Lung Cancer Session with leading UK thoracic experts Sanjay Popat, Meenali Chitnis, Eric Lim, Kevin Franks and Riyaz Shah

Drug treatment of operable NSCLC in the UK

In the fourth roundtable in a series of Lung Cancer Sessions organized by VJOncology and the British Thoracic Oncology Group (BTOG), thoracic experts Sanjay Popat, Meenali Chitnis, Eric Lim, Kevin Franks and Riyaz Shah discuss drug treatment of operable NSCLC.

Part 1: Neoadjuvant chemo-IO vs surgery

‘The results for CHECKMATE-816 represents the best overall outcomes with regards to neo-adjuvant, adjuvant, and perioperative trials to date. And so this is a very important aspect or game changer in our practice. In addition, the costs are relatively less compared to the adjuvant or perioperative strategies. ’

Part 2: Post-surgical radiotherapy & genotyping

‘The surgeon needs to be comfortable or confident that they can achieve a complete technical, complete resection. If that is not the case, then they should not have neo-adjuvant chemoimmunotherapy. And just as a clear point of distinction, I think we as a thoracic community need to clearly define between neoadjuvant and induction.’

Part 3: Neoadjuvant osimertinib as a treatment option

‘The area that I think is really important for HCPs to really appreciate is how important it is, what is said to the patient. Because the post -operative treatment of early lung cancer is incredibly complicated. It’s not all EGFR mutations. It’s only certain mutations. It’s only certain sizes,  this, that, and the other’

Part 4: Managing disease progression

‘It’s very important when counselling patients exactly as Eric outlined, they need to be aware that this is an amazing treatment when it works, but there’s a chance it won’t. It’s really difficult to tease out any clear signal because everyone manages the issue depending on what they see in front of them. ’

Part 5: Pathology

‘In terms of prognostication, prediction, and in the future, probably hopefully a personalized approach to who has further adjuvant treatment based on the responses you see is going to become very crucial that it is standardized on everyone everywhere as reporting it in the same way so we can make proper treatment decisions’

Part 6: Disease staging

‘The final thing to comment on is we need to make sure we have excellent surgical quality assurance right in that we do follow our guidelines to make sure that we are having R0 resections and not R-UN resections and need to make sure that either appropriate complete dissection or sampling is implemented ’

Full transcript

Part 1: Neoadjuvant chemo-IO vs surgery

Well, hello colleagues, and welcome to this roundtable discussion hosted jointly by VJOncology with BTOG. My name is Sanjay Popat, I’m a consultant on Medical Oncologist at the Royal Marsdon Hospital, and I’m joined with our illustrious colleagues here today to deep dive into the thorny and complex issue of drug treatment of operable lung cancer. I’m joined by several experts today. I have Dr. Riyaz Shah from the Kent Oncology Centre, Professor Eric Ling from the Royal Brompton Hospital, Dr. Kevin Franks from the Leeds Cancer Centre, and Dr. Minali Chitnis from the Oxford Cancer Centre. And what we’re going to be discussing is very much phrased in where we are recording at the moment, which is September 2023, and in England where we have chemotherapy with nivolumab reimbursed, and we also have adjuvant atezolizumab reimbursed as well.

So, let’s just start off and talk about the new exciting data that we heard about, which has resulted in reimbursement for neoadjuvant chemoimmunotherapy.

Riyaz, we had the CHECKMATE 816 trial which evaluated this, which demonstrated a marked disease-free survival, or event-free survival improvement with chemoimmunotherapy. But which patients are suitable for this in your practice and in your MDT? Who are you choosing to undergo neoadjuvant chemoimmunotherapy, and who are you saying actually go straight to surgery?

So, the pathway in our MDT is to first obviously discuss the case and decide whether this is operable or not, and I think once it’s been established that the patient is felt to be operable, the next decision is whether they need a neoadjuvant strategy, and that’s really about the staging. And so we just follow the CHECKMATE 816 entry criteria – remember this trial was done during the seventh edition era, so Stage 1b to 3a, but in our current eighth edition era, that’s sort of Stage 2a, and goes all the way up to some 3b, so any of those patients would in general be offered an opportunity to come and see me to have a discussion. And how do you make any decisions on the basis of PDL-1 status and in UK we have a reimbursement strategy which excludes patients with eGFR mutation and ALK positive disease so do you wait for those results to come through before you make decisions or do you make a general decision assuming it’s going to be wild type and then see the patient – how does it work?

Yeah so in my centre for many years we’ve decided that upfront reflex testing is simply the way it has to be done. You cannot wait for full molecular, particularly in the era of NGS, and so we have rapid Cobas systems to detect eGFR and IHC for ALK so that that’s often known very very early on – albeit NGS still awaited. I think that those patients basically just come to my clinic and I mean it’s important to know that somebody is MDT receptable which is one decision but the MDT doesn’t always know if the patient is physiologically receptable, and that often needs a face-to-face consultation with the surgeon it’s very obvious for some patients but not all so I think we just need to be very clear that this patient is almost definitely going down surgery by the time I initiate this treatment I want absolute confidence that the patient is indeed definitely going to be operated on, and so the surgeon will have seen the patient and spoken to me to confirm that.

And before I bring in Eric to this conversation, I’m just going to bring in Minali to this conversation I’m just going to ask her thoughts on the neoadjuvant pathway. Is there a patient selection process that you have in your setting? Or is it very similar to, as you’ll discuss the patient, or the case will be deemed surgically operable, there may be some pathology pending and you’ll see those patients, or are you saying, well, this group of patients goes directly to surgery and should have consideration of adjuvant thereafter? This group of patients, we separate them out. How’s things working there? So, in principle, very similar to Riyaz, all patients who are eligible for this treatment should really have the opportunity to discuss. In practice, this is a whole new setup for us, it’s a whole new pathway that we’re having to develop.

And capacity is an issue all around in terms of clinics, etc. So while we’re developing that, certainly in our centre, we’ve looked initially to the group of patients who might have the most benefit, perhaps, of driving the positive data in the trial. So the Stage 3 patients, rather than maybe the early smaller tumors, no negative. So we focused on them initially, as the patients we wanted to most definitely see in our clinics, not turning anyone away, but focusing on them. And then, molecular is not quite so straightforward. Ours are NGS panel based, so we don’t always have the results at the time we see them. But the caveat is that we have to check them before they embark upon any neoadjuvant sort of setting route, because you have to make sure they’re EGFR and ALK negative. So, for us, it’s very much a MDT discussion as to operability, just like Riyaz said, but clinical discussion on feasibility, performance status, are they fit enough for treatment? And ultimately, there will be some patients who will go straight for surgery. That’s partly based on what we’re probably going to discuss, worries about complications that might ensue if you delay surgery, hemorrhagic obstructive complications, etc, but also not to forget the group of patients we don’t have EGFR ALK in. Do we then just go for surgery and avoid the neoadjuvant setting route?

Thank you. I’m going to bring Eric into this. So Eric, you’ve been a proponent for surgery, for clearly for Stage one, Stage two, and selected Stage threes for many years now. And this is your time now, I guess, in many respects, right? Because we’ve started in the UK now to want to operate on Stage three APN2, N2A1, for example. What is your view on patient selection for neoadjuvant or directly to surgery and should really be considered for adjuvant systemic therapies thereafter? Do you really look to your oncologist or do you have strong views? And furthermore, what is the general view of your UK thoracic oncology at the moment?

This is a great question, Sanjay. Thank you. I think that this is a complex pathway and at the moment the results for CHECKMATE-816 represents the best overall outcomes with regards to neo-adjuvant, adjuvant, and perioperative trials to date. And so this is a very important aspect or game changer in our practice. In addition, the costs are relatively less compared to the adjuvant or perioperative strategies. So I think at the moment, it represents the most cost effective strategy for the UK. And therefore, it’s really important for surgeons, oncologists, and chest physicians all to come together in MDT. So I serve several MDTs and one of the MDTs I serve is the Royal Free MDT. And we have a very good setup in that the pathway is complex enough because you need to check for the molecular status. You need to check for, like you said, the Stage, like other people have said, the operability, so on and so forth. We work together at the Royal Free MDT for many years, that is 15 years of my position here, and I implicitly trust them to be able to select patients for surgery. And so we have imputed a pathway within our MDT where all patients who are Stage appropriate for surgery, in which surgery is considered, go straight down to the neoadjuvant chemoimmunotherapy route in order to minimize delay. And one of the important checkpoints is that the surgeon needs to agree that this is resectable and that can be easily done in the MDT and once that has been sanctioned, patients see the oncologist as the first point of contact, have the treatment and then re-refer to surgery on the last cycle of the chemoimmunotherapy and then we then arrange for an operation day within four to six weeks because it takes three weeks to finish the last cycle and with that we tend to have a much, much smoother process for all our all our surgery resectable patients.

And is that a feeling that operable patients should undergo induction treatment with chemoimmunotherapy reflected generally with your colleagues as surgical? Or is there still an anticipation really that you know operating after induction may be complex, may result in more morbidity for patients or really is that is that here in our past? Another very very good question – quite a challenging question – I think surgeons still hold very different views across the country so it’s not I don’t represent the global consensus view of surgeons across the United Kingdom but what I can say is that ultimately my in my own personal belief is that it’s not after the surgeon anymore if you have results that show that you can achieve improved event-free survival with a 45% reduction in the risk of death or events then the surgeons need to adapt. Let’s always talk about the surgery becoming more difficult after induction chemoimmunotherapy and for my own limited experience today – because it’s only relatively quite new – there are a handful of patients in which it’s difficult but so far the a good proportion of patients I don’t actually perceive any difference and even if there was a difference it would be up to the surgeon to manage it, do a good job, and get on with it as opposed to question you know it’s at the other day it’s not about the inconvenience of a surgeon or the slight increase in technical difficulty. It’s about the welfare for the patients that we care for.

That’s a great repost and great to see these views being up taken by many parts of the UK.

Part 2: Post-surgical radiotherapy & Genotyping for early lung cancer

Kevin, I’m going to bring you into this discussion. So you’re the radiation angle on this discussion. And the UK has been very conservative previously with Stage 3A and 2 positive disease, really not previously being very keen on operating on these patients. We are now taking a very radical change in our view to operable N2 positive 3A, where we are now wanting to operate on these patients after induction chemo, that creates perhaps a difficulty in patient selection between those patients that may be suitable for surgery, may also be potentially the patients we were treating last year with concurrent chemoradiotherapy with durvalumab consolidation. How do we square this? How do we make sure that we give patients the right treatment for their right Stage of disease? We don’t want to be operating on patients and resulting in R1 resections and not completing the whole course of the regime. But similarly, we don’t necessarily be wanting to treat them with radical treatment with chemo radiation operatively when we may not necessarily know whether there’s an advantage to that or not. So this is complex decision making. How does it work in your centre?

So again, I agree that it’s very difficult and we’re trying to embrace this rapidly but trying to do that in that pathway is challenging. I think hopefully with this specific data, we’re much more keen to chemoradiation for inoperable Stage 3 disease, but clearly, you know, this shouldn’t be affecting our new, this pathway. This is an operable patient. So I think the first thing we say on MDT is that this new data shouldn’t change what you think is operable and what isn’t operable. As Eric says, what you should be going for is an R0 resection. A few little caveats. I think for Pancoast tumors, I’m still not sure what this fits in terms of neoadjuvant chemo-radiation versus chemo-radiotherapy followed by surgeries. I think there’s still a bit of work to think on that. So, I think that’s often a debate. I think, but I think going forward, I think we would, we’ll get patients a choice. So, we will see them and say, “This is the option”. And I think if they’re PD-L1 or negative, that should that influence thing? I’m not sure how it should influence things, but I think it’s very difficult for us to navigate this to the pathway for patients. I think the key thing, I think we’re getting better with this as we’re doing more cases. I think we’re getting better to know who’s going to get through the chemo-IO better.  And our surgeons will see patients up front and say, “Actually, I’m not sure they’re going to be operable 12 weeks down the line”. So, I think it’s always a challenge when you’re trying to deliver trial treatment to non-trial patients. They’re not the same population. So, I think we have to be really careful of that. So, I think we would give the surgeons fit patient, N1 disease, it’s resectable. They think they can get R0 resection at the MDT, not after new argument therapy. We would say, give them option of surgery as a first choice with chemoradiotherapy, then we’ll have an operation. And I think that’s the way forward. And I think we’re learning as we go through who we perhaps of those grey cases, and we know quite a lot, the grey cases are difficult. Which one’s may favour the other way, and I think it also makes the argument for dedicated Stage 3 MDTs even more relevant because the more people get doing this more regularly, rather than just a few people doing it from smaller MDTs, the better it is, I think, as you learn from how you decisions. Thanks, Kevin.

I’m going to bring Eric back into the discussion. So, Eric, this is a big sea change. I mean, yes, we want to perhaps be operating on our N2 positives Stage 3A, but we want to be operating on patients that are deemed technically operable, they know at presentation, not borderline operable, that might get there in the sort of olden area, you know, we were sometimes giving induction chemo to see where we went, and if they then became operable, we would then operate and then perhaps if not radiation back in the day. How do we get this message across to some of our keener surgeons that actually this case is definitely not operable and we can’t take the risk by going down a chemo-IO route, because if they’re then not operable that may cause problems with their downstream management of local and systemic therapy. Or actually is this not a problem and you know folk don’t really want to operate on these cases anyway.

I think that we have to keep the indications quite clear for the neoadjuvant chemo IO, the patients need to be operable from the outset. So the surgeon needs to be comfortable or confident that they can achieve a complete technical, complete resection. If that is not the case, then they should not have neo-adjuvant chemoimmunotherapy. And just as a clear point of distinction, I think we as a thoracic community need to clearly define between neoadjuvant and induction. So neoadjuvant means it’s resectable from the outset and induction means you have your treatment which is downStage to become resectable. And I think for the purpose of this discussion that’s not what we’re talking about. So if we stick strictly to the rules of the game, it should be resectable from the outset. If it’s not resectable from the outset, which means that you can’t technically achieve an R0 resection, then they should go down the pacific regimen. And once again, this should be focused on best patient-centric outcomes and not what maybe the oncologist or surgeon thinks that what they can or cannot achieve. You know, they obviously will be great cases in this area, but where possible, we should try to be clear and stick to the necessary drug licensing guidelines.

Thanks, Eric. And Minali, I’m going to bring you into this so inevitably despite us all being super keen on the neoadjuvant chemo IO there will be patients who for a variety of reasons will go straight to surgery they may be unsuitable for immunotherapy, autoimmune disease, other , they may not be the best candidate for starting with chemoimmunotherapy, they may just say look I hear you, but you know I just want it out okay – I’ve seen a primary surgery is really what I want and you know we have a broad church here so how do you manage patients that have had primary surgery that come to see you that haven’t had neoadjuvant IO, and you’re thinking you’re making decisions around PDL-1 status, molecular testing and thinking about adjuvant consolidation whether it’s immunotherapy or osimertinib. What’s your approach, how do you how do you handle those patients in your clinic?

So the patient comes to see us after surgery now the hope is that we also have some reflex upfront testing molecular pathways and usually a biopsy pre-surgery, so the hope is that the majority of patients who come to see us in clinic will have a PDL-1 expression level already there and hopefully also the EGFR status at that point – so that you can the best ways to guide your initial discussion on any form of treatment giving up the whole picture. In reality this is not always possible but we always talk about, we always assess their recovery from surgery, their fitness at the point they’re seeing us in clinic and then we discuss the options which could be either just adjuvant chemotherapy alone with the small survival benefit we’re all aware of, but if they have a high PDL it’s very important at the Stage of chemotherapy to be able to tell them that actually in your particular case there is an improvement for you in terms of recurrence rates if you actually have a year of immunotherapy – if you don’t have that information at the start the patient is just facing that decision on a five percent survival benefit with full cycles of chemo – so I think it’s really crucial to have that PDL. With the EGFR status again it does guide that discussion but of course patients can have osimertinib in the adjuvant setting, with or without chemo, so again it’s important that if anyone, if we don’t have the EGFR status in that clinic appointment, and someone says they do not wish to have adjuvant treatment, I think for oncologists it’s very crucial to have chased up that EGFR afterwards, because if it does come back as positive, we really are obliged to let that patient know the result and perhaps even re-discuss what their treatment options might be.

I think this is a really critical issue, Minali, and thank you for flagging this. So whose responsibility is it to chase up that EGFR genotyping result at some point of the pathway to make sure that in the one in 10 patients or higher or lower frequency, depending on your population prevalence of EGFR mutations, we don’t miss those patients that are EGFR mutation positive. Eric, is that what the surgeons should be following up right? Because sometimes I think is the surgeon only interested in the technical aspects of the resection? And well, the molecular genotyping, that’s all the fancy stuff the oncologists do afterwards.

Eric? Yeah, so we’ve been retraining surgeons now and for me and my team in my under my care, we both report the TNM Stage as well as the molecular status and the two mandatory molecular status that we need to report after our operations are EGFR status as well as PDL-1, because they have both licensed indications for treatments. We see our patients one week after surgery, so very often we can get the PDL status but not the EGFR, so we put that as pending, but in our clinical correspondence, we tend to report back to our referring physicians what the molecular status is and I think increasing across the country, surgeons need to pay more attention to these results because we are always so aware of our long-term survival and clinical outcome results, and I keep explaining to surgeons that these molecular treatments have the potential to increase overall survival and so therefore your surgical results technically will be better if you report them back and patients receive the appropriate treatment. So I personally think it starts with the surgeon and pathologist and then to the MDT. And the other thing will be all our responsibilities to ensure that we get the best outcomes for our patients.

Yeah thanks Eric and Kevin so in this setting in Leeds how does it work right? Because you know there’s a large throughput of patients being discussed. How do we prevent patients not having their eGFR status known? I’m particularly worried about the 3 centimeter node negative tumors who aren’t usually candidates for chemotherapy, who aren’t candidates for adjuvant immunotherapy but are candidates for adjuvant osimertinib and oncologists wouldn’t necessarily see in their clinic afterwards. So how do we how do we stop these patients from being missed?

So previously it’s been the onus of the oncologist to say this needs to be eGFR testing and you have to be on your ball because you’re going to end up with case 75 just to make sure you remind that. I think we’ve been having discussions in turn about this, and Matt Callister has produced this lovely flow chart. So we now have a laminated flow chart that has a lovely kind of say who’s candidate for Osimertinib, who’s a candidate for neoadjuvant therapy who’s a kind of adjuvant and that makes a big difference because everybody’s got that. The key thing is once you then ask for it who’s responsible to chase it and our system doesn’t tell you when it’s been reported, so then it’s probably very efficient. We’re looking for it, the laminated flow we’re looking for at the end if you’re looking for it and then hopefully you get it back within 10 weeks or you can start it. So it’s a real challenge so I think we’re pushing I think ideally, as I said, to get it tested up front in the original biopsy would be much better because you don’t have that angst because our pathology waiting times are longer every other than we’d like them to be. It’s actually getting in post-op pathologies quite delayed and then to do the testing and I think we are moving to reflex testing but again we do NGS so you know you can get quite close to the wire – so it’s really important to try and stress to get a test early, reflex it and ideally do on the original biopsy, which is a change in practice.

Part 4: Neoadjuvant osimertinib as a treatment option for patients

Thank you Kevin and Riyaz in your setting how do we make sure that that all potential patients for osimertinib, I guess, we haven’t seen the data yet, but we know ALINA is positive. We’re going to have a similar discussion about adjuvant alectinib before long. How do we make sure that all molecular eligible patients get their targeted therapy? What’s your setup?

Yeah, I mean, we discuss this at the MDT, and usually it’s enough weeks down the line that these results are known, usually. But the area that I think is really important for the audience to really appreciate is how important it is, what is said to the patient. Because I have seen, you know, it’s very, the post -operative treatment of early lung cancer is incredibly complicated. It’s not all EGFR mutations. It’s only certain mutations. It’s only certain sizes,  this, that, and the other. And it’s very devastating for a patient who’s been told, you know, you’re going to see an oncologist, but you’re just going to have chemo to then be told, you can, you know, how about three years of tablet -based therapy,  or actually, you were told you were going to have osimertinib, but in fact, you’ve got the wrong EGFR mutation. So I think that is an area that I think we really need to hone down on. Just make sure that, you know, in the immediate post-operative setting, patient needs to know they’re going to see an oncologist for an opinion, and that’s pretty much it. You know, going into too much detail is very likely to result in the wrong information being given, not least because the people talking to the patient are not going to be experts on the blue-tech reimbursement criteria for that particular indication, which, you know, as oncologists, we do that stuff all the time. So, yeah, I mean, it’s down to the MDT, seeing the patient, I think issues can happen when, you know, most MDTs don’t have a multitude of oncologists sitting on them. So when the oncologist, who’s the champion of adjuvant osimertinib, who’s on annual leave, is it possible that a patient could slip through? I mean, who knows? But we do need robust systems.

Thank you for that. And Kevin, I’m going to just ask your views on the other issue that sometimes happens as we see a patient, they’ve either had neoadjuvant or they’ve not had neoadjuvant, they’ve gone straight to surgery. And, you know, we’re discussing adjuvant radiation. You know, we now have Phase III data, which suggests that it’s not suitable for the general group of patients that are N2 positive. But, you know, who do we select still select it for? Or actually, is adjuvant radiation post-surgery just completely off the cards now completely? For example,  if you had a patient really who was strongly PD1 positive, and you’re thinking about a atezolizumab and there are zero tumor, is there really a rationale for radiation additional local control in that setting?

I think I break it down. Obviously, with the Lung-ART study and showing no clear benefit for N2 disease, I think, and I’ll remind us that that was completely receptive to R0 disease. And I don’t think there’s a role for adjuvant rare therapy in that setting currently, particularly with some of the concerns about radiotherapy and cardiac toxicity. And the more nuanced thing is when you’ve got some of these, got an R2 resection, particularly on R1 resection. And we’re really struggling in terms of the quality data to answer that question. There’s a number of patients in the paper last year showing that probably no benefit from an adjuvant rare therapy in R2 section. But again, retrospective reviews of old data. So I think we really don’t know what the scenario is. I think you have to weigh it up on an individual basis. So if you’ve got somebody who’s got a significant amount of residual disease, or the chance of local recurrence is high. So I would then have wanted to have a conversation with them about radiotherapy,  particularly as visible disease left on, you know, if you have an image and there’s still more sort of residual disease rather than post-operative scarring, I think it becomes more difficult, depending where the location is. So that recurrence is sitting right next to the heart, and it’s R1, then my worry about giving adjuvant radiotherapy, that setting when the data is double as strong is higher. So I think, I don’t say never, but I think across all of the clinical oncologists, the use of adjuvant radiotherapy and the port analysis to Lung-ARTs now is getting less and less. We don’t particularly like doing it, because afterwards, particularly for patients who have had a lobectomy, we do see a little chronic scarring. It does cause long-term side effects. So I think in my mind, less and less, there’s going to be a few cases where it’s possible in residual R2 disease, particularly in the disease you might want to think about,  whether concurrent chemo radiotherapy, some patients do that, and not sure its standard in the UK, or adjuvant chemotherapy or the radiotherapy. But I think they’ve got to be on PDL-positivity. You could just try and make them R0, because I think there’s going to be more of a benefit from the year of, I don’t know, 50% of idealism out there from radiotherapy, which has got questionable benefit.

Thank you, and Eric, I just wanted to bring you in some of the decision-making around the pre-operative treatment. We’ve been talking about some of these sort of, I guess you would argue, aggressive tumors that may not have responded well to pre-operative. We’ve still got an R0 area resection. One of the problems that we’ve seen with the pre-operative data sets is patients never getting to surgery. There’s a small, but finite group, of patients that start pre-operative chemo immunotherapy that for a variety of reasons,  it’s not very clear from the data sets, I think, don’t get to the definitive resection. Is that still a concern for the surgical community? I guess it’s probably a concern for the oncological community, but how do you mitigate that in your decision-making when you’re discussing the case? Is there a bias to say that these small tumors that would be eligible? Well, it’s PD-L1 negative. The magnitude of benefit is not going to be huge. Maybe I’ll just do surgery anyway. Or even thinking, well, that patient, I really need to ensure that they get to surgery. Does the sort of risk of not getting to surgery feature on surgeons’ minds?

Yeah, I think that when we speak to patients about neoadjuvant chemoimmunotherapy, it’s important to inform them that about 15% don’t actually make surgery for whatever reasons. But if you take a step back and from a clinical trial perspective, what we’re also saying is that, however, if all things being equal, if we have two groups and we have one pathway for the two groups, the overall outcome is that if you can make it through and have your surgery as planned, for example, then your risk of events or death reduces by 45%. That’s a huge number. Unfortunately, with every treatment, you cannot ascertain or guarantee that you will definitely make it to surgery. And if that’s the case, then that’s the kind of the gamble that you would take. I personally think it’s not really up to doctors to decide. It’s really important for us to explain it to our patients. And for those who I’ve spoken to are quite reasonable. And as long as they understand the risks and benefits of neoadjuvant chemoimmunotherapy, they go in it with their eyes open. So far, I haven’t really had any patients decline neoadjuvant chemoimmunotherapy yet, but it’s still early days.  The vast majority understand the trade-off and they actually do go for it. I think what’s several more interesting questions is that if you do progress on the chemoimmunotherapy, then what happens then? And in those circumstances, I think we need to fall back to the CHECKMATE-816 trial design. If you progress beyond surgically-resectable limits, then you’re definitely not going to have the operation. It’s the grey zone if you progress slightly, but still within surgically-receptible limits. And as far as I understand the trial design, you actually still progress to surgery.  And often for surgical trials, we often use that caveat. If you progress a little bit on treatment, but you’re still within resectable limits, then we would still advocate for patients to go ahead with surgery. But clearly, if you are very unwell from the chemo-IO, if you are developing bad complications, or if progress beyond surgically resectable limits, then surgery in these cases, I don’t think would be suitable. The problems you can’t put it beforehand.


Part 5: Managing disease progression with chemoimmunotherapy

Thank you, Eric. Can I bring Riyaz into the conversation, right? So this is a thorny issue, right? We’re planning for three cycles of neo-adjuvant chemoimmunotherapy. How do we handle patients, the small number of patients that may well progress on treatment? You do a scan pre-operatively, and there’s an equivocal new node that pops up, or, you know, there’s some question that brings in the suitability of surgery. How do we handle that? Well, it’s very difficult. I think it’s very important when counselling patients exactly as Eric outlined, they need to be aware that this is an amazing treatment when it works, but there’s a chance it won’t, you know? And 20 %of patients progressed, and there has been some publications, data from 816 about the outcomes and the patients that progressed. And it’s really difficult to tease out any clear signal because everyone manages the issue depending on what they see in front of them. So yes, some patients do progress to surgery. Some patients have salvage, radical radiotherapy. Some patients end up on palliative pathways. I’ve treated enough patients now to have come across patients who’ve progressed, and it’s soul-destroying, actually. It’s really, really depressing, and some patients do very badly. So I don’t think there’s a clear, I don’t think there’s any clear thing I can say to the audience about what to do, because I just think it’s bespoke management depending on what the pattern of relapse is, what the patient’s fitness is. Some are salvageable with some sort of radical approach. some are totally palliative.

I think that’s very correct and if you can bring in Kevin to this, one of the challenges we have is just turning around radical plans because these patients, if they’re obviously not resectable, we would want to try and salvage radical radiation for these patients but getting radical plans set up is not straightforward in many centres. The time it takes, they’re already progressing on their chemotherapy so how do we manage this in real life? We want to get radical radiation into them, but it may take some time.

We’ve taken the elected decision to do our CT scan to two cycles rather than after three, I think with a trial you had to have it within 14 days of surgery and I think for us we don’t have the three streamlined services to adapt and react quick enough. So, we took the pragmatic approach after two cycles, if they’re not responding or they’re progressing in surgeries an issue, then we look at considering other options. Now, I agree exactly what Eric said, they’ve progressed a little bit but not surgical. We have had a few patients we’ve operated after two cycles who said actually we can’t risk this, they’re fit but we operate. We have patients who are no longer surgery-operable and we’ve then gone to radical radiotherapy but I think doing that CT scan earlier, I think gives you that indication. Now, obviously there’s going to be a few caveats, you might miss somebody who gets progression, I think that’s unlikely but I think given the way it takes on average at least two, three or four weeks to go from seeing a patient dying of radiotherapy, you can’t be doing that for four weeks after they finish their chemo-io because they’re going to progress if they’re going to compromise. So I think pragmatically doing your scan earlier is a better way forward and also you perhaps have re-discussed the MDT that Stage because the surgeon is more time to look at that as well. So that’s how we’ve managed it in around Leeds and around West Yorkshire.

Part 6: Pathology

Great, thank you. And I’ll bring Minali into this. So the other issue for the neoadjuvant space is how our pathology colleagues handle the specimen in the laboratory, how it’s cut up, how it’s sampled, how it’s evaluated, and the confidence that we can have that a major pathological response or even a complete pathological response that’s reported by you and your colleagues is exactly the same as by Kevin and his colleagues, Eric and his colleagues, and Riyaz and his colleagues. And everybody’s probably doing something slightly different because this is new for us as oncologists, new for us as surgeons, and definitely going to be new for our pathology colleagues. So tell me what discussions have you had with your pathology colleagues to say, hey, this is a neoadjuvant case coming through. Are you guys cutting it up according to the ISLC protocol? Do I really know that you’re comparing the pre-operative with the post-operative to tell us what the rate of pathological response is? Or is that all just a bit of a mess needing to sort itself out?

So I think we’re lucky here in Oxford that we have very proactive pathologists who’ve already sort of jumped on the whole neoadjuvant space and the pathology before we’ve had the discussions.

So when we’ve brought it up as we’re going to be doing this, what do you think of the pathological complete response and the reporting? They’ve already said, we’re looking at it, we’re looking at the guidelines, we’re going to see how to report it and how to standardize it. So I think to be honest with you, Sanjay, I’ve left it at that. So I haven’t delved any further because I have full confidence in our team. However, you’re absolutely right because these in terms of prognostication, prediction, and in the future, probably hopefully a personalized approach to who has further adjuvant treatment based on the responses you see is going to become very crucial that it is standardized on everyone everywhere as reporting it in the same way so we can make proper treatment decisions.

That’s absolutely correct. And I’ll leave the final word, Eric, on the pathology and the relationship between pathologists and surgeons, which is clearly a long-term relationship to you, Eric. Are our pathologists and the surgical relationship you have, often you’re doing frozen sections in theatre, speaking to pathologists about whether to proceed or not? Has that changed with the advent of neoadjuvant chemotherapy?

I think some clear changes, we need to bear in mind is about 20 to 25% actually have a pathological complete resection and that’s kind of new for all surgeons. If we don’t often ask for frozen sections during surgery, but you can imagine a situation where if you have a very peripheral nodule and get a frozen section and it is pathologic complete resection then do you still go ahead and remove the entire lobe? I think the neoadjuvant chemoimmune-option really introduces more questions in this in this manner. But in terms of assuring the completion of resection, additional nodules, I don’t think that’s changed. But something we need to watch this space, this is a very very fast -moving exciting field.

Thank you, and Riyaz, final comment from you? Yeah, one area that’s concerning me are the patients that come who are pathologically upstaged into node positivity and they come to your clinic and you know they were thought to be no negative went straight to surgery. And I think we do as a community in the UK need to think about our preoperative staging of the mediastinum. You know, mediastinoscopies are almost never done, eBus is often a diagnostic procedure at many centres and not what you would call a surgical staging procedure. So it’s you know we know that about 20 percent you know a significant percentage of patients are being upstaged. So that’s not a discussion for me as an oncologist but I’m really interested to know what my thoracic positions and surgeons think about that.

Part 7: Disease staging

Well this is very good point and trying to have everybody say the final word I’m going to go back to Eric for the final final word on staging. And I’m sure you know we need to understand the type of disease we’re dealing with that baseline right. So do we need to Stage differently for a neoadjuvant approach or is it the same staging?

Another very good question so in the past where we said if you had say so if the patient is N0 or N1 disease then the staging is relatively straightforward I believe if you have N2 disease then it becomes a bit more challenging now in the past before the neoadjuvant chemo immunotherapy options were there people the oncology community would move to preoperative chemoradiotherapy and in that case ascertainment of the location of PET positive of disease positive lymph nodes becomes important now that you’re giving a systemic treatment upfront without the addition of radiotherapy then we could argue that the need to actually ascertains precision on knowledge becomes less important as long as technically respectable because a proportion of these won’t  have any more disease and if you can get complete technical reception then theoretically the same outcomes same good outcomes would result in association CHECKMATE 816 so that in that case in that manner has made quite a paradigm shift for preoperative staging.

I tend to agree and I think the final thing to comment on is we need to make sure we have excellent surgical quality assurance right in that we do follow our guidelines to make sure that we are having R0 resections and not R-UN resections and need to make sure that either appropriate complete dissection or sampling is implemented Eric.

Just to add a little comment and please understand that R0 uncertain may not always be the fault of a surgeon or R1 so for example you can get complete resection if your highest lymph node station is positive that will be R0-UN if you have extra capsular disease from the lymph node even though you’ve completely resected it as considered R1 and so whilst you can achieve a technical complete resection sometimes you get R0-RUN as a technical result from the TNM nuances of TNM staging.

Indeed and hence really really, all of us as an MDT need to ensure that we’re talking to each other and our pathology colleagues and our respiratory colleagues as part of the staging to make sure that this highly complex pathway is implemented at the best that we can.

And with that, I’d like to bring this discussion to a close. I’d like to thank all of our colleagues for their immense time and knowledge, really highlighting several complexities which still need to be resolved.  I think we’re in a much better position in the UK now than we have been at the time that 816 was first implemented. We now have better acceptance of this strategy and we are starting to see some really great things happening in people’s clinics. I’m very grateful to colleagues for sharing their time. I do hope that you, as an audience, found this very useful and do make sure you share this information with your colleagues. And I look forward to joining you again at another discussion hosted by VJOncology with BTOG. Thank you very much for your attention.

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October 2023