Round 1: Managing Patients With High Disease Burden

The debate begins with a patient with extensive, symptomatic metastatic disease. Faculty explore how tumor burden, the need for durable disease control, and treatment tolerability influence the decision to intensify therapy upfront.

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

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

Dr Rodriguez: We're going to go over a case. So this is a 59-year-old male presenting with stage IV adenocarcinoma. Hopefully you got molecular testing relatively fast for this patient that has a bulky lung mass, extensive liver metastases, no brain involvement, and presents with weight loss and fatigue. So these are the patients who are young and sick, and you have to make a decision. Let's make this case like the patient is symptomatic, is in the clinic, not in the hospital, not hypoxic that you need oxygen. 

Dr Sabari: I think, Julia, I agree with you. When you meet a new patient in the clinic, you have no preconceived notion of what they're going to want. We don't know what we're going to select for that patient at the end of the day. I think it's our job to discuss all three regimens. So single-agent osimertinib, osimertinib and chemo, and amivantamab and lazertinib, preferably the subcutaneous formulation. And I think hearing what this patient wants is going to be critically important. So my two cents, this is a patient with large-burden disease—liver, also has some bone involvement, bulky lung metastases—I want a quick response. And I think with a single-agent TKI, either osimertinib single agent or off-label lazertinib single agent, I think that's how we're going to achieve the quickest response. What are your thoughts on that? 

Dr Rotow: Yeah. So I think in this way we have three cases today. This is I think our most standard case. This is what lung cancer often looks like when it presents to us in clinic as a diagnosis. And some symptoms, bulky disease, we're worried about upfront response. We feel pressure for speed of initiation of therapy. And I agree, for all of our three frontline regimens, that upfront response data is very similar, right? And we see high response rates to monotherapy, we see high response rates to combination therapies, and we see fast response rates. So I do agree, I think this is a debate, but of course we want it to be valuable to everyone for real-life practice that my priority in this kind of scenario is starting an EGFR inhibitor as fast as I can. Anything that stands in the way of that, I'm ignoring. I want the EGFR inhibitor onboard as quickly as I can for this patient. 

Now that said, here, very much my default, the consent form I would've printed and the educational materials I would've brought in with me would be a combination regimen. Now, that might be osi-chemo, probably more commonly osi-chemo for me, but it might be ami-laz as well, depending on the patient's preferences around the nature of toxicities and nature of side effects that are acceptable to them. But it would be a combination regimen by default. And I think here this is a nice case to talk through just briefly some of our frontline combination data that we have. 

Dr Sabari: Dr Rotow, what I'm hearing from you is that the response rate is similar for a single-agent TKI, osimertinib and lazertinib versus osimertinib and chemo or ami-laz. Response rates are about 80%. And what I'm also hearing from you is that patients are anxious, they want to start therapy quickly, and that you agree that starting an EGFR-directed therapy quickly is going to allow them to achieve response. Are you gaining a lot by giving the chemotherapy, or the amivantamab in the ami-laz regimen, upfront in that patient who's anxious and wants to get started on therapy quickly? 

Dr Rotow: Yeah. And here, I think the reason we would consider this to be our default, of course, deals with durability of effects. 

Dr Rodriguez: When we talk about shared decision-making visits, what does that mean? How does a patient preference come in? 

Dr Rotow: Yeah, I think in any scenario where you're balancing issues of toxicity and efficacy, patient wishes around care, they matter and they have a big impact how we think about how we treat our patients. I do think here that it's always on us as oncologists to come in, though, with a recommendation. I think I always feel when I go to my patients who are newly diagnosed and I say, "What do you want?" It's important to hear what matters to them, but they're often still looking for me to make a recommendation, since I've had patients I've talked to over the years who do patient advocacy who express frustration when their oncologists weren't willing to give them their advice too. They want to be told a little bit of what we think would be helpful. Here, I think we talked about frontline responses being similar. I agree, but here the durability of effect is really what we're talking about when we're talking about these frontline therapies. 

And we know, and I think it's a real pitfall to use the upfront response rate to gauge whether a patient needs a combination. As soon as I hear this being said, “We can just start a TKI and if in a month or 6 weeks, the scans look great, and they're tolerating it well, we can leave things be and they're going to do just fine because look at this wonderful response.” Everyone's on average going to have a really nice response upfront. It's the most common outcome, but it doesn't predict for durability of effect. So here that's my strong argument that for this patient, the default goal should be to get them an upfront combination. I even go so far as to say when I'm speaking with a patient about this, an upfront combination here is the treatment I tell them that we should use. And then monotherapy I really reserve for those patients unlike this one who are too frail for an upfront combination who tell me that they're not seeking prolonging life as their primary goal. They're seeking quality of life. 

I think our field has really shifted very strongly that way towards making a combination our default, recognizing that there will still be some patients for whom because of their preferences, a monotherapy could be appropriate. 

Dr Sabari: I'm going to cede the durability to you. We have prospective data from two trials, both MARIPOSA, amivantamab and lazertinib, as well as FLAURA2 with osi-chemo showing durability. But we talk a lot about high-burden disease, liver metastases, bone metastasis. And this patient doesn't have brain metastasis, but I put that in the high burden of disease. I would argue that what we're trying to achieve upfront is a response. So are you telling me that there's a different biology in a patient with a lot of disease versus a little disease? And maybe we should be looking at that and not using the more aggressive or toxic regimen in all patients. So I do believe in a patient with high-burden disease, where I want to achieve rapid response, it's the EGFR TKI that's driving that, and I prevent the side effects. We'll talk a lot about side effects and I think you may cede to me on the side effects of combinations over a single agent. 

And patient preference is critical, right? I would say half of my patients after hearing the discussion on all three regimens, and I do my best to be balanced in all three regimens, half of my patients still will select for single-agent osimertinib despite there being durability data. Why? They want quality of life in their clinic or in their home life. 

Dr Rotow: I think this is always hard. You're meeting a patient who's newly diagnosed. They've just had... Has to be the worst news of their life, right? They're reeling from this diagnosis. They have never heard any of this before. It's a very complex subject even for oncology practice, a lot of experience with this. And they're overwhelmed, and they're afraid of side effects, and they've been seeing how pop culture portrays cancer therapy and cancer side effects, and they don't feel ready to feel, they're not just making a decision for cancer therapy, but also making a complex decision about what that treatment might be. 

Dr Sabari: And I'll cede to you that in some patients, combination strategies make sense because of durability. But in most patients, I think single-agent TKI is sufficient, and on the back end we could escalate or use other lines of therapy. 

Dr Rotow: All right. So you fed that one to me very effectively.  

Dr Sabari: I did. 

Dr Rotow: Thank you. It was a gift. The next line therapy… 

Dr Sabari: Gave her a softball. 

Dr Rotow: The chances of next-line therapy. Thank you. This is the other problem, right? We know that in real life, for a lot of patients, more than we want to believe, their frontline therapy is the only treatment they receive. Even in clinical trials, 30% to 40% of patients never get a second-line treatment. These are clinical trial patients. These are the fittest sort of marathon runners of our lung cancer patient population who had access to a major academic center, enrolled in a trial, were motivated enough to go on to a randomized trial. And even then, 30% or more don't get a second-line treatment. That really means that we think we can salvage whatever we give frontline with our second line, but in real life we can't. And we look at, I don't think we show the data here, but there's all these studies looking at second-line post-osimertinib monotherapy therapy, whether that's MARIPOSA-2, which is ami-chemo, whether that's COMPEL, which is osi-chemo. 

But in both of these settings, it looks good. You see some few months in OS, you see 6 months PFS, very similar to the PFS you gained from combination therapy. These are those patients who actually went on and got a second-line therapy and were fit enough for a clinical trial in the second-line setting. It eliminates all of those 30% of patients who never got anything at all and that fraction of patients who were not eligible for a trial. So it's really, again, doesn't give you a true look at what you can recapture in second line. So I really feel pretty strongly because of that. In oncology, always the answer is your best drug, your best combination first.