Dr. Suresh Ramalingam:
Hello, welcome to Optimizing the Care Continuum for EGFR-Mutant Non-Small Cell Lung Cancer an ASCO Post Roundtable. I'm Dr. Suresh Ramalingam, Professor of Hematology and Medical Oncology, and Executive Director of Emory Winship Cancer Institute. Today I'm joined by two esteemed guests, Dr. Zosia Piotrowska, and Dr. Helena Yu. I'm going to pass the mic over to first Dr. Piotrowska to introduce herself and then to Dr. Yu.
Dr. Zosia Piotrowska:
Hi everyone. I'm Zosia Piotrowska, thoracic medical oncologist at Mass General Brigham Cancer Institute here in Boston. Great to be here.
Dr. Helena Yu:
Hi everyone. I'm Helena Yu. I'm also a thoracic medical oncologist over at Memorial Sloan Kettering in New York, New York.
Dr. Suresh Ramalingam:
Great to have you both on this program. Our first case will focus on the first line treatment of EGFR-mutant metastatic non–small cell lung cancer. So let me introduce the case. This is a patient who is a 66-year-old woman. She originally presented with pain in her right hip and at that time she didn't have any prior medical history. She was in very good health overall. She had a less than 5 pack-year smoking history, having smoked during her college years and does not smoke anymore. Her performance status is really good and you can see during the workup for the right hip pain, she had a CT scan of the chest and imaging of her hip. On the scan on the slide, you'll see that she has a spiculated lesion in the right upper lobe. There were also hypermetabolic lesions in her pelvis on the right side. There was a hard area on the liver.
And further workup revealed that in the brain she had 4 subcentimeter lesions, which did not have any surrounding edema, midline shift, or any of the scary features. She ended up going for a biopsy of the right upper lobe and that confirmed the diagnosis of adenocarcinoma of the lung with lepidic pattern. The patient also had, as part of her diagnostic workup, EBUS and a sacral node was biopsied that also showed adenocarcinoma. Tissue was sent for next-generation sequencing and the findings are summarized in the slide. She had an EGFR exon 21 mutation. There was also a p53 mutation. She had MET protein expression at 3+ by immunohistochemistry and her PD-L1 status was negative. So in this background, let's talk about what's the recommended first-line treatment option from a systemic therapy standpoint. This patient had some palliative radiation to the hip to provide pain relief as the first step. By the time the NGS results came back, she was already done and had pain relief. So Zosia, let me start with you. How do you go about making decisions that we have more than one option for first line therapy now?
Dr. Zosia Piotrowska:
Yeah, I think this is a great case. Really illustrative of many of our newly diagnosed patients with classical EGFR mutations that we see in clinic every week. I think that over the past couple of years, this landscape has really evolved. A few years ago, we were really relying heavily on osimertinib monotherapy as our mainstay of treatment. Over the past couple of years, of course, we've seen the data for two different combinations. Osimertinib combined with first-line platinum pemetrexed chemotherapy data from the FLAURA2 trial, as well as the combination of a different third-generation EGFR inhibitor lazertinib in combination with amivantamab, the bispecific antibody targeting EGFR and MET. And initially we had seen meaningful improvements in progression-free survival with both of these combinations when compared to osimertinib monotherapy. And now over this past year, of course we saw the overall survival data from these studies and we've seen that both of these regimens do improve overall survival by about a year on average for these patients.
And so I think that has really changed my practice to lean towards combination-based approaches. We have to acknowledge that of course these do add toxicities, they add more frequent visits. These patients have to come for infusions, although now also for, we can consider subcutaneous injections with amivantamab, they add toxicities. But I think given the survival benefit for a patient like this with a good performance status, no other major comorbidities, and overall good health, I would be leaning towards a combination. And I think the real question to discuss with the patient and think about altogether is which of the combinations is the most appropriate for a patient like this? And I can pause, we can all discuss together and I can certainly put my nickel down as well.
Dr. Suresh Ramalingam:
Right. Helena, what are your thoughts on this case?
Dr. Helena Yu:
Yeah, I agree completely with Zosia. I do think we obviously are afforded several options. I think that the pendulum really has swung with the overall survival data where my practice is really to talk about and recommend combination therapy with sort of an opt-out. I think the idea of the default being combination therapy and then of course we have to take into account patient preferences and comorbidities, high-risk features. But agree, I think that we think about the two combination options. I think they have, as Zosia mentioned, additive toxicity. I think the toxicity of the two regimens are quite different. And so sometimes that's a discussion with patients. Based on patient's profession and their personal lives, they might—not that we prefer toxicity, they but might lean towards one regimen or the other based on that.
For FLAURA2, for the chemotherapy plus osimertinib, obviously there's that risk of cytopenias. And then there are potentially fatigue, nausea, and then there are some longer-term potential issues with pemetrexed. But these are all toxicities that we're all comfortable with managing as oncologists. And then of course with amivantamab and lazertinib as a dual EGFR and MET targeted regimen, we see more EGFR wild-type toxicity—so rash, paronychia, scalp rash in particular. And then some of the MET-directed toxicities like hypoalbuminemia and lower extremity edema and anasarca. So again, it really becomes a personalized discussion with our patients. And I do think that as Zosia mentioned with the subcutaneous amivantamab, that might change things a bit in terms of frequency of visits and chair time we talk about, or the kind of medicalization of our patients. I'll start by saying that generally I lean towards the combination of osimertinib and chemotherapy for patients, but I think that, again, I'm open to both and we have a full discussion. Interested to hear your thoughts.
Dr. Suresh Ramalingam:
Yeah, thank you Helena. I would admit that prior to 2025 when we saw the survival data for both osimertinib plus chemotherapy, and amivantamab and lazertinib, I was still leaning towards using monotherapy for my patients, but I think when you look at the survival hazard ratio, the median improvement in overall survival in the FLAURA2 study was a little over 10 months. That did sway me towards going in the combination route. And I think that there are relative pros and cons for both combination. From a toxicity standpoint, I feel that the chemotherapy plus osimertinib is slightly better tolerated by patients and that tends to be my go-to regimen in my EGFR-mutated patients. Zosia, you were going to wait until the initial round of discussion to tell us what you do. So let me ask you.
Dr. Zosia Piotrowska:
I agree with you. I think we all have a lot of comfort using chemotherapy and even combining it with osimertinib. And we've done that for patients in later-line settings for quite a while. So I think we all have a lot of sort of familiarity with that regimen and it generally is fairly well tolerated. I will say I think that the amivantamab plus lazertinib regimen, great strides have been made and the sort of improving the tolerability of that, the COCOON regimen, prophylactic antibiotics, prophylactic topical medications, all of that has helped. Of course, the subcutaneous administration of amivantamab helps with that infusion-related reaction that we saw quite frequently with the IV formulation. I think all of those things have really improved the tolerability of amivantamab and lazertinib. But on balance, I still for most patients, lean towards the FLAURA2 regimen. I think an interesting point about that regimen is also when we speak with patients about what this longer term is going to look like, we have to keep in mind that many of these patients actually didn't stay on chemotherapy for the duration of time that they were on this regimen.
In fact, the median duration of pemetrexed exposure was about 8 months in FLAURA2. And so when I speak with patients, I'll tell them that we will continue on the chemotherapy as long as they were tolerating it and doing well and their disease is stable. But that for many patients over time, there are reasons whether that be cumulative fatigue, cumulative nephrotoxicity, other sort of factors that may play into it that lead to the fact that many patients do end up having a period of time when they end up on TKI monotherapy. And I think that's important. And again, it's nice to have that period of time when patients are having that oral only regimen as well.
Dr. Suresh Ramalingam:
Absolutely. Thank you. Now this patient's NGS profile and then associated molecular testing revealed MET positivity by immunohistochemistry as 3+. Does that sway your combination choice in any way?
Dr. Helena Yu:
Yeah, that's a great point and maybe I glossed over that a little bit. I think it brings up the point that I would love a predictive biomarker. I do think that there are patients and perhaps upfront MET positivity, high expression by IHC could be a potential biomarker. We don't know, but I suspect there are patients that would probably benefit from dual EGFR-MET inhibition more than others upfront. And so I think we talk about high-risk features. I remember the case also had a concurrent p53 mutation within the tumor, liver metastases, brain metastases. These are all sort of higher-risk features, which I think both studies have done a really good job of demonstrating benefit of the combination over monotherapy in patients with these high-risk features. But it doesn't allow us to distinguish between the two.
I do think that, and I'd be curious to see what you guys think. I think that the MET 3+ is interesting, and again, I'd like to see data about whether that does predict a longer-term benefit with amivantamab and lazertinib, but I have heard of people using MET amplification, MET IHC upfront to dictate or potentially choose amivantamab and lazertinib over the FLAURA2 regimen. Does that affect either of your opinions on the case?
Dr. Suresh Ramalingam:
I was just going to add that we don't know what the efficacy of chemotherapy plus osimertinib is in that MET-positive group. Right. So that's the other variable for which we don't have much information on. And it's a key question. I think we may not have a prospective trial address that, but this is an opportunity for some real-world data to look at the pros and cons of the two combination regimens. Sorry Zosia, you were going to say something?
Dr. Zosia Piotrowska:
No, I was just going to say I think this is actually coming up. This is a real-world case. This is coming up in my practice at least because our pathologists have really incorporated MET IHC now into the standard panel that's done for newly diagnosed non-small cell lung cancer. And so I have had this scenario come up a few times as part of the initial information that we get for a patient. And I think it's an intriguing question because a few years back at ASCO, we did see some data that MET IHC seems to be associated with amivantamab and lazertinib response in later lines of treatment in that treatment resistance setting. But I would say we have to be a little bit careful because that data, to my knowledge, has not been recapitulated in the front-line studies. It hasn't been shown to be the case for the MARIPOSA regimen.
I hope that perhaps we will have that data in the future, and certainly it sort of raises the question of more of a MET-dependent sort of cancer. But I think we don't know yet how either of these regimens will specifically work in the setting of MET protein overexpression. I think for a patient like this, you want to make sure that your NGS has tested for MET amplification as a baseline finding. I think it would be helpful to make sure to see whether that's present or not, because that has been shown when present at the time of initial diagnosis to confer at least sort of primary resistance or a shorter duration of response to first-line TKIs. But I think for now it wouldn't sort of directly impact my thinking.
Dr. Suresh Ramalingam:
Right. Well, the last point I want to discuss about this patient is the brain metastasis management. None of you said we have to do anything specifically for the brain in the era of targeted therapy. If you can provide some guidance to our audience on when you do local therapy for the brain vs just rely on systemic therapy, I think that would be a good takeaway point as well. So Zosia.
Dr. Zosia Piotrowska:
Yeah, I would say I think these are cases where it's really important to see these patients in a multidisciplinary fashion with our radiation oncologist, but also to be really, have good communication with the radiation oncologist to really relay the fact that this is a patient who's going to go on to a systemic therapy that we hope is going to have really good CNS penetration. Really regardless of which regimen we choose, even with osimertinib monotherapy or the FLAURA2 or MARIPOSA regimen, we hope that these will be highly CNS active therapies. So for a patient like this who has subcentimeter asymptomatic CNS metastasis, our approach usually would be to see them together with a radiation oncologist, but to defer radiation therapy, start systemic therapy, and obtain a short interval follow-up MRI usually about 4 to 8 weeks after starting treatment. I think if the patient has symptomatic CNS metastasis there, often we will think more strongly about using upfront radiation for a symptomatic lesion or local therapy. But for a patient like this with asymptomatic disease, I would hold but monitor them really closely.
Dr. Suresh Ramalingam:
Thank you. Helena?
Dr. Helena Yu:
I agree with Zosia. I think that this is an area where we could generate more data because although our first-line treatments are very good at treating brain metastases, we know that there is still significant morbidity and mortality with brain metastases later in the disease course. There was a retrospective study that was published in JCO, the TURBO study, which looked at kind of risk factors for potential eventual CNS progression. And one of those that kind of was most prominent was a size greater than one centimeter at diagnosis and actually atypical or uncommon EGFR metastasis. So I think we didn't really discuss that in this case. But I agree with Zosia. I think if brain metastases are larger, and certainly if there are any thought that the patient's cancer will respond less well to systemic therapy, perhaps with an uncommon or atypical mutation, those would be people that I might consider RT upfront.
Dr. Suresh Ramalingam:
Right. Well, this has been a great discussion. So let's summarize for our audience the key clinical takeaways from this patient's situation. I think it's fair to say first-line therapy for non-small cell lung cancer with classical EGFR mutation now is leaning towards using treatment intensification. Certainly high-risk features that were mentioned earlier, such as brain metastasis, liver metastasis, and p53 co-mutation, all signal towards the choice of treatment intensification in these high-risk creatures. Toxicity management is key when you use either of these regimens, but more so with the amivantamab/lazertinib regimen and that can ameliorate the patient experience. So this brings us to the end of the case. To our audience, please see the other segments for further discussion about the latest research in lung cancer or visit ascopost.com. Thank you.
