European Multidisciplinary Conference in Thoracic Oncology (EMCTO) 2013

The sub-typing of lung cancer and squamous cell carcinoma

Dr Martin Edelman - University of Maryland Medical Center, USA

Martin, the whole thing about lung cancer is that it is in categories, it used to be just non-small cell and small cell but then a whole lot of targeted therapies came in. Can you tell me why you’re particularly interested, and focussing at this conference here in Lugano, on squamous cell carcinoma?

It’s been very interesting, when I was in training not that long ago, actually it’s now getting back 25-30 years, but really until about ten years ago all that we cared about was small cell versus non-small cell lung cancer as a practical clinical approach. Small cell was just treated differently than non-small cell. About ten years ago, as we had the emergence of the EGFR inhibitors, we began to understand or began to see a pattern that it was mostly the adenocarcinoma patients who were responding. Then with bevacizumab we saw that you couldn’t treat squamous carcinomas because of the risk of haemoptysis and then with pemetrexed we saw that there was a relative selectivity of at least that chemotherapeutic agent for non-squamous carcinoma. In the last five or six years there has been an increasing understanding of specific targetable mutations almost all of which occur in non-squamous, particularly adenocarcinoma, such as the various EGFR mutations, EML4-ALK, Ras and RET, again almost exclusively in adenocarcinoma. In about the last 12-24 months we’ve had a number of studies that have been done that have looked at various aspects of squamous carcinoma and this is an important disease, this is 25% of non-small cell lung cancer.

So, in a nutshell, squamous cell carcinoma has been difficult to come up with new treatments for but now hopefully things are changing.

Yes, it’s a very common disease, again 25% is probably more the Western world, probably a higher percentage in Asia, particularly among smokers who are in the developing world. We just haven’t had anything that was really specific for squamous carcinoma, we were using pretty much the same chemotherapy regimens that we had developed during the 1990s.

Could you give me some of the landscape as far as targetable mutations are concerned in squamous cell carcinoma?

What’s very interesting is that there have been a number of papers that have come out and two rather different approaches that converged. One was a study done by investigators at the University of North Carolina, a paper by Dr Wilkerson that found that there were really, if you looked at patterns of gene expression, that actually there were four different kinds of squamous carcinoma with different aspects of their biology having to do with proliferation and adhesion, squamous differentiation, immune modulation. And then there have been studies, most notably that from the Cancer Genome Atlas group that looked at actual genetic mutations. What’s interesting is these approaches have converged and have shown us a number of targetable mutations.

And immunotherapy directed against T-cells is also part of the picture, isn’t it?

Just to go backwards one little bit, on the targetable mutations they’ve included things like FGFR and DDR2 and particularly of interest DDR2, which means discoidin domain receptor 2, where a very elegant paper by Dr Hammerman both found that this mutation was present in several per cent of lung cancer, that it was transforming, that if you silenced it the cells would be killed, that various tyrosine kinase inhibitors, including some that already exist such as dasatinib, could in fact target this in a probable patient who had a DDR2 mutation, who responded to a dasatinib combination. So clearly that was a targetable mutation. Then in a more general sense it appears that some of the emerging immunotherapeutics, particularly the anti-PD1 and anti-PDL1 antibodies that were presented last year at ASCO and published in The New England Journal of Medicine by Dr Brahmer and others from Johns Hopkins, demonstrated activity in non-small cell in general but seemed to in particular be active in squamous carcinoma.

It’s reached a point where it’s very, very fascinating; there are some clear leads. What should the cancer doctor be making of this at the moment?

The problem is some of my colleagues always like to say, “Well we have this and that actionable mutations.” The reality is that as of May, June 2013, we really don’t have anything that we can write a prescription necessarily for; perhaps DDR2 but we have no validated assay for this. So right now in 2013 we do not yet have a therapeutic that we can point out that we have a target, we have a drug, you can write a prescription, unlike, say, the situation with EGFR mutations where you have a deletion 19 mutation, we write a prescription and clearly with a high degree of probability get benefit for a patient.

But do you see the momentum going in that direction so that we can go from the adenocarcinomas into the squamous non-small cell lung cancers and actually treat them with these targetable agents, targeting agents?

Yes, definitely. I think that there are now a large number of studies that are on-going which are exploiting these leads. I would suspect that within the next 2-3 years we’ll have a fair amount of results. I think one of the very critical things that has changed in all of this has been the fact that now we are getting biopsies that are adequate with tissue. Again, if you go back as little as 10-15 years ago we had convinced everybody the only thing we needed were enough cells on a slide to say is it non-small cell or small cell. We now have a clear therapeutic reason to be able to differentiate both histology: adeno versus… or squamous and non-squamous for the therapeutics and non-squamous, plus we have good reason to do molecular analysis, again predominantly for mutations present in non-squamous. But the fact is we have the technologies and we’ll have the ability to analyse for these potential mutations and thereby enter these patients onto the appropriate studies.

OK, is this then words of distant promise for the average clinician at the moment or how would you wrap it up, the message coming now?

I would say that right now is a time for people, if they’re not actually involved in these trials, to be aware that these trials are on-going, they’re in the United States, Europe and Asia. Patients should be referred, at least make sure that there’s enough tissue so that patients who are progressing have this opportunity to at least be evaluated for these studies. This is the crucial thing that’s going to change this landscape. If we’re ever going to do anything in the disease we’re going to need to be able to target these therapies.

Martin, thank you very much for joining us on ecancer.tv.