Round 2: Managing Frontline Brain Metastases

The discussion turns to a patient with small, asymptomatic brain metastases and additional high-risk features. Faculty examine how CNS efficacy data, molecular characteristics, and the potential role of CNS-directed therapy influence frontline treatment selection.

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

To see arguments related to establishing the frontline standard, see Round 3.

Dr Rodriguez: So Round 2, brain metastases. So this, to me, is a big, important risk factor. So how should asymptomatic brain mets influence your treatment? I will discuss the case and we'll have a poll. So a 65-year-old male, stage IV, light smoker, no prior treatment. EGFR deletion 19, a co-mutation of TP53, detectable ctDNA at baseline. So they gave us more higher-risk features. Disease burden, not only lung, but significant brain. But we don't know if the patient is symptomatic from the brain. They didn't tell us, but they said no prior... Oh, they say asymptomatic, no neurological symptoms. Four lesions, all less than a centimeter, and no visceral mets. So this is lung and brain with some co-mutations here. Okay, Dr Sabari, monotherapy in brain mets. 

Dr Sabari: Yeah, this one's a tough one. I'll do my best here. Again, this idea of brain metastasis, 30% of my patients de novo, upfront, will have CNS mets. Upwards of 40% to 50% of my patients will develop brain metastasis over time, and we're talking about parenchymal disease. We're not even talking about leptomeningeal disease, which we do see in heavily pretreated patients. But interestingly, Julia, I just saw a de novo LMD patient upfront. So these are very tough cases. Brain disease is serious, and we know that patients can become symptomatic from their disease. This patient, thankfully, is asymptomatic, so I'm guessing we're talking about sub-centimeter brain mets, no vasogenic edema. They're not on any steroids, but this is high-risk disease. So again, I'll ask you a simple question. What's the response rate for single-agent TKI in the brain, both lazertinib and osimertinib? Is it different than it is extracranially? 

Dr Rotow: It is mildly lower in the CNS. It's still not bad. That's why, of course, for our patients with CNS mets, even if they elect for monotherapy, I recommend systemic therapy upfront, not additional radiation as well, especially if they're asymptomatic. So it's not that I would introduce radiation immediately if patients chose monotherapy, because upfront response is not bad, but we know that it is deeper, at least in the FLAURA2 study with the combination, than with monotherapy. And we also know that for both regimens, the duration of effect is better in the CNS, including in patients with CNS disease if they have combination upfront, if you look at long-term and outcomes for these patients. 

Dr Rodriguez: We have some data here. 

Dr Rotow: Perfect. So this is the original FLAURA data. So this was the easy transition, right? This was osimertinib versus the first-gen TKI. We, of course, moved very quickly to osimertinib with none of these debates because it was better tolerated and more effective than first-gen therapies and had better CNS activity. Now, of course, with the FLAURA2 and MARIPOSA regimens, there's more conversation and debates like this because we're getting better efficacy, but also, of course, adding additional burden on patients in terms of logistics and toxicity, so it made it a little more challenging. So this is the FLAURA2 data. This is the CNS PFS data, and this is the MARIPOSA intracranial PFS data shown a little bit differently because MARIPOSA did have serial brain MRIs, so we have an actual true intracranial PFS for these patients, which is nice. And I'll highlight here, the data looks very different, right? 

The FLAURA2 data, you see a little higher CNS response. You see some shift in the medians. The MARIPOSA data, the medians overlap more, but you do see differences long-term in outcomes for these patients. Again, I think reflecting that TKIs, their medians sit right around that one-and-a-half to two-year range there. If they start to lose effect, you need a combination therapy to maintain control. So I think, if anything, among all the cases that we show today, I do think CNS disease is the most clear-cut one, where I am biased with my patients and I very strongly push them to combination treatment. Even if they really are hesitant about the idea, I really strongly encourage it more than any other risk factor. 

Dr Sabari: So I agree and I already ceded to you on this case. I would not use single-agent osimertinib or lazertinib in this population, but just to be somewhat controversial, look at the medians here. 

Dr Rotow: It's not good. 

Dr Sabari: 25.4 months for ami-laz. Look at osi, 22.2 months. And look at 24 months. There's really no differences in the curves. So explain to me the biology here. Teach me about the hazard ratio. And how would you educate? Because I very commonly hear from the community, "Look, they're performing very similarly." 

Dr Rotow: Yeah. And this is tough. This is intracranial PFS, not specifically PFS in patients with CNS disease. So the numbers where we see positive hazard ratios are that broader PFS in patients with CNS involvement. Again, maybe getting that not just the CNS disease but something about disease biology, the kind of disease that presents with CNS involvement versus doesn't. There could be other factors at play than simply control of the CNS lesions. I think any advantage, in terms of intracranial CNS control, is worth pursuing in general for these patients, because you so quickly run out of CNS-active options in EGFR mutant lung cancer. Radiation carries toxicities. These patients are living long enough they get radiation necrosis. I don't want to radiate them if I can avoid it in the CNS. So I think absolutely, CNS disease justifies a more aggressive strategy. 

Dr Sabari: If you're a statistician, which maybe you are, or if you're in academic institution, which you definitely are, hazard ratio here is 0.79. It crosses 1 in the conference interval. If I remember, this was pre-specified. So is there really a difference in ami-laz versus osi? Clearly, I see a flattening of the curve there on ami-laz. Clearly, I see a separation at 3 years, which a lot of our patients don't get to. There is clearly a difference, right? 36% of patients progression-free in the brain on ami-laz, versus about 18% on osimertinib alone. But what about most of our patients? Look at the medians. They're pretty close to each other and it's not stat sig. How do you interpret that? 

Dr Rotow: Yeah, I think I'll go with the broad shape of the curves and the broader CNS PFS, broader PFS in patients with or without CNS disease, and say we still have enough signals for benefit that this doesn't make me think that there's not an advantage in the CNS. We know that broadly, if you look at the net PFS for these patients, it'll be just over a year with a single agent, and it'll be closer to what? I want to say a year-and-a-half, I think I'm misquoting the data there, so don't hold me to that, with a combination. 

Dr Sabari: So are you telling me that the benefit for the combinations are not upfront, but maybe down the road durability wise? 

Dr Rotow: Absolutely. That is exactly what I am saying. Thank you, Josh. 

Dr Sabari: I cede the case. 

Dr Rotow: Yeah. This one, I think we'll see, but we want to go to the next case, which is the low-risk disease, and they are a struggle. 

Dr Sabari: I'm setting up for my next case for you. 

Dr Rotow: Yeah, this is the one where Josh has a fighting chance, so we're going to give him an option. 

Dr Sabari: Oh, come on. I had a fighting chance at every case. 

Dr Rodriguez: I did want to ask both of you, for older patients that we see in South Florida, is it Alimta (pemetrexed), or carboplatin that you need? And why do you need to give these two chemos with a really good agent that goes in the brain, like osimertinib? 

Dr Sabari: All of my older patients going to South Florida are playing pickleball. They're driving around their fancy cars- 

Dr Rodriguez: No, it's the other ones. 

Dr Sabari: ... so be careful with the South Florida New Yorkers. 

Dr Rodriguez: Yeah. 

Dr Sabari: It's not age, it's functional status, and I think that's critical. A PS-2 patient who's 60 is different than an 85-year-old who's PS 1. So I give ami-laz. Oh, I said it. I give combination in a patient who's 85, even if they have an age that is somewhat we think, "Oh, you can't give that regimen to," if their PS is good. 

Dr Rotow: No, I do agree. For my patients who are hesitant, or I'm hesitant, whether they're going to tolerate a combination, I tell myself, "And then, we're going to dose modify around 1 if we need to. We'll give carboplatin AUC 4 if we're worried. We're going to stop the carboplatin early, and we'll keep them on the maintenance phase, either pemetrexed or amivantamab. So I think you want to really reassure patients that the thing we start on, we can dose modify and we can dose hold as needed, and that's really important to patients who are nervous about toxicity.