Professor Sanjay Popat is a medical oncologist and thoracic oncology professor whose life was shaped by a career spent advancing lung cancer and mesothelioma treatment through research, clinical trials, and patient-centred care.

In this episode of Breathe Strong, Professor Popat answers patient-led questions on early-stage and stage four EGFR lung cancer, treatment decisions around Osimertinib, trials, vaccines, menopause and HRT, mesothelioma immunotherapy, genetic testing, and the promising therapies now emerging on the horizon.

Sanjay leaves listeners with a sense that while these diseases remain complex and difficult, real progress is happening through science, better understanding, and the willingness of patients and clinicians to keep pushing treatment forward together.

What's coming through are what are called personalised vaccines. So these are taking a sample of the patient's tumour and generating a vaccine against that individual's tumour.

Wow. Welcome to Breathe Strong. I'm your host, Rachel. I'd like to welcome you to this next episode.

You may remember, in our last last podcast, we talked about relationships and friendships and I saw a post on Facebook from a lady called Jess, who is non Hodgkin's lymphoma, about this very topic. Her words really resonated with me and so I wanted to share them with you today. Jess said, I know a cancer diagnosis is uncomfortable.

I know stage four cancer, incurable cancer, chemotherapy, PET scans, biopsies. It's heavy, it's scary, it forces people to face their mortality. But silence is louder than anything you could possibly say wrong.

When someone is living with cancer, the world already feels smaller.

Life shrinks into oncology appointments, blood works, treatment plans, scan results, side effects, fatigue, and trying to act normal in between all of this. And that's when we notice who quietly fades away. It's not usually dramatic, it's subtle.

Texts slow down, invitations stop, let me know if you need anything turns into nothing. We see it. And here's the part people don't say out loud. Cancer is isolating enough without feeling abandoned by the people that you love.

You don't have to fix it. You are not responsible for curing us. You don't need a perfectly worded message about our cancer journey.

You just need to say, send a text, make the call, sit with us in that awkward silence, ask how the treatment is going and actually listen to the answer. Because when you disappear, it adds another layer of grief on top of the diagnosis.

It makes us question our worth in the middle of already questioning our future. We are already carrying the loss of so many things. Don't let us carry the loss of friendships too.

So I hope that that just resonates with you as it did with me. And we're going to go into our podcast now. And this podcast, we're very excited because this is our very first Ask the Expert podcast.

And I'm delighted that our very first expert is Professor Sanjay Poppat.

Now, many of you have heard of Professor Sanjay Poppat, but for those who haven't, he is a medical oncologist at the Royal Marsden Hospital in London. He is the professor of thoracic oncology at the Institute of Cancer Research. He also held the post for 13 years as the BTOG chair.

And for those of you who don't know what BTOG is. That's the British Thoracic Oncology Group. They are a large group and hold a national conference every year that all the key opinion leaders go to.

He has also led on many trials which have changed global practice in both lung cancer and mesothelioma. So it gives me great pleasure to welcome into the studio today Professor Sanjay Poppet.

Hi, Rachel, Great to be here. Thank you.

Thank you very much. Now, I'm going to go through some questions with Professor Poppet. All of the questions that we go through today have been sent in by patients.

So the first set of questions I'm going to talk to you about, Professor Poppat, is early stage EGFR lung cancer. And the first question that I've been sent in is, what do you see as the future direction of adjuvant targeted therapy in early stage EGFR cancer?

Well, I think we've got three questions that we need to answer. Number one, at the moment we are not treating all operated EGFR mutant lung cancer with post operative osimertinib or similar drugs.

We are reserving it for those with reasonable or higher risk of relapse, the stage one BS and above. So the question is, do some of the stage 1A patients derive a benefit from osimertinib? That's an unknown question.

There is a trial that is fully recruited called the ADORA 2 trial, in which patients with very early stage EGFR mutant lung cancer were randomised to the standard of care, which is currently follow up and surveillance versus osimertinib.

And that trial will report in a few years and that will inform us whether the benefits are worth it for that group of patients or whether we can actually push the goalpost forward for those patients. You have to remember, many of these patients may well be cured anyway and we're over treating those patients if we give them osimertinib.

So it's very important we actually understand the data so that we can understand the risk benefit ratio. So that's question number one.

Question number two, in those patients with stage 1B and above that we are giving postoperative osimertinib to how long do you need to give it for?

The data that we have was from a trial called adora, in which patients were randomly allocated to either receive no osimertinib, which was the standard at the time, or osimertinib for three years. And what we saw when we've had longer follow up of those patients is that not in all of them, Rachel.

But in some of those patients, when the osimertinib stopped, we tended to see a higher frequency of relapses than we would have done otherwise, indicating that that osimertinib was really important in holding back the disease. And stopping in some patients of high risk allowed the cancer then to relapse.

So that really brings the question, is osimertinib actually really curing patients of their microscopic disease that we can't see after surgery, or is it just holding it at bay? And if it's holding it at bay, maybe we need to carry on beyond three years and to five years.

I mean, of course, we have extended postoperative drug treatments for many cancers. For example, after breast cancer treatment, many ladies are on hormone manipulation with hormone tablets for many years. And the length that, that.

That we've been doing has increased over years. So that's one question that we need to answer.

And there's a trial which has recruited, which we will get some data on in the next few years, called the target trial, which looked at patients in this setting, and everybody had osimertinib for five years. So that will give us some data. And the third and final question is.

Well, the data that we have is restricted to patients with the common EGFR mutations, something called L858R and something called Del 19. And there are a small proportion of patients who don't have common mutations. They have what we call uncommon or atypical mutations.

And we don't really know whether osimertinib or its similar drugs are beneficial to that group of patients and what the risk benefit ratio is. And so the target trial also took a small cohort of those patients with atypical or uncommon mutations and gave them osimertinib.

And we'll see that was for five years. And we'll see what the outcomes of those patients are, and that will help us in the decision making as to what we do with these patients.

So, essentially, I can see a scenario where for everyone but the absolute smallest risk of relapse, we might want to be considering osimertinib. We're not quite there yet.

We still need to generate that data because, of course, osimetinib has side effects and it's not straightforward for a lot of patients. And we need to clearly understand the benefits versus the risks. And of course, no tablets or healthcare is free.

And so the economics then also play into it.

Yeah, that's very interesting. So there's lots of things to look out for in the future. So, going on to question two, what is.

And it follows on from that nicely, what is your view on expanding adjuvant treatment to patients with tumours smaller than 30 millimeters following a surgical resection? So you've covered some of this and again, I think you've covered about the. Treating the lower risk patients with those trials that are coming up.

Yeah.

So, I mean, at the moment, I don't think we have sufficient data to say, right, you know, we can very confidently prescribe osimertinib to patients with lower risk disease. I mean, it's not licensed for use and therefore not covered in the nhs, not covered by many private providers.

We don't know what the risk benefit ratio is. So, you know, there are some limitations on that decision making. So I think we have to generate that data to better understand it.

But that's not far off. That's not far off. I think the bigger question that we've got really is, are these treatments actually curing people? Right, and who.

And how do we better figure out who needs that treatment?

Because, of course, there are a group of patients who've had their surgery that will have been cured by that surgery, in whom the cancer will never come back.

And by giving every patient with that stage of disease tablets, a group of those patients who are over treating and exposing them to the side effects of a drug that they don't need.

Now, the problem is, within that group, there's also a reasonable proportion of patients who are destined to relapse because of microscopic disease that we can't see by blood tests and we can't see by scans that do benefit from osimertinib. And those patients, it seems to be that not all of them are deriving a benefit just from three years. We may need to continue thereafter.

So the question is really, how do we identify those that really need it and those that don't? And actually, is osimertinib really a drug you should be thinking about for life in some respects?

Not that it's funded to do so, that we have data for it, but it's one of the questions that we as oncologists are asking, are we really curing patients with this tablet or just pushing out the time to relapse until another future time point? And that's quite an important philosophical question.

Yeah, very important. And I think for me, what's coming out is the importance really of being diagnosed early.

And it's interesting that lung cancer screening at the moment doesn't really COVID patients who are non smokers and yet this group we're seeing can have that opportunity of cure which is, you know, in our day, back in when we started was just unheard of.

Yeah, I mean, I think that's right. I mean, about 20 years ago it was, you know, we had very poor knowledge of what lung cancer is in the general community amongst physicians.

And workup of patients, identifying them, getting them properly investigated is very different now to what we were doing 20 years ago. So we are really selecting people who do derive the greatest benefit from surgery and doing a wide variety of things. So we'll operate on them.

We, they may need to have chemotherapy afterwards. That's an area of controversy in EGFR mutant disease. You know, what does chemotherapy bring? I'm a believer that I think it does bring an advantage.

You know, we have these targeted therapies that we are using now.

There are newer treatments coming on board in the metastatic setting and eventually we'll be thinking about how we then move those into the early stage as well over the, the next few years. So there's always innovation ongoing in oncology.

Yeah. And I think that's why it's so important we continue to have our clinical trials that give us this evidence.

Yeah, fundamentally.

And I think, you know, if it wasn't for the good natured way our wonderful patients give up their spare time and contribute to science by enrolling onto clinical trials, we would never have moved forward. We would still be in the dark ages. It's only because of the fantastic work that patients do by volunteering to participate in clinical trials.

Can we generate data, can we identify benefits, can we then convince people that drugs are worth it and then convince payers that it's worth paying for them? And if we didn't have any of that, it's just conjecture, it's just argument. It's not science.

Yeah, yeah. And it's good to hear you talking about the patient being front and center.

Oh, absolutely. I mean, you know, this is, you know, we're all in it to actually improve the outcome for our patients.

And we recognize the great burden that being in a clinical trial places on them. Because in a clinical trial you have to attend hospital appointments at fixed times. There's not a lot of flexibility.

Patients often travel for long distances to receive medicines which are unproven at that point in time. So it's very much noted that what patients put themselves through is very welcomed by the entire community.

Thank you.

Following on from that, one of our patients has asked about, what are your thoughts on continuing osimertinib beyond the current standard 3 year duration in patients who are tolerating it well and their disease is either free or very much under control. I'm not sure in private practice whether patients have the option to continue beyond three years.

And if so, what's your experience with the patients that have had that opportunity? Has it been of benefit? What's the side effect profile like?

What are your thoughts? Yeah, I mean, so, I mean, the data is really at the moment for only three years.

So if you are continuing beyond three years, then it's a data free zone. I mean, that's the first thing to explain to your patients is that the risk benefit ratio of continuing thereafter is unknown known.

Now, the decision making and the other thing to recognise is that in England at least, the duration of treatment that the NHS pays for is only three years. Now, we have no data to suggest that carrying on thereafter is beneficial, but we know that in very high risk cases.

So, for example, patients with stage three disease that has been operated on, we do see a reasonable rate of relapse thereafterwards. And, you know, some would argue that carrying on osimertinib after three years might mitigate that risk of relapse.

We don't know because we haven't got that data.

Others would say, well, look, if you relapse with a small, little, tiny little nodule somewhere else in the lung, well, it's stage four, you're gonna get osimertinib anyway because it's stage four. So actually, is that necessarily a big deal? I mean, I think conceptually relapse is always difficult. So, you know, should we do it?

I think there's a nuanced approach to that. It is a data free zone. I certainly wouldn't say it's carte blanche who should be doing it for everyone.

The problem is we don't know the benefit of what we're achieving because it's not like we've got a lump that we're seeing get smaller and goes away.

You're starting off with a patient without any cancer on board, on a scan, you're giving them a tablet and then conceptually having to make a decision whether you stop or not. You can't measure anything to know the magnitude of the benefit that you've achieved in that patient.

So it becomes difficult to say, well, look, I've tracked this particular marker or lump and it's, it's gone. And then now, you know, you're safe to discontinue because we've got no metrics on that. The other issues about tolerability.

I mean, in general, if you've tolerated it fine up to three years, it's unlikely you're going to run into more problems. But, you know, osteomythem is not the most toxic drug we have in our armamentarium, but it's certainly not without its problems either.

You know, skin problems, drying of the mucosal membranes, problems with the scalp, problems with the eyes, problems with the nails, problems with mouth ulcers. You know, these all minor things, but minor things over a long period of time can really drag people down. Right.

So I think there's some nuanced decision making to be made there.

I suspect we'll get to a position over the next few years where we will have extended therapy, but we need to generate that data to have confidence that that is the right way forward.

Yeah.

And I think from thinking about it from the patient's point of view, it's about being reassured by your oncologist that when you stop treatment, what the plan is going to be to look after.

Yeah, totally, totally. I mean, I do think you need to keep an eye on the patient. You can't just stop the drug and then, you know, goodbye. Tell me if there's a problem.

You know, you do need to have some scans because we know that in high risk patients there is a, there is a risk of relapse. The contra coral is actually in low risk patients. So stage 1B, there's a very good chance of cure anyway.

And remember I said that over treating some patients who have been cured anyway.

So, you know, for a low risk patient, I'm very comfortable at stopping at three years because I'm probably over treating a group of those patients anyway. So, you know, there's a lot of nuanced decision making to be had in that, which is very much dependent on the individual patient circumstances.

Brilliant, thank you. And I hope that that provides some reassurance to patients that are about to come to that decision with their oncology team.

So with regards to the treatment of landscape for EGFR positive lung cancer, are there two first line treatment options for people newly diagnosed or is ozimertib the only licensed drug on the NHS at present?

Yes.

I think, Rachel, you're talking about stage four disease rather than early lung cancer, because in the metastatic or stage four disease, we actually have now at least three different options. We've got the first generation and second generation EGFR inhibitors, which we tend not to use these days.

They're on the NICE guidelines, but, you know, they've been Overtaken by the third generation EGFR inhibitors, Osimertinib specifically.

And with stage four disease, there's an ongoing question, you know, should you be receiving just osimertinib by itself or what we call intensification treatment? And that means more than than ATKI or more than osimertinib?

And our two new options that the NHS has funded are osimertinib with chemotherapy and Lazertinib, which is another version of osimertinib, different manufacturer, same thing, plus a biological agent called amivantamab. So you're not just having a tablet, you're having tab.

So the three options are essentially tablet alone, tablet plus chemo or tablet plus biological agent. And whenever you're adding in agents, you're adding in side effects.

But we know that when we add in chemo and we add in the biological agent, we are pushing out the time that the cancer is under control. That's something we call progression free survival.

But also what's really important is we're pushing out overall survival, we're making patients live longer.

So the question is, for the individual patient you've got in front of you, you is a tablet by itself followed by chemotherapy and other biological agents, the right way forward or should you just front load everything?

Because we know that front loading thing seems to be associated with improved survival, but definitely is improved, with more side effects and more hospital visits and less ability just to live a relatively normal life. So that's the discussion that we have to have with our patients.

Yeah, and this was one of the topics at the recent BTOL conference that seemed to be pertinent in a lot of the presentations was discussing this very thing.

One of the things that I was thinking about is if you front load a patient with the, with osimertem and chemo, for instance, when that patient relapses, what you do then? Yeah, it's a good question that there's new treatment come by then, because it may be several years down the line.

Yeah, it's a good question.

I mean, so generally, if you look at the data, the majority, a reasonable proportion of those patients were getting some form of similar chemotherapy again.

Right.

And many of those patients didn't have chemotherapy for the entire duration. They had to stop because of side effects or other issues.

So a lot of the time, patients who have chemotherapy and osteoarthritum upfront will likely be re challenged with chemotherapy again moving forward.

But you're right, you know, it is a question that we have to ask is about the utility of chemotherapy in that situation, it seems to be active because at the end of the day it's resulted in survival gain.

And you're right, there are other new treatments coming online and we'll have to see how these all pan out and whether healthcare systems can fund them and what the magnitude of benefit they're actually giving us.

Okay, brilliant. Moving on to stage four EGFR questions, one of the questions has been what is the future for local consolidated treatment for stage four?

Or we're aware that some are having surgery or radiotherapy, for example, is this hospital or trust dependent? Is this something that is advised by the guidelines?

So it's been an area of controversy for some time because essentially if you have a patient with quite widespread metastatic disease or even small volume metastatic disease, and then their tumour shrinks down very nicely, you could make an argument that, you know, taking out the residuum that you can see might change the natural history of what would happen to that patient.

And there have been several trials without a randomized comparator, but several trials where patients with EGFR mutant disease have received radiotherapy to consolidate their treatment.

That's culminated in a moderately sized randomized trial trial that was presented at the European meeting ESMO meeting last year called the North Star trial, which took patients with common mutant lung EGFR mutant lung cancer and randomly allocated them to either the standard, which is just osimertinib by itself, or osimertinib with local consolidation treatment, which is a combination of radiotherapy and oral surgery. And what it showed is in the general population, it did push out the time to relapse.

Of course, you have the side effects of all of that to deal with, right? So that's one of the things that you need to bear. But the other thing that you need to bear in mind is who are the right patients to do this on?

And actually what it showed is the more of the disease that you had at baseline that you can actually consolidate, the better the outcome.

So if you had widespread disease at baseline and all you're doing is consolidating a small amount that you can see now, then actually that's not really giving you that much benefit. And the less sites of metastatic involvement that you had at baseline, I. E. You can then consolidate them.

Those are the ones that are deriving the greatest benefit. And we certainly don't know whether it's making patients live longer.

Right.

And we don't know whether it's impacting on their quality of life.

And that's really important.

So, you know, this is one of the commonest questions I get asked is, why aren't I having my lung taken out? Or why aren't we having, you know, the residual taken out? Which in some patients makes absolute sense. Right.

Because they don't have that much cancer on board in the first place. You're taking out pretty much everything you could see that could start off with recognizing we're not curing patients.

This is all about pushing back the time.

And so then you have to balance about are they fit for these procedures, what sort of side effects Are we going to have to pause the osimertinib during radiotherapy? And if you do, for how long, is that going to mean that you have an increased risk of brain relapse? These are things that we have to think about.

And many patients that ask this question just, I would perhaps postulate, aren't necessarily the best candidates for it because of the extent of widespread disease they had at the baseline. Not convinced that it's going to meaningfully change the natural history of what we see in their. In their paradigm.

So this is an area of ongoing work on, ongoing discussion and ongoing research. I'm sure it will. It will change. Your question was, is this implemented? Well, it can be, in part.

Radiotherapy is actually funded different, differently, depending on the type of radiotherapy that you're doing. And this is very much an NHS specific issue.

So NHS in England has limitations on whom stereotactic radiotherapy or SBRT or sabre or cyberknife, these are all words for the same thing in whom the NHS will fund that on. There's quite tight regulations on that. Surgery doesn't have as much limitations.

So, you know, who gets it depends on patient selection, fitness, is it the right thing for them? Is it funded within the health system that they're in? All those things need to be thought about. So it's quite a complex decision.

Yeah. And I think that's why it's so important that we have specialist lung MDTs, multidisciplinary teams.

That's where the group of experts sits in a room and discusses each patient's case, because then all of these things can be taken into account.

And I think the other thing to point out is the decision is an oncological decision, which is fundamentally driven by the burden of disease at baseline that the patient had. You know, often, you know, people will say, well, look, this is what I've got now. You know, why don't you cut it out?

It's not really a surgical decision. I Mean, surgeons, sure, they can cut stuff out, but actually, is that the right thing for the patient? Right, that's an oncological decision.

You have to understand the trajectory and the nature of your, of your disease that you have.

And that's in part, you know, very much why an oncologist is central to all of that, because they can understand where you've come from and where you're going and what the other treatment options are in the future, what the natural history of your disease is going to be like, as well as the baseline burden of disease.

Yeah, thank you very much, that's great. So just in the interest of time, I'm going to jump forward to talking about trials, new drugs and vaccines.

So one of the questions, and this is a really important question, how can patients stay up to date on which trials are available and to whom? Because I know from thinking about our mesothelioma patients, they are often asking what trials are coming up? Are there any trials coming up?

And they're a very engaged community, as are the lung cancer community.

So, you know, where would they, where would be a good place for them to go and keep an eye so that the trials that they're looking at are actually evidence based and, you know, going to be of worth.

Yeah, it's not easy is the short answer. Even for professionals, it's not easy. And the reason? Well, there are databases you can look at.

I mean the commonest one that we as professionals look at, I see no reason why patients can't look at it either is ClinicalTrials.gov It's a website, it's a US funded global database of clinical trials.

And you can put in your disease nsclc, you can, you can put in other terms EGFR and you can put location, you can put right UK and then you click on it and it will give you a list of all trials for EGFR mutant non small cell lung cancer which are ongoing in the uk. The problem is that whether those trials are really active or not, because trials can sometimes close, the website may not have been updated.

They can sometimes open. The website may not have been updated.

Many trials are what we call phase one trials where they're evaluating different groups of patients and the trial can sometimes, well, we've treated x many number of patients, we don't need that to know any more information. So that arm closes, another arm will open up. So whether that's relevant or not is an issue.

We actually do have a UK website which does a very similar thing. It's called bepartofresearch.nihr.ac.uk I'll make sure we give you the link for.

Yes, please.

And that's the UK NIHR website database for all trials going on in the uk. So the NIHR is the UK division of the Department of Health that funds the research and the research infrastructure.

So they have a database of trials and again, you can put in the terms like nsclc, EGFR and click and it will. Or give you a list of trials. It's a bit clunky, but, you know, it's not bad.

And again, the problem with all of these databases is that they are not necessarily up to date. There are a number of companies that you could register with that will look on your behalf for trials and reach out to centers directly.

But, you know, the best thing is just try and ask your oncologist what's going on and have that ongoing dialogue. Right. You know, know, in the future I might need this. What's happening in this space? And they can ask. Right.

You know, because oncologists speak to each other.

Yeah.

And, you know, we're always asking each other, you know, have you got something in this space? What's going on in this space? So there's always active dialogue. It's a dynamic area.

Yeah. And I think also it's important to remember our patient advocacy groups as well. Oh, yeah, very much of UK and.

And the ALK patient advocacy group, because they often will be engaged.

Yeah, and that's a really good point. So. So the patient advocacy groups have got a very good handle on what's going on because they know from their members what's going on.

They may have directly liaised with some of the investigators about what's going on. And certainly Meso UK do a fantastic job of this in the MESO space.

Yeah, brilliant. Thank you. So, thinking about lung cancer vaccines, I know vaccines are often talked about in cancer.

What's your view on the potential of lung cancer vaccines? Do you see them as more promising in the adjuvant setting after surgery?

Could they be realistically effective in patients with established or advanced disease?

And the person is asking, why can't it be trialed on EGFR patients with low PD L1 to see if it improves the immunity or the own body's responses and possibly PD L1 reading?

So cancer vaccines are really important and they're, I think, going to be a major new advance that we have moving forward. And there are different types of vaccines, so there are what we call MRNA vaccines, like Covid vaccines.

Where effectively you're taking a vaccine and what's coming through are what are called personalized vaccines. So these are taking a sample of the patient's tumor and generating a vaccine against that individual's tumor. Wow.

And these trials are ongoing globally at the moment.

In fact, there's been a very nice trial of this technology in melanoma of a Moderna vaccine called V940 and, and that demonstrated, it's a very small study, but it did demonstrate some benefit. And that is being rolled out further in lung cancer as well.

We have in the UK a trial called lungvax, using a DNA vaccine which is going to be trying to immunize patients after surgery. And I think really where these vaccines are probably going to have a major role is going to be after surgery.

But I can see, I can see a world where we do it to fit healthy people to prevent lung cancer as well. I mean, for example, hpv, we give HPV vaccines to prevent head and neck cancer because we know HPV causes head and neck cancer. Right.

So, you know, you can see a world where that would be the case for the healthy individual, you know, visiting their primary care physician or gp. We're not anywhere near that, but we are trialing these in the post operative setting.

I'm not so convinced that with the burden of metastatic disease that we have, that they are really going to make that much difference in widespread metastatic disease, because you're dealing with a variety of different tumors of different immunogenic potential. So the immune system has a lot to take on in that setting, whereas the tumor is a bit more simple in an early operable setting.

Your patient question was about the EGFR mutant population and about PD L1.

So one of the problems that we have with a lot of what we call oncogene addicted lung cancer, such as ALKs, ROS, Rett or EGFR, is that the biology of these tumors are quite silent, so they're not very immunogenic. And what it means is that stimulating the immune system is really hard in that group of patients for a variety of biological risks reasons.

And so immunotherapy doesn't play a major role in the treatment of those patients.

In patients without those genetic alterations, we look at the PD L1 status and the higher the PD L1 status, the greater the benefit from immunotherapy. But actually it's a poor biomarker. I've got loads of people who've done fantastically well on immunotherapy as PDL1. Negative and vice versa.

PDO 100% who've done terribly. So it's not very tight BioMarker.

And in EGFR mutant lung cancer, you can generally ignore it because the PD L1 level does not predict the benefit from immunotherapy.

Right.

So in general, the immune modulation has still got a long way to go in EGFR mutant lung cancer, which is why these patients aren't really the target of trying to figure out whether your vaccine works or not, because you're not testing it on the right group of patients.

Right.

You want to test it on other patients where it's likely to work. And then when you can prove it, then you can try and figure out how you can make it work in other patients where it's unlikely to work.

Okay, lovely. Thank you.

And then one of the questions that comes up quite frequently, especially with patients being younger now, is about when they go through menopause.

So are there any advice, Is there any advice or studies into the use of hrt, for example, with EGFR positive lung cancer for perimenopausal or menopausal patients? And I think what they want to know is, are there any different or higher risks in using HRT if you're on things, drugs such as ozimertinib?

Yeah.

So she was asking about that.

Yeah. So that, you know, the concern is always, I've got lung cancer and I'm having my menopause. Is it safe for me to have hrt?

You know, that's, that's, that's, that's the key issue. Right.

And, you know, the, the, the, the data is not great and the data is quite conflicting, but in general, we don't think that EGFR mutant lung cancer, or most lung cancers in general, to be honest with you, are hormonally driven.

Right.

There is some theoretical risks in petri dishes, but really we've never seen any meaningful risk. And certainly the data on outcomes in patients with HRT haven't picked up any big signals of risk for lung cancer.

So I'm very relaxed about lung cancer patients in general having hrt. I think the benefits of HRT are quite significant, and of course, that needs to be discussed at the individual level between the patient and the gp.

But I don't think the lung cancer per se is a particular, you know, issue where you'd say, no, lung cancer, you cannot have hrt, unlike breast cancer, where there are, you know, there are issues with that. So I think, I think we're okay.

Brilliant. Thank you. So we're going to go on to ask about some of the mesothelioma questions that have been sent in.

Now, one of the questions that I get asked a lot as a nurse is why do some people get asbestosis and others go on with the same sort of exposure to asbestos and they get mesothelioma?

So we don't really know is the answer.

But the important thing is that just because you've had exposure to asbestos, you ain't necessarily going to get asbestosis and you ain't necessarily going to get mesothelioma. Of course there's an increased risk, but that may not pan out in your lifetime time, which is actually quite a good news story in some ways. Right.

So the risk of developing mesothelioma after asbestos usage is. Is quite complex because it depends on the dosage that you've inhaled.

Right, right.

You know, inhaling a lot over a long period of time is going to be at much higher risk compared to, you know, minor exposure. And the type of asbestos that you've been exposed to is also important. You know, blue and brown.

Brown asbestos is of much increased risk compared to white asbestos, but white asbestos is still carcinogenic, still causes mesothelioma. We shouldn't forget that. You know, we see that if you.

If you look at studies of patients that have had asbestos exposure, you know, Perhaps only about 10 to 20% of those patients are getting mesothelioma in their lifetime.

So there's a lot of other factors that come into play, such as how long you've had asbestos exposure, dose, type of asbestos, and the lag period as well. It can take 20, 30, 40 years from exposure to developing mesothelioma.

So that may not be relevant if your exposure to asbestos is late on in your lifespan.

Okay, brilliant. Thank you.

Another thing that comes up quite regularly because with the emergence now we have immunotherapy for our mesothelioma patients, and some patients are actually getting through two years of treatment.

And a lot of patients get very anxious when their cancer's being controlled, particularly as mesothelioma has such a poor prognosis and the outlook's usually very bleak.

So when someone's had control of their cancer with the use of ipilumumab and nivolumab, and then they get to the end of two years and they're told, we're going to stop treatment now, that causes a lot of anxiety. And people have been saying, you know, what's the experience of people who have Got to the end of their two years, do they relapse straight away?

Have they got a, many of them have a period of, have control over their cancer? It just. In your past experience, what would you know?

Well, we've got data on this now, so we published the five year outcomes from the CheckMate743 trial in the American journal Journal of Clinical Oncology recently. So we know exactly what happens to those patients.

And essentially, if you got to year two and you're alive and cancer free, you've got a pretty good chance to get to year five and be alive at cancer for a free. Wow.

And actually, you know, biologically, this is the same issue that we see in nearly every cancer because nearly in every cancer we stop at year two and we see exactly the same sort of thing.

If you're, if you're alive and cancer free at year two, then you've got a reasonable chance of, of getting to year five and being alive and cancer free. Now it's not a guarantee, but it's, it's, it's a good news story.

I think you've got to remember that in mesothelioma we're giving two immune agents, right. Nivolumab and ipilimumab. Ipilumab, you know, causes a lot of difficult side effects.

And in most cancers we're not giving as much ipilumumab as we are in mesothelioma. In melanoma you might have three or four doses and that's it for your whole lifetime. Right. You don't need that much to activate the immune system.

And in many other cancers you just need a limited course. Right. So there's eight. It depends on the schedule. For various reasons, we've ended up with this schedule in mesothelioma.

The other thing is, remember, the drugs aren't treating the cancer, it's the patient that's treating the cancer.

Right.

What the drugs are doing is changing the patient's immune system and it's the patient's immune cells, that patient's T cells, which are than treating the cancer. So once the immune system's activated, do you really need to keep flogging it with the drug? Right.

Once you've got the cruise control on, do you really need to press the accelerator?

Yeah.

Do you take my point?

Absolutely.

So we've got lots of data now starting to emerge in many other cancers that, you know, we don't have head to head data. Right. But indirect data suggests that, that maybe you don't need to carry on treating after Two years.

In fact some of the data we're starting to generate in lung cancer says that actually treatment every three weeks or six weeks that we're doing is probably too much. Right. After an induction period you probably don't need that frequent dosing, you can get less frequent dosing.

So this is an area of ongoing interest.

I'm quite relaxed on about stopping at two years, very relaxed about stopping at two years, especially ipilimumab because the risks I think of carrying on ipilumimab are quite significant. The immune related problems that we see with IPI are quite, quite difficult and we see very good, very good cancer free rates after two years.

Of course this is an individual discussion to have between patients and their oncologists because there are nuances is into all of this but in general I don't sort of, I'm not sitting there knocking on number 10 saying why aren't we carrying on after two years? Because actually if you think about the biology, mechanism of action, the data that we have, we're in a very good place after two years.

And it's interesting what you said there about the melanoma patients having three lots of the ipiluminab.

When we see such quite terrible in some cases side effects for our meso patients and, and often patients don't realise that they can just have the nivolumab

as it's absolutely fine if you've run into problems to stop the ipilumumab and if your oncologist thinks it's safe to do so just to have the nivolumab that's a reasonable, reasonable strategy.

So it may be worth if patients are struggling to have that conversation with their oncologist about just continuing on.

Yeah, I mean of course it depends on the, on the seriousness of the immune problem that they had. Right. And that's where the individual decision making.

Yes, absolutely Perfect. Lovely.

So another thing that's come up and I know that we're waiting for the Systems 2 trial, I think it is where we're going to be looking at patients, biopsies in more detail to look for genetic problems. What do you feel about genetic testing for patients with mesothelioma?

So when we talk about genetic testing for mesothelioma patients, we're talking about two different things. We're talking about genetic testing of their cancer or genetic testing of them.

I think mostly genetic testing of the cancer to see if a spec, like with lung cancer where we test for EGFR et cetera, is there.

So there's a lot going on in that. That space. We understand the biology of mesothelioma far better now than we ever did.

We know that a reasonable proportion of patients have something called MTAP loss or CDKN2A loss. A sizable number of patients have loss or mutations in a gene called BAP1.

And a proportion of patients have mutations or loss of fibroids function of a gene called NF2. And those three things are potentially useful to think about for drug therapy selection.

So we are already, and we will be continuing to evaluate a class of drugs called PRMT5 inhibitors in patients with mesothelioma with a particular abnormality called MTAP loss, which you can detect by genetic testing or also just staining or immunohistochemistry of the mesothelioma tumour. If tumours have got something called MTAP loss and or we call it CDKN2 a loss as well, it causes upregulation of something called PRMT5. And if you.

And there are now drugs which switch off PRMT 5, they're looking quite encouraging in non mesothelioma cancers like lung cancer.

Right.

And we're in the first infancy of these drugs, right?

These are generation one drugs, so these are coming through with newer, more potent versions and we want to evaluate how they work in mesothelioma because it's a very strong biological rationale that they would work in mtap lost mesothelioma. So these trials will be coming online.

We also have a class of agents which we initially thought might only be active in NF2 loss mesothelioma, but actually they seem to be active in a small proportion of all mesos regardless of NF2. And these are called tied inhibitors, TEAD inhibitors.

What we see is that patients with NF2 mutations or NF2 loss upregulate something in the mesothelioma cells called YAP HIPPO pathway. And if we give something called a TEED inhibitor, it switches off that pathway.

Right?

These are phase one studies and other studies of these agents. How active? We've got some data.

Some of the earlier TEED inhibitors are modestly active, but some patients within that who derive benefit, derive durable benefit, which is really, really interesting. So this, I think, is very exciting and we're going to get more data on over the course of the next few years.

And wouldn't surprise me if we end up incorporating these into traditional care, probably in combination with immunotherapy at some stage over the course of the next five, ten years or so.

Brilliant.

And as our time draws to a close, Professor Popper, I'd just like to say, thinking about both lung cancer and mesothelioma, what is on the horizon that you find most exciting about what's coming in? Treatments, et cetera?

Wow. There's so much going on. It's never been a more exciting time to be an oncologist because we've got massive advances in science.

We're understanding the biology of these diseases better.

We've got new advances in medicinal chemistry, which means we've got new classes of drugs coming through which allow us to drug both lung cancer, egfr, mutant lung cancer, and meso in different ways we never thought possible as well. And we've got great advances coming through in liquid biopsies as well, helping us select our patients better as well.

So, listen, things are never going to be static. They're going to change. We're going to have evolution, we're going to have innovation, and, you know, the future is definitely bright.

Thank you. Thank you very much.

And I think having gone to conferences such as World Lung and btog, it is amazing to see that real buzz in these conferences that we're really fighting to understand these cancers better and to form treatments for them.

So it's encouraging to know that that behind the scenes, there's all this activity going on which will hopefully change our global practice of lung cancer and mesothelioma. So I'd just like to say thank you very much, Professor Papat, for coming and being our inaugurous Ask the Expert.

So thank you for your time in coming. I always like to try and end our podcast with a thought for the podcast and my closing comments for this podcast is that.

And as people, we can't calm the storm, so let's stop trying. But what we can do is calm ourselves because inevitably the storm will pass. So thank you once again for joining us.

Our next podcast will be looking at side effects of treatment and the impact that our people living with both mesothelioma and lung cancer have had from treatment. We hope you'll join us for that.

Please do remember that you can email in to breathestrongassag.co.uk if you have any questions for us or if you'd like to share your own experiences with us. So thank you very much and I hope to see you next time.

Sam.