IMPAKT Breast Cancer Conference 2013

Next wave of successful drug therapy strategies in HER2-positive breast cancer

Dr Hans Wildiers - University Hospital Leuven, Gasthuisberg, Belgium

Hans, you’re one of the key people here and you are doing just about everything in breast cancer it seems, especially targeted therapies. So your address here on the next wave of successful drug therapy in HER2-positive breast cancer is very interesting. Can you tell me about studies that are being done because they’re combining some of these very interesting agents aren’t they?

Yes, the HER2-positive disease is one of the fields in breast cancer where most advances are made. We have now two drugs that are entering the clinic, new drugs that seem to improve the efficacy of our current treatments with the addition of very little toxicity.

That’s pertuzumab is one of them.

Pertuzumab is the first one; it was recently tested in a large phase III trial, the CLEOPATRA trial, and was shown to improve progression free survival by six months and also overall survival with nearly no additional toxicity.

Now what’s the difference between that and trastuzumab?

Pertuzumab is also a monoclonal antibody against the HER2 receptor but it binds a different domain of the HER2 receptor; it binds the dimerization domain. So trastuzumab just blocks the receptor from signalling while pertuzumab also blocks the dimerization with HER1 receptor, HER2, HER3 receptor.

And then there’s also a conjugate as well, a trastuzumab conjugate, TDM1, isn’t there?

That’s the second drug, TDM1, it’s a completely different approach. There trastuzumab is linked to an old cytotoxic drug, emtansine, so it’s an antibody-drug conjugate. They are bound together and they travel through the blood together without toxicity and it’s only at the HER2 receptor that it binds. The trastuzumab allows internalisation of the conjugate and it’s only within the cell that the link is cut and that the DM1, or emtansine, is released.

And you’ve got another study in which you’re combining two targeted agents, pertuzumab and trastuzumab. Tell me about that, please.

Yes, so in the CLEOPATRA trial pertuzumab and trastuzumab were combined with docetaxel chemotherapy but for older individuals the toxicity is more a problem and we have seen in a neoadjuvant study that two monoclonal antibodies alone, without chemotherapy, can be very effective also with very little toxicity. So we are now testing this in an EORTC trial in older patients with HER2-positive metastatic breast cancer and it might be possible that we are able to stop and control disease for long periods without needing chemotherapy.

So you are beginning to look forward to an era where you can not use chemotherapy in metastatic breast cancer?

That’s what we hope. For younger people we probably still need chemotherapy because they have a long life span and we use everything we have but in older people the life expectancy is also influenced by other causes of comorbidity and as long as we can control disease there for years they might eventually die from other causes.

Of course, trastuzumab made an impressive leap forwards in controlling HER2-positive disease, how much of an additional contribution do you think these new targeted agents will make?

I think they have about the same impact. If you look at the gain in progression free survival it’s about the same additional benefit with adding pertuzumab.

So what kind of message would you give to doctors coming out of these new targeted agents that are now being applied, some of them, of course, already licensed?

Yes, pertuzumab is licensed in the US last year and since March here in Europe so we will be able to use them in daily practice very soon. Some countries have issues of reimbursement, of course, but there is European Union approval.

What’s your message to doctors?

They should use it; it’s the new standard in first line metastatic HER2-positive breast cancer to use pertuzumab in addition to trastuzumab and a taxane.

Now, apart from those agents, is there anything else coming down the highway?

There’s lots coming down the highway. There’s a huge amount of studies in HER2-positive disease with signal transduction inhibitors at various levels but it’s not so far advanced yet. An additional problem is that also in the adjuvant setting we are improving. Pertuzumab has been tested also in the adjuvant setting and we are waiting for the results. So less and less people become metastatic with HER2-positive disease and sometimes it’s even difficult to find the patients for the trials.

Well that’s an impressive situation, isn’t it? Can you describe to me how things are lining up now? Because you have adjuvant therapy, you have therapy for metastatic disease, you also have potentially neoadjuvant therapy with these targeted agents, how do you see them all being used?

Yes, there have been two important neoadjuvant studies, one is the NEOSPHERE trial where pertuzumab was added to neoadjuvant chemotherapy regimens and, as expected, it was only when you gave chemotherapy plus trastuzumab plus pertuzumab that the pathological complete response doubled compared to the other arms.

With chemotherapy only?

With chemotherapy and trastuzumab only, yes. And in that neoadjuvant setting there was also one arm with trastuzumab-pertuzumab without chemo and there the pathological complete response was still 17%, so it was not 45% like in the triplet combination but the combination pertuzumab-trastuzumab without chemo was active.

So do you see the potential for neoadjuvant therapy without chemotherapy coming up in the future?

Well the pathological complete response was still lower than when chemo was added so I think in the neoadjuvant setting we will still need chemo for a while. But there are now studies being set up where TDM1 is combined with pertuzumab so the TDM1 contains chemotherapy but it’s a linked drug with very little toxicity and there we might end up with regimens that have hardly any toxicity.

And do you see an increasing role for the targeted therapies after surgery?

Yes, that’s a very different setting. I think we need to develop more clinical trials where patients who did not obtain a pathological complete response receive new drugs, other drugs in the adjuvant setting. It’s a domain where we need to evolve in a better way than we do at present. I didn’t mention yet but there is also another category of HER2 targeting drugs, it’s the tyrosine kinase inhibitors; lapatinib was the first one, we’ve had it available since a few years. We know from recent data that lapatinib by itself is slightly inferior to trastuzumab but when it’s combined to trastuzumab it’s also very active and that has been seen in another large neoadjuvant study, the NeoALTTO trial where the combination of lapatinib and trastuzumab also gave a pathological complete response of about 45%.

Right, how do you advise doctors to understand all of this complexity because there are now a number of agents? How do you advise the average doctor to use them all?

Well, we don’t have it available yet in that setting but if available… There is some difference in toxicity profile though. I think that pertuzumab in general has a better tolerance profile compared to lapatinib. It might even be that the three drugs together work best but they are from different companies and it’s always difficult to set up this kind of…

And do you see this, when these drugs are all on-stream, then do you see the guidelines floating to the top and it becoming easy to plug in to use these therapies to individualise your best cancer treatment?

Yes, in HER2-positive disease we have not been very successful in individualising therapy. The only predictive and prognostic factors that we have until now are HER2 and that’s it. We cannot select yet which HER2-positive patients benefit and don’t benefit.

So there’s a case for empirically using different agents?

At this point yes, I think the studies have included all HER2-positive patients so we should use them where they were used in the trials.

And finally, briefly, you wear another hat with geriatric oncology. How does this mix in with all these exciting studies on targeted agents?

Geriatric oncology is a relatively new field and it’s extremely important because people are getting older. On the one hand that’s very clear and on the other hand cancer is a disease of older people so these two factors together mean that we will encounter more and more old people in our daily clinic and we need to be prepared for that. And I am active internationally in the domain of geriatric oncology. On the one hand there is SIOG, the International Society of Geriatric Oncology, I have been on the board for the last years and we have been developing a lot of guidelines on available evidence in older people. Older people do not always need the same therapies as younger. In breast cancer, for instance, there is less benefit of adjuvant chemotherapy but you need to select the right patients because if you say we don’t give any adjuvant chemotherapy in old people you are under-treating patients and this is wrong and leads to increased breast cancer death. But on the other hand you should not over-treat them and you should not give all 88-year old ladies adjuvant chemotherapy, then you are killing them. That’s the big difficulty in geriatric oncology: you do not only have the tumour but you also have all these general health-related issues that you need to tackle and therefore you need geriatric evaluation. We are working very hard within SIOG and also within the EORTC to develop standard guidelines for geriatric assessment.

And in just a few words, how would you sum all of this up, the sorts of things doctors should remember about this geriatric oncology?

It’s important that oncologists do not only look at the tumour but also look at the general health-related status of patients. In that case you have a better view on the whole medical problem of your patient because they have often other problems – they have comorbidity, they have functional problems. You should integrate all these aspects in treatment decisions; you should follow functional decline. Sometimes the tumour can disappear but the patient can be knocked down by the therapy and then you haven’t helped the patient either.

Hans, thank you very much for joining us on ecancer.tv. We look forward to hearing lots more.

Thank you.