Round 3: Establishing the Frontline Standard

In the final round, faculty consider a fit patient with relatively limited metastatic disease, exploring where osimertinib monotherapy may remain appropriate and how efficacy, tolerability, patient preferences, and treatment burden inform the decision to intensify treatment.

To see arguments related to managing patients with high disease burden, see Round 1.

To see arguments related to managing frontline brain metastases, see Round 2.

Dr Rodriguez: So I think we're going to spend a little bit more time on this last round because actually when I think of these patients that are actually no risk features and I think I don't want it to cause any harm. So for a fit patient with newly diagnosed EGFR-mutated patient, what would be your preferred approach? It's a 63-year-old woman, stage IV, ECOG performance status of 1, which means they can walk into clinic. Never smoker, hypertension well controlled. Here they give you the PD-L1 information which we don't really need, but we have no co-mutations, just EGFR exon 19 deletion, which we talked about earlier. And the disease burden is low, bilateral lung nodules, two small bone metastases, no brain metastases. So this is a patient that is relatively asymptomatic with newly diagnosed metastatic EGFR-positive lung cancer. 

Dr Rotow: But this to me is actually one of the hardest newly diagnosed cases I see. I could have made it harder. It could have been a 50-year-old person or a 42-year-old and they're walking in without a lot of high-risk features asking, "Do I really need an upfront combination?" But they're fit and healthy and the overall intention-to-treat studies say overall survival advantage to a combination. So what do I honestly tell a patient? Do you need this or not? Should you take on the risk of side effects and the quality of life impact of side effects? I think that's the hardest case that we see in the frontline setting right now. 

Dr Sabari: So you're ceding a lot to me here. So I think in my debate training, I have to become more aggressive to win over. I agree with you here. I think in a patient with low-volume disease, what is the benefit of causing harm in this patient with side effects? And low-volume disease, I may treat for X amount of months with single-agent TKI, and that X amount of months is still unknown. It's up in the air, but we want to treat for maximal response. In the literature, I think the NORTHSTAR study said about 6 months if I remember correctly. 

Dr Rotow: Six weeks. 

Dr Sabari: Six weeks, sorry, 6 weeks. But we don't know the true maximal response timeframe. In my clinical practice, I wait a little bit longer in that 6- to 9-month range. And maybe I would resect the dominant lung lesion and maybe radiate those other lesions. These patients do very well on third-generation EGFR TKI. This might be the 7- or 8-year patient that we see in our clinical practice setting. Why subject them, Julia, to the side effects? So remind me, what are the side effects for osimertinib and chemotherapy and what are the side effects for amivantamab and lazertinib? I forgot. 

Dr Rotow: Before I do that, I was going to take your debate training and turn it on you and get more aggressive here. I would argue that this patient with low-risk features has the most to gain from a combination maybe, right? We know their hazard ratios are very similar across these low-risk features. They're still gaining time over a better baseline. And in many settings, the more effective the systemic therapy, the more they have to gain from aggressive consolidation strategies as well. So maybe this is the patient we should lean in. They're fit and healthy and maybe we can get them really long duration effect by more aggressive upfront therapy, more aggressive consolidation. 

I will say for these patients who do well, I'm quicker to stop the combination arm of the regimen if they're not tolerating. Well, I'm not going to push forward hard against it. But you could even argue maybe these are the patients if they're seeking aggressive treatment where they should lean in the strongest because they have the most to gain, but we'll do the poll. 

Dr Rodriguez: I did jump this question; if you can answer. 

Dr Rotow: And then we'll do toxic. 

Dr Sabari: At what cost, though? 

Dr Rodriguez: What cost? Ooh. 

Dr Rotow: Yeah, no, I think this is a fair point. And this is I think where the cost of therapy in terms of quality of life weighs upon me the hardest, because we're not sure about the benefit as strongly. And you're right, chemo... So these are very different tox profiles, and chemo, we are looking at things like cytopenias, I think weigh on me most strongly when I think about what's risky to a patient. I worry most about neutropenia and infection or other cytopenias. I think there's the other ones that we think about like fatigue and GI toxicities. These to me are not as frightening to an oncologist. But of course to a patient, I think especially for pemetrexed, long-term fatigue is real, does impact quality of life. And I think it's a silent or invisible toxicity. So it's easy to accidentally ignore it or under count it, I think, for our patients. So thinking about dose modification or extending dose intervals starts becoming more important for this one. 

I think CKD is also something we watch for on pemetrexed, and that's one I think it's also easy to accidentally ignore because it tends for pemetrexed nephrotoxicity, it's a very slow, gradual change. If you're looking from cycle to cycle, you're going to miss the toxicity because you're not looking back to the true baseline. So I make a really careful point for my patients on pemetrexed maintenance to look back at their baseline pre-treatment regularly to make sure how much has changed. 

Dr Sabari: What about MARIPOSA? 

Dr Rotow: Yeah, I think ami-laz has its own distinct toxicities, and I think these are real, and I think these are the ones that patients are often thinking about because they're not silent, they're not invisible toxicities. They're not likely to be life-threatening toxicities, which is nice from an oncologist perspective, but they are certainly visible. So it's the skin rash, the paronychia, the scalp rash, fluid retention, and in theory, VTE risk as well. I think we mitigate that with anticoagulation, but patients don't like the idea of being on anticoagulation. I've actually had that come up a lot. So I will say that this is an agent where, as with maintenance chemotherapy, I think these patients, especially with lower-risk disease, want to pay very close attention to dose modification and dose holds. And dose, modifi[ying] dose, it's a long-acting regimen. So early intervention for tox rather than late intervention for tox really matters on this one. Yeah. 

Dr Sabari: Which combination regimen would you use? So let's say I'll do ami-laz, you do FLAURA2. And that's a perfect question. So you're saying, why don't we use FLAURA2? It's 4 cycles of chemotherapy with osimertinib followed by osimertinib maintenance. Julia, remind me the design of the trial. 

Dr Rotow: So I think a key point on FLAURA2 is that this was indefinite chemo. So both regimens are an indefinite combination. So it's 4 cycles of carbo-pem then pem maintenance. Yeah, so pem maintenance to toxicity or disease progression, right? 

Dr Sabari: If you look at the range of cycles of pemetrexed, it goes from 0.7 to 59, I think, 60 months. What's the average time you're able to give pemetrexed in your clinical practice setting? And the real question is, are you stopping it because you want to stop it or the patient wants to stop it? 

Dr Rotow: I think it's usually the patient, honestly, in my practice. It's more common, but that's the fatigue. It's the silent side effect. I can tell a patient, based on your cytopenias or based on your creatinine numbers that I want you to stop, but fatigue is a toxicity. I think it's often patient driven, the decision to discontinue. And that's a little unfair. They put that on our patient to decide when is the fatigue too much. It's a hard question to ask anyone to answer. Yeah. 

Dr Sabari: What's the data, Dr Rotow, on the time on therapy and the overall survival? Do we have it broken down there or just a median? 

Dr Rotow: We do. We do. So there is data, and here I'll talk about the FLAURA2 trial looking at median PFS based on duration of pemetrexed maintenance. 

Dr Sabari: Not PFS, overall survival. 

Dr Rotow: I don't know if they have overall survival. I've seen the PFS number. 

Dr Sabari: Never been published. 

Dr Rotow: Yeah. I've seen the PFS data. This is tough. I've seen the PFS data. It's really biased, right? I think we all know that a patient who does well, who responds longer is on treatment longer. So of course, the patients with longer PFS on combination are on the pemetrexed longer. Now there is some gradation. The longer you're on it, the longer you tend to be on for PFS. I don't take much of that except the trial does not prove that you don't need maintenance pemetrexed. But yeah, the trial's not designed to answer the question of what is the optimal duration of treatments? We can't really quite get it from the data that we have. And that would apply both, by the way, to the FLAURA2 data and the MARIPOSA data where an indefinite course of therapy is indeed indicated. 

Dr Sabari: So what's the median time? So now to argue the MARIPOSA regimen here, what's the median time on amivantamab and lazertinib on the trial? 

Dr Rotow: So that one actually is interesting and that goes towards your point. So it's about, I think 15 months on the amivantamab component. So this I think speaks to feasibility when patients are managed appropriately. It also speaks to those patients needing to be on their toxic combination regimen longer on average than monotherapy, which is a double-edged sword, yeah. 

Dr Sabari: I think also a lot of it is our familiarity with the regimen and the fact that you mentioned, “oh, give 4 cycles of carbo-pem and then stop,” you feel comfortable doing that, right? Versus amivantamab. And patients feel comfortable doing that versus amivantamab, we don't have a lot of... I have a lot of comfort, but many in the community do not have comfort yet with that regimen. So if I'm going to start FLAURA2, I want to continue chemotherapy until progression or intolerance. And I'm not a tyrant, right? I dose reduce, I hold, I let people go on vacations. I think that's really important both for FLAURA2 and for MARIPOSA, but I don't kid myself that I'm gaining durability by giving 4 cycles of chemotherapy. And I think that is one of the biggest misconceptions about FLAURA2. 

So for FLAURA2 versus MARIPOSA, you mentioned a lot of side effects for FLAURA2, and I'll talk about the side effects from MARIPOSA as well. What are your pre-medicines? What are you doing for FLAURA2? Is it clicking a button or are you doing a lot there? 

Dr Rotow: 

Yeah. And this, I think it helps, I think for oncologists, we're very familiar with carbo-pem as a regimen. I think we find that supportive care regimen straightforward. It's folic acid and dexamethasone. We know how to do that. We manage patients historically routinely on this. MARIPOSA, that is a newer regimen for us. I think we're still learning how to implement that. I think we're still learning how both to prophylax effectively and also how to reactively manage toxicities when they do emerge. And here I do appreciate all the work that's gone on to, trying to understand managing the EGFR and the cutaneous-related toxicities of the regimen. 

Of course, these agents are effective, they're active for our patients. We want our patients to have access successfully to all possible effective classes of therapy. So it's always terrible if a patient can't receive an effective therapy against their cancer if the toxicities are holding them back. So I think really aggressive approaches to managing the toxicities of this are going to matter and are important for our patients.