Case 1

Dr. Sandip Patel:

Welcome to a new installment in the JNCCN Video Roundtable series. I’m Dr. Sandip Patel, a medical oncologist at the University of California, San Diego. Joining me today are two of my colleagues. Greg, could you introduce yourself first?

Dr. Gregory Riely:

Hi, I am Greg Riely. I’m a medical oncologist at Memorial Sloan Kettering Cancer Center.

Dr. Sandip Patel:

And Jessica?

Dr. Jessica Bauman:

Sure, I’m Jessica Bauman, and I am a thoracic and head and neck oncologist at Fox Chase Cancer Center in Philadelphia.

Dr. Sandip Patel:

And today, we’ll be discussing the management of patients with EGFR-mutated non–small cell lung cancer, focusing on the use of targeted therapy in three cases across different clinical settings, starting with case one, which will be moderated by Dr. Greg Riely.

Dr. Gregory Riely:

Thanks, Sandip. This is, I think, a case typical to what a lot of us see in our clinic. She’s a 68-year-old woman. She presented with a few months of lingering cough. I think this is common presentation. But for her, there was an initial abnormal x-ray, and then her primary care doc referred her for a CT scan. The CT scan showed bilateral subcentimeter nodules, with a larger tumor that you might call the primary tumor up in the left upper lobe. Based on that abnormal CT scan with relatively clear metastatic disease, she went straight to a transthoracic needle biopsy. The pathology from this showed well-differentiated adenocarcinoma. It was TTF-1–positive, and the PD-L1 score was 20%. At our place, we get ALK IHC off the bat, and that was negative as well. Ultimately, the patient did have rapid molecular testing, and that testing showed an EGFR L858R mutation. Maybe before we go on with more of the descriptions of the patient, I’ll ask: What’s your molecular testing panel like at your institution or how you treat patients? Jessica, maybe we’ll start with you.

Dr. Jessica Bauman:

Sure. So, I think one of the biggest challenges, as we know with a new diagnosis of non–small cell lung cancer is how quickly we can get the information from molecular testing. And we’ve worked many years to have essentially a reflex panel sent so that, as soon as the pathology touches the pathologist, even before they see a medical oncologist, the molecular testing starts to cook. And I think that is an ideal scenario because it is hard if the testing isn’t sent, the patient lands and medical oncology 2 or 3 or sometimes 4 weeks later, and then we get the testing sent. And for us, we send a broad molecular profile that includes both DNA and RNA, so we’re able to get as thorough as information as we can as fast as we can and hope for the best. Sandip, I’m curious for you. Is it the same at your institution?

Dr. Sandip Patel:

Yeah, I think some things are similar, and some things are slightly different. You know, for the external referrals, meaning the biopsy was at an outside facility, that tends to drive a reasonable number of our new patient accruals. And I imagine at your institutions, as well, especially to see folks like yourself who are nationally and internationally known. And so, for us, what tends to happen is, when we see the patient in a medical oncology clinic, we’ll order cell-free DNA as well as DNA plus RNA tissue NGS, not with the goal of getting duplicative molecular testing, but, oftentimes, the cell-free DNA result will be back in 5 to 7 days, even before the tissue has been sent for sequencing. The flip side being, if we get QNS quantity not sufficient for cell-free DNA, which is distinct from a negative test, which, you know, I think is important. Right? Then at least we’re a week ahead of where we would be in terms of tissue-based testing, given, Jessica, as you nicely summarized, time is of the essence here.

Dr. Gregory Riely:

You know, you guys both illustrate the complexity of this process and all the local solutions that we’ve developed to deal with this. So, I think we all have the highest priority of identifying these mutations in as many patients as have them and identifying those mutations as quickly as possible, so we can get started with appropriate therapy.

So, this patient had completed staging evaluation with a PET scan, which confirmed that the left upper lobe mass was FDG-avid. The subcentimeter lesions were a little bit avid, but they’re subcentimeter, so the radiologist didn’t make much of it. There were two FDG-avid lesions in the spine at T7 and L3. The CT did not have any corresponding bone lesions at those sites. Brain MRI showed two parenchymal metastases. The largest was 6 mm. There was no edema, and the patient did not have any prior symptoms related to that. The patient had additional molecular testing and confirmed that EGFR L858R. This is the full NGS panel at this point and showed the TP53 point mutation and CDKN2A deletion.

So, and maybe we’ll start with you, Sandip, the patient presents with metastatic disease, two subcentimeter lesions in the brain, no edema, and no symptoms. How do you think about that? You know, I think when I was learning to be an oncologist back in the day, there was a widespread belief that any CNS lesion should be treated with radiation first and foremost. Do you still take that approach, or do you think about systemic therapy first?

Dr. Sandip Patel:

Yeah, I think, Greg, to your point, it’s all about personalizing therapy, not only with the molecular information but based on the overall clinical context. For this patient with two small lesions, no edema, no symptoms in the CNS, at our institution, and in my own practice, I would start targeted therapy and get a follow-up brain MRI in 1 to 2 months. And I can’t remember the last time I had to have the radiation oncologist in this particular mutation, even with small-molecule inhibitor therapy, have to go back and do radiation. It’s pretty rare to have even any disease to see. And so, at my institution, we would start with systemic therapy but close monitoring. And I think the biggest issue I see in this patient population are folks who get whole-brain radiation, which is very toxic for multifocal brain metastases, even if symptomatic. The CNS response rates with small-molecule inhibitors are over 80%. What does this look like in your clinic, Jessica?

Dr. Jessica Bauman:

So, I completely echo what you say. I think the one scenario that would be different is if there was a symptomatic brain lesion. I think that changes the equation. But these small asymptomatic brain lesions sometimes are so small that they can’t even target them effectively. Ultimately, we know that the systemic therapies, thankfully, now penetrate the CNS remarkably well. And so, starting systemic therapy certainly would be my approach as well.

I would also say this is one of the reasons why it’s so critical to get the information back as fast as you can. Right? Because you do have widely metastatic disease in the sense that you have bone mets, you have brain mets, and they can become symptomatic with time. And so, I do think this highlights also the imperative nature of getting the information as fast as we can, so we can make a decision for the best treatment.

Dr. Gregory Riely:

Yeah, I think that’s exactly right. And oftentimes, I meet patients, and I have their brain MRI result, but I don’t have the molecular testing result. Sandip, you highlighted that, for this target, you know, we have great success with treating CNS lesions with systemic therapy. I think when, I'll be honest, no matter the oncogene or absence of oncogene or subcentimeter lesions, I feel relatively comfortable beginning with systemic therapy. But I think, for those kind of borderline lesions, I often send them off to radiation oncology and tell the radiation oncologist this is sort of in case I don’t find something that I can target systemically and sort of get the patient plugged in, if you will.

Dr. Sandip Patel:

Absolutely.

Dr. Gregory Riely:

Alright. So, speaking of systemic therapy, I think our next question is, what initial systemic therapy would you recommend for this patient? You know, when I sort of make a multiple-choice option here, I’d say, you know, option A would be erlotinib, option B would be cisplatin plus pemetrexed and osimertinib, option C would be amivantamab plus lazertinib, and then option D would be osimertinib as a single agent as compared with chemotherapy. So, those are the options that sit in front of us today in clinic.

You know, I think we could kind of go on and on about data that we see for patients with metastatic disease and first-line therapy. The trials that are kind of fresh in our heads and not even so fresh is FLAURA. That was 5, 6 years ago now. That trial showed that osimertinib, of course, is better than erlotinib or gefitinib. So, kind of cross off erlotinib on our list here of choices.

But the more recent trials include FLAURA2, which compared single-agent osimertinib to osimertinib plus chemotherapy. Now, in that trial, we saw improvements in median progression-free survival that were relatively significant, and, similarly, with amivantamab plus lazertinib. Lazertinib is a drug that’s pretty similar to osimertinib, and amivantamab, of course, is the EGFR/MET bispecific antibody. When you give amivantamab plus lazertinib in the MARIPOSA trial, we saw a median progression-free survival that rivals what we saw with osimertinib and chemotherapy.

So, we have a lot of data in this situation. Unfortunately, there’s not a lot to help us figure out, you know, what’s the best thing for this patient in front of us? Maybe I’ll start with you, Jessica. What do you consider when you think about front-line therapy for a patient with EGFR-mutant lung cancer?

Dr. Jessica Bauman:

So, I think that, I would say this is the million-dollar question right now because I think we don’t necessarily have a perfect answer. I think that, eventually, we’re going to see more mature data from both FLAURA2 and MARIPOSA, which will hopefully include more of a question about what does the survival difference look like if there is a difference because really what that’s asking is, do we sort of throw everything upfront at our patients to give them sort of the best initial chance of response and duration of response, or is there merit in sequencing therapy?

And I think the challenge is we don’t necessarily know the answer to this right now, and so we’re then caught with this question of, well, how do we approach first-line therapy? Do we do monotherapy with osimertinib, or do we do combination therapy with an EGFR inhibitor with either chemo or with amivantamab. And the trouble is that, with osimertinib plus chemo or amivantamab plus lazertinib, you do see a significant increase in toxicity, even though you do have better progression-free survival, at least when you compare the trials numerically. And so then I think that, with that, it really is a conversation with patients and their families about their own values, sort of our expectations of treatments, what they’re willing to tolerate in terms of their treatment, and that makes it a really rich and important conversation but a challenging one, because we don’t have the perfect data to allow us to answer this.

Dr. Gregory Riely:

Yeah. It’s a really tough situation. And, you know, we do try to personalize this based on patient preference. And so, you know, a lot of people have very clear ideas that they don’t want to come for chemotherapy very often, or they have other clear ideas that they want the most aggressive treatment course you have to offer.

Sandip, when you look at the data that are out there, is there anything that you look at? Maybe it’s about sites of metastases, molecular background, or other factors that really push you toward one treatment or another.

Dr. Sandip Patel

It’s a great question. I think there are only two things I strongly believe in this scenario. One is erlotinib is probably a subpar option compared to the others. It doesn’t have CNS penetration, and so I think that would probably be the one answer that would be less reasonable. The other is sometimes we’re talking about biomarker testing and the kinetics. You can actually have a PD-L1 greater than 50% in about 40% of patients with EGFR mutations. And so, if you knee-jerk react to that, and you start that patient on an immunologic, I think that’s also the incorrect answer. I think between chemo plus osimertinib (FLAURA2), amivantamab plus lazertinib in the front-line (MARIPOSA), and osimertinib by itself (FLAURA), I think these are all reasonable options for patients, and I discuss them all.

I think, for the majority of patients, the one thing I strongly believe is they should get a small-molecule CNS-penetrative TKI, chemotherapy, and amivantamab in their first two lines of therapy. And so, really, the question is, do you need to use all your arrows in the quiver upfront? Maybe for a patient in extremis with high-risk features, p53, maybe, you know, are shedding cell-free DNA, or are not having the response you expect a couple weeks in. I think these are the questions we’re really struggling with.

We saw topline, at least press release, from MARIPOSA with an improvement in the median survival. But what does that look like for patients? And can you get therapy maybe later on with amivantamab, spare yourself not only the direct toxicities of these agents, which with amivantamab are skin and GI, but also time toxicity? The amount of time you spend in the infusion center. But this may be improved at least with subcutaneous administration.

So, I think we’re frankly left with more questions than answers in the front-line space. I think this is where Jessica’s point about shared decision-making and the patient’s priorities matter. You know, this patient, I think is 68 and if she lives 2 hours away and has multiple comorbidities, maybe she just wants a pill, so I think osimertinib is the clear option. Maybe it’s a younger patient, thinking in terms of front-line treatment options, maybe that from MARIPOSA or FLAURA2 may be more up that person’s alley. So, I think, we talk about personalized medicine from a genomic standpoint. Here, it’s equally important from a social standpoint of the patient’s goals as well.

Dr. Gregory Riely:

Thanks. I think we have really highlighted the challenges in thinking about first-line therapy for patients with metastatic disease and look forward to thinking more about how we target EGFR in other disease settings in the next cases.