European Multidisciplinary Conference in Thoracic Oncology (EMCTO) 2013

Treating adenocarcinoma with bevacizumab

Prof Ken O’Byrne – St James’s Hospital, Dublin, Ireland

Ken, this is indeed an exciting meeting here in Lugarno because there are targets for non-small cell lung cancer and you’ve been given the task of summing up what’s happening in the case of adenocarcinoma. You have got quite a list, haven’t you? To begin with, anti-angiogenesis, that’s an interesting area, isn’t it, and one that seems to have yielded a harvest so far.

Yes, angiogenesis was seen to be a target for therapy in many tumours, lung cancer being one of those, and a drug called bevacizumab entered into clinical trials and produced a positive phase III result in the US with a two months’ improvement in median survival from 10½ with the chemotherapy, approximately, to 12½ months for the combination. There has been, however, difficulty in reproducing that survival benefit but what is clear is that with bevacizumab attached to chemotherapy we’re seeing higher response rates and progression free survival is also improved so there is activity. The issue is which are the patients, or who are the patients, that are benefitting from this therapy? Looking at angiogenesis in a broader sense there are a number of drugs, tyrosine kinase inhibitors, that have been tested and none of them have produced a survival benefit, that’s to date. However, all of them, or not all of them but a significant number, are producing progression free survival benefits and higher response rates. So again we know there’s a subset of patients benefitting but the problem is we don’t know who those patients are.

Is this, in fact, because of the epidermal growth factor receptor or could it be other issues?

The target for bevacizumab is vascular endothelial growth factor and most of these tyrosine kinase inhibitors that are used for angiogenic treatment are targeting receptors that are associated with angiogenesis, so they might be the vascular endothelial growth factor receptors themselves, they can be platelets, there are many others that we can look at, other receptors that may be involved: fibroblast growth factor receptor, others that may all play a role in angiogenesis or in that whole process. So, from my point of view, the research that we’ve been doing in our laboratory suggests that maybe angiogenesis is not the target and that maybe there’s a subset of cancers that have certain receptors expressed in them that might actually be the targets for these drugs. So that by mopping up the EGF you reduce the stimulus to the cancer cell to grow. One of those receptors is an interesting one, it’s one that’s normally expressed in neural tissue called neuropilin and neuropilin 1 and 2 are the two main receptors. We have found that VEGF stimulates the growth of cancer cells themselves that over-express this receptor. So perhaps by taking biopsies, staining for this receptor, or indeed other receptors like VEGFR-2 or even VEGF itself in the cancer cell, we might get a better handle on which group of patients are benefitting from the therapy. So I think this is the way we need to move forward, we need to personalise this medicine and deliver to the patients who are going to get the most benefit.

But before we leave angiogenesis, what is the score with bevacizumab right now?

Bevacizumab has some activity but it’s at best a marginal benefit and because of that some people will use it for treating patients and some people will not use it for treating patients, remain unconvinced about its benefits. There is a significant cost to using the drug so it is a controversial area.

And you’ve got new areas, heat shock protein is one of them too.

That’s correct. Heat shock protein is a very exciting area because heat shock proteins are present in all cells, both malignant and normal, but in malignant cells the heat shock proteins tend to be maybe slightly over-expressed, or sometimes quite a bit over-expressed, and tend to be activated so that they play a role in folding around and completing the folding itself of proteins that are involved in cell signalling. So they play a role in ensuring the mature shape and active form of oncoproteins, cancer causing proteins.

And how do you target that?

You can target it specifically with drugs that stop the heat shock protein binding to the oncoprotein and hence stopping the oncoprotein attaining its mature form and activation.

There are other molecules involved in cancer, quite well known like KRAS. How are you targeting those?

This is very interesting because when you look at the genome studies that are done in non-squamous or adenocarcinomas you see a whole series of genes that are mutated and abnormal. It is the most commonly mutated gene that is potentially a driver mutation that is KRAS, about 30% of adenocarcinomas will have a mutation in KRAS. So there are very interesting early phase studies looking at the combination of MEK inhibitors, which is part of that pathway, with chemotherapy showing response rates, improvements in progression free survival and a hint at overall survival. They’re now going into phase III trials. This is a very exciting area.

And there’s also the BRAF pathway as well, isn’t there?

Yes, so the BRAF pathway is a little bit like the ALK story. In ALK, as we’re aware, about 2-3% of patients probably have rearrangements of the ALK and they can be targeted by crizotinib licensed. If we look at the BRAF story, in melanoma it’s a huge issue because about 35% of melanomas will have the mutation, the V600E/K mutation, but it looks like about 3-4% of non-small cell lung cancers have the same abnormality and the preliminary indications are that perhaps these tumours are actually sensitive to the drugs such as vemurafenib or dabrafenib that target this factor.

That’s all very fascinating but what’s the clinical setting where you’re likely to use these targeted agents? Is it advanced disease?

It’s advanced disease. At the moment we have no evidence that any targeted therapy has a role to play in either locally advanced or resected disease, either in the locally advanced setting or in the adjuvant setting. But in the advanced disease setting what we’re getting is a gradual expansion of the number of patients we can treat with specific targeted therapies. They obviously need to be proven in large phase II and phase III, ultimately, trials comparing the new drug with the best previous treatment which is often chemotherapy in that group of patients. And I think it’s nice we had EGFR mutations in the Caucasian population, 10-15% of Asians then we had ALK coming through, 2-3% probably is the real figure, some people say a bit more, up to 7%. Then we have BRAF coming through which is 3-4%, KRAS, so potentially a big group of patients and if we could prove that targeted agents given selectively in a personalised way to those subsets work, then undoubtedly we’re going to improve the outcome for patients with lung cancer not just in terms of survival but also in symptom control, higher response rates and quality of life.

But how much do you feel has been achieved so far with targeted agents in real terms, in the real world?

In the real world for a hundred patients coming into the room, not a huge amount yet in terms of overall survival benefit. But in those subsets of patients who have these mutations, significant benefits for them so that their quality of life, their symptom control, their disease control is better. And through molecular biology that number of patients is expanding and that’s very exciting.

And how do you counsel doctors to take note of these markers, these molecules and the potential targeted treatments for them at the moment?

I think that obviously the main ways we do this are through publications in major journals, we do it also through meetings and I think using the internet such as this.

It’s fascinating but is there enough of a harvest at the moment for the average cancer doctor to take encouragement from this?

I absolutely think there is because all you have to do as a clinician is have one patient who comes in who does extremely well and then your whole view of making the extra effort to get the tissue samples, to get the diagnosis made actually becomes much more positive and that’s what we’re seeing is happening.

What’s your feeling about how much benefit this could produce over the next few years if some of these phase II studies, phase III studies get there?

I think over the next few years that could be quite dramatic because not only do we have the targeting of patients who have got mutations in the gene, activating mutations in the genes, that are stimulating the cancer to grow and we can block those but the other big targeted area that’s coming through are the immunomodulatory agents, so anti-PD1, anti-PDL1 antibodies, ipilimumab, anti-CTLA-4 antibodies. These are in some cancers, not necessarily lung cancer yet, are showing really prolonged survivals for individuals. So I think this is a very, very exciting area and again it’s an area that I’ve covered in my presentation. Then the other area that’s very exciting is the antibody drug conjugates where you attach a very poisonous drug to an antibody, deliver that in a selected way to the cancer and that drug then goes in and kills the cancer cell. We’ve seen the TDM1 data with Herceptin in breast cancer showing, again, a prolongation in survival, progression free survival, and we think that that’s going to have a role in some patients with lung cancer.

Of course these things are very promising.

Absolutely.

The whole targeted magic bullet has been very promising for a long time but not necessarily fulfilling, perhaps, until now with the breast cancer, as you just said.

Absolutely and I think that the reason why the magic bullet worked in the breast cancer setting is you had a very clear target and a very clear way of delivering the drug. Once you do it once that whole area is just going to expand. So I’m very positive about this.

People have been depressed about lung cancer and not too encouraging so how do you advise doctors to be from now? Do you think the situation will change?

I think it will and I think people just need to think about where we were with leukaemia and lymphoma fifty years ago as our knowledge of the biology began to expand and our ability to deliver good treatments expanded then those patients became cured. I think in lung cancer we’re going to see the same evolution that not just lung but also colon cancer, breast cancer when they’re advanced diseases; we’re going to see a steady progression in our ability to deliver effective treatments that will lengthen life, improve symptom control and quality of life.

Ken, thanks very much for joining us on ecancer.tv.

My pleasure.