Chapters Transcript Video EGFR Mutations: What is New and Different Back to Symposium OK, great. Well, thank you for this opportunity to speak. You know, as we know, mutations in EGFR are common uh particularly among those who are never smokers. However, I do want to emphasize and I think most of us here appreciate this, that EGFR alterations can really occur in anyone including those with a smoking history. So it is of utmost importance really to test everyone. And of course, thankfully, we have some targeted therapies that we can use for our patients with EFR disease. However, there's been a flurry of activity within the last year. There's some new FDA approved options stemming from the flora two trial, as well as the meri posts studies, which I'm going to talk about here today as well as just briefly kind of touch on other kind of exciting future options, including the role of antibody drug conjugates and immunotherapy combinations. So, like I said, there's been a flurry of activity uh just within the last year. So this is kind of a scheme I'm gonna be referring to kind of throughout my talk and kind of revisiting. We have a number of different options now available for our patients, uh who are newly diagnosed. Let's start with the kind of the tried and true and really what's been kind of the king here over the last several years, I think many of us have become, most of us have become very comfortable offering this as monotherapy to our patients highly efficacious. Many patients have long durable responses with a very uh generally low minimal toxicity profile. And the FLO study, this was the original phase three study looking at ostomy as compared to an early generation TKI, which shows significant benefits both in PFS as well as OS and has really been the standard just up until recently. Um I'm not going to talk too much about our lat nib plus rami serum. E um it's, I think it's probably a combination that most of us haven't really favored thus so far. However, having said that there's certainly probably a role of combining anti veg F with uh TT I and certainly there's clinical trials ongoing looking at oar plus uh anti vegf. They're all kind of eagerly waiting the results on. So kind of the new kids on the block here, we'll start start off with aer plus uh chemotherapy. This is based off the results that were presented for the first time last year in Singapore, the World Lung Meeting from the Floor two study, which really looked at moving platinum based chemotherapy from the second line and incorporating in the first line in combination with OSER as compared to osser alone. And so ultimately, they did find significant progression free survival benefit hazard ratio of a 0.7. Um If you look at the subgroup analysis, you generally see benefits across all the predetermined subgroups. The couple of things I do want to highlight here in particular, looking at the EJFR mutation subtypes, you know, the L A 58 R mutant uh tumors, we generally think don't do quite as well with single agent Osser nip. However, you can see there is that kind of additional added benefit for those patients as well when you incorporate chemotherapy. And then another striking result that I want to highlight here is in regards to CNS metastasis, I think some of us were kind of surprised by this just because we don't necessarily always think of chemotherapy as being the most kind of CNS penetrate drugs. However, you're seeing that there is a significant added benefit with adding chemotherapy to those uh to o or or to those patients with CNS disease and whether it has a ratio of 0.4 as far as toxicity, no real surprises here. Aside from that, you know, there is more toxicity when you're adding chemotherapy, I don't think any of us are really surprised by that. But ultimately, the type of side effects that we saw are kind of what you would expect with additional chemotherapy in particular things like hematological toxicities. And then the other new player is really the the combination of laser nib plus Amy Van Nab Lazer. NIB uh as we know is another third generation TT I not too dissimilar from osimertinib. Amy Vab is a BCI uh antibody that targets both EGFR and met. It actually works at several different levels, not only at the reception level, but actually something that sometimes people I think overlook is the fact that it also has some immunomodulatory properties. The actual the FC portion of the antibody helps kind of mediate antibody dependent cytotoxic cytotox cytotoxicity as well as kind of help promote uh troy tosis by macrophages. So in the mariposa study, you know, there, there are three different arms here, but the ones I really want to kind of pay attention to here is the combination of Amy Van Nab versus uh Amy Van Neb plus Lazer Nib as compared to O or N. And you can see here a significant uh progression free survival benefit. They also had an arm just for Lazer Nib alone, just to kind of be able to tease out what the contribution of each of these uh components were and really kind of ultimately determined to make sure Oer Nib and and laser were more or less equivalent. So for both this study, as well as the floor two study, uh while we're still waiting on a kind of mature overall survival data, there are strong hints in both of these studies that there's likely going to be an overall uh survival benefit. Uh with mariposa looking at the subgroups again, here again, no real surprises. You're really kind of seeing uh a benefit across all the predetermined subgroups again, with CNS metastasis. Um Ultimately, you know, Amy Van Nebb probably has a fair amount of CNS activity. I mean, we know the third generation TT is have good CNS penetration, but Amy Van Nebb probably has a fair amount of activity as well. And you're seeing that here as far as toxicity. Yes, there there is more toxicity with this particular combination. The toxicities to kind of expect are are different than from what you would really expect from kind of chemotherapy. First and foremost, the risk for infusion reactions, they're likely going to happen with our patients, especially with the IV formulation. In fact, on the early on their on the mariposa studies was about 65 66% of patients actually had an infusion reaction, but it generally happens with the first cycle and then on subsequent cycles that risk decreases significantly. Now having said that there's actually a sub Q formulation of Amy Van as well. That's being a evaluating clinical trials and data on this was actually presented at this most recent as O and the risk of infusion reactions does decrease pretty significantly down to about 12 or 13% with the sub Q formulation. Something else I do want to highlight is the risk for a venous thromboembolism is actually a high percentage of patients experience that on the mariposa study. And in fact, even with the recent FDA approval of this regimen, that just really just happened within the last several weeks or so, uh they do recommend uh uh prophylactic anticoagulation for the first four months, other kind of chronic toxicities. Now, generally, these toxicities were considered low grade. However, these are chronic and most definitely could potentially impact quality of life for our patients or things like Perin nia rash. That's largely because the ambit does hit kind of egfr wall type as well as kind of the met inhibitor type of side effects, things like hyperopia as well as edema. All are possible side effects. Ok. Moving into the second line, you know, there's the tried and true carboplatin plus PEMEtrexed, but there's also from the mariposa two studies where they examined the combination of platinum based chemotherapy with that same bis specific antibody amain. And they saw a significant benefit in respect to progression free survival. They also actually had an arm where you had a A plus chemotherapy and laser. It, but ultimately, there wasn't really much added efficacy by adding on in that particular arm if anything, it just increased toxicities. But when you look at Ivan plus chemotherapy, there is a significant benefit over chemotherapy um in regards to intracranial efficacy. Once again, there is probably a fair amount of CNS activity with this Amy. And if you just look at the media intra progression free survival. You can see that there is a significant increase in medium pfs with the addition of Amy Van to chemotherapy. OK. And then as far as later lines, you know, there's our not so favored dose of Taxol plus ramier aab, there's other kind of standard chemotherapies or single agent checkpoint inhibitors, which we generally think don't work very well in patients with EGFR disease. So what's really coming down the pike that might be exciting. So antibody drug conjugates, of course, that's on the forefront of everyone's mind. There's one in particular, I want to highlight here, Patri Dix Aam which targets her three. There's been some promising data in patients who have been previously treated with TT I as well as chemotherapy, you know, response rates about 30% medium PFS, about six months. You know, actually her three is probably expressed in in probably the majority of patients with ear tumors and usually at De Novo. And there's, in fact, there is a current phase three study looking at uh Patri Mere the can as compared to standard platinum based chemotherapy as a second line option. So this is probably something coming to our clinics in the near future. Now, how about immunotherapy? So we all know, I think everyone in this room kind of well appreciates that single agent immunotherapy really does not work with this patient population very well by itself. There's probably a small subgroup that benefits, but really the vast majority don't benefit from single agent immunotherapy. So what what happens if you add on chemotherapy? So there have been two large phase three trials that are reported in the last year, a year and a half, which show that adding chemotherapy to immunotherapy is not going to do the trick. It's not, they did not meet their end points, negative progression, nonsignificant progression free survival as well as overall survival. However, if you take that same combination of chemotherapy immunotherapy and then also incorporate anti an anti veg F agent. It seems like there is some potential synergy with those four agents. And there have been several studies looking at this with uh with significant progression free survival with that kind of quadruplet type regimen. And in fact, we have an ongoing investigator initiated study at Fox Chase, looking at a similar of carboplatin PEMEtrexed taoism with bevacizumab in patients with EGFR disease, as well as those who are never smokers without any oncogen alteration. And the total uh trial size 100 and 17 were actually about a dozen patients short. So we are pretty close to meeting our accrual goals. But certainly, you know, anyone in the audience who has patients with each of our disease are looking for a good trial, please. We'd be happy to see them and then I'm going to just bore you for about 30 seconds with some kind of interesting work that I do with some of my laboratory colleagues. You know, I have a very keen interest in looking at estrogen estrogen species and what it might do to the tumor micro environment, particularly in those with Egfr mutant disease. There's actually a fair amount of research from the breast cancer world that suggests that estrogen actually leads to an immunosuppressive or whole tumor micro environment. And we've actually found in our own patients with EGFR disease that they have higher levels of particular reactive estrogen species. So we have an EGFRL A 58 R mouse model that we're running experiments in. And some of our preliminary work actually showed that just by giving these mice an aromatase inhibitor, not only did we see anti tumor effects, but we also saw increased infiltration of CD these cells into the tumor micro environment. So kind of building on this preliminary work, you know, we've since garnered some additional NIH funding to perform larger studies using this EGFR mouse model to really see if anti estrogen plus checkpoint inhibitors can actually list at the response that we're hoping for. And we actually have experiments that will probably be done here in the next couple of months and we're hopeful they might lead to a promising clinical application. So really to kind of to conclude here, you know, the million dollar question is, you know, we have a number of different options. We're fortunate in the sense that we have a number of different options available for our patients in in the first line how do we go about choosing what is the best treatment for our patients? Well, I have to say me personally and there's no right answer here. But for me personally, I still generally favor Oer Nib as a monotherapy for probably the majority of my patients. Not only because it's highly efficacious and for a sub for a large group of patients, it does lead to kind of long term uh responses I do still and with a relatively low toxicity profile, just with the monotherapy, I will say that Amy Van most certainly has a role as far as kind of the the treatment journey of a patient. But I generally think about observing that in the second line, I do think it adds something to just platinum based chemotherapy and not only that it does have likely CNS activity which I really like um in in the context of a second line option if you're starting to lose. Uh if you're worried about losing CNS control when you, if you have to discontinue ostomy. But of course, there's certainly other ways of approach approaching this laser plus, Amy Van Nab would certainly be also a reasonable uh front line option. And maybe this is something you would consider maybe in a in a younger patient who's highly motivated, who wants that kind of upfront uh durable progression, free survival benefit and are willing to take on some of the additional kind of toxicities that might come with this combination therapy now, certainly what you do in the front line influences, you know, clearly what you can do in the second line. Or it might make sense in some patients to give the Osser plus chemotherapy, the flora two regimen, maybe in those patients who have a higher burn disease, the patient that's coming in with symptoms when you, when you first meet them, uh it might make sense to go with a more kind of intensive combination regimen. And once again, it does kind of then limit you what you do in subsequent lines. So who needs more intensive first line treatment? And this is the question that everyone's been kind of asking themselves. And ultimately, it's, it's not an easy answer. There's no necessarily right answer. But you really think it comes down to weighing the potential benefits of giving the more intensive treatment while also weighing it with the potential increased risk uh for toxicities. And when I do that, I really kind of think about uh patient characteristics, first and foremost, age fitness, you know, other kind of relevant kind of comorbidities I really take into consideration disease burden sites, a disease, you know, in particular CN metastases, maybe liver metastases uh have have great relevance here where you think with those particular patients, they have a poor prognosis, you may want to kind of tense intensify treatments for those individuals. How about molecular factors? Now, this is certainly garnered a lot of attention just within the last year or so. We've already started talking about, you know, circulating tumor DNA. They certainly has a role in this context as well. There's a number of studies that now suggest that if you have baseline circulating tumor DNA or in particular, if you don't clear your circulating tumor DNA after starting a treatment that could lead to the sooner progression on oser nip. We've already kind of talked about EGFR mu mutation subtype. The L A 58 RS may not do quite as well. We can think about maybe intensifying treatments for them. TP 53 COTS I think has really been on the forefront of a lot of investigators' minds. It really seems like those with a commutation. TPTP 53 doesn't seem to do quite as well with monotherapy with oer. And it might make sense to kind of intensify for them. But ultimately, it's not just a single one of these factors, it's really looking at all these factors. And if you have multiple check marks as far as high risk, that's what I'm really thinking intensifying the treatment. And then lastly, and probably most importantly, you know, we, we talk about shared decision making all the time and on college and I think it really applies here. This is a decision that cannot just be made by the provider. The patient input is, is, is essential. Thank you. Created by Related Presenters J. Nicholas Bodor, MD, PhD, MPH Assistant Professor, Department of Hematology/Oncology, Fox Chase Cancer Center
