Chapters Transcript Video EGFR: Second Line and Beyond Metastatic All right, so my name is Nick Boder. Thank you for this opportunity. I'm gonna be talking about metastatic EGFR. I'm really looking at the subsequent line space. My disclosures. Um, so, as, as we know, you know, mutations in EGFR are, are quite common. I always wanna highlight this fact because if you look at the statistics kind of worldwide, it's estimated that close to 30% of all non-small cell lung cancers actually have an EGFR-driven, uh, kind of mechanism, which I actually find quite striking. And not only that, of course, I think we all well appreciate that it's really the individuals with little to no smoking history where we're kind of really highly attuned to see if they have an EGFR mutation. But something I always kind of wanna start every talk by highlighting is the fact that even smokers, even people with heavier smoking histories, it doesn't make them immune to the possibility of getting an EGFR-driven lung cancer. So certainly from a provider clinician perspective, it's just. Uh, incredibly important that we test all patients, uh, for, for to look for one of these targetable mutations. And so as we just kind of reviewed and discussed, you know, there's a number of, uh, great frontline, uh, strategies that can be highly effective, but unfortunately the cases for nearly for all patients that disease progression is inevitable. So certainly we need to be thinking a lot about what we give to our patients and the subsequent. Line setting and so there are FDA, a number of FDA approved options in the subsequent line and certainly there's a lot of kind of novel agents, therapy combinations that are quite exciting that are currently under investigation. So over the next 98 minutes, 89 minutes here I'm gonna try to go over, uh, many of these and so it was already nicely outlined as far as the, the the frontline treatments that we think about for our patients so I won't go over that again. But as far as the second line and later lines, in regards to second line treatment, what's really been the tried and true up until recently has really been carboplatin pemetrexate plus minus bevacizumab, as we all know, but certainly data from the Mariposa 2 study now supports the use of carboplatin pemetrexate. Uh, with Amybantabab, um, as this, as kind of the, the, the FDA approved, um, kind of standard of care second line option. And as far as later line options, you know, of course, there's the historical dose of Taxel rimuserumab that we can certainly kind of go to. They're single agent. Anti-PD1, which I know most of us aren't very enthusiastic about, but certainly could be an option we could turn to in a later line. And then there's a recent FDA approval for Datapodumab, droxican or Dao DXD for our patients with EGFR-driven disease as a subsequent option. And I'll just quickly add as far as in the second line, this is not something I'm necessarily gonna go into today because it'll be a little bit too much, but I know some of us in our clinical practice and, and certainly something I've done as well, um, our patients who have been on perhaps who've been on osciertinib for some time are doing well, have good CNS disease control, we may even consider adding, uh, carboplatin pemitrexate to, uh, and continue the osamertinib. And so in regards to carboplatin, Pemitrex, and Amivanabb, that data is from the Mariposa 2 study, which was in brief, a phase 3 study looking at that combination as compared to chemotherapy alone. There was also an arm looking at Amivanabab plus chemotherapy plus lasertinib. However, they found that that particular arm wasn't necessarily more efficacious than the Abivanneb plus chemotherapy and probably only led to uh increased toxicity, as was kind of already discussed. You know, ambivanabb is a bi-specific antibody that targets both EGFR, um, as well as met, but it also has a number of other kind of immunomodulatory properties. The tail of the antibody is, is felt to promote both antibody-dependent cellular cytotoxicity as well as macro uh trogocytosis, uh, through kind of myeloid, uh, based, uh, immune cells. So there's a number of different mechanisms of action with the Amiantab drug. And what this clinical trial found was a significant progression-free survival benefit. Uh, the OS data are, we're still following that and waiting on full maturity. However, there's a strong indication that there's probably gonna be an OS benefit with this regimen as well. But there was a, a, a strong significant benefit with regards to Amy Vanne plus chemotherapy. As, uh, compared to chemotherapy alone, if you look at the Subgroups, really kind of all the subgroups seem to kind of benefit uh from this combination over chemotherapy by itself. And not only that, Amy Van Neb is thought to have a, um, um, as was kind of previously discussed, some level of CNS uh penetration, especially in combination with chemotherapy, and they did find an increase, uh, significant increase in, uh, progression intracranial progression-free survival. OK, so, uh, the new kid on the block is, uh, antibody drug conjugates or ADCs. Of course, certainly we've all been very excited about this just in the, uh, lung cancer space in general. However, uh, there is an FDA approval within, uh, within, uh, EGFR-driven lung cancer, and this is for, uh, Dato DXD. Um, as, as many of you probably already know, again, this has, uh, this is the kind of the smart, quote unquote smart bomb type of approach, uh, where you have an antibody that's targeting a particular antigen. In this particular case with Data DXT, it's, it's trope 2. And again, uh, there's a, a number of different mechanisms of action, not only with the antibody, with the, with the kind of quote unquote cytotoxic payload or smart bomb get internalized by the tumor cell. Um, and lead to death of that particular tumor cell. There's also thought that there's a bystander effect where the actual cytotoxic chemotherapy then also impacts and kills tumor cells that don't necessarily even have the antigen that's expressed. And then again, the, the tail of the antibodies is felt to also have immunogenic, immunomodulatory, um, uh, component as well. And, and similarly kind of promote antibody, uh, dependent cellular cyto cytotoxicity. Uh, so with respect to EGFR data DXD, uh, this was based off pooled data from the, uh, Tropeon studies where they found an overall response rate of 43%, median PFS of, of close to 6 months and overall survival about 15 months. So this was recently FDA approved. This is also an option we have for our patients. So after they've had at least in my own practice after they progressed on potentially carboplatin, Pimmitrexate, Abivantab, this is what I typically turn to next, and I probably kind of prioritize this over, uh, overdose of Taxel ramiserumab, at least in my own practice. Now, as far as other stuff that's coming down the pike, that's very exciting, and these are very recent data, uh, another 80, 2, both of these are 80s, 1, uh, both of these are antibody drug conjugates. The first one being cescetuzumab, uh, termetecan or SATMT for short. Very exciting data that was just presented, uh, recently, uh, at ESMO just a few weeks ago, which showed a significant progression-free survival benefit as well as an OS benefit against the kind of the tried and true historical, uh, second line standard of carboplatin pemetrexate. So this, this. Actually has shown a lot of promising efficacy head to head with docetaxel, but I think what's particularly striking here, especially in the context of, you know, recent data with the HER 3 ADCs and uh the negative result as compared to carboplatin pemetrexate, this showed a significant benefit compared to that historical uh second line standard both in regards to PFS NOS. One caveat though, it is that this trial was done just in China. There is a global study that's currently in progress that of course we're all eagerly waiting on the, the result for. And then another, uh, uh, potentially. uh, by specific ADC is a drug called Isarin. It, it targets both EGFR as well as HERR3, and a data that was just presented at this most recent World Lung meeting in Barcelona showed a striking median PFS of 12 months, uh, with this agent and patients who post progression who developed resistance to TKI, however, were chemotherapy naive. So, um, there are a number of additional studies looking at both of these drugs, both in the subsequent line setting as well as in the frontline setting combined with, uh, TKI. And in my last couple of minutes here, let me just talk about a couple of other quick options. Like I said, you know, single agent immunotherapy is not something that we necessarily find that attractive for our patients with EGFR-driven disease, largely because most of these tumors do tend to be pretty cold and don't seem to respond well to single agent immunotherapy that's been demonstrated in a number of studies, uh, over time. However, what I would like to highlight is there's probably a small percentage, probably anywhere from 6 to 8% of patients with EGFR-driven disease that might actually, uh, obtain some level. durable response. The problem is we have a, we've been having a lot of challenges as far as identifying that small subgroup of patients, but certainly just in my own practice or even a lot of my, the anecdotes from other colleagues, everyone seems to have maybe one or two patients that seem to have derived a pretty, a pretty significant benefit from single agent immunotherapy. But really, in regards to immunomodulatory agents in the EGFR space, I think there's probably a little bit more uh promise. However, you know, some of these results have been kind of disappointing with regards to combined. Combining immunotherapy with other agents. There have been two major phase 3 trials looking at chemotherapy. They both kind of missed their mark in regards to both PFS and OS. However, again, I would say there's probably a subgroup of patients in those, in those trials that probably did obtain and do benefit, kind of a durable benefit from chemo immunotherapy. And there's probably a little bit more hope when it when it comes to combining immunotherapy with chemotherapy and anti-VEGF. This is largely based off the original Empire 150 subgroup analysis which showed a pretty striking PFS. It missed. The mark on OS. Some of the other subsequent large trials have been kind of mixed on this. Um, there's been some excitement with this, uh, Ivanisumab, which is a bi-specific bi-specific antibody, uh, targeting anti-PD1 and anti-VEGF in this space combined with chemotherapy. And then I wanna just kind of quickly highlight an investigator initiated clinical trial that's been led by us here at Fox Chase for the last several years. A number of other big sites have also been involved, including Stanford, Hopkins, Moffat, as well as others looking at the same question, the same kind of. Population of patients with EGFR-driven disease. The original sample size was supposed to be 117 patients. We ran into some issues with accrual over this last year, just given the very kind of competitive landscape of EGFR-driven lung cancer. And so we actually did close to accrual just two weeks ago. We have 109 patients. It shouldn't really impact our power. And so there should be results looking at the combination of immunotherapy, chemotherapy, anti-VEGF in this space as well from this clinical trial data is probably gonna report sometime early in 2026. And then last thing I wanna kind of conclude just a quick, uh, kinda, uh, uh, uh recognition of another trial that we have open at Fox Chase. There's a particular agent called LP 300, which is a small molecule. Uh, this is an industry trial, not an investigator initiated trial, but this is an industry trial that we lead at Fox Chase and it's open globally, a number of sites in the United States as well as, uh, in, in Asia. Looking at the small molecule LP 300, which is felt to inactivate, uh, tyrosine. His oncogenes. And we're looking at that in combination with chemotherapy. There's a lot of promising data from prior phase 3 trials, many of them done in, in Asia, where the actual trial itself was negative in the overall intent to treat population, which included, you know, all patients, smokers, uh, wild type, uh, EGFR, uh, but what they found was in the subgroup of patients, especially those who are Never smokers and in particular those who are female never smokers, and this is in Asia, you would anticipate that the vast majority of these patients had uh kind of actionable oncogens, in particular EGFR and they found a doubling of overall survival among those patients with this, with this particular regimen. So now we have a phase 2 trial, 90 patients, um, where we're looking at this exact regimen in the kind of the oncogene addicted tumors. OK, thank you. Created by Related Presenters J. Nicholas Bodor, MD, PhD, MPH Assistant Professor, Department of Hematology/Oncology, Fox Chase Cancer Center
