Treatment of non-small cell lung cancer and adenocarcinoma

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Published: 15 May 2013
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Dr Keith Kerr – University of Aberdeen, UK

Dr Keith Kerr discusses the molecular characteristics of adenocarcinoma at EMCTO 2013 in Lugano, Switzerland.

With non-small cell lung cancer, there are a large number of abnormalities and mutations, but very few that offer a therapeutic option. At the moment, the two most important mutations, with available drugs, are patients who posses EGFR and ALK fusion protein abnormalities.

Dr Kerr also discusses the need for all patients to be assessed for these and other abnormalities early in diagnosis.


European Multidisciplinary Conference in Thoracic Oncology (EMCTO) 2013

Treatment of non-small cell lung cancer and adenocarcinoma

Dr Keith Kerr – University of Aberdeen, UK

Keith, there has been big progress in treatment of non-small cell lung cancer and adenocarcinoma has been quite fortunate to have some molecular targets. What are you doing at the moment and in your talk about molecular characteristics of lung adenocarcinoma what did you highlight?

In the presentation the aim was to discuss the large number of molecular abnormalities that there are in pulmonary adenocarcinomas but also to focus on those particular molecular abnormalities which are a very small number of the thousands that exist that actually offer us a therapeutic option in terms of a drug and a target in order to try to influence the tumour growth.

And some of them have already and there are returns on that, aren’t there?

Absolutely. Probably the two most important currently with available drugs are drugs which target the EGFR proteins and also those that target ALK fusion proteins.

Have we reached a stage where every patient needs to be assessed for EGFR and ALK?

I think so. I think it’s now regarded as standard of care. Obviously it’s driven by the different availability of these drugs in different countries and different practices but it would be regarded in an equal world as a standard of care now to test for EGFR mutations and for ALK fusion genes.

And when you discover, for example, EGFR then you’ve then got the decision of whether to use a monoclonal antibody or a small molecule.

The mutation testing that we currently carry out is only for selection of patients to be treated with the small molecule TKIs. They require the presence of the mutation. The monoclonal antibody is not predicated on the presence of the mutation, the data suggests that those patients respond better to the monoclonal antibody when the total protein level in the tumour is high. So it’s a different type of test and it’s actually asking a different type of question.

And in the case of ALK you’ve got a lot of inhibitor that has already been shown to work.

There are a number of inhibitors, one currently more advanced than the others in terms of its licence – it’s fully licenced and it’s currently available, not in every country but in most countries, it depends on their health systems. For ALK there is a drug called crizotinib and it is showing similar very good responses in the presence of the ALK fusion.

And what other molecular characteristics are emerging as significant players when you’re considering possible treatments for lung adenocarcinoma?

There are a number of emerging targets. ROS1 is another fusion gene, or ROS is a gene which can be involved in a translocation and a fusion, which is also targetable by crizotinib. And I guess, even though ROS1 is a relatively rare genetic event because it also appears to be sensitive to the effects of crizotinib, so a drug is available which makes it more interesting to us. Another emerging target is up-regulation of the MET oncogene. This is not a mutation it just seems to be an up-regulation and an over-expression of the protein. But there are inhibitors of MET out there which have shown promising results and we are moving hopefully towards a situation where clinically this will be an option for those patients.

You’re painting a very interesting picture here of a tumour with many therapeutic possibilities. What should doctors make of these options and potential opportunities?

I think doctors have to be aware that they are available or at least they are potentially available, as I alluded to earlier. One of the issues is whether or not the drug is available within their particular health system, and this is dependent on all sorts of issues relating to regulation and reimbursement. But it comes down to awareness; it comes down to knowing whether the testing that is required to provide the evidence to have the drug prescribed, whether that testing is available readily for that physician. And then being knowledgeable enough to select the appropriate patients for testing because it’s very inefficient to test everyone for everything, it’s simply not possible.

And at the same session where you gave your talk there was talk about heterogeneity and evolution of tumours. That could throw a spanner in the works, couldn’t it?

Well it could indeed potentially. It’s quite a concerning issue; I think it has concerned many of us for a long time but it’s only now that there is good molecular evidence beginning to emerge. It rather depends on the target. One of the points that did emerge from the talk was that many of the targets that we are likely to be chasing in these tumours are targets which are very fundamental to the evolution of the tumour from its very earliest existence, even before it was technically a malignant tumour. Some of the evidence suggests that those very fundamental molecular abnormalities are retained; the acquisition of other molecular abnormalities in different parts of the tumour may affect the biology of the tumour to some extent but provided the key driver mutation which initiated the tumour is still playing a role then one might expect interference with that genetic abnormality to be therapeutically successful.

That’s a relief. Could you put these developments, though, and the knowledge of the molecular characteristics in the context of your standard tried and trusted chemotherapy, radiotherapy, surgery in non-small cell lung cancer? How big an effect has it been up to the present time and how much more can we affect for the average doctor?

That’s a very good question and I think we are all a bit guilty of perhaps getting a bit carried away with these drugs but I think with some justification. It’s still a fact that the only cancer doctor that cures any patient of lung cancer, more or less, is the surgeon. However, in the context of the successes we’ve had with chemotherapy, and there of course have been successes, the effects in appropriate patients of these molecular targeted drugs in a situation where the target is one of those so-called addictive oncogenes, and not all of the targets that we have discussed in this interview have been addictive oncogenes, but for the addictive oncogenes the results are really quite spectacular in the short term because we have learned that this is not, in most patients, a long-lasting effect with the drug. The patients or the tumours eventually find a way around the blockade and the disease unfortunately relapses.

But you could buy time and you could buy quality of life in the meantime?

Absolutely. And we buy more time than ever before and the evidence suggests that the quality of that time is excellent.

So, coming out of your talk here in Lugano, how would you sum this up for the average doctor with patients to treat now? What are the considerations to be borne in mind about all these molecular characteristics?

I think the considerations to be borne in mind are maintaining an awareness of what is happening, it’s a very rapidly moving field, so keeping up to date with all the potential targets that are out there; bearing in mind in your clinical diagnostic practice on a day to day basis that in order to select patients you have to identify the target or the biomarker for the drug and in order to do that you require tissue. Not infrequently the tissue that we have for core diagnosis is insufficient to allow us to progress on to molecular testing. So when getting material for diagnosis to maximise the amount of material that you have and to make sure it’s available in a form that allows the biomarker testing and then to think about using the biomarkers in their licenced indications in appropriate patients, provided you have the biomarker test results available.

So just in a couple of words, is it all very promising?

Of course; it’s very, very promising indeed. It’s complex but it’s definitely promising. It’s the best news we’ve had in lung cancer for a long time.

Keith, thank you very much.

My pleasure.