA studies a drug called TDM1; TDM1 is a new class of drugs that we call antibody drug conjugates. It is traditional trastuzumab or Herceptin, which is a humanised monoclonal antibody against HER2, with a special link to a few molecules of a chemotherapy called maytansine. Maytansine is an old chemotherapy, we studied it many years ago and found it to be too toxic but it was quite potent. The idea here is that we are using the trastuzumab to bring the drug right to the HER2 positive breast cancer cell.

This is the classic idea of a guided missile.

Exactly. I like to think of it as a Trojan horse because it gets brought right into the tumour cell, it releases its toxin and we can achieve much higher concentrations of chemotherapy in the cancer cell than if we gave it intravenously.

And of course capecitabine is a sort of Trojan horse as well in its own right, being a cytotoxic that’s only active…

Well capecitabine is more of a traditional cytotoxic, it’s similar to giving 5FU.

A pro-drug rather than a…

Yes, somewhat. The TDM1 has been studied in a few previous studies in heavily pre-treated patients and showed response rates in the 30-40% range with remarkably little toxicity because there really is very little bystander effect. So there was a phase II study done in the first line setting where patients received trastuzumab and taxane, which is a very traditional first line regimen, or received TDM1. This was data presented at ESMO last fall. The patients who received the TDM1, not only had a longer progression free survival, but also had basically half the rate of grade 3 serious toxicity compared to those that got chemotherapy. So really remarkable early results. The EMILIA study is the first phase III study we have with TDM1 and it’s designed to be a registrational study with the hope that this will lead to FDA approval for this drug. The study was designed to look at patients who had previously had a trastuzumab based regimen, so they had progressed through trastuzumab either in the metastatic setting or soon after receiving it in the neoadjuvant or adjuvant setting. This study was done worldwide and accrued almost a thousand patients, 980 patients. They were randomised in a one to one fashion to a standard second line regimen which is the oral capecitabine with another oral HER2 directed drug, lapatinib. Lapatinib is a small molecule tyrosine kinase inhibitor of HER2 and EGFR and that’s an FDA approved regimen.

OK, the data on this, of course we’ve been hearing quite a bit here at ASCO, but progression free survival was the outcome. Overall survival not yet significant, but what are your feelings about the data? What are they, in brief?

There was a co-primary endpoint of progression free survival and overall survival. The data reported by Dr Kimberley Blackwell today demonstrated a statistically significant prolongation in progression free survival from about four months to close to about seven months. So it was about a 3½ months progression free survival benefit. For overall survival the data is not quite mature; there is already in the interim analysis a statistically significant benefit but it hasn’t yet crossed the threshold where we can officially say it’s positive.

This is being described as a new option, what are your thoughts?

The other important part of this data is it was extremely well tolerated with less toxicity seen with TDM1 compared to the more traditional chemotherapy based regimen and more patients were able to finish therapy without dose reduction or having to come off therapy for toxicity. So not only was it more active but it was also better tolerated. This data will, I believe, go to the FDA and I would certainly hope will lead to approval of this drug for patients who have previously been treated with trastuzumab.

Let me take you down another tack, if I may, because you’ve been delivering a talk about neoadjuvant therapy in Education session, where are we with neoadjuvant therapy, this is in breast cancer?

Neoadjuvant therapy or pre-operative therapy is a very important part of how we treat locally advanced breast cancers and sometimes even cancers that aren’t necessarily locally advanced. We know from decades of data that there’s no detriment in survival in leaving a tumour in place and giving systemic therapy first. There are also several advantages: we can downstage a tumour and allow a woman who previously would have been told she needed a mastectomy to have breast conservation.

It’s a time honoured principle, I’m thinking of Gianni Bonadonna, for instance.

And now we’re in a new age where we’re trying to do less and less surgery. Additionally, we can actually see what happens with the tumour – how does it respond to therapy? We do not get that information when we give adjuvant. Also the results we have at surgery can be prognostic and help us make some predictions about risk. Furthermore, it’s an excellent research platform so we really try to bring a lot of our new therapies in in the neoadjuvant setting.

Great ideas then, what’s your advice to clinicians about using neoadjuvant therapy routinely?

One of the things that comes up for anyone who uses this routinely is although there are advantages, often this presents a lot of clinical challenges, particularly in local regional management. What are the right surgical decisions, both before and after systemic therapy? What are the right radiation oncology decisions? Who are good candidates for radiation? Are there patients who have such a good response that we perhaps don’t need to be providing them surgery and radiation which we normally do provide?

And your brief guidelines are what?

What we found in our session, we had a multidisciplinary session where I as medical oncology was there and I had really esteemed colleagues: Lori Pierce from University of Michigan from radiation oncology and Dr Emiel Rutgers from The Netherlands Cancer Institute was our surgical oncologist and we battled it out on multiple challenges. I think our take home messages are, first of all, neoadjuvant therapy requires a multidisciplinary approach. From day one a patient needs to meet with specialists from all three fields and those doctors need to work together throughout to make all of the important decisions about imaging, treatment and follow-up.

But neoadjuvant therapy is, in your view, quite an important modality?

I think it’s important and it’s growing. Overcoming the challenges that we identified will hopefully allow people to feel more comfortable using it as we move forward.

I forgot to ask – with what?

Most of what we talked about is with chemotherapy but we actually, based on questions from the audience during this session, had the opportunity to speak a bit about neoadjuvant endocrine therapy. There’s a really growing literature on the ability to identify patients who are probably unlikely to respond well to chemotherapy. Their tumours might be slow-growing or of a certain sub-type where we really think they’re not going to do much with chemo but the cancers are sensitive to hormones.

We’d like to try to avoid having to give chemotherapy to these women and instead just treat them with a hormone pill.

And neoadjuvant molecularly directed therapies?

We already have a lot of data about these HER2 directed therapies in the neoadjuvant setting. There are some very large trials, including NEOALTO and NEOSPHERE which have demonstrated that the addition of HER2 directed therapies like lapatinib and pertuzumab can be really helpful.

Now, a really quick one, a few seconds but you’re author on a paper on comparing a cheap drug with a number of more expensive options – paclitaxel compared head to head with nab paclitaxel and ixabepilone. It seems weekly paclitaxel came out on top, what’s your take on that?

This is a study that was run through the Cancer and Leukaemia Group B, the CLGB, so a multi-institutional study led by my colleague Hope Rugo. Patients in the first line metastatic setting were randomised to one of three chemo regimens: weekly paclitaxel, which is a very traditional regimen; a newer drug, nab paclitaxel, which is a reformulation of paclitaxel and ixabepilone, which is a newer anti-tubule agent. There was also the option to add in bevacizumab as part of the treatment.

That was used in this study but it’s now been discarded, of course, the actual practice.

Right, that was an extra part of the study. The end result of this study essentially indicated that weekly paclitaxel had the best result in terms of activity and tolerability with the other agents having some problems with neuropathy, something we know well. Paclitaxel is a generic drug, it’s not expensive, it’s well tolerated and it’s something which we’ve always felt comfortable using in the clinic. It’s a wonderful confirmation that what we’re doing is the right thing.

And your conclusion about this, then, is a reassuring message.

I think so, it helps us feel comfortable using the tools that we’ve always been using.

But a warning too?

It’s a warning that the nab paclitaxel and ixabepilone are, first of all, not agents that have really been studied well in the first line setting. Also that we can’t be so quick to discard some of our more traditional therapies until we’ve really proven that our newer agents have an efficacy and toxicity edge on them.

Erica Mayer, good to hear from you.

Thank you so much for having me.