ASCO 2012, Chicago, USA

Effects of lapatinib and trastuzumab on progression free survival

Dr Nancy Lin – Dana Farber Cancer Institute, Boston, MA, USA

Dr Lin, you’re at the Dana Farber Cancer Institute, you head up breast oncology there. You’re working at the moment on dual blockade of the HER2 receptor in patients with breast cancer. A lot has been done on this already, hasn’t it? For instance, using the agents that you’re using, lapatinib and trastuzumab, there’s neoadjuvant data so far and other data. Can you run me through what has been found already?

So in the neoadjuvant setting there are a number of randomised trials that have been reported, essentially randomising patients to chemotherapy trastuzumab or chemotherapy lapatinib or, in many trials, a third arm of chemotherapy plus the doublet that is both trastuzumab and lapatinib. In these neoadjuvant trials what has been demonstrated is the pathologic complete response rate in the breast has been higher in the patients who received the triplet that is chemotherapy plus trastuzumab plus lapatinib. Now whether these are going to translate into any kind of survival benefit is yet to be seen.

So in the neoadjuvant setting you get some kind of thermometer, some kind of measurement of what might happen in the future?

Right. And in the metastatic setting what we have is data from several studies. One is a randomised trial in the refractory setting so patients who had received many prior therapies for their disease and who were randomised to receive either lapatinib alone or lapatinib with trastuzumab. And that study showed an improvement in progression free survival and some suggestion of an improvement in overall survival with a doublet compared to lapatinib alone.

There has been work in refractory and also first and second line?

That’s right. So we conducted within the Translational Breast Cancer Research Consortium a trial of trastuzumab-lapatinib without chemotherapy in the first or second line metastatic HER2 positive patients and we also demonstrated a fairly intriguing level of activity in both the first and second line settings.

When you say an intriguing level of activity, can you put some numbers on that?

Sure. In the first line setting we saw a response rate of about 45-46%, and remember this is without chemotherapy; in the second line setting the response rate was in the twenties. So I think it was interesting for a regimen that did not include cytotoxic chemotherapy.

And have there been any downsides though? Because you’re doing a heavy blockade, it’s bound to have consequences.

In the trials it doesn’t look like there’s an increase in cardiac toxicity and we also saw that again today in the presentation of NSABP41 which is a neoadjuvant trial. On the other hand, there are toxicities associated with lapatinib, and those include rash and diarrhoea most prominently, and there were somewhere in the range of 5-8% of patients, depending on the study, with moderate to severe diarrhoea, that is grade 3 or higher diarrhoea with a combination regimen.

At the moment you’re now looking into maintenance with this dual blockade. Why is that so important and what are you hoping to get out of it?

Traditionally, the way that we generally treat patients with metastatic disease is give an induction period of chemotherapy with trastuzumab for anywhere between 3-6 months typically and then transition patients to trastuzumab monotherapy to preserve quality of life by omitting the chemotherapy portion of their treatment and many times we can have prolonged disease control before patients have to go back on cytotoxic chemotherapy. The idea with this trial is to see whether we can extend that chemotherapy-free interval by the addition of lapatinib to trastuzumab. And although the combination does have additional toxicity compared to trastuzumab alone, I think overall it’s often better tolerated than many of the types of cytotoxic chemotherapies that one might otherwise consider.

What are the sort of feelings you have about how this might be going? The sort of benefits that you are hoping could come out of this?

Our hope is that we would be able to see a significant prolongation in progression free survival in patients treated with the combination as maintenance as opposed to patients who are maintained on trastuzumab alone. Again, our hope is that the clinical benefit part of things has to do with essentially the time to need for next cytotoxic chemotherapy. I think it’s important to recognise that the HER2 space is a very exciting space right now and there are many compounds in clinical development, including pertuzumab and TDM1, and I think one of the things to sort out over the next years will be in which patients, which drugs and which combinations are the most helpful.

In terms of practical medicine, how do you counsel the oncologist to fit this into their practice and their overall plan for a patient? Because we’re trying to individualise therapy wherever possible.

I think that this idea, this maintenance idea, of the dual blockade is certainly not ready for prime time, it’s the reason why we have an on-going trial and I wouldn’t necessarily recommend it outside of a trial. There’s a lot of interest in understanding what are the predictors of response and duration of response to treatments and, for example, in the TBRC trial that we’ve completed we actually did metastatic tumour biopsies and are currently planning to do whole genome sequencing or whole exome sequencing of the tumour samples to try to get a better sense of which tumour in which patients the treatment may be particularly effective.

Of course there has been a big step forward by using single blockade of HER2.

That’s right.

Do you think that by refining this and individualising therapy further we can make gains of a similar magnitude to that or are we talking about small increments?

It’s hard to say, I think this study is looking at, relative to what the ultimate goal is, which is to cure metastatic disease, on that scale this study is a small increment. We’re not attempting to cure metastatic disease and we’re attempting to improve progression free survival but the study is not powered to look at any type of overall survival difference. The space of HER2 targeted agents and agents that are targeted at resistance mechanisms that are HER2 targeted agents is a very fruitful one and I do think that eventually my hope is that we will, and I have a lot of optimism about this, so we’ll find the right way to treat individual patients. I don’t think we’re quite there yet.

So what would you tell doctors at this moment, the brief things to remember from the news that you now have on HER2 blockade and dual blockade in particular?

One is that in refractory patients, based upon the phase III trial that was published by Kim Blackwell, I do think that it’s a reasonable option to consider in those patients who have progressive disease and who would have fit the eligibility criteria for her trial; I think that the tolerability of the regimen is reasonable. In the maintenance setting we don’t have the data at this point of whether that has any additional clinical benefit and because of the additional toxicity I wouldn’t recommend it in the maintenance setting outside of the trial.

But it looks as if this whole area has quite a lot of interest in future?

Indeed, I think that there’s a very interesting future and, again, as more agents are developed in the HER2 space one of the challenges will be how does one best combine them? Because you can imagine you could actually give five drugs altogether to all patients but we probably don’t want to do that and there may be patients in whom one drug will suffice and other patients in whom you have to give the kitchen sink and I think that we don’t have a way to individualise therapy properly yet.

Nancy Lin, it’s a pleasure to hear from you.

Thank you.