ASCO 2015

Round-up of the latest research on lung cancer

Dr James Spicer - Guy's Hospital, London, UK

Many cancers are driven by a whole host of membrane receptors so our concern is that being very specific about how we target those, for example having a specific EGFR inhibitor, may not be enough because the tumour gets around that inhibition by controlling its growth through one of the parallel pathways. So one of the answers to that is to develop a drug which is a bit more promiscuous, in other words it inhibits a whole range of receptors, hence the jargon name for this drug, a pan-ErbB inhibitor, so it’s an inhibitor of EGFR, of HER2 and of another related receptor called ErbB.

I gather from some of your work this can be reversible too?

Yes, so what that’s referring to is the molecular mechanism of inhibition. There are some drugs that have been developed, one of them is afatinib, which actually covalently bind to a receptor. This one actually happens to be reversible which is what that means. It doesn’t covalently bind to the receptor but it is a very potent inhibitor of those receptors and a very broad receptor inhibitor as well.

If you have more promiscuous drugs could they be more toxic?

That’s the potential concern. We talk about these drugs colloquially as being dirty drugs and in some contexts that can imply more toxicity. But these are very specific receptors and their upregulation is quite specific to tumour cells so we do see some on-target off-tumour toxicity but, as we’ve found in this particular case, quite often that’s surprisingly manageable.

I want to ask you about next generation EGFR inhibition as reported here at ASCO, but first could I ask you about another topic that you’re looking into: ASS1 deficient tumours. What is that all about and what is happening there?

What we’re doing there is exploiting an Achilles heel of many tumours which is that those tumours, during their evolution, have lost the ability to make some essential amino acids. So without those amino acids they can’t proliferate. So if we can develop a drug which actually deprives the tumour cell of those amino acids we can inhibit its growth. So this drug is actually an enzyme and prevents the development of essential nutrients for the cancer cell.

And why is that particularly relevant for lung cancer?

It’s seems to be important, both in some lung cancers but most especially in mesothelioma which is a disease that I treat a lot. The biology is such that we find that many of those cancers are deficient in this particular enzyme and so they are liable to be targeted by this new therapy.

What topics concerning EGFR, next generation EGFR, inhibiting have floated to the top in this year’s ASCO?

We’ve got a group of now what we call third generation drugs coming through. They are exemplified by AstraZeneca’s AZD9291 and a compound from Clovis that’s now called rociletinib. For the first time we’re developing those in randomised trials. We don’t have randomised data at this meeting but we do have two important bits of information. On the one hand, the 9291 drug has been shown in an expanded part of the phase I trial of that drug to be active in the first line setting. So that’s addressing patients who have an EGFR mutation and for whom the standard of care at the moment is one of the first generation drugs, erlotinib or gefitinib or a next generation drug, afatinib. So those drugs are all approved in that setting, the question is are these third generation drugs even more effective and the preliminary evidence suggests that they might be. So we’re seeing a response rate which is at least as good as those earlier drugs and we’re seeing a progression free survival time which is well beyond the year, which would be unprecedented, really, in this context.

What might cancer doctors make of this right now, then?

It’s too early for us to be thinking about changing standards of care but these drugs, for sure, are attracting a lot of attention. They’re now entering first line trials so we will be comparing these third generation drugs with the earlier drugs head to head and answering the question do we displace the earlier generation of drugs with these therapies which may be hopefully no more expensive but work for longer.

Now, here at ASCO, PD1 blockade has been the hot topic in melanoma but also in lung cancer. What’s been happening here?

There really aren’t very many disease types now which are untouched by this tidal wave of reform through the immune therapies. So lung cancer we’re following very closely on the tails of the melanoma field and at this meeting we’ve had, in particular, two randomised phase III trials which really have the potential to change practice. So there are at least four drugs in this class which are being developed but the one which is most far advanced in lung cancer at the moment has been studied in a phase III trial, both in non-squamous non-small cell lung cancer and in squamous non-small cell lung cancer. So we have two trials in those two specific areas of this disease.

What should cancer doctors be thinking about the potential applications of that in the near future then?

It’s reasonable to say that the standard of care is changing on the basis of these trials. It’s never too early in this context to mention cost effectiveness and that’s going to be a very major issue with these very expensive drugs. But for the right patients the impact is very major and so they are going to have a role.

And the right patients is another crucial topic. What have you seen here about the sorts of markers, molecular markers and so on, that can help you select which patients should get these interesting new therapies?

There’s a huge amount of debate here in Chicago about how to use these biomarkers. The main biomarker that has been explored at the moment is, unsurprisingly, PDL1, part of the target for these drugs. So there are really two schools of thought at the moment, some people say certainly in these lung cancer trials that even patients who don’t express the target seem to benefit. So, for example, they’re getting a benefit which is equivalent to docetaxel, toxic chemotherapy, without those side effects. So why would we bother using the biomarker at all, why don’t we just give this drug to everybody in that context? The other party says these are incredibly expensive drugs and really to justify their use we’re going to need to see a very major improvement in outcomes as well as just less toxicity. So the jury is out on the role of the biomarker and very much the jury is out on whether that’s the right biomarker to use.

Do you get the feeling other biomarkers might be in the pipeline?

Absolutely. So there’s a lot of work being done there and PDL1 is only part of the story. So things like looking for CD8 positive T-cells which are the other part of the equation that actually do the damage to cancer cells, are one of the many other biomarkers that are being explored.

I’m delighted to say that there seems to be some news on small cell lung cancer here at ASCO. What’s the latest?

As I mentioned a minute ago, there aren’t very many diseases where these drugs are not beginning to have an impact. So we’ve seen some promising non-randomised data at this stage in small cell lung cancer. So patients who are multiply pre-treated and who have a dismal prognosis, really, in the absence of really paradigm shifting therapies, but we’ve seen response rates in excess of 35% in those sort of patient groups which is really very promising.

So in small cell lung cancer you can also use PD1 blockade potentially?

Potentially, these are early phase trials and signals for hypothesis generation and they need to be tested in randomised trials. But, as we’ve seen at this meeting, the randomised trials happen very quickly in this context.

So you’ve spent a few days here at ASCO in Chicago, are you now refreshed with ideas and full of promise?

I think we’re extremely excited about the new data. All the time we have to temper that excitement with some concern for the health economics of this scenario. So many of us are contributing to a lot of work to develop new drugs and we just need to make sure that we can actually deliver those drugs in a way that society can afford.

So your bottom line advice to clinicians dealing with lung cancer would be what?

You need to keep up with the data, this is moving very fast. We also need to encourage our regulators and our funders to support us in this effort but at the same time to be realistic in our expectations .We need to demonstrate very big benefits for some of the very big costs that are being implied here.