This podcast features nurse practitioner Elizabeth Krueger and physician associate Sam Vafadar, discussing their approaches to individualizing first-line treatment options for patients with EGFR-mutated NSCLC based on the latest evidence and how they work with patients to promote adherence and manage adverse events.
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In this episode, Elizabeth Krueger, NP, and Sam Vafadar, DHSc, PA-C, discuss how they optimize first-line EGFR-targeted therapy for patients with EGFR-mutated NSCLC, including:
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Presenters:
Elizabeth Krueger, NP
Center for Thoracic Cancers
Mass General Brigham Cancer Institute
Boston, Massachusetts
Sam Vafadar, DHSc, PA-C
Physician Associate
Department of Thoracic Oncology
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida
This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Personalizing EGFR Mutation Positive NSCLC Care: Case Challenges and Skill-Building Strategies for the Advanced Practice Provider
Today, we are talking about EGFR lung cancer. Lung cancer is the leading cause of cancer‑related mortality worldwide. Unfortunately, most patients present at advanced stages when curative approaches are not feasible. Eighty percent of these lung cancers can be classified as non‑small cell lung cancer, which opens a door to diverse molecular landscapes.
Today, our focus is on EGFR or epidermal growth factor receptor‑mutated lung cancer. EGFR‑related lung cancers make up about 17% of all oncogenic driver mutations in lung cancer, with a higher prevalence in non‑smokers and Asian populations.
The most common drivers are exon 19 and L858R, which constitute about 85% of EGFR lung cancers. There are other less common drivers, one being exon 20, that has some specific tailored therapies.
As we start to talk about EGFR lung cancers, Sam, when you have a newly diagnosed patient with metastatic EGFR lung cancer, what are the therapies that you begin to think about?
Sam Vafadar (Moffitt Cancer Center): Within EGFR lung cancer, it is interesting because for a long time, I have struggled to define precision medicine. Now in EGFR lung, there is no better example than this space. The most important shift to realize for us APPs is to recognize that first‑line EGFR‑mutated metastatic non‑small cell lung cancer is no longer a standard conversation. For the common EGFR mutations that you mentioned, the exon 19 deletion, L858R, I think about it as a strategic decision point with three choices: osimertinib alone, osimertinib + platinum‑pemetrexed chemotherapy, and amivantamab + lazertinib. Each is a unique strategy, and they represent different philosophies of care.
Osimertinib alone is a very simple oral therapy that has been around for years now and initially was approved in the second‑line setting, but now we know that it is essentially the standard first‑line approach upon which the other two regimens are built.
Osimertinib alone is simple, effective, very CNS active, and generally manageable long term. Then we think about adding intensification treatment with chemotherapy. Osimertinib + chemotherapy as an intensification strategy where we are trying to improve disease control and survival upfront.
Amivantamab + lazertinib is a chemotherapy‑free intensification strategy that target both EGFR and MET biology together. Clinically, I don't frame the question as what is the one standard? I frame it as, which strategy best fits the patient's disease biology, symptoms, comorbidities, goals, logistics, and tolerance for toxicity?
Liz Krueger: I would echo what you say. It is a complex landscape now, deciding among these three options for patients. When I think about the first treatment option that you mentioned, just osimertinib alone, we know that that was approved based on the FLAURA regimen that demonstrated improved overall survival as compared to earlier generation TKIs like erlotinib.
When we use osimertinib, I often reach for this single line of therapy in individuals that are maybe more frail, have significant comorbidities, where travel could be either cost‑prohibitive or too difficult for the individual. Maybe their performance status is not quite up to par, and they might not be able to tolerate the more intense therapy with either osimertinib + chemotherapy or amivantamab/lazertinib.
When we think about osimertinib with chemotherapy, it is exciting to learn some of the newer FLAURA2 data that demonstrated improved progression‑free survival and overall survival as compared to osimertinib alone. We are seeing that the median overall survival is four years now, or 10 months more than osimertinib alone.
When we think about the two intensified options, either osimertinib with platinum‑pemetrexed or amivantamab/lazertinib, I think about a few things when making a choice between those two more intensified regimens. For carboplatin and pemetrexed + osimertinib, we might choose that for individuals with more CNS disease, given the CNS penetrance of both osimertinib and pemetrexed. Individuals that are at higher risk of venous thromboembolism, we might reach for this given the increased risk of clot with amivantamab + lazertinib. Those with pre‑existing dermatologic conditions, we might avoid the latter.
Amivantamab and lazertinib, as we have seen with the MARIPOSA data, that amivantamab + lazertinib compared to osimertinib alone demonstrated an improved overall survival with this combination. The median overall survival has not been reached yet, but projected to exceed more than 12 months as compared to osimertinib. This is a great chemotherapy‑free option with ways that we have learned to support our patients to tolerate this regimen.
Sam Vafadar: Yes, exactly. I think of it in this way. FLAURA established the backbone essentially. FLAURA2 supports osimertinib‑based intensification. MARIPOSA supports chemotherapy‑free intensification with amivantamab and lazertinib. You touched on an important thing, especially with regard to CNS disease, because we know that with lung cancer in general, this is a high‑risk population with metastatic disease to the brain very much a reality.
With CNS disease being a major factor, I would not say that CNS involvement automatically means escalation to osimertinib + chemotherapy. Touching on your point with bulky disease, that is another consideration that should remain when selecting one of these therapies.
Osimertinib remains by default, just very important because of its CNS activity. If a patient, let us say, is asymptomatic, has limited CNS disease or controlled CNS disease, and otherwise lower systemic disease burden, I think osimertinib alone sometimes is a very appropriate option. However, if CNS disease is part of a broader high‑risk picture, multiple lesions in the brain, active systemic burden, symptomatic disease, our practice generally is intensification with chemotherapy. CNS disease is an additional layer of context when choosing these options too.
Liz Krueger: Yes, that is true. As we guide our patients in making these decisions, the improved overall survival really becomes significant, and it is an individual decision for each patient that is it quality of life and ease of administration, or is it a deeper, longer response that is more important? That is different for everybody.
Sam Vafadar: One recent update from ASCO this year that I became aware of was for classic exon 19 deletion and L858R. The main EGFR update I would share is the CHRYSALIS‑2 cohort C, which looked at amivantamab + lazertinib in atypical EGFR lung cancer. We will get too much into that today, but it is worth noting that the EGFR space in general has become a dynamic subset of adenocarcinoma.
Liz Krueger: Yes. That gives hope to these individuals who have the less common EGFR mutations and traditionally and historically have not done as well on TKI or other directed therapies. This brings hope to the smaller subset of patients that are hoping for deeper and longer responses.
Another important update that I learned about has to do with MARIPOSA and amivantamab + lazertinib versus osimertinib. A really meaningful outcome is that we are seeing that early dose modifications of amivantamab, whether it be a skipped dose or a dose interruption or dose reduction, is not impacting progression‑free survival. I think that is going to make it easier for patients to tolerate. In the end, there is less pressure to stay at higher doses of amivantamab if they are having an uncontrolled toxicity that we can feel and know and be more comfortable with a dose reduction for our patients to hopefully improve adherence, outcomes, and just their ability to remain on the drug long term.
Sam Vafadar: I wanted to ask, what do we do in this space where our EGFR patient, let us say, has been on therapy for some time, either of these three regimens, and they are essentially on maintenance. Unfortunately, we know progression is an inevitability. We do not know when we have data to guide us. What does reassessment look like in your practice? How do you handle the different scenarios where somebody might progress?
Liz Krueger: Sure. That is a great question. It depends on what they have progressed on that will help us determine our next line of therapy. I can say, for example, second‑line treatment progression after being on osimertinib alone,
MARIPOSA‑2 data led to FDA approval of amivantamab in combination with platinum‑pemetrexed for EGFR‑mutated exon 19 deletions, or L858R, after progression on osimertinib alone.
Individuals saw a significant improved progression‑free survival over chemotherapy alone. The addition of amivantamab following progression on TKI has shown significant positive results for our patients. It is something that we are reaching for all the time.
I can say it can be tricky for patients who have been on TKI for a long time to leave the osimertinib and change therapies, but it has been extremely successful in controlling disease for these patients in the second line.
Sam Vafadar: Yes, that is a great point. It makes me think of how different it is usually with the standard chemotherapy approach, where my thinking is either it works, or it does not. It can be frustrating when somebody is on osimertinib on maintenance, and they have what we call oligoprogression in one site. Do we abandon treatment altogether, or can we spare it? I think about it in three ways: what is the pattern of progression? If it is oligoprogression, then local therapy could be continued in a reasonable way in select patients.
Second, is there CNS progression? If CNS is the only site, we might need just radiation oncology input, neurosurgery in rare cases, and careful thinking about whether to continue osimertinib if systemic disease is still controlled.
Finally, with MET amplification, what is the genomic profiling? What is the resistance mutation? What could we find when we repeat a biopsy?
I think that biology matters because post‑osimertinib progression, we are discovering is very heterogeneous. Some patients might have a targetable resistance mechanism, and others might not. Unfortunately, we know that small cell transformation is a reality, too.
Liz Krueger: Right. Yes. You cannot really understate the importance of repeating biopsy at progression. Obviously, the tissue is the gold standard, but checking circulating tumor DNA, too, if biopsy is not feasible, to help come up with a precise treatment plan for patients at that time.
Adverse Events: Identification and Management
Sam Vafadar: When we think about these studies, I want to shift to adverse events identification and management. Liz, what are you watching for with these osimertinib‑based regimens and amivantamab and lazertinib?
Liz Krueger: Yes. There are some overlapping toxicities with these drugs, but then there are some that are distinct. For osimertinib alone, we know that there are normal EGFR receptors throughout the GI tract. We monitor for stomatitis, we monitor for diarrhea. How do we manage diarrhea? With adding antimotility agents, brief dose holds, or dose modifications if necessary. The same goes for stomatitis. If there is mouth irritation related to osimertinib: baking soda rinses, adding a PPI, and then having a low threshold to check labs to make sure that the neutrophil count is within normal range. Sometimes we see more mouth sores if there is concurrent neutropenia.
Other do‑not‑miss things with osimertinib is pneumonitis: new shortness of breath, dry cough, and then monitoring labs closely. Q2 weeks typically for the first six weeks, and then every one to three months thereafter, looking for LFT elevations, and then following CBC.
Other considerations are rash. This is where it begins to overlap a little bit with some of the other regimens. For osimertinib, it is typically an acneiform rash that can be managed with topical clindamycin or oral minocycline, doxycycline if needed, and then dose modification or dose hold if necessary.
When do we start to think a little bit more about amivantamab‑containing regimens, particularly amivantamab + lazertinib, the skin toxicity prophylaxis actually is something that is a little bit more detailed than what we would use with osimertinib alone.
When starting a patient on amivantamab + lazertinib for skin prophylaxis, we begin doxycycline 100mg bid weeks 1‑12. After week 12, then we use topical clindamycin lotion to the scalp daily. This oral antibiotic helps with acneiform rash that can be on face and chest, but also the scalp. The scalp can be affected, particularly with this combination, and so instead of reacting to a dermatologic toxicity, preventing that toxicity with the COCOON regimen, which includes the oral antibiotic, and then topical clindamycin can be very, very effective.
Additionally, we think about paronychia or irritation to the nail bed, so using chlorhexidine to the fingernails and toenails daily for the first 12 months on therapy can also help in preventing any paronychia or infected nail beds.
We know that skin can become dry and irritated, so using a ceramide‑based moisturizer daily for at least the first 12 months on therapy can also be very helpful.
Something unique to amivantamab + lazertinib is the addition of venous thromboembolism prophylaxis for the first four months. That has shown to prevent the incidence of DVT, PE, which has decreased the incidence of VTE in individuals on this regimen.
Other things specific to amivantamab + lazertinib that I also follow for is pneumonitis: lung inflammation, any shortness of breath, cough, bowel changes, more likely diarrhea.
The other that can also be trickier to manage is oedema or hypoalbuminemia related to drugs, so making sure that patients are using compression, moving, but then elevating their legs when they are at rest. On occasion, sequential compression devices can be used at home if the edema becomes significant.
The important thing that we learned is that dose modification is not affecting progression‑free survival in this patient population. We can dose‑modify, we can dose hold in order to make this regimen more tolerable if needed. We have seen that, know that in other drugs, but now we have that data and can take that to our patients and provide reassurance as they begin their therapy or encounter other adverse events.
Sam, is there anything that you would add to that or that you do differently with your patients on these regimens?
Sam Vafadar: You hit the nail right on the head. That is exactly how we would manage our patients with the EGFR mutations and on treatment. I think about toxicity by treatment class. Really, the toxicity considerations go hand‑in‑hand with the treatment selection, and who the patient is that we are recommending treatment to.
You mentioned osimertinib; we have a lot of experience managing over the years. Even with the older EGFR inhibitors know what to expect based on that class effect of the EGFR receptor. Think of it this way, with essentially intensification strategy of treatment, you get intensification of toxicity. By no means necessarily should it scare us from choosing the intense treatment. However, I think it matters who the patient is, who the right patient is for that treatment.
For instance, it is no surprise that with osimertinib and chemotherapy, with the FLAURA2 regimen that we are going to see myelosuppression, fatigue, nausea, renal function, of course, as a possibility, just with chemotherapy alone, neuropathy, or just cumulative tolerability.
With dose reduction strategies and chemotherapy, as well as with osimertinib, there are mitigation strategies. I think you touched on the very important points, especially with the unique side effects with amivantamab and lazertinib: VTE risk, hypoalbuminemia, and the ocular symptoms too, and pneumonitis, of course.
Liz Krueger: In that same vein, another really important update that we have seen in how we make treatment more tolerable to patients is, how do we mitigate the infusion‑related reactions that we have seen with intravenous amivantamab. With the advent of subcutaneous amivantamab, the drug has been much more tolerable for a patient. We have eliminated the need for split IV dosing. We have cut down their chair time. Some of that opportunity cost for patients having to come back and forth to clinic for extended periods of time. These patients are sick. Their time is limited. As much of that time we can give back to them is really invaluable.
Subcutaneous amivantamab has really been a wonderful change moving forward. I can say that we rarely use intravenous amivantamab. That subcutaneous has been better tolerated from an infusion‑related reaction standpoint and time. That has been significantly mitigated with that change.
We have seen that data come out in the COPERNICUS study, where prophylactic supportive measures are minimizing the dermatologic venous thromboembolism risks and then the infusion‑related reactions. That has been an important step forward. That helps with compliance, too. Now that amivantamab can be given subcutaneously once every four weeks, either with chemotherapy or alongside oral lazertinib, that is less time in the clinic for patients and more time back for them.
Sam Vafadar: Exactly. It is nice that ‑ and you mentioned this earlier ‑ that we have the COCOON and SKIPPR studies to guide us for those, especially on the IV formulation. For this regimen in particular, I would say, going along with that intensification schema with amivantamab and lazertinib toxicities, the management should be proactive. We mentioned this in the beginning. We are educating our patients in the very beginning, "This is how to take dexamethasone." I find written handouts especially helpful with a calendar for those patients, especially on the IV formulation to start dexamethasone two days prior, one day prior, eight milligrams, just as the package insert says. Our plans have premedications with IV dexamethasone, diphenhydramine, and acetaminophen as premeds before the infusion.
You're right, the subcutaneous has certainly been a logistical and quality‑of‑life game changer. We are doing all of these studies to where we are measuring endpoints such as time to disease‑free survival, overall survival. It makes me question if we do these long chair times and things like that, how much time are we truly giving back to the patients? I think, again, factoring in quality of life with our treatment decisions is really important.
Sam Vafadar: I wanted to ask, Liz, what strategies do you utilize to support adherence for these, especially the oral therapies such as osimertinib and lazertinib? How are you ensuring that patients stay on the pill therapies? I know in my clinic, sometimes some patients may be a little reluctant to admit they had to hold off on a dose or had to dose‑reduce themselves. An interesting way to approach this with our patients.
Liz Krueger: Yes. Making sure that the lines of communication are open, including family or support persons in all discussions, and then letting people know that it is okay if you miss a dose. It is okay. Often, we hold, and that is the beauty of daily dosing, that we can hold for toxicity and then restart right back when we need to. Providing reassurance that it does not need to be perfect, but we want them to take it as much as possible to prevent progression and any other changes.
Sam Vafadar: It makes sense that we use osimertinib as a backbone, and we know we can intensify treatment with chemotherapy. It stands to reason can we use osimertinib earlier in earlier‑stage lung cancers? What is your strategy on this approach?
Liz Krueger: Yes. That is, as we have talked about, the landscape for EGFR lung cancer is constantly changing. The ADAURA Phase III study has shown that adjuvant osimertinib used after resection in stage 1B through to stage 3A has led to a significant improvement in overall survival. There is a longer disease‑free interval than placebo, and there is a decreased incidence of metastatic disease, particularly in the CNS, because of the CNS protection that osimertinib has provided.
Individuals are on it up to three years after therapy, but sometimes longer. We are finding that in our clinics, there is more discussion about once you have hit that three‑year period of being on adjuvant osimertinib, is that the right time to stop, or do we continue it? Often, patients are hesitant because they see that as their lifeline and something that has protected them for the preceding three years. That is something that will continue to evolve over time as well.
Sam Vafadar: Yes. It is a three‑year investment. I think that many of my patients want to know what is next, even after a curative surgery and definitive chemotherapy. A lot are okay taking a pill therapy to prevent recurrence or to reduce the risk and offer that CNS protection that you mentioned. Some may not be, some may want to never see us again. That is the goal where we work. Never to see us again. That is a nuanced discussion still. I think we should still follow these patients pretty closely as we would in the metastatic setting, especially with toxicity and managing that, and dose reducing when needed or when appropriate.