Sabrina Serani: Welcome back to this special minisode of Treating Together. I'm your host for today, Sabrina Sorani, and I'm really glad you're here for this one. We sat down with Dr. Joshua Reuss, a thoracic oncologist at Georgetown University, to discuss updates to the Asco guidelines in stage for driver mutation negative non-small cell lung cancer. Dr. Reuss is actually coauthor of this round of updates. So we are very lucky to hear about these updates right from the source. In this episode, Dr. Reuss walks us through what's changed in these updates, what they mean in practice providers, I think you'll really find this conversation genuinely useful and interesting. If you'd like to find the full guidelines updates, it will be linked in our show notes so that you can take a look at those. But without further ado, let's get into the episode. Serani: Let's actually start out a little bit about you and your background and maybe what brought you to, this place? Joshua Reuss, MD: I'm a thoracic medical oncologist at Georgetown. I graduated fellowship right in the throes of COVID from Johns Hopkins in 2020 and then took this job at Georgetown. I've been here since. So, been here about five and a half years now, which is crazy. I've always been involved with ASCO. You know took a real interest in the guideline development. I think it's interesting how you know data is assimilated and compiled and how you kind of take in all this data and try to spit out like a clean, concise recommendation. for folks to follow, which obviously is, can be quite challenging at times. And so, I joined the ASCO Living Guidelines Committee. I think it was about two years ago now. something in that ballpark. It all blends together at this point. But before last year, was, extended the offer to join as co-chair, which I was very honored and privileged to do to, to accept. And, I've served in that role now for the past year. And, yeah, it's definitely, it's busy. It's, it's demanding, but it also is good because it helps to keep me a little bit more on the ball of, what's the new data, how do we interpret it and how do we think of it? Not just through the lens of one's personal practice, but through kind of a more widespread guideline level recommendation. Serani: So what prompted this particular round of updates? Was it kind of like it's time to do this, or was there a notable swath of data that wasn't accounted for in the guidelines yet? Reuss: Well, I guess all of the above in a way. Periodically we do a full guideline update, which is kind of regardless of the extent of like recent burst of data. So like we were due for this full guideline update, regardless of kind of where we were at with new approvals, new data. I think there were some differences in kind of the quantity and expanse of new data that was, for example, published in this guideline versus the driver positive guideline, which, saw really an explosion up at the last minute of new data, new approvals that made for kind of scrambling and how we how we adjust the guideline for that. so it's a little bit of both. We definitely want to give folks an update on where we stand with the data, but we also want to review our current recommendations. Where do we stand on those? If there's been small update level data that's been filtering in over the past year, we want to summarize that. So maybe it doesn't, you know, meet the criteria for like a change in level recommendation or it's something that we didn't highlight in a mini update, but something we want to put together as a more comprehensive update recommendation. Serani: Are there any really notable updates that have really differed from past practice? Reuss: would say a notable challenge of the driver negative guideline. So there's two main guidelines, right. For the stage for non-small cell living guidelines. One is the driver positive guideline or with driver mutations those activating genomic alterations gene mutations fusions for which we typically have targeted therapies as a frontline treatment. And then we have the driver mutation negative guideline where, this is basically everybody else. that's where, you know, typically immunotherapy based, plus or minus chemo. so it's made challenging though, because there are multiple regimens that one can utilize. And not only that, the guideline is kind of broken up. I wouldn't say artificially, but, but into several distinct sections. The first is non-squamous. So adenocarcinoma versus squamous cell carcinoma. And from there we break it down into three PD-L1 kind of tertiles. I would say a high level of expression. So greater than or equal to fifty percent, a low level of expression, one to forty nine percent, and then a negative percentage, which is less than one percent. So if you do the math, that leads to six unique subsets, for which we provide guideline updates where we try to, put in data from these trials, many of which were not designed to just look at that one subset, right? So you're looking at subset level data, subcohort level data and trying to make a recommendation, which can be challenging because obviously the confounder, you know, it's hard to interpret these subsets. But you know, I'd say one facet of the update is we were looking at kind of some of the long term data from some of these more seminal studies to say, all right, what's the durability of these regimens? Are they kind of holding out in terms of their durable efficacy over our previous standard chemotherapy? In some cases, we're seeing that and others the durability is less clear. And I think that while overall the frontline level guidelines didn't see major changes, I would say a more notable one where I think there's some inconsistency on what regimen might be best is the PD-L1 negative squamous population, where the committee didn't necessarily feel that one regimen clearly stood above the others. but any time one is deciding on a frontline treatment, it's challenging because there are a lot of options. And I think at the end of the day, it's important to look at subset level data, but it's also important to look at the patient sitting in front of you. We actually have a whole section, patient physician kind of what our key thinking points one should be considering when making a decision. You know, what are some talking points with patients? Because obviously there are patient specific factors, whether it's comorbidities, time in the treatment chair. Toxicities that could develop, that can help to inform this decision. there are still there's data that we're looking to come out in the future that can hopefully further inform decision making. There's a phase three study called the INSIGNA study that is hopefully going to say, well, in those with PD-L1 expression and high expression, do we need the chemo? there is some molecular subsets, particularly in mutations like STK11 and KEAP1, which we think are associated with immunotherapy resistance, where we're asking questions of, do we need to adjust the immunotherapy regimen? Do we need to incorporate a molecule called CTLA-4, for which there's retrospective data from some of the checkmate studies and the Poseidon study that suggests that might be beneficial. But adding in these therapies are not without more toxicity. So, it's definitely a challenging guideline to say, we'll never say this is the one regimen you should give up. But what we want to do is provide the information so that clinicians can look at this, put it in the context of the patient sitting in front of them to make an informed decision. but there are a couple things that are new in this guideline that I think are worthy of highlighting. Number one is we put at the top of this guideline the importance of molecular testing, which we hope that, you know, anyone taking care of a non-small cell lung cancer patient knows. And this is something that had previously been at the top, you know, top level of the guideline for the driver positive non-small cell guideline. You know, it's kind of easy to infer. All right. Well, if you find a driver mutation, then you know that takes you down that path. But the absence of a driver mutation is obviously just as significant. And it's important to wait for that mutation testing results before starting down the path for treatment. We know there's data that that even leads to better survival if you give a patient directed treatment. So we felt that it was necessary to make that kind of the top level, first point that people see in both guidelines because it is so important in, you know, informing treatment, decision making. while if you get in a bind and you say, hey, I can't wait, you know, you can always start chemo, you can always give a round of chemo to try to buy patients time while you're waiting for these results. But before you start down, particularly in immunotherapy based treatment, you really want that molecular data in hand. Because if you start immunotherapy based treatment and then you find one of these driver mutations, we know there's a bulk of data from a lot of kind of different targeted therapies that you could run into significant issues with toxicity. So you really don't want to shoot yourself in the foot from, you know, an efficacy tolerability safety standpoint. I would say the other place where we've seen some new therapies enter the realm has been in the subsequent line space. So antibody drug conjugates are a class of therapeutic that I think are getting very hot right now. And we're starting to see them enter the recommendation, the approved, guidelines, for non-small cell lung cancer. Probably the most notable one is trastuzumab deruxtecan or the trade name Enhertu, which is a HER2 targeted antibody drug conjugate that's approved in the subsequent line for Her2 mutated non-small cell lung cancer and also approved for patients with Her2 overexpressing non-small cell lung cancer, which can happen both in your traditional driver positive and driver negative. That's already been in the guideline, but there's a second molecule called telisotuzumab vedotin, Teliso-V. And so that is actually a met targeted antibody drug conjugate. And so it is now carries an approval for patients who have a high level of met overexpression on the surface of the cancer cells defined by three plus overexpression and greater than or equal to fifty percent of tumor cells. So there's data to suggest benefit in that population. It is an accelerated approval. based off of single arm data. So we definitely are awaiting a larger phase three randomized study to confirm that, but that now is an option that we have. And again, what we view as a traditionally driver negative population. That's why it's placed in the driver negative guideline. but again, I think it further reinforces the need for mutation testing and molecular testing because these are while this is not a classic again, driver mutation, it does require additional testing looking for protein levels of of that molecule of met on the surface of the cancer to inform treatment decision making. Serani: in this patient population stage four lung cancer. What do you see as the big questions that we still need answers for, we need stronger research in? I know that's a weighty question. Reuss: Quite a question. particularly in this driver negative population. Well, for one, I think we need more data on which regimen is is right for which patient. Right. We have all these I mean any one of these subsets, we list like five six regimens at times. And so I think it can be very overwhelming to say, well, which regimen is right for my one patient? And I think right now the short answer is we don't know. a lot of what we're doing to kind of tease out particular regimens come from subset data, whether that's on concurrent mutations like Stk11, Keap1, or other patient specific factors, PD-L1 levels. And I think we need more prospective data to say, all right, in what populations is that that elevated risk of toxicity worth the potential benefit? Um, we know there was a phase three study out of Japan that probably didn't get a lot of attention here. It's been published now called the NIPPON study, which actually compared nivolumab plus ipilimumab plus chemotherapy versus pembrolizumab plus chemotherapy. And in an unselected population of driver mutation negative non-small cell lung cancer. It was actually a negative study that was stopped early. the added combination immunotherapy did, led to increased toxicity, which is why the study stopped and there was really no clear signal of of enhanced benefit. Now that doesn't mean there's a subset that would warrant that additional, combination immune checkpoint blockade, particularly in those unique molecular subsets. But I think we need more prospective data to say, all right, in whom you know, is that, um, is that going to help? I think the same goes for just the addition of chemotherapy. Now, I think there's also a lot of interesting molecules on the horizon. I mentioned the antibody drug conjugate, these quote unquote smart chemos where you're trying to kind of deliver the chemo more effectively and I guess more eloquently to target to the cancer cell. There's another class of molecules called bispecific antibodies, which look to basically do a two for one and they're targeting, one molecule, but targeting two things. there's particularly data on a on a medicine called ivoncescimab which targets both PD-1 and VEGF. And what's intriguing is that the data for this molecule looks better than the PD-1 molecule by itself or pembrolizumab and intriguingly just just seems to be doing better than, than, than if you gave these two medications kind of together by themselves. So I think the science behind why that is, I think we need to flesh out more, but I think there's potential changes in standard practice in the future if kind of the data we're seeing come out of China, continues to hold water in a more global population. Serani: That does it for our episode today. Thank you so much for tuning in with us. If you want to stay on top of the latest updates in oncology, you can check us out at targetedon.com or follow us on socials at targetedonc. Thanks again for listening and we'll see you next time.