Future Horizons in Lung Cancer
Recent advances and emerging therapies in lung cancer
Prof Gordon McVie - Kings College London, London, UK
Prof Caroline Dive - Cancer Research UK Manchester Institute, Manchester, UK
Dr Marianne Nicolson - Aberdeen Royal Infirmary, Aberdeen, UK
Prof Michael Seckl - Imperial College London, London, UK
GM: Welcome to ecancer in London where we’re putting on a fantastic lung cancer meeting. The co-Chairman is Michael Seckl, here on my left.
MS: Hello.
GM: Supported by Marianne Nicolson and Caroline Dive.
CD: Hello.
GM: The meeting has brought together groups of scientists and clinicians and that’s really the essence of where we have to be in the management of all cancers but particularly lung cancer. We’ve heard how miserable a disease it is and how much apathy there is amongst populations who won’t give up smoking and amongst doctors who really don’t think there’s any point in diagnosing or screening or whatever. So we’ll start with multidisciplinary approaches and Caroline, you start with that.
CD: Yes, I think it’s been great to see the scientists and the clinicians talking together, listening to each other’s talks and actually beginning to speak each other’s languages. As targeted therapies for lung cancer are now taking impact in this terrible disease it’s seen that merger of the lab and the clinic even more and it can only do better as we go forward. One of the new areas, not so new now, but certainly very pertinent to lung cancer is the liquid biopsy space. We know getting biopsies from lung cancer patients is invasive for the patient, not without risk always to the patient and certainly doing it over and over again is really not tenable. So the liquid biopsy revolution which is happening in cancer research right now is particularly important in lung cancer. We work a lot in small cell lung cancer and there circulating tumour cells are telling us an enormous amount about the biology. We can use them to make new mouse models, again to look at the biology and test new drugs in this dismal type of lung cancer. What it has done is really bring scientists and clinicians together, co-ordinating the collection of clinical samples, co-ordinating the lab-based interrogation of them. So actually I’m actually very optimistic, I think this whole area is burgeoning now and it’s going to do nothing but help lung cancer patients.
MN: But one of the things, if I may interrupt, Gordon, is that one of the things that we mustn’t lose sight of is the importance also of having a tissue diagnosis. One of the tensions with the MDT approach is that our respiratory physician colleagues often are happy to make a diagnosis when they give the pathologist a few cells from an EBUS but even if we’re looking at PDL1 marker status, for example, they need the architecture of the biopsy in order to diagnose that. So much as we work in parallel and we all work together to achieve as much as we can from small volumes of tissue, we’re not yet away from requiring biopsy diagnosis in many patients.
GM: But I’m old enough to remember a time when we didn’t even do the diagnosis, we looked at the chest X-rays – lung cancer, home to die. So we’ve moved on a long way from that.
MN: Exactly.
GM: Other things in the areas of imaging, apart from the X-ray?
MN: Yes, well I think we’ve, as you say, come a long way from imaging. We’ve gone chest X-ray, now the CT scan, obviously; we’ve got PET scans. Now the PET scans, they’re ubiquitous, most centres will have a PET scan available somewhere but they’re very often guarded quite jealously by the academics and it’s difficult to make PET scan part of routine management. We know it is, no surgeon now will put knife to skin for a patient with lung cancer without having a PET scan done, but while we’re speaking about intensifying some treatments we probably need to bring those PET scans in earlier. In small cell lung cancer, for example, it’s much more sensitive than CT scan and we already have publications showing that it’s better than a bone scan to pick up bone mets, better than a CT scan to show distant metastatic disease; we need to be having that as part of our routine staging.
GM: And we are saying PET, you really mean PET-CT?
MN: Precisely.
GM: And there’s a big step forward now in prophylactic cranial radiation as a part of the management for small cell lung cancer and now, first of all, you do a CT-PET of the brain.
MN: Yes. You should do because evidence now suggests that those patients who do not have evidence of disease in their brain and do not have distant metastatic disease who get complete remission, they may well not need PCI. Now, it’s early data, we need bigger trials but here we are with another question with a good small cell study that can be organised and done to give us a definitive answer.
GM: Now non-small cell has hit the headlines with the immuno-oncology drugs appearing over the hill from nowhere apparently and they’re really impressive. I heard somebody saying that we’re salami slicing lung cancer according to the genomes, EGFR is now important and ALK is now important and now you mention PDL1, Marianne. What’s your take on that?
MS: What’s so exciting is that we are dissecting out various forms of lung cancer. You and I, we can cast our minds back and we thought, ‘Right, it’s a lung cancer diagnosis,’ everybody had the same lung cancer. What we now appreciate is that we’ve all got different lung cancers and the genetic information that has come through over the recent years has clarified for us that not everybody’s lung cancer is the same. Because we can now salami slice those lung cancers out you can actually identify specific targets that we can use new drugs for. This has made a real impact for the outcome of our patients. So Marianne and I can remember the time when we were looking at patients and thinking, ‘What can we do?’ we threw our arms up. Now we have a vast array of new drugs that we can take out and specifically give to individual patients. The challenge is when do you give those drugs, how long do you have to give those drugs for? The immunotherapies that have recently hit the headlines, they are continuously given and do we really need to give these treatments continuously or once you’ve actually achieved a response can you actually stop and give the patient some quality of life without having them to have to come to the hospital every two or three weeks for an infusion? So there are lots of questions that are now arising out of these new molecularly targeted therapies that we need to address, not least of which are the combinations.
CD: But Michael, the big, big question in immunotherapy is who to treat.
MS: I completely agree.
CD: And I think we are now in that situation where reverse translation from some of the big clinical trials, we have to collect the tissues properly, we have to really bring big brains to big questions around what the predictive biomarkers for immunotherapy and lung are going to be.
MS: I completely agree and this whole story around PDL1 for which we had a very exciting debate yesterday…
GM: Which I lost.
MN: Did you?
MS: Gordon freely admits he lost.
MN: That’s unusual.
MS: But it was a well- run debate. It really emphasises the principle of do you take a pragmatic approach and say, well, PDL1 is the best that we’ve got, therefore use it, but on the other hand you end up losing patients who might still benefit from these treatments who are PDL1 negative.
CD: But I think that’s why the collection of tissues through those trial conditions are so important.
MS: I completely agree. I completely agree with you.
MN: And repeat collection as well. It’s one thing to have the diagnostic biopsy; we know how difficult it is to have a repeat biopsy but we need to make that standard practice.
GM: And for the we know that we’re going to get resistance for all of them, all the and that’s really quite disappointing. Can you just sum up the immunotherapy data? Two drugs have come through quite quickly on lung cancer approval – nivolumab and pembrolizumab.
MS: Indeed. So both nivolumab and pembrolizumab have got single agent activity in the relapsed setting; they’re clearly better than the chemotherapy alternative. Both are now licensed in that setting so widely used, although in the UK we lag behind. Scotland I think is an exception for a subtype of non-small cell lung cancer but for the rest of us we don’t have access to these drugs and are desperate to have access in the UK; of course I realise around the rest of the world it’s different. In the up-front setting there have recently been releases in the press although none of us have seen the data showing that pembrolizumab is active and better than combination chemotherapy, so we’re led to believe, in front-line treatment. The story is not the same for nivolumab, again none of us have seen the data, and we’re all gasping to have sight of it really.
CD: But the small cell data with PDL1 PD1 targeted therapy is even more intriguing because the tumour cells have very, very low expression, if any. So it’s working in a proportion apparently, and I think those trial data are not yet fully read out, but if that’s the case what is the biomarker because it’s unlikely just to be PDL1?
MS: No, I think PDL1 is going to turn out to be not the best biomarker in my humble opinion.
GM: You didn’t vote for me, though, when I was trying to say that!
MS: I didn’t vote either way because I was the Chairman of the discussion and, of course, as Chairman you’re not supposed to vote. I think because you influence the rest of the audience, don’t you?
MN: The other interesting thing is that when each company has its own marker you’ve got the companion diagnostics, my interest as well is who is going to say which drug we’re going to use? Will the pathologists buy in the biomarkers and say, ‘Right, this is the one we’re doing, this is the drug you can use’? Or will it be the clinicians who say, ‘No, I want to use drug X, you have that marker in and run it for me.’? Or, indeed, will it be the funders who actually say, ‘This is what we can afford and this is the one you must have’? There are so many questions because we don’t have that harmonisation in terms of the testing that needs to be done.
GM: But these questions are based on really exciting data and that’s the great thing.
MN: Yes, of course.
GM: If we look at coupling the technologies we’ve seen here with absolutely state of the art imaging and imaging tracers coming down the line for PET the access to tissue through Caroline’s models with circulating tumour lymphocytes and the building of new models, although somebody pointed out there are not very many good models yet for the immunotherapy drugs because you need an immune system to test them out. We’ve got potential biomarkers for it, which are exciting, and we’re spoiled with choice in a sense. They’re all going to be expensive, the diagnostic and the drugs, that’s down the line, and it’s good to have these kinds of questions which we haven’t had in my forty years of looking after lung cancer patients.
MS: Gordon, doesn’t it feel like the era of cisplatin all over again? When cisplatin arrived in 1977 suddenly it was the big wonder drug and it had been splattered around all the different cancers with activity in many and this is exactly what we’re seeing with the immunotherapies. It’s wonderful.
GM: I don’t want to get bogged down on the cost side of things but it is really quite important globally. Can you imagine having this discussion in sub-Saharan Africa, totally bizarre, in China where there will be one million deaths according to Richard Peto from cigarette smoking within about five years? So this is a big global issue and looking at the population base we should point out the importance of the low dose CT scanning trials which have been done in the United States and which were beautifully presented here. Now countries, maybe with a little bit more money, a little bit more foresight, are actually now adopting screening for early lung cancer and lives are being saved and people are being cured because of these screening techniques. They’re not yet finding everybody but they’re sure finding an important number of people who have 1cm sized lung cancers. Now, this is something for the old people in the audience to sit up and think, ‘My god, 1cm lung cancer…’ that’s not in my area. Again, the cost of the screening is going to come into the mix. Last thoughts?
MS: The question that you raised about cost is relevant because we can’t bankrupt our health services around the world with these incredibly expensive new drugs. I think it would be really important as we move forwards to be thinking about trials where we look at when can we stop giving the drug? Because this may give a huge cost saving but it might also spare the patients having to come up all the time for more treatment and spare them continuing toxicity.
MN: I think also in any situation if we look at the targeted drugs getting the maximum we can out of each drug before changing therapy and understanding why we’re changing therapy and what the ethos is there is vitally important.
GM: And the only way we’re going to get repeat biopsies is with you.
CD: I think there are several things there. Going back to the early detection space, which is fundamentally important for lung cancer, this is all about sensitivity. So if you’re looking for molecules in whatever your clinical sample is going to be you’re going to need a really sensitive technology. I guess the other multidisciplinary angle is biotechnology, bioengineers. It’s not just clinicians and bench scientists like myself, we need the bioengineers in there, we need ways of talking to patients because the problem with early detection is false positives. So what is that piece where we’re educating individuals about tests we’re not fully 100% sure about where sensitivity is key, where specificity is key? That’s a very difficult space and again that’s where the multidisciplinary research, to go back where we started this conversation, is absolutely required.
GM: And a good place to finish. Thank you very much indeed Caroline, Marianne and Michael and this is Gordon McVie signing off from ecancer in London.
