Optimizing Frontline Therapeutic Strategies in EGFR-Mutated Advanced NSCLC

In an Around the Practice program hosted by CancerNetwork®, a panel of experts in thoracic oncology convened to discuss how to properly choose and sequence front-line therapeutic options for patients with advanced non–small cell lung cancer (NSCLC) harboring EGFR mutations. The group weighed the efficacy, safety, and administration profiles of regimens including osimertinib (Tagrisso) monotherapy in the phase 3 FLAURA trial (NCT02296125), osimertinib plus platinum-based chemotherapy and pemetrexed in the phase 3 FLAURA2 trial (NCT04035486), and amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze) in the phase 3 MARIPOSA trial (NCT04487080).^1-3 Furthermore, they discussed the adequate conditions for selecting one approach over another in the context of 2 clinical scenarios.

The panel was moderated by Zosia Piotrowska, MD, MHS, an instructor at Harvard Medical School and co-clinical director of the Massachusetts General Hospital Thoracic Medical Oncology Program. She was joined by Heather Wakelee, MD, FASCO, a medical oncologist and Winston Chen and Phyllis Huang Professor at Stanford Medicine; and Samuel Rosner, MD, an assistant professor of medicine at the University of Maryland Cancer Center.

Patient Case 1: Higher-Risk Disease and Intensification Considerations

Piotrowska: A 61-year-old man with former light smoking history presents with newly diagnosed metastatic lung adenocarcinoma. He undergoes a biopsy and then molecular profiling, which shows adenocarcinoma with an EGFR exon 21 L858R mutation and, like many of our patients, a TP53 comutation. He undergoes a PET scan and brain MRI, which show fairly high-volume disease. He has multiple lung nodules, and liver and bone metastases, and his brain MRI demonstrates 2 small sub-centimeter asymptomatic brain metastases. His ECOG performance status is 0, and he has no significant comorbidities. This is a healthy man who has good hematologic reserve, good renal function, and good liver function.

Walk us through how you approach a patient like this, how you present these different treatment options, how you would counsel him, and which regimen you would likely settle on.

Rosner: As you alluded to, there are certainly several aspects of his case that put him in that high-risk category, where we're probably thinking about escalation of therapy. Also, the fact that he has a great performance status, is fit, and has no significant comorbidities made me think that I wouldn't be worried about combination strategies. I'm certainly going to be talking to him about both FLAURA2 as well as MARIPOSA. I'd mention FLAURA, but probably color it by saying, "I am worried about your disease, so we have these options that show an improvement at keeping the cancer away longer, as well as a potential overall survival benefit." That probably leans us into that part of the conversation.

This is probably one of the few instances where I might have a bit of a preference between the 2 [options]. The one subgroup where there tended to be a bit of a signal in favor, perhaps, of FLAURA2 was patients with the L858R alteration, particularly when you have a comutation with TP53, where the MARIPOSA regimen showed pretty limited significant difference or magnitude of benefit with the addition of amivantamab in that particular cohort. I would probably lean toward FLAURA2 [while] explaining the regimen well, explaining the chemotherapy and the [adverse] effects associated with that, and how we would try to mitigate them. Assuming that the schedule worked with him, that would probably be what I would recommend. But honestly, you could go either way.

Piotrowska: Heather, I am curious to get your thoughts on this case and what you would recommend. If you can also specifically comment on the brain metastases, which are a common problem for our patients, how does that influence your treatment decision?

Wakelee: This is a patient where single-agent osimertinib would not be the right choice. How you choose between either FLAURA2 or MARIPOSA is difficult. When you look at all the subgroup analyses, I'm not sure that I was convinced by any of them differently across the trials. To me, if there's MET overexpression or something else, that would tip me toward amivantamab, and [for] anything else, I still tend to do more of the FLAURA2 regimen. We have a lot of experience using amivantamab/lazertinib in the second line because we did some of the trials in that situation, so I think about them working well there, where it's harder to get a patient to consider chemotherapy doublets in the second line and beyond. But again, there are so many ways of looking at that, and either one is the right answer.

When you bring in the central nervous system [CNS] metastases, adding chemotherapy to osimertinib or giving amivantamab plus lazertinib both have superior brain efficacy to osimertinib alone, which in and of itself has very good brain efficacy. Again, you don't get to one being better than the other in this setting; they're all better than single-agent osimertinib, which is much better than anything we had in the past. You can also give amivantamab and lazertinib when there's CNS disease, even leptomeningeal disease, after osimertinib. [Alternatively], if you've gone with amivantamab and lazertinib and you end up with lots of brain metastases or leptomeningeal disease, you can give higher-dose osimertinib. Pemetrexed and bevacizumab [Avastin] have worked in the brain long before we had tyrosine kinase inhibitors [[TKIs].

The good news is we have lots of options, and patients with brain metastases can do well.

Piotrowska: If we're picking FLAURA2 here, walk me through a bit about how you're monitoring these patients for toxicities. How often are you seeing these patients when they start on the FLAURA2 regimen? Are you starting both drugs on the same day? What are some of the practical considerations when you're giving the FLAURA2 regimen?

Rosner: One of the benefits of FLAURA2 is it's a little more flexible. You can oftentimes get the TKI approved once you get the EGFR mutation. Sometimes, patients are starting that a week or 2 before while waiting on getting chemotherapy, discussing chemotherapy, getting consent, and then authorizing it. Starting the TKI upfront is something that we tend to do, but it's certainly not wrong to try to make it coincide.

Usually, based on how the first cycle goes, that'll determine how the second cycle schedule goes. We're looking particularly at cytopenias, so whether we need to add G-CSF for that second cycle; the majority of the time, [we do] not. Some cumulative toxicity can [also] develop over those 4 cycles. But following those 4 cycles, we're seeing these patients every 3 weeks for the purposes of the infusion of the pemetrexed, and that is something we talk to the patient ahead of time about.

Sometimes, we run into issues in terms of renal function—not as much anemia, but certainly something that we're watching—as well as fatigue and the time toxicity of coming in every 3 weeks. Based on some of the encouraging data of patients who discontinued pemetrexed on FLAURA2, I'm not too hard on continuing it indefinitely, and I certainly am talking with the patient about whether we need to take treatment breaks or hold pemetrexed altogether. That's our general flow for FLAURA2, specifically.

Patient Case 2: Tolerability, Comorbidity, Access, and Single-Agent Considerations

Piotrowska: Our second patient is a 76-year-old woman with no smoking history. Her past medical history includes some chronic kidney disease—with a creatinine clearance that lives around 40 or so—and a history of a prior pulmonary embolism 2 years ago; she's on apixaban [Eliquis] therapy for that. She's also newly diagnosed with metastatic lung adenocarcinoma harboring an EGFR exon 19 deletion. Her overall disease burden is limited to the lung and lymph nodes, and her brain MRI is negative, so her disease burden is a bit more modest than our other patient. She is highly functional, independent, and lives alone, but she does live a bit further away from your clinic—about 2 hours away—and her family is a bit further away. Her ECOG performance status is about 1 to 2, and labs are notable for creatinine that's around 1.6; normal liver function.

Walk us through your approach to a patient like this. How do you think about the treatment options for someone like this?

Wakelee: This case is designed to be the case where you can still think about single-agent osimertinib. You will see patients like this in real life, and many of them will have at least one thing that makes you think about the combinations, so it becomes a conversation with the patient that weighs all these things. This is someone who doesn't have any of the obvious higher-risk features where we're worried that she's more likely to develop progression on single-agent osimertinib. From a clinical standpoint, this is a case of maybe [using] single-agent osimertinib, maybe with some circulating tumor DNA [ctDNA] follow-up—I don't do that routinely yet, but we think about it a lot—and close follow-up initially.

It will be important, from those first conversations, to have those "what if" conversations. What do we do a year from now, or 2 years from now, when you're not as independent, your disease is going to need some additional treatment, and you're by yourself? It is important to bring those conversations in early with someone where you do realize that, as you get later in the disease course, they're not in an ideal situation to be able to get care. What other support do they have?

For this patient, single-agent osimertinib would certainly be a reasonable option. I don't worry so much about the prior pulmonary embolism; that's not an exclusion for amivantamab and lazertinib.

Piotrowska: Sam, how would you approach this patient? How would you have that conversation with them?

Rosner: I totally agree. This case was designed both from a disease biology perspective and from a support-system, external-factors perspective as well. If [her disease is] amenable to local therapy following initial treatment, I would talk about that and almost pitch that as a way for escalation in a very catered way toward her case, assuming that it was amenable to that.

Piotrowska: For a patient like this, I would certainly be thinking about that as well. Heather, how about you?

Wakelee: Absolutely. That is something I bring in with most of my patients. After X period of time, usually 2 to 3 months, we'll see what the imaging looks like, we'll maybe think about getting a PET, and decide whether this would be someone where additional consolidation hopefully allows [for] a longer TKI response.

Piotrowska: How often are you seeing patients? At what intervals are you getting scans for a patient who's on osimertinib monotherapy?

Rosner: Normally, I'll do a couple of toxicity checks early on, like a 2-week check and then a monthly check. Ultimately, patients are graduating, and I'll normally get a scan right around that 2- to 2-and-a-half-month time point, where we tend to see the peak effects of osimertinib. That's my initial point where we've decided, especially based on response and tolerability, we can start creating some independence from our clinic, and ultimately get patients to an every-3-month schedule.

Depending on what their labs are and how well they're tolerating [treatment], we’ll sometimes do monthly lab checks, particularly in the beginning, especially if they have some sort of cytopenia that we're watching. But that is one of the benefits of it: you get a lot of freedom from us. They get to forget about coming to clinic for a long time. There is a liberalization to it.

Key Takeaways for Optimizing Frontline Care

Piotrowska: As we close, I want to bring things back to basics and ask you each to share one key message for our community oncology audience about how to personalize and optimize first-line therapy for patients with advanced EGFR-mutant lung cancer.

Rosner: Building support systems in place to be able to safely guide patients through combination therapy is incredibly important. It's easier said than done, and not every clinic has the resources for it, but that's going to set you up for success. We come in with our own preconceived notions but really hearing out what the patient has to say and their goals of care can oftentimes drive the discussion and ultimately the decision. Those 2 things certainly came up a lot in our conversation.

Piotrowska: Heather, how about you?

Wakelee: For the community oncologists, make sure to do [molecular] testing. Don't assume you know what's going on with the tumor without doing the testing. Especially with ctDNA and a lot of the companies out there, we can get those results back fast enough to have it be meaningful for the patient. Don't leap to whole brain radiation until you've got all that information.

Then, there is a lot to talk through with the patients, but if there's higher risk because of comutation with TP53 or disease burden, don't talk about single-agent osimertinib too much. Focus on why those combinations have better survival. Then, at the point of progression, don't be afraid to repeat testing to understand the mechanism of resistance because that often can give you the best next-line therapy. Thinking about trials, I know a lot of community sites have great trial options, and those partnerships with your academic partners might work out as well.

References

1. Ramalingam SR, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662
2. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434
3. Cho BC, Lu S, Felip E, et al. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498. doi:10.1056/NEJMoa2403614