Updates in Second-Line EGFR-Mutated Non–Small Cell Lung Cancer

Samantha Conlin:

Hello and welcome to JADPRO's roundtable discussion on Updates in Second-Line EGFR-Mutated Non–Small Cell Lung Cancer. My name is Samantha Conlin, and joining me today are my colleagues, Mary Ellen Flanagan and Hailey Hunter. We are thoracic nurse practitioners at Washington University School of Medicine in St. Louis, and I'll let you both introduce yourselves.

Mary Ellen Flanagan:

Hi everyone. I'm Mary Ellen Flanagan.

Hailey Hunter:

I'm Hailey Hunter.

Samantha Conlin:

Thank you both for joining me today. In this first video roundtable, we'll be focusing on the current treatment landscape of EGFR-mutated non–small cell lung cancer with a focus on second-line therapy as well as future directions.

Mary Ellen Flanagan:

Thank you, Sammy. It's a real honor to be presenting with the two of you. It's a really exciting time to be advanced practice providers in thoracic oncology. Just a brief review to start off: more than 50% of patients with non-squamous non–small cell lung cancer have oncogenic drivers that potentially impact treatment choices. EGFR, which stands for epidermal growth factor receptor, is a protein located on the surface of cells that helps them grow. When there's a mutation in the gene, it causes the cells to grow too much and is the basis of cancer. Two mutation deletions in exon 19, and the amino acid substitution in L858R and exon 21 are often referred to as classical EGFR mutations. These two mutations together account for around 85% of EGFR mutations in non-small cell lung cancer. And for the purposes of our discussion today, we'll be focusing on these two alterations.

As shown here, there are three approved frontline regimens for treatment of metastatic EGFR-mutated lung cancer. As we will discuss, each approved therapy has benefits and risks making this an interesting topic of discussion. Results from the FLAURA trial were published in the New England Journal of Medicine in 2018. This trial randomized patients to receive osimertinib versus a comparator EGFR TKI, either gefitinib or erlotinib. The side effect profile favored osimertinib as did progression-free survival and overall survival findings. This was practice changing. Osimertinib monotherapy has become the gold standard. We're familiar with the dosing of 80 mg daily. We're also familiar with the side effects including diarrhea, skin toxicities, and nail changes.

Moving on to FLAURA2, this trial was published a few years later and in the New England Journal of Medicine in 2023. It investigated osimertinib with or without chemotherapy, in these patients with EGFR mutations. The addition of platinum and pemetrexed had improved the overall response rate from 76 to 83% and the duration of response from 15.3 months to 24 months. The median progression-free also improved from 16.7 to 25.5 months. The favorable outcomes for the chemotherapy and osimertinib arm in FLAURA2 in regards to duration of response, however, did not come without a cost. As indicated here, adverse events were higher in the combination arm and the chemotherapy arm had significantly higher grade 3 or higher events. Hailey, I wanted to ask you, what are some thoughts that go into your decision to treat a patient with single-agent osimertinib? What does this patient look like?

Hailey Hunter:

That's a great question, and when you're having these first-line discussions with your patient, they're just learning that they have a metastatic lung cancer, their livelihood's going to change how they move about their daily life. But are they young? Most of these EGFR-mutated patients are younger. They're parents, they have full-time jobs. These are all factors that play into your treatment decisions. If they're relatively healthy with not a lot of disease burden, single-agent osimertinib can be a great treatment option. Single-agent osimertinib works really well for patients that want to avoid chemotherapy, they want to avoid the every-3-week intravenous treatments. It could also be an elderly patient that may not have enough performance status to do chemotherapy in combination with osimertinib. The other thing to consider when choosing treatments for these patients is do they have another co-mutation that makes the cancer a bit more aggressive in which those patients would benefit from chemotherapy plus osimertinib in the first-line setting.

Samantha Conlin:

Hailey, I agree with your comment about these lifestyle changes in these young patients. Considering what they do for work, can they be off work to see us every 3 weeks for treatment? These are all things we have to factor in and use that shared decision making with our patients as to what extent we can use to treat them.

Mary Ellen Flanagan:

It's a tricky time and there's so many things that factor into how we handle this. Moving on to MARIPOSA, this is a phase 3 trial that investigated the combination of amivantamab. Amivantamab is an EGFR and MET bispecific antibody. This trial investigated amivantamab with lazertinib against osimertinib in previously untreated patients with advanced EGFR mutation–mutated non–small cell lung cancers in the frontline setting. Lazertinib overall seems to be comparable to osimertinib in terms of efficacy and the toxicity profile. The MARIPOSA study results were first presented at ESMO in 2023. They were then published in the New England Journal of Medicine June 2024, and based on the results, it was approved by the FDA for frontline treatment in August 2024. Findings showed a statistically significant improvement in progression-free survival for the combination arm when compared to osimertinib.

Recently, the overall survival data was presented at the European Lung Cancer Congress in March 2025, and it showed that the amivantamab arm may extend life by 1 year or more when compared to the osimertinib arm. The big question is for us is it worth it? Yes, the data is compelling, but amivantamab certainly comes with some baggage. Later on, we'll discuss some of the tools we use to overcome the skin toxicity and infusion-related reactions in particular.

Sammy, I want to ask you, is there a patient that you have in mind that you think, "This would be a MARIPOSA patient that I want to use this regimen in the frontline setting?"

Samantha Conlin:

Thanks, Mary Ellen. This is really rare, but if I had a patient with a MET amplification at baseline, I can definitely consider myself encouraging the combination of amivantamab plus lazertinib. We're personally getting more comfortable with these drugs and how to manage these toxicities, and obviously the overall survival data is convincing in certain patients. Again, the shared decision making comes into play in these conversations on how we would treat them based on their age, their comorbidities, and again, can they tolerate these long infusion days, that sort of thing.

Mary Ellen Flanagan:

This is a debate that I love to discuss, and I know Hailey and Sammy do as well. It touches on everything important to us as providers. It's highly individualized and it's important that we as providers understand not only the data associated with the three frontline options, but the potential impact on our patient's quality of life. I sometimes have a tendency to want to do a cross-trial comparison, especially with such a debatable topic. However, it's important to know that there were certainly differences between the frontline trial options. For example, the serial brain MRIs were required for all patients in the MARIPOSA trial, but not in FLAURA2, and no crossover was allowed in the MARIPOSA trial, but access to sequential chemotherapy in FLAURA2 was allowed.

Hailey, what are your thoughts? What are your key takeaways from this debate?

Hailey Hunter:

Again, as we said before, you really have to think about the patient when you're choosing their frontline treatment options. And overall, you're not the one choosing the option, the patient essentially is, but it is your job to educate them with the data and what each regimen would look like for them on an everyday basis. I don't like to choose my frontline options assuming failure, but in these EGFR metastatic patients, we know eventually that they are going to develop a mechanism of resistance and have disease progression at some point. We just don't know when that is. Of course, we want to give the patients the best frontline treatment we can, but we need to be smart. We need to be methodical because we also know that our second-line options are really dependent on the first-line options.

Mary Ellen Flanagan:

Thank you, Hailey. That's a perfect segue into the topic of looking at second-line options for our patients with classical EGFR mutations. We could truly discuss frontline options for hours because it's such an exciting time. This is the definition of precision medicine, and we're providing care that's highly individualized. Nevertheless, the treatment landscape in the second line, just like the frontline, continues to evolve. Moving to the second-line and beyond used to be very straightforward. We would treat with osimertinib, we would evaluate for a mechanism of resistance at progression in the tissue or blood, and if we didn't find anything, we would add chemotherapy.

Sammy, tell me your process now in the current treatment landscape, what you do if you start a patient on osimertinib and they have disease progression.

Samantha Conlin:

What we do on a patient when they start to progress on osimertinib is we would first see where exactly they're progressing. Is it one site of disease? Is there multiple sites of disease? Can we radiate and keep osimertinib going? We also would like to exhaust that option before moving on to other options. I like this chart here because it shows the options of when we go from osimertinib, is there extensive progression? Is there oligoprogression, and has there been any transformation? Where Mary Ellen was mentioning the tissue biopsy versus the liquid tumor biopsies to see if there's any mutations that we would then lean on next before choosing our next line of therapy.

Mary Ellen Flanagan:

Thanks Sammy, it's a tricky time. We were able to attend ASCO this year, and ASCO is at the beginning of June, and the data presented is already outdated because following ASCO, datopotamab-deruxtecan was approved. In light of our ever-changing field, we have to think about our options, and it's an incredibly exciting time. As we discussed, patients with advanced EGFR-mutated non-small cell lung cancer benefit greatly from treatment that targets the actual mutation. As Hailey mentioned, though, these patients inevitably have disease progression and develop mechanisms of resistance.

Once therapy with the EGFR inhibitor and standard platinum-based chemotherapy are utilized, the options are quite limited. Now we have datopotamab-deruxtecan, or dato-DXd, and it represents a new alternative for these patients. The FDA granted accelerated approval to dato-DXd for patients with EGFR-mutated non–small cell lung cancer who have received prior EGFR-directed therapy and also had platinum-based chemotherapy. When we look at the two clinical trials that looked at dato-DXd—TROPION-Lung05 and TROPION-Lung01—there were 114 patients with EGFR-mutated cancer who had received prior directed therapy and platinum-based chemotherapy. Out of these patients, 43% experienced tumor decrease with dato-DXd, and the treatment response often lasted more than 6 months. Side effects of special interest, which we'll talk to during our next video, including mucositis, eye toxicity, and pneumonitis. This is a new and different way of treating cancer. And I'm curious, Hailey, how do you describe antibody-drug conjugates like dato-DXd to your patients?

Hailey Hunter:

Thanks, Mary Ellen. Essentially, I try to keep the explanation of how these drugs work fairly simple, but antibody-drug conjugates essentially work like a guided missile. They are composed of an antibody that's going to bind to a target on the cancer cell, and in the case of dato-DXd, the target on the cell is Trop-2. The drug then binds to the specific protein on the cancer cell and essentially takes the chemotherapy directly to the cancer cell. The reason this becomes important is it delivers a concentrated dose of chemotherapy directly to the cancer cell, which minimizes the damage to the healthy cells.

Mary Ellen Flanagan:

It's certainly a new weapon in our tool box. Looking at the future, it's exciting. We've mentioned, and I think researchers are looking at how to utilize this unique class of drugs that Hailey just described, these antibody-drug conjugates like dato-DXd alone, and in novel combinations for patients with EGFR-mutated non–small cell lung cancer.

Sammy, what are you excited about when you look at the future of these patients?

Samantha Conlin:

Thanks, Mary Ellen. When I started working as a thoracic nurse practitioner 8 years ago, my mentor that I worked alongside closely would always say that we're going to war with two bullets. And over the last several years, we've really transitioned into these newer, more effective treatment lines, giving our patients more options. And being a part of Washington University and being able to be alongside these clinical trials, it's awesome to be able to experience these firsthand and be able to, again, give ourselves more treatment options for our patients.

Mary Ellen Flanagan:

The key takeaways from this first video are, as advanced practice of providers, we need to understand the three approved frontline treatment and how to implement them, and the importance of shared decision-making with pharmacy, our patients, our collaborative physicians, and then at the time of progression, incorporating repeat biopsies, both liquid and tissue, and having a good understanding of our ever-changing second-line options.

Samantha Conlin:

Thank you so much, Mary Ellen. That was a great discussion to get us started today. This concludes our discussion on the current treatment landscape of EGFR-mutated non–small cell lung cancer. I'd like to thank Mary Ellen and Hailey for joining me today and for more information and to view our other discussions on Updates in Second-Line EGFR-Mutated Non-Small Cell Lung Cancer, please visit JADPRO.com.