A four-part VJSession featuring lung cancer experts Sanjay Popat, Samreen Ahmed, David Gilligan and Neal Navani, who discuss the latest advances and hot topics in lung cancer from the 19th BTOG Annual Conference 2021.

Welcome to The Lung Cancer Sessions with the Video Journal of Oncology (VJOncology).

This roundtable discussion features Sanjay Popat (The Royal Marsden NHS Foundation Trust London, UK),  Samreen Ahmed (University Hospitals of Leicester Trust, Leicester, UK), David Gilligan (Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK) and Neal Navani (University College London Hospitals NHS Foundation Trust, London, UK).

The panel examine the impact of COVID-19 on lung cancer diagnostics and care, results from the CheckMate 816 and ADAURA trials, advances in radiotherapy, as well as novel agents including KRAS inhibitors and antibody-drug conjugates.

COVID-19, SBRT & pleural effusions

“We need to have the appropriate capacity in secondary care, not just diagnostic capacity, so not just EBUS lists and space, but actually workforce capacity as well to help us really get back on track. There’s going to be a backlog that we need to sort out and then we want to get back to where we were and then we want to continue on our path to improvement as well. Hopefully we can re-galvanize our efforts again after, now that hopefully we’re recovering from COVID and really start to make improvements again for our patients.”

     – Neal Navani

KRAS inhibitors & ADCs

This is a major, major breakthrough for clinical practice in the world, I would say for lung cancer. [KRAS] is the target we’ve been trying to drug for many, many years. And it seemed as if it probably wasn’t a mutational driver because we weren’t able to drug it, but because of our fantastic drug design technology and the way that these drugs have been designed. What was really interesting for me to see that crystallography and that molecular structure and it was this little gap that they found between the receptor that they designed [sotorasib] and all that time, it previously just wasn’t possible.

     – Samreen Ahmed

Radiotherapy

“I think that we are looking at hopefully a major step forward in the treatment of stage three disease…if we concentrate on chemoradiotherapy together with adjuvant immunotherapy, obviously the key paper that we all use to quote and clinically experience is the PACIFIC study, which as you say, is just published its four year survival data, which is excellent showing 49%, just under 50% survival in that group. And that really is the backbone of which we’ve got to work from.

     – David Gilligan

CheckMate 816 & ADAURA

Finally moving to an area where hopefully we’ll be curing lung cancer rather than just palliating symptoms. The key points in my mind, when I sort of reiterated that in my talk was A, is it safe to give the treatment upfront? Because we don’t want to compromise a potentially curative surgery by making these patients not fit for surgery…The second point is, are there any surrogate markers we can use rather than the usual disease free survival and overall survival?

     – Samreen Ahmed

Full Transcript
Sanjay Popat:
Well hello, everyone. Welcome to the Lung Cancer Sessions hosted by the Video Journal of Oncology. My name's Sanjay Popat, I'm a Consultant Medical Oncologist at the Royal Marsden Hospital and chair the BTOG steering committee. We're going to be deep diving into a number of topics that were discussed with the recent annual meeting that we had of BTOG. And I'm delighted to be joined by three experts and leaders in the field.

First, I have my colleague, professor Samreen Ahmed Consultant Medical Oncologist at Leicester. I have my colleague, Dr. Neal Navani Consultant Respiratory Physician at University College Hospital and my colleague Dr. David Gilligan Consultant Clinical Oncologist at Addenbrookes. Colleagues, we've had a really exciting time at the BTOG annual meeting. We had a lot to discuss and I wanted just to deep dive into some of the topics that we went into. I just wanted to ask off by Neal, asking you about what we've all been through in the course of the past year. We had a difficult year in the health service with COVID-19. It's had a huge impact in oncology service provision. Can you just tell us about the impact that it's had and how perhaps we might recover from this?

Neal Navani:
Thanks Sanjay. First of all, I think it's worth thinking about briefly the state of play prior to COVID. And I think we were making some real headway in terms of improving lung cancer care. There was a lot of optimism about the National Optimal Lung Cancer Pathway, we were improving early diagnosis with awareness campaigns and we were implementing a CT screening. We shouldn't kid ourselves though, things were far from perfect. Things like our Tobacco Cessation Services were I think not adequate. The number of CT scanners per population in the UK is still horrendously low, I think. 10 per million compared to 70 per million, for example, in Japan. And we've done an organizational audit by the National Lung Cancer Audit that showed actually our services were not up to scratch in terms of the service specification.

We were addressing that. We were making progress. I think there was actually a lot of cohesive planning and optimism in the lung cancer world. And I think that planning and that optimism was being translated into patient benefit. Then as we know, we were really severely hit by COVID. And I think the first of all, one major issue that's occurred is simply a drop in incidence. During BTOG, we saw a great talk from Professor David Baldwin. He showed how there had been a 30% reduction in incidence of lung cancer in the nine months of 2020 since the pandemic really hit. And that I think is for three main reasons.

One, we know how about the overlap of symptoms and the government's messaging was very strong about asking people to stay at home and not present. And many of those people may have had lung cancer. Secondly, our screening programs, which were either established or just kicking off were paused. And I think thirdly, and I think also really importantly, we were doing far fewer CT scans generally and it's a really important way of picking up lung cancer diagnoses incidentally, particularly early stage disease by carrying our CT scans. I think those factors due to COVID caused a significant reduction in incidence. We then had the situation where there were more emergency presentations so people were presenting at later stage and also with worse performance status. All the good work that we had done perhaps in the years leading up to COVID, unfortunately in that time had really unraveled and David Baldwin again, in his presentation, likened it to a natural experiment of how COVID had undone a lot of the work that we'd put in place that really has set us back considerably.

You asked Sanjay, what do we need to do now? I think we need to have a call to arms, I think of lung cancer services. First of all, we need to reestablish screening services. And I think that's been done really impressively. The major trials that are running screening and the 10 hubs that are screening are all up and running. I think that's really good. I think we need to increase awareness again and I know that there is a NHS England campaign currently ongoing that is trying to switch that messaging now a little bit and trying to get people to re-present again with respiratory symptoms to their GP.

And then I think the third thing and possibly the most crucial is we need to have the appropriate capacity in secondary care, not just diagnostic capacity, so not just EBUS lists and space, but actually workforce capacity as well to help us really get back on track. There's going to be a backlog that we need to sort out and then we want to get back to where we were and then we want to continue on our path to improvement as well. Hopefully we can re-galvanize our efforts again after, now that hopefully we're recovering from COVID and really start to make improvements again for our patients.

Sanjay Popat:
Multifaceted, multi-pronged approach to recovery and perhaps one of these prongs is around stereotactic radiotherapy for patients with early stage lung cancer. David, I want to bring you into this conversation. Prior to COVID, we had an announcement that we were going to have a more services commission for stereotactic radiotherapy. Has that really panned out over the course of the last year? And is that helping with patients getting treatment where they wouldn't have got it otherwise?

David Gilligan:
Thank you, Sanjay. I think I have to say that despite the announcements, I think it's still very patchy and I think that's something that we do need to focus on from a number of points of view. First of all, I think the big deficit is that there still is not a national rollout so that every single radiotherapy department can offer SABR for early stage lung cancer. A secondary matter, perhaps less important to what we're talking about is that it's even more patchy when we're talking about treatment of oligometastatic disease, which can of course include lung cancer and lung metastasis. But I know that in my own region, the rollout which should have taken place, hasn't and when you interrogate why has it not taken place? There are all sorts of small but very irksome reasons why centers are not being able to do it. Peer review of cases isn't taking place as it should do. And that does cause a problem. The problem that we've had is lack of equity in care. And the problem is that patients will not travel long distances to have their treatment.

And so I think it's something that we have to just push on further. We have to really push and try and get this implemented. I'm sure we will get there. It's just like most of these things, it just takes a lot longer in getting there than we originally thought or wanted to. One thing that did come out of COVID particularly right at the very beginning in the first wave was the very quick and collaborative discussions that were had about fractionation. How many treatments do you need? And indeed, I think most people felt that you even within SABR, you could reduce the number of fractions for treatment and that improves patient experience because there's no evidence that particularly if you're doing it with guidelines that you can give treatment and less treatments and also has less impact on department workload. And even taking it one step further there was one poster in BTOG which actually looked at the environmental benefits. Someone actually looked at the less miles that were taken for patients to travel and worked out how many trees that saved. That was a very quirky, but very interesting poster that we enjoyed.

Sanjay Popat:
Thank you, David. I'm hearing from colleagues and there have been several posters looking at this, that patients are presenting later. We're seeing much more advanced disease now than we were perhaps. More patients coming through with brain metastases, patients perhaps with malignant pleural effusions. And I'm going to ask Neal, we had a very interesting debate about malignant pleural effusions at BTOG. What was the summary of those discussions? How should we be managing these effusions?

Neal Navani:
Thanks, Sanjay. Yeah, so we had a really interesting discussion. There were a number of options open to us aren't there, when managing a pleural effusion. We've got an indwelling pleural catheter, we've got recurrent pleural aspiration and then we've got the slightly more traditional pleurodesis. And obviously with pleurodesis, again, there are a couple of approaches either via a standard intercostal drain or via medical thoracoscopy or via a surgical approach. A number of options open to us. What we're very fortunate to have in the UK is a really strong pleural group and really high grade evidence now for a lot of our interventions for malignant pleural effusion. We were very fortunate to hear from Professor Rahman from Oxford, who's led together with Professor Maskell in Bristol, some of the really key, internationally leading randomized trials in the management of pleural effusions.

We heard about the benefits of an indwelling pleural catheter, particularly perhaps less pain for patients, shorter inpatient stay was a really key aspect, perhaps more cost effective. We found that we had a significant proportion of patients with an IPC auto-pleurodesis. You might put an IPC in and then find that actually you can take that out subsequently. We also heard from an Naj Rahman that, the benefits of a more definitive, initial pleurodesis where we see simply seal the pleural space with a high success rate, over 80% for virtually all the methods. And then to top that all off, we had some data on the IPC-PLUS trial, again run in the UK that actually combine the approaches of putting an IPC in and then actually introducing a sclerosing agent into the pleural space via the IPC.

It's been a number of approaches open to us, Sanjay. I don't think we solved it, I don't think there's one answer. I think it has to be a discussion with the patient. I think there are pros and cons to those broad two approaches, but a lot of nuances and clinical trials in this area are being developed as we speak. Perhaps the real answer is recruitment to those trials going forward.

Sanjay Popat:
Absolutely. We should never forget research. And I really take my hat off to the pleural group for top grade evidence that the UK is producing in this space. And I was really delighted that we were able to showcase some of this work here at our annual meeting. With our patients with metastatic pleural effusions and other metastases, it's been a highly evolving time of new systemic therapeutics in patients with lung cancer. We've had lots of changes to systemic therapeutics and drug classes over recent years. And Samreen, I'm going to ask your thoughts on some of the newer drugs that are coming through. In our translational session we had sort of highlights on where we might be going for tomorrow's drugs today.

One of the key areas I think is of huge interest, are the direct KRAS inhibitors and other drugs which are being developed for this pathway. We know that KRAS mutant advanced non-small cell lung cancer is a sizable proportion of the numbers of patients that we see. KRAS mutations, for example, account for nearly 25% of the variants that we see in adenocarcinoma. We now have two drugs which have shown some efficacy inhibiting a very specific KRAS genotype, something called KRAS G12C, these are direct KRAS inhibitors. We had a very good discussion about these at BTOG, what are your thoughts about drug in KRASes? Is this useful? What's the early data that we've seen so far? Are you really excited by this? Or is this just more tosh that is irrelevant for the UK?

Samreen Ahmed:
Okay. Thanks, Sanjay. I don't tweet very often, but one of the slides I did tweet was when KRAS, the waterfall plots for sotorasib was presented at World Lung. Just to reiterate really, this is the target which in terms of numbers is equivalent to all our other targets that we have so far. This is a major, major breakthrough for clinical practice in the world, I would say for lung cancer. This is the target we've been trying to drug for many, many years. And it seemed as if it probably wasn't a mutational driver because we weren't able to drug it, but because of our fantastic drug design technology and the way that these drugs have been designed. What was really interesting for me to see that crystallography and that molecular structure and it was this little gap that they found between the receptor that they designed that drug and all that time, it previously just wasn't possible.

And it's more an allosteric type of obstruction. You block it and so therefore it's not acting as a driver. Definitely I think we can definitely say it's a driver for lung cancer. And the G12C variant that you mentioned is probably the first one to be tested for. That's our first challenge will be about the testing. Won't go into that too much at this point in time. But once we've identified those patients who have this G12C mutation and we've got two drugs, sotorasib and adagrasib, and they both look as if they're on target effects and just looking at the waterfall plots for individual patients and the response rates that they're getting, it looks the same as your EGFR, ALKs, ROSes, so I'm really pleased that this is what's coming out. And finally, we can say that, yes, it's a mutational driver and we've got two very good drugs and plenty more coming that way. Very impressive data so far.

Sanjay Popat:
One of the areas I always think about with these drugs is KRAS is a difficult disease, isn't it? KRAS mutant lung cancer tends to be seen in our patients with significant or reasonable tobacco exposure. These patients often have comorbidities. I don't think we've seen much in the way of CNS data as yet. I think that's something that's currently awaited. The response rates were reasonable whilst the waterfall plot was impressive, the response rates weren't what we've seen so far with the EGFR or ALK inhibitors and neither was the progression-free survival. Are we really that excited? Or is this going to be tomorrow's flash in the pan when other drugs come through?

Samreen Ahmed:
I think we're going to have to be a little bit wiser in how we use these. Probably a combination of chemotherapy and inhibitors is going to be the way because it's probably not a pure driver, but it contributes significantly to propagation of the cancer. We're probably going to have to look at it slightly different to what we've done with these pure drivers like ALK and ROS1 but I'm very excited that these are two very useful and looks like very good safety arena drugs. We haven't seen horrible safety signals coming through. I think we could easily combine these with chemotherapy and that's probably the way forward, because as you say, these are in smokers so there's probably a little bit of polygenic mutational sort of potential there.

Sanjay Popat:
Thanks, Samreen. The other class of drugs coming through or something called the ADCs, otherwise known as the antibody drug conjugates. These are generally a antibody which is directed against a particular target to which there is a toxic payload, which is then delivered through novel linkers. We now have a number of ADCs coming through targeting proteins which we know about. HER2 for example, HER3 and also Trop2. And many companies are developing these ADCs. Now we've had a lot of failure with ADCs before, Rova-T I think was the one that we were all excited about. And Dr. Naidoo at BTOG really highlighted in her talk about ADCs, how we're all very excited about DLL3 targeting agents in small cell and that really bombed out in the randomized trials. What are your thoughts on ADCs? Do you think really this is going to be another flash in the pan? Or will the randomized data pan out? Or are some of these targets such as HER2 so rare, we'll never get randomized data or just have to have single arm data?

Samreen Ahmed:
Yeah, I've been treating breast cancer for the last 10 years, so I'm very used to using these and these were pioneering drugs. To imagine it's like a heat seeking missile, so you find the target, get to the target, release your payload. How more sexy is that? The most important drug development point was the linker actually. They had the two, the antibody and the chemotherapy for a very, very long time and it was always that linker which was very difficult to develop. Having used ADCs for a long time in breast cancer, I'm really delighted to see them come into the remit in lung cancer, but I worry that it's always the target, as you alluded to, it's always a target that's going to be important thing because however sensitive your cell may be to the chemotherapy, unless you get the correct target it's just like any other chemotherapy. Trastuzumab deruxtecan is actually only is about to hit breast cancer actually and also has seen some activity in lung cancer. Again, I'm a little bit hesitant to say that these are going to make a huge difference in our clinical practice because I'm not sure that we've identified the target in order to be able to deliver those drugs effectively. Whereas in breast cancer, we know it was a very clear oncogenic driver and that's why it works so effectively. Yeah, excited, but tentative.

Sanjay Popat:
That's a very fair summary. We've seen really very exciting data I think with trastuzumab deruxtecan, both in the HER2 lung setting and as you point out, in the HER2 breast setting. One of the adverse events we've seen with that is pneumonitis. Are you worried about the rates of pneumonitis we're seeing with these ADCs? Or is that something that my colleagues such as Neal will be able to deal with without much significant concern?

Samreen Ahmed:
Well lung cancer patients are very special because obviously they have underlying either lung disease or their cancer has caused some damage. In breast cancer patients, we hardly saw any pneumonitis problems, but I'm really worried that we're going to see a completely different spectrum of toxicity here. And it doesn't look like as if it's off target effect. This is what the worrying thing is that our patients are susceptible. They are probably not going to be able to have that second insult that another drug toxicity entails. Yeah, I'm worried that this will be the limiting factor of widespread use of these drugs.

Sanjay Popat:
And when we're using ADCs, we're effectively using smart chemotherapy, aren't we? We're just depositing chemotherapy closer to home so are we seeing febrile neutropenia and other significant myelosuppression as adverse events in the same way as we would do with systemic chemotherapy? What have our colleagues got to look forward to and our acute oncology physician colleagues got to manage in the acute setting?

Samreen Ahmed:
There is a bystander effect. Even though you're trying to get to that particular cell of interest and of target, once the chemotherapy is released, there is effect of the cells around it so it's not truly targeted. And therefore with Trastuzumab deruxtecan, we see thrombocytopenia, we do see myelosuppression. That's fairly limited. And hair loss, no hair loss. And I've used these drugs in breast cancer as well. We do continue monitoring, but you can give these drugs for 12, 18 months just like immunotherapy so it is very different to our blunder busting all come chemotherapy.

Sanjay Popat:
That's brilliant. Two new classes that we need to look out for, the ADCs and the direct KRAS inhibitors. Of course, the masters of dealing with pneumonitis, are our clinical oncology colleagues who have been using radiotherapy with sometimes pneumonitis as an adverse event occurring. And of course our chest physicians have been dealing and solving all our medical oncology pneumonitis problems for many awhile. David, I wanted to bring you into the conversation about combining radiation, particularly some of the more modern forms of radiation with immunotherapy. I would say that we now have four year survival data from the PACIFIC study, which shows a spectacular survival improvement. We really have markedly changed I think the face of inoperable stage three lung cancer with the data from that trial. Where are we going with IO and radiation in general in stage three and perhaps earlier?

David Gilligan:
I think that we are looking at hopefully a major step forward in the treatment of stage three disease. And we might want to widen that discussion a little bit more to other modalities, but if we concentrate on chemoradiotherapy together with adjuvant immunotherapy, obviously the key paper that we all use to quote and clinically experience is the PACIFIC study, which as you say, is just published its four year survival data, which is excellent showing 49%, just under 50% survival in that group. And that really is the backbone of which we've got to work from. I think at the meeting, Corinne Faivre-Finn gave a very good overview, but fundamentally, as we all know is actually making sure that every single patient who would benefit from this sort of treatment actually has access to it. And I'm not convinced that we're anywhere near there yet.

And we can look at it from a number of perspectives. There were quite a number of posters in the poster session of single center experience with people doing concurrent chemoradiotherapy and durmaluvab and actually looking at them there was quite a variation in practice of how many people have been treated over a period of three or four years previously. And some centers were using concurrent chemoradiotherapy for some time, others had started using it. And so it's a good thing that the PACIFIC trial, I think has actually let people up their game. Where people were going to be a little bit nervous about giving chemotherapy and radiotherapy together, they were more maybe in the sequential camp. A lot of people have moved to the concurrent and I'm going back to what you said a few moments ago, the radiotherapy technologies that we have, the intensity modulated radiotherapy using arc therapies or VMAT or similar, allow us to deliver much better doses of radiation without other organ damage and it allows bigger or more complex tumors where the primary and the lymph nodes are further apart to be given.

That's really good, but I think we do need to still bang on and go back to what Neal said about the optimum lung cancer pathway. We really need to make sure that patients are getting access to the full range of staging. Because one thing that's really important is accurate mediastinal staging. We need to know what we're treating. And I think that we need to really fully push forward the fact that patients who've got stage three disease on a PET scan, do need full mediastinal staging because we need to know what we've got to treat and whether we treat it surgically or whether we treat it with chemoradiotherapy.

And it was interesting, one of the selected poster sessions from Manchester was looking at stage three disease where patients had been staged having single station disease on full mediastinal staging, but actually at surgery, a third of them had more advanced disease than we originally thought. Even with state of the art mediastinal staging, we perhaps need to be careful that we're not putting patients forward for surgery that might have more advanced disease that might be better treated with chemoradiotherapy followed by adjuvant immunotherapy.

And I think the other important thing is that we perhaps need to focus on is making sure that people know how to manage the immune related toxicities in the adjuvant setting. Clearly pneumonitis is the one that we all worry about. And I think that we have got most centers, I think and I hope have got good pathways for managing these immune related toxicities, but also just making sure that people who maybe marginally eligible. Patients say with rheumatoid arthritis who might shy away from giving immunotherapy, we actually maybe are a little bit more adventurous in actually trying to give immunotherapy and working with the site specific doctors like rheumatologists to make sure that you get through the perhaps less severe immune related talk for immune related diseases that might normally exclude people from these therapies.

Sanjay Popat:
Absolutely agree. It really is about maximizing the opportunities for all of our patients at every stage. And part of this, as you pointed out is accurate staging. I'm going to bring Neal into the conversation. Neal, you've done a lot of work with colleagues around the UK about defining standards for staging. It was sort of discussed in part at BTOG, but perhaps you could summarize for us about mediastinal staging and who needs mediastinal staging. Often I hear, well, it's just an N1 node on PET. That patient should go straight to surgery. Should those patients undergo EBUS staging? And if you have N2 nodes on PET, does EBUS add anything more to staging? What's the current recommendations?

Neal Navani:
Thanks, Sanjay. Yeah, we have very clear national guidance and it's consistent with international guidance as well from the US and Europe now. We have very clear indications for when to carry out an EBUS. There are four or five main indications. Firstly, any PET avid lymph nodes. In the example you just gave of an N2 node being positive on a PET, that needs confirmation. That there's a 30 to 40% false positive rate, you don't want to assume that that is a malignant node. Similarly, PET does miss lymph nodes in the mediastinum, particularly small ones so it has a sensitivity of around 80%. Invasive staging with EBUS is really crucial. Any PET positive lymph nodes. Any lymph nodes that are greater than a centimeter in sure taxis should be sampled.

Thirdly, if there is an N1 node, we know that the risk of occult N2 disease is around 20 to 30% so they should be sampled. If you don't do that and send them straight to surgery, you're missing out on a conversation with the patient on going through the treatment options. Your MDT is not fully informed of the patient's stage to discuss clinical trials, induction treatment and so on. Other indications include if the primary is central or if the primary has low FDG avidity or a maximum diameter of greater than three centimeters. There is actually a large selection of patients that should undergo invasive mediastinal staging. All guidelines now suggest that should be done by EBUS as the initial investigation combined with EUS if possible. And it's actually a nice quality standard that we invasively stage patients with stage three disease as well. Hopefully Sanjay, there is a growing swell of respiratory physicians out there with their EBUS scopes who know when to put their hand up at an MDT and say, "This patient needs invasive mediastinal staging."

And then when they're approaching the case in the endoscopy suite, they know that they need to be doing a systematic approach where they're sampling N3 nodes, N2 nodes and N1 nodes in that order and sampling any nodes that are greater than five millimeters and always including paratracheal and subcarinal nodes. Quite a lot of information there and quite a lot of things that we can do is as pulmonologists in this area. But I think really vital, particularly as we move into an era where we're going to be discussing immunotherapy prior to surgery perhaps or other neoadjuvant treatments or even adjuvant treatments after the well. We need to get more accurate mediastinal staging. Also my last point there would be when faced with a patient with any of those factors in the mediastinum, always think about brain imaging earlier on in the patient pathway. It can save a week or two trying to get an MRI later on.

Sanjay Popat:
Thank you, Neal. David, I'm going to bring you into, just to follow up from the discussion about mediastinal staging, because some patients will go onto have surgery and have identified N2 involvement at the time of surgery, either intentionally or unintentionally. Now there's always been a debate about these patients and adjuvant radiotherapy. We've had the Lung ART trial reported previously and at BTOG Dr. Le Pechoux gave a very nice overview of that study. Maybe you can summarize for us, I think the overall message of that trial, which randomized patients postoperatively to either adjuvant radiotherapy or not was that there was no benefit, but is that really the case? And is there still a question on who should get adjuvant radiotherapy? David?

David Gilligan:
Yes. There's still very much questions about adjuvant radiotherapy. I think what the Lung ART established is that at the moment for pure N2 disease that has been completely resected, so an R0 resection, then radiotherapy is probably not something that we would recommend at the moment. And although the Lung ART study showed that recurrence rates, local recurrence rates were less in the radiotherapy group, there were excess deaths in that group, which we think were probably related to cardiac or cardiovascular toxicity from the radiation.

Now looking forward, that might be something that we should focus on in the future to see if there are better ways of directing the radiotherapy, be it with better imaging or defining the cardiac organs or defining people who might benefit or be at increased cardiac toxicity or using protons for instance. But I think that's a possibility, but maybe it's better to try and get things done in the neoadjuvant setting and getting it right and selecting patients for surgery who shouldn't ever need to have postoperative radiotherapy. And that brings me onto the group that still, I think, do need to have adjuvant radiotherapy. And that's the R1 and R2 resections. Whether it's microscopic or macroscopic residual disease or indeed whether it is extracapsular spread. The disease has extended out of the lymph node and Cecile mentioned this in her talk that there are a proportion of patients where the disease has actually escaped from the lymph node and they should not be counted as R0.

I think in practice, certainly where I work, we very, very rarely see R1 disease so we're really focusing on R1 microscopic residual disease. And there is data which does definitely suggest that there is a benefit in postoperative radiotherapy, but that's a challenge because first of all, it's not that common. And I think oncologists, you don't see a terribly large amount of cases that fall into that R1 category. And the second I think is really an unmet need that when someone is decided in the MDT that someone needs postoperative radiotherapy for an R1 resection, there really needs to be a full MDT discussion about what is the target volume? Because you can't see the tumor, it's been removed. It's been microscopically, perhaps not removed, but you cannot see it. What you need do and it's really important.

I do stress this to all our trainees is that you need to sit down with the surgeon, with the radiologist and with the pathologist and actually define best you can. And it's still maybe an area where it is the weakest link in the chain, define the target volume for that particular patient as to where the resection margin was N1 and where it is on the CT scan and what's that risk. Sometimes clips can be put by the surgeons for help, but I think it's something that we really do need to sort of up our game on and actually it's very difficult and difficult to define area of giving radiation. But I think it's a really important one. But maybe, what we need to do going forward is with newer therapies, better staging, actually have a much better profile of people who will hopefully I think an ideal would be that no one needed postoperative radiotherapy. That we have other treatments, which means that that is not needed and that we should reserve radiotherapy for where we know there is really, really major benefits like inoperable stage three disease.

Sanjay Popat:
Thank you. And we're having new preoperative therapies starting to come through, perhaps this is going to reduce the number of R1 resections that we see. And we have previously got very good data to say that neoadjuvant chemotherapy has similar effects to adjuvant chemotherapy. And for various reasons, we've all settled on adjuvant chemotherapy. Seen some very impressive results with a neoadjuvant immune checkpoint inhibitor as monotherapy in experimental early phase trials and the CheckMate 816 trial reported at the AACR meeting. This was a randomized phase three trial of preoperative chemotherapy plus or minus nivolumab. Samreen, you talked about this a bit at BTOG. Are we right to be excited about this study? Tell us about the study and what your thoughts are.

Samreen Ahmed:
Okay. Finally moving to an area where hopefully we'll be curing lung cancer rather than just palliating symptoms. The key points in my mind, when I sort of reiterated that in my talk was A, is it safe to give the treatment upfront? Because we don't want to compromise a potentially curative surgery by making these patients not fit for surgery. There's a number of phase twos that were done looking at getting adjuvant chemo together with immune checkpoint inhibitors, various combinations and looking at safety, tolerability, getting to surgery, et cetera. And that that's been proven, that that's safe to deliver upfront before surgery and not compromising the surgical resection.

The second point is, are there any surrogate markers we can use rather than the usual disease free survival and overall survival. And complete pathological response like we've seen in other cancers, such as breast cancer, looks like as an emerging surrogate marker for disease free survival and overall survival.

And then there's a specific entity which we've identified in lung cancer, which is major pathological response. And this is defined by less than 10% of viable tumor left after your systemic treatment. And both those endpoints, complete pathological response and major pathological response look, as if they are as good as it gets at the moment for surrogate markers for disease free survival. That's the second caveat.

The third caveat is are we going to see disease free survival and overall survival differences between giving chemotherapy versus chemotherapy immunotherapy combination? And as you've just mentioned, the CheckMate 816 study looked at the primary endpoint in this study was complete pathological response. And then a secondary endpoint was a major pathological response. And just those two entities reported at AACR. And we're looking at in the study of caught it up to 40%, 39, something like that percent of response rates with combined checkpoint inhibitors and chemotherapy versus 10% chemotherapy response rates. There was a major difference in responses to start off with. I'm hoping that this will translate into disease free survival and overall survival, but the other main endpoint that we want to think about this is this laying down long-term immunity in our patients? Even if we can't eradicate microscopic disease with our systemic treatment, are we able to lay down memory cells and long-term immunity which will fight against emergence of metastatic disease further down the line? And that's going to be really the panacea that we're all waiting to emerge in lung cancer.

Sanjay Popat:
I think that's right. In a few weeks time, we'll have the EMPOWER 010, a randomized phase three trial dataset, hopefully reading out at ASCO which randomized patients postoperatively to adjuvant atezolizumab or not. And we've had a press release highlighting that we have a positive trial. I for one am very much looking forward to this information. Finally, the other hot topic was the ADAURA trial in which patients that were EGFR mutant or an exon 19 deletion of L858R, who had undergone complete resection, were randomized to receive adjuvant osimertinib or not with a primary endpoint of disease free survival. And the study was massively positive for disease free survival, the hazard ratio in excessive .2. Neal, what does that mean for our patients?

Neal Navani:
I think so far to my knowledge, osimertinib is still being assessed by NICE. Currently no change, but a lot of excitement. And I think people paused. I think one of the big changes that's going to have to take place is the concept of molecular profiling in early stage disease. And I'd like to think a lot of multidisciplinary teams are already primed for this. We've been one of the things that's part of the optimal pathway to achieve that, to get molecular testing back in 10 days, we're all advocating the use of reflex testing. And therefore, hopefully it won't be too much of an extension to also get that reflex testing done for our patients with early stage disease. And I think it will also change our conversations with patients upfront as well, particularly if we have the result of an EGFR test as they're being referred for surgery. As respiratory physicians, we're very used to discussing the possibility of adjuvant treatment with patients based on clinical staging. I think it will affect MDTs in a number of ways potentially assuming obviously in the UK that approval is granted.

Sanjay Popat:
Well, I totally agree Neal, and I think that's a really exciting note with which to end on. I'd like to thank all of you around the table for your insights, your expertise and your knowledge and sharing your learnings from the BTOG 21 annual meeting. Thank you very much, Neal, Samreen and David for your insights. And I'd like to thank the audience for listening to us and I hope to join everyone again at another edition to the Lung Cancer Sessions on VJOncology sometime soon. Thank you, everyone and goodbye.

Disclosures
Sanjay Popat:
Financial fees in the form of honoraria or advisory roles from:
Amgen, AstraZeneca, Bayer, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, GlaxoSmithKline, Guardant Health, Incyte, Janssen, Lilly, Merck KGaA, MSD, Novartis, Pfizer, Roche, Takeda

Received research funding from:
ARIAD, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Clovis Oncology, Daiichi Sankyo, Epizyme, GlaxoSmithKline, Guardant Health, Janssen, Lilly, Mirati Therapeutics, MSD, Novartis, Roche, Takeda, Trizell, Turning Point Therapeutics

Received travel, accommodations and expenses from:
Boehringer Ingelheim, MSD, Roche

Neal Navani:
Financial fees received for speaking or advisory roles from:
Astra Zeneca, Bristol Meyers Squibb, Lilly, PeerVoice, OncLIve, Pfizer, Amgen, Olympus, Takeda.

David Gilligan:
Funding and financial honoraria and consultancy fees from:
Astra Zeneca, BMS, Boehringer Ingleheim, Daiichi Sankyo, Lilly, MSD, Pfizer, Roche, Takeda

Samreen Ahmed:
No conflicts of interests to disclose

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