Alright, well thank you, Hass. Um, thank you all for having me. It's really, um, great to be here. I, I will certainly leave some issues unresolved as I don't think there's a sort of clear answer to the topic that I've been, um, that I've been tasked to discuss, which is the frontline treatment of metastatic EGFR mutant non-small cell lung cancer. So certainly if there are issues they leave unresolved, please feel free to find me afterwards and inform me of that. Um, but we'll start off, uh, with our, our topic. So these are my disclosures. So rather than just sort of go through the data for, you know, Flora 2 and Mariposa and, and kind of leave you with a lot of questions, I sort of tried to think about how can we really structure our thinking around EGFR mutant lung cancer as we review these data and think about our patients in the clinic and what I sort of. Sort of coalesced around is that there's sort of I think a few key steps that we have to think through in order to make the best treatment decisions for our patients and I've tried to focus my talk around these steps. So I've kind of come up with a five step process to selecting the optimal frontline therapy for patients with EGFR mutant lung cancer. I think, you know, the first step and most important perhaps is identifying the correct EGFR mutation. I have chosen to focus on classical EGFR mutations for now because there's so much data and it's the majority of our patients, but of course you could have a whole separate talk on Exxon 20 insertions and atypical mutations. I think the second step is really to understand the pros and cons of each treatment options and the data for them. The third, which is arguably the most important, is really to understand your patient, you know, are they an appropriate candidate for combination therapy? Does combination therapy align with their goals and preferences and really trying to get at that? There's not data to show you here. I think it's more of a really a discussion with your patient, but it's probably the most critical point. Then you have to select the frontline therapy, and, um, I'll talk a little bit about sort of risk factors and how we think about, you know, selection of treatment. And then once you've selected your treatment, I think an equally important part, and we'll come back to this in a separate talk is managing the toxicities, monitoring these patients on these therapies because they can be on them for quite a long time and you really want to ensure that they have the best quality of life possible and then a sort of a bonus six step just hot off the press, I, I did add just a slide about. Sort of local consolidative therapy and whether we should be thinking about that for our patients, thinking about things like radiation or maybe more provocatively even surgery from based on the North Star data that was, um, presented at ESO just a few weeks ago. I think it's still not quite ready for prime time, but I thought it was worth, worth at least mentioning. So let's go through these in a little bit more detail. So step one is to identify the EGFR mutation. Hopefully this is old news to all of you, but just, uh, you know, as an important reminder, when we see EGFR in an NGS report, you can't stop reading after the four letters EGFR. You really have to know what type of mutation you're looking at. Um, you know, the majority of these are the classical EGFR mutations, which are the Exxon 19 deletions and the LA858R mutation. Sometimes the Exxon 19 deletions can be a little bit tricky to discern if it doesn't specifically say Exxon 19 deletion. And so I put the amino acid sort of numbers that correspond to each Exxon on these slides as a reference, but I found that the NGS companies are pretty good now about actually saying, OK, this is an Exxon 19 deletion, this is an Exxon 20 insertion. But we're gonna focus on that first group for the rest of this talk. But just briefly to say that if you see a patient with an atypical or uncommon EGFR mutation, these are the G719 mutations, S768I L861Q. These can go down a slightly different pathway. Afaib is the only approved therapy for these right now. We often use osamertinib. Sometimes we consider things like Flora too, but you know, they tend. Not to do as well as the classic mutations. And then the other important subgroup to be aware of are the Exxon 20 insertions, which really have a whole different treatment algorithm. Both of these last two categories are about 10% of all EGFR mutations in lung cancer. And so we used to think of these as very rare, but actually now I think as we're recognizing them and have treatment options, we find them not infrequently in our NGS reports and. I would say commonly we've maybe still have grown a little bit because we know that these options are not quite as good as the classical mutations, but it is really important because again these are all gonna have sort of different treatment options based on, you know, how, um, with the specific subtype of, of EGFR mutation. So for today I'm really gonna focus on the classical EGFR mutations and because we have all this rich data to review for these patients, but again, if you have patients about the questions about the other EGFR mutation subtypes, I'm happy to talk about them in the Q&A or afterwards. So I think the next step is to really understand the treatment options for these patients, and this is just an overview to say we really now have 3 main regimens that we are considering for a patient with newly diagnosed metastatic, uh, EGFR XN 19 deletion or L858R positive lung cancer. Our old standard of care was the flora regimen, ossuartinib monotherapy. In 2018, we saw the results of Flora, which very clearly showed that ossuertinib improved progression-free survival, led to improved overall survival, and improved safety compared to the first generation EGFR inhibitors. And with that, I would say things were fairly simple for a number of years, you know, there was really not much debate as to whether we should be using ossuertinib first. It quickly became the standard of care. You saw these patients, you said, great news, you have EGFR. You gave them an ossuertinib prescription. And things were pretty straightforward, but at the same time, you know, these patients were living 38.6 months. That was the median overall survival, and we knew that we could do better, um, and so we have now a few different combination strategies that were tested and shown to improve outcomes. So we have Flora too, and I'll go through these in more detail where. Platinum pemitrexate was added to ossuertinib as frontline therapy, and we saw improvements in both progression-free and overall survival, but of course, also detriments in terms of side effect profile and the frequency of visits and things like that. And then we have Mariposa where the bi-specific antibody targeting EGFR and met evanumab. Um, was added to a different 3rd generation EGFR inhibitor, lizarinib, and again we saw improvements in both progression free and now also overall survival, but once again detriments in terms of safety profile increased toxicities, and so really I think the question for today is how do we sort of pick between these options? And in order to do that, I did want to spend a few minutes going over the Flora 2 and Mariposa data in a little bit more detail just to sort of frame our discussion. So starting with Flora 2, this is the study design. I think you're all familiar with it. Relatively straightforward. These are newly diagnosed patients with classical EGFR mutations, and they were randomized 1 to 1 to the experimental arm, which is platinum, Pitrexate, um, with osciertinib. There was a 4. Cycles of platinum hemitrexate and then pemitrexate maintenance thereafter, or a control arm of osamertinib monotherapy. The primary end point here was progression-free survival by investigator assessment. And it was a large study, about 560 patients were randomized 1 to 1 to these two arms. These are the PFS primary endpoint in the overall survival data which are now mature, presented at World Lung earlier this year, and we can see that adding chemotherapy to Osamardib improves both PFS and overall survival. Um, I think in a clinically meaningful way, the median PFS of OC chemotherapy is about 25.5 months, and the median overall survival of the study reached about 47.5 months with OC chemotherapy. Um, so clearly showing you can see the landmarks here, the improvements in overall survival when you think about adding chemotherapy. I think an intriguing point to sort of keep in mind as you think about how we apply these data to our clinic is that when we look at the duration of treatment exposure, actually, you know, while this was a study of ossuartinib chemotherapy, most of these patients actually only ended up receiving chemotherapy for the initial portion of their treatment. Um, you know, the median exposure to pemitrexate, even in that maintenance phase was about 8 months. And so I think there is a lot of debate in our practice as to how we should apply this data, how we should think about the duration. Of chemotherapy up front, you know, I think in my own practice I still will tell you, I don't tell patients you'll be on it for 10 cycles or 10 months. I say, you know, you're gonna be on it as long as you're sort of tolerating it, as long as you're not having cumulative side effects, and as long as, you know, you're doing OK. But for many patients we will come to a point where we'll stop the chemo and, and just continue on osciertin and monotherapy, and I think we can feel reassured by the Flora2 data that that's an OK thing to do at some point on treatment. Um, so those are, you know, so now we can say Florida to improved PFS and improved overall survival with a magnitude of about 11 months of overall survival improvement. But as you can imagine, of course, it did add toxicities. I think all of us who've given Oamartin to monotherapy can say that it's very well tolerated. Patients, you know, tend to have relatively modest side effects. They can have some diarrhea, but it's mostly grade one. Some skin toxicities and paranychia. I don't want to downplay this too much because I've, you know, I've had, I sometimes give the example of a patient I had in Boston winter who came and said, I have paraychia in my toes. It's no big deal, but I can wear sandals all winter and it's totally fine. Which is not, you know, that's not a quality of life that we want for our patients in Boston winter and probably in Philadelphia winter either, but nevertheless, usually we can manage these. When you add chemotherapy to ossuertinib, you add, I think, the chemotherapy side effects as we might expect. We see more myelosuppression, and I will note and point out that if you look in particular at the rates of neutropenia and thrombocytopenia, they can be significant. You have about a 23% of grade 3 or 4 neutropenia when you add OC to chemotherapy. So something to be aware of and you know you really do have to monitor the counts closely. Similarly, about a 14% rate of grade 3 or 4 thrombocytopenia. But if we look at the sort of cadence of these, we can see, as you might predict, that that really the majority of these side effects peak within the 1st 3 months of treatment during the platinum exposure, and then they tend to get much better. And so these patients then tend to have really, I think more similar to what we're used to with osciertinib type of side effects in those later months of treatment. And again, recall that these patients are on treatment for 2 years. So in the grand scheme of things, I think that the intense side effects really cluster at the very beginning. Let's talk briefly about Mariposa. So this was actually a three-arm study, but we're really only gonna focus on the blue and gray arms here. So this was combining aivantumab, a bi-specific antibody targeting EGFR and met, with lasertinib, which is a different 3rd generation EGFR inhibitor. There was a control arm of osciertinib. There was also a separate control arm of lasertinib monotherapy, which was designed to kind of identify the contribution of each component, and the lasertinib arm performed very similarly to ossuertinib. So we won't sort of come back to that. Uh, the primary endpoint here was progression free survival once again in this case by blinded review, and one, important point to make is that there was no crossover to Avantumab in later lines of therapy. And as we'll hear about, you know, in the second line setting, avantumab is also an option, and I think that is something that's important to keep in mind as we look at the overall survival data from this study. These were the primary outcome of progression-free survival. Once again, we already know that it's, it's significantly improved. Median PFS is about 23.7 months with Amiantamablizertinib. And also actually um Mariposa was the first study to show mature overall survival data, and we saw that OS was improved. Um, these are the, the landmarks. The hazard ratio here was 0.75, and actually the median OS has not been reached in the, um, Evantamab lizard NBar. It's predicted to exceed one year of survival benefit, but we haven't seen those final numbers and certainly we can see, you know, a nice kind of continued separation of these curves over time. So again, Mariposa certainly improves PFS. It also improves overall survival, but it does add toxicities, and I would say it adds different toxicities than what we're seeing with flora too. So with the anti-EGFRN met antibody, as you might predict, we are seeing toxicities related to those sort of two pathways. So we see quite a bit of dermatologic toxicities, and we're gonna talk about. About the different ways that we have to manage those toxicities, but we do see rash, peronychia, dermatitis in the majority of these patients. We do see some diarrhea, but maybe not, not as much as we do the skin toxicities. Over time you can see cumulative hypoalbuminemia and edema with this regimen, and so that is something sort of akin to the, the MET inhibitors that you have to monitor for. And then an important kind of two other important points to be aware of. One, you've all know this, if you've ever given amavanumab, the infusion-related reactions, which are very common with the first infusion. The, the dosing is split over cycle one, day one and day two. Now we have the steroid prophylaxis, which does decrease that risk, but patients have to get weaker. Infusions for the 1st 4 weeks to sort of mitigate this, um, in the future this will be hopefully some a thing of the past because subcutaneous amivantumab, which is not yet approved but hopefully coming soon, does really essentially, you know, close to eliminate these infusion or we'll have to call them administration related reactions with the subcu formulation, um, and so therefore it also improves chair time and overall patient satisfaction. And we'll talk in the toxicity, um, section as well. Overall, though it doesn't improve all the other stuff like skin toxicities and others, so it only sort of addresses one issue. And then VTE, so clots were seen in nearly 40% of these patients and now derma uh sorry, anticoagulation prophylaxis is recommended for these patients. So a different but also notable safety profile for our patients. So as we think about these sort of three options osim monotherapy, Osi chemo, or Amivanamablazerib, I think the next and most important question is first to determine is a combination right for your patient? Is your patient a good candidate for a combination? And I think that comes down to sort of first the fitness factors. So is your patient's functional performance status good enough for a combination. Um, you know, is the, the patients sort of have the support they need, are they able to travel with Flora too? You're having to come every 3 weeks for treatment. With Mariposa initially it's weekly for the 1st 4 weeks and then every 2 weeks. And then I think another important point is we'll talk about sort of the prophylactic regimens in the, um, in the toxicity management section, but does your patient have the support. They need to comply with somewhat complicated prophylactic regimens, anticoagulation, antibiotics, topicals. Do they have the support they need for that? And then last, but maybe most commonly, does their organ function adequate for particularly chemotherapy for Pemitrexate? This comes up a lot with our older patients where their creatinine clearance maybe isn't quite good enough for Pemitrexate. And then the second is, do these goals, do the patients' goals align with a combination, you know, we can talk all the time about, yes, there's a survival benefit and these are better, but I have lots of patients who go through all of this data and, and talk, we talk through it and they say, I want a drug that will give me the best quality of life. I wanna come to clinic as little as possible. I wanna live my life and I think for those patients, if you have a kind of a shared decision making conversation and that aligns with their. Goals, Osamartin and monotherapy is still certainly a reasonable option for those patients and also for those patients who are sort of, um, maybe more frail and you're worried about a combination. You know, I think for most patients with the survival data, the combinations have become my standard of care. These are many of these are young and well patients, but I do think we have to acknowledge that Osamertin and monotherapy still remains a good option for our patients where we don't think a combination is appropriate. Now how do we select between these different regimens? This is where I think the um unresolved part of this comes in. I don't know that I can stand here and tell you you should always use Flora too or you should always use Mariposa. They each have their own pros and cons, you know, when we think about sort of risk factors and, and where we might think about sort of high risk disease, there's been a lot of work done on this. Um, here on the left I've shown you some, um, data that was just presented a few weeks ago by Doctor Yanni at ESMO looking at sort of high risk, um, prognostic factors and overall survival outcomes from the flora. Two study and you can see here and sorry from my perspective it's a little bit hard to read, but you can see some of the high risk features that we think about baseline CNS disease, baseline liver metastases, bone metastases. Each of these we know is a high risk factor and in each case, obviously adding chemotherapy improves outcomes compared to osimertinib. I think that's not surprising. Similarly, if we look at sort of tumor-based factors, the Exxon 19 deletions versus L858R, we know that L858R patients tend to do a little bit worse overall than Exxon 19. Um, I think we'll come back to this, but somewhat intriguingly, the presence of detectable baseline circulating tumor DNA has been shown to be sort of a high risk feature, and conversely, the lack of baseline CTDNA really does seem to pretend for good outcomes, and I'll come back to this. Because I think the data on the CTDNA negative patients actually looks quite good for Oy Martin and monotherapy still as well, but overall I think, you know, if we kind of take all of these, it's hard to find a patient in clinic who doesn't check off one or more of these boxes. And so all of our patients, I think, are high risk to a certain extent. For Mariposa, we haven't seen sort of the risk groups broken down for overall survival in as much detail, but once again you can see that, you know, overall pretty much everyone is benefiting from emeantamablizertinib, and so there's not a clear sort of group of patients where I would say we should definitely be using one or the other. Um, CNS metastases come up as a specific topic, you know, and, and I think there's good data for both combinations here. You know, the Flora 2, study did show some nice outcomes in the patients with baseline brain metastases, showing that in terms of progression-free survival, there was a particular benefit to those patients where chemotherapy was added, and I think that these waterfall plots are quite compelling. If we look at the intracranial responses in patients who got not just osciertinib, which we know is a highly CNS active therapy, but also chemotherapy, you can see that there's really quite a lot. A lot of deeper responses, more CRs, and so I have personally found that to be quite compelling for the Flora2 study for patients with baseline brain meths. Both of these regimens have shown improvements in intracranial PFS with the Mariposa regimen. There's this intriguing sort of later separation of these curves over time. I don't know that I can quite explain why that's happening quite yet, you know, we don't know if this is something related to sort of immune mediated effects or why this. Is happening, but again, for patients with baseline brain metastasis, I think a combination makes sense. And personally for me, knowing the CNS activity of Pemitrexate, that's usually been the regimen that I've sort of reached for still in close communication with our radiation oncologist as well because, you know, we don't often sort of jump to radiation up front unless patients are highly symptomatic, but we do want to monitor these patients very closely as they may need SRS along the way. Um, and then I think just I sort of alluded to this, but is there a group of patients where we might not need a combination? And I think this remains to be seen, but, but I do think we have pretty compelling data for those patients where there was no detectable baseline plasma CTDNA, you know, this is the overall survival curves from Flora too and small numbers of patients here, but you can really see that both groups do. Quite well and if you look at, you know, 3 year landmark survival, they're really quite good in both arms and so I think if you have a patient who has low disease burden and no baseline CTDNA, we do start to really wonder about whether those patients might do OK with ossuertinib monotherapy and I have started to sort of routinely look at that result as one of the factors in my decision making. Um, I think somewhat similarly the P53 wild type patients here detected on tissue NGS. Again, you can see that if you're P53 wild type, you do relatively well in both of these confidence intervals for the hazard ratios cross one. These are exploratory analysis in small numbers, but I think if you have a non-P53 mutated patient with low disease burden, no brain mets, and no detectable baseline CTDNA, which is a very small fraction of these patients, but there I think you might start to think about whether monotherapy is appropriate. Um, so this is a slide that I borrowed from Susie Scott who presented this at, um, at DC Long, but I really like this sort of framework. Essentially what we have to do now is sort of integrate all of these data points, take into account our patient factors, and then really try to make a shared decision as to which of these regimens is the best for each patient, and it's a long conversation with these patients. There's no easy answers here. Um, the last kind of two points, and I won't belabor this because we'll have a separate talk on this, but, you know, once you pick a regimen, you really have to monitor patients closely and ensure that you're really optimizing the toxicity management to help them have the best quality of life, and so we'll come back to that. And then in the last minute I just wanted to really highlight, you know, the potential future role of local consolidation therapy. This was an interesting abstract that was presented at ESMO a few weeks ago. I had the privilege of discussing it. This was a study, a randomized phase two study from MD Anderson where patients were on, uh, with advanced EGFR lung cancers, had induction of sertinib monotherapy, and then received local consolidative therapy to all sites of residual disease after a period of 6 to 12 weeks of induction of summartinib. Compared to those patients who just went on osciertinib alone, you can see the types of, um, the LCT here. The majority were radiation, but intriguingly, about a third of patients actually had surgery as part of their, um, LCT, and I think that's still an open question as to where, where we should be considering surgery for our patients with advanced disease. But I think, you know, there was an improvement in progression free survival here, about 725.3 months in the LCT arm. The study design I think left a lot of open questions. We really don't know where LCT fits in, who should be getting it, what sites of disease, you know, how we should be thinking about this. So we need, I think, larger and better studies to answer these questions, but I, I do think that these data suggest that we should at least be incorporating our radiation colleagues into these conversations, and there may be some role for consolidation therapy for a subset of these patients. And in the future I think this field is gonna get even more complicated. There's a huge number of frontline studies ongoing, many of them with ADC based, um, compounds which you'll probably hear about in the second line sort of lectures as well, but. Once again with each of these, I think that's gonna be really a, a balance of safety and efficacy and trying to think about the best option for each patient. So stay tuned for even more complicated talks. So, um, I think in the future, you know, or for now, Riley, I think that, you know, the key steps are one, you have to know what type of EGFR mutation your patients have. For classical mutations we have these different treatment options. You really have to understand your patient and their goals and talk about them. And then once you pick a regimen, I think you have to just really monitor patients closely to ensure that they're having the best possible quality of life. So with that, thank you very much.
Related Presenters
