In a CancerNetwork^® Face-Off event, experts in thoracic oncology divided into 2 teams to debate the utility of notable frontline therapeutic strategies for patients with EGFR-mutated non–small cell lung cancer (NSCLC): the phase 3 MARIPOSA (NCT04487080) regimen and the phase 3 FLAURA2 regimen (NCT04035486). The 2 teams—Purple Reign and Thriller—competed across 3 domains: clinical data updates on the aforementioned trials, hot topics in the EGFR-mutated NSCLC space, and patient cases.

Team Purple Reign included:

• Misako Nagasaka, MD, PhD, an associate professor in the Division of Hematology and Oncology, Medicine at University of California Irvine Health
• Estelamari Rodriguez, MD, MPH, associate director of Community Outreach in Thoracic Oncology at University of Miami Health System
• Luis Raez, MD, medical director and chief scientific officer of Memorial Cancer Institute at Memorial Healthcare System

Team Thriller included:

• Mary Jo Fidler, MD, a medical oncologist at Rush University Medical Center
• Hatim Husain, MD, a professor of Medical Oncology at University of California San Diego Moores Cancer Center
• Jonathan Riess, MD, MS, director of Thoracic Oncology and an associate professor of Medicine at University of California Davis Health

What is Face-Off? It is an educational program designed as a competition for teams to present to and against each other.

How does it work? There are 3 rounds: data presentations, topics, and patient cases. During each round, both teams can present and defend their ideas and challenge the other team. The judge determines who is worthy of the top prize.

Round 1: Data Presentation

Team Purple Reign on MARIPOSA

Presented by Estelamari Rodriguez, MD, MPH

In the international MARIPOSA trial, 1074 patients with locally advanced or metastatic NSCLC harboring documented EGFR exon 19 deletions or L858R mutations were randomly assigned 2:2:1 to receive amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze; n = 429), osimertinib (Tagrisso) monotherapy (n = 429), or lazertinib monotherapy (n = 216).¹ The trial’s primary end point was progression-free survival (PFS) per blinded independent central review (BICR), and key secondary end points included overall survival (OS), overall response rate (ORR), duration of response (DOR), intracranial PFS, and safety.

Of note, the median age was 64 years (range, 25-88) in the amivantamab/lazertinib arm and 63 years (range, 28-88) in the osimertinib arm; most patients were female (64% vs 59%) and Asian (58% vs 59%). Additionally, most patients in each arm had exon 19 deletion mutations (60% vs 60%) and adenocarcinoma histology (97% vs 97%).

Data showed that the median PFS was 23.7 months (95% CI, 19.1-27.7) in the amivantamab/lazertinib arm vs 16.6 months (95% CI, 14.8-18.5) in the osimertinib arm (HR, 0.70; 95% CI, 0.58-0.85; P <.001). Additionally, the median OS was not reached (NR; 95% CI, 42.9-NR) vs 36.7 months (95% CI, 33.4-41.0), respectively (HR, 0.75; 95% CI, 0.61-0.92; P = .005); the ORRs were 86% (95% CI, 83%-89%) vs 85% (95% CI, 81%-88%).

The amivantamab regimen produced a PFS benefit across subgroups based on the presence of TP53 co-mutations or wild-type disease; improvements occurred regardless of the presence or absence of circulating tumor DNA (ctDNA). Furthermore, the median intracranial PFS was 25.4 months (95% CI, 20.1-29.5) and 22.2 months (95% CI, 18.4-26.9) in each arm (HR, 0.79; 95% CI, 0.61-1.02; P = .07); the intracranial ORR was 78% (95% CI, 71%-84%) vs 77% (95% CI, 71%-83%).

Regarding safety, any-grade adverse effects (AEs) occurred in 100% of the amivantamab/lazertinib arm compared with 99% of the osimertinib arm, and 80% vs 52% experienced grade 3 or higher AEs. The most common AEs of any grade that were related to EGFR inhibition in each arm included paronychia (68% vs 28%) and rash (62% vs 31%), while the most common AEs related to MET inhibition included hypoalbuminemia (48% vs 6%) and peripheral edema (36% vs 6%). Key AEs over time, such as rash, venous thromboembolism, and interstitial lung disease, occurred most frequently during the first 4 months of therapy, with toxicities decreasing during months 5 to 8 relative to the first 4 months.

The team also highlighted early findings from the phase 2b COPERNICUS trial (NCT06667076), which evaluated subcutaneous amivantamab (Rybrevant Faspro) every 4 weeks plus lazertinib vs subcutaneous amivantamab every 3 weeks plus carboplatin and pemetrexed among those with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or L858R mutations.² With a data cutoff of March 16, 2026, AEs were mostly grade 1/2, with no new safety signals identified. Additionally, 8% of patients discontinued amivantamab due to AEs, and 6% of the total cohort discontinued due to treatment-related AEs (TRAEs). There were no grade 3 or higher bleeding events observed.

Team Purple Reign vs Team Thriller on Interpreting MARIPOSA

Fidler: What do you think about the duration of prophylaxis for some of the aspects of the COCOON [NCT06120140] regimen? For example, 4 months of the deep vein thrombosis [DVT] prophylaxis and the oral antibiotic prophylaxis that changes to clindamycin [Cleocin] shampoo.

Riess: To follow up on Fidler’s question, in terms of supportive care management, that definitely is helpful in terms of reducing AEs, but it comes at a price for patients. What’s the burden on patients to do all of this? You have DVT prophylaxis with apixaban [Eliquis], the rash, the oral antibiotics, the topicals, and the management of the paronychia in terms of these EGFR AEs that are potentiated. What’s it been like in your experience, in terms of burden on patients regarding time and getting access to DVT prophylaxis?

Raez: The first 4 months are the most difficult ones. We have people now on amivantamab for 2 years or more, and the degree of rash is much better…. Now, the degree of DVTs with the subcutaneous formulation [of amivantamab] is markedly less; you may not have to worry too much anymore. But the other thing you have to realize is that we have to give this regimen anyway. The only debate here is if you’re going to use it in the first line or the second line, but the patient has to go through this because we don’t have a lot of options. There are only 3 lines of therapy for EGFR, and then we go to conventional chemotherapy. The debate here is whether you want to do it first or you want to do it next year. We have to do it anyway.

Nagasaka: When you start a patient on first-line amivantamab and lazertinib, yes, it is true that all of the prophylactic supportive medications can feel overwhelming to some patients at first. But if you think about it, is it that overwhelming compared with osimertinib monotherapy? If you think about osimertinib and chemotherapy in that regimen, we are already having patients use folic acid, and dexamethasone for prophylaxis. Most times, patients do go home with some sort of nausea medications, whether it be olanzapine [Zyprexa] or prochlorperazine [Compazine] and ondansetron [Zofran]. I am actually dispensing a very similar number of new medications at the time of their frontline treatment, whether it be chemotherapy, osimertinib, or amivantamab. To me, the amount of counseling we have to do and the number of medications that the patient needs to fill are very similar.

Husain: I’ll also reflect on a point, perhaps on a different topic than supportive measures. I’ll recount one of my patients, who was diagnosed with metastatic disease and a brain metastasis at the time due to insufficient testing; They had surgery for the brain metastasis, radiation, and then started on chemotherapy. When we saw the patient, we did testing and found EGFR mutations. At that time, this predated osimertinib; the patient was started on erlotinib [Tarceva], and around 2017, for better tolerability, switched over to osimertinib. When I reflect on this case, this patient is now 10 years out from the diagnosis, including 7 or 8 years with osimertinib. I wonder if this patient, in today’s time, could have gotten a MARIPOSA-type regimen, but has had 8 years without any kind of tolerability concern with single-agent osimertinib.

In reflecting on MARIPOSA, what is being done to figure out who doesn’t need this escalated approach? What biomarkers or other things can we better invest in to figure out who actually needs the intensification and who does not? I know that there are some clinical parameters and some genomic signatures that can speak to this, but how invested are we in defining the best candidates for this [regimen]? Do you feel more is necessary in this regard?

Raez: The problem is, as I understand it, that if you come from carboplatin/paclitaxel, everybody dies in 1 year. Saying your patient has 10 years of survival on osimertinib, they are probably the only one who started osimertinib 10 years ago, because everybody else is not here. That’s why with osimertinib alone, the survival is [typically] 3 to 4 years. That’s unacceptable. You cannot put a patient on a drug and think it is acceptable to survive for years; the patients want to be cured. That’s why, the way I see it now, when we have these 2 regimens, the standard of care is the combination, and we are debating today if it’s FLAURA2 or MARIPOSA. Even the combination is not going to cure more than half of the patients, so we still have to raise the bar and do much better. That is why I don’t think that monotherapy is a standard of care anymore.

Team Thriller on FLAURA2

Presented by Jonathan Riess, MD, MS

In the international phase 3 FLAURA2 trial, 557 patients with nonsquamous NSCLC harboring EGFR exon 19 deletions or L858R mutations and no prior systemic therapy for advanced disease were randomly assigned 1:1 to receive oral osimertinib plus pemetrexed (n = 279) or oral osimertinib alone (n = 278).³ The primary end point was investigator-assessed PFS per RECIST v1.1 criteria; secondary end points included OS, ORR, DOR, and safety.

The median age was 61 years (range, 26-83) in the combination arm vs 62 years (range, 30-85) in the monotherapy arm, and most were female (62% vs 61%) and Asian (64% vs 63%) in each group. EGFR exon 19 deletions were reported in 61% vs 60% of each group, and 99% of both arms had adenocarcinoma histology.

Data showed a median PFS of 29.4 months (95% CI, 25.1-not calculable [NC]) in the osimertinib/pemetrexed arm and 19.9 months (95% CI, 16.6-25.3) in the osimertinib monotherapy arm (HR, 0.62; 95% CI, 0.48-0.80; P <.001), with respective disease control rates (DCRs) of 95% (95% CI, 92%-98%) and 93% (95% CI, 90%-96%). According to the final OS analysis, the median OS was 47.5 months vs 37.6 months in each arm, reflecting a statistically significant improvement with combination therapy (HR, 0.77; 95% CI, 0.61-0.96; P = .02).⁴

Across the central nervous system (CNS) full analysis set (n = 222), the median CNS PFS was 30.2 months (95% CI, 28.4-NC) with osimertinib/pemetrexed vs 27.6 months (95% CI, 22.1-NC) with osimertinib alone (HR, 0.58; 95% CI, 0.33-1.01; P = .0548). The CNS ORR was 73% (95% CI, 64%-81%) vs 69% (95% CI, 59%-78%) in each arm (OR, 1.19; 95% CI, 0.67-2.14; P = .5492).

Any-grade AEs were reported in 100% and 97% of the combination and monotherapy arms, respectively, with 70% and 34% experiencing grade 3 or higher AEs. The most common AEs of any grade across each arm included anemia (48% vs 11%), diarrhea (47% vs 42%), and nausea (43% vs 12%).

Team Thriller also discussed details from the phase 3 TOP study (NCT04695925) assessing oral osimertinib plus carboplatin/pemetrexed followed by osimertinib/pemetrexed maintenance vs osimertinib monotherapy among patients with untreated stage IV or recurrent EGFR-mutated NSCLC.⁵ The trial was designed to zero in on a high-risk subset of patients with TP53-mutated disease.

Initial efficacy data showed a median PFS of 34.0 months (95% CI, 24.9-36.4) in the combination arm vs 15.6 months (95% CI, 13.0-18.3) with osimertinib alone (HR, 0.44; 95% CI, 0.32-0.60; P <.001), with respective ORRs of 82.9% (95% CI, 75.8%-88.6%) vs 71.6% (95% CI, 63.6%-78.7%). Any-grade TRAEs occurred in 97.9% and 94.6% of each arm, and 62.4% vs 14.9% experienced grade 3 or higher TRAEs.

Team Thriller vs Team Purple Reign on Interpreting FLAURA2

Nagasaka: Let me first ask about the TOP study. I agree that it’s practice confirming; however, I don’t really agree with the design and how it was conducted. We already knew from FLAURA2 that TP53 mutations [make up] a high-risk patient population. Why would I feel okay to randomly [assign] such patients to osimertinib monotherapy? Was the study design acceptable? Was it even an ethical type of study?

Fidler: We did receive the survival data a little bit later for FLAURA2—the uptake of therapy intensification is still slow in the EGFR space—but the uptake for therapy intensification based on PFS was not 100%. There was crossover in FLAURA2, and about 70% of patients went on to receive chemotherapy upon progression; the actual uptake in clinical practice was slow even when we had positive PFS data. With studies being designed, enrolling, and maturing, the OS data lagged a little bit behind. I would prefer not to put a patient on the TOP study if it was open at my institution right now, but I think, ethically, [for] many of our colleagues across the country, it was the great debate: do you do dose intensification with a PFS benefit?

Riess: I agree, the current standard here for TP53-mutated, EGFR-mutated lung cancer would include chemotherapy/osimertinib. In terms of the control arm, in addition to what Dr Fidler said, I think this study was done [outside the] US, and access to some of these drugs is a real problem in multiple low- and middle-income countries, where they may not even have access to osimertinib vs an earlier-generation EGFR tyrosine kinase inhibitor [TKI]. That’s probably a topic for a whole other discussion about how we can improve access to cutting-edge therapies that improve survival in low- and middle-income countries, but it is, as was mentioned, practice-affirming for chemotherapy.

Husain: It’s my understanding that, in FLAURA2, the subset for TP53 mutations was an exploratory subgroup that was not powered for statistical significance. I think there is value in TOP and seeing a prospective study that’s powered in this way for that design.

Raez: Following what Dr Husain said, we cannot do more studies without biomarkers because we really need to figure out who needs what therapy. That’s why I think in all the studies we have in cancer, we should do at least the ctDNA or something to guide us in the therapy. I know a lot of people don’t believe in ctDNA, but in bladder cancer, we just got the first approval to guided therapy based on ctDNA within the IMvigor011 study [NCT04660344], so it’s becoming a reality. I understand that, for this sector, you want to have good ctDNA, but I think that’s a very good biomarker available now for most of the studies.

Round 2: Hot Topics

Team Thriller on FLAURA2-Based Intensification in Frontline NSCLC With Brain Metastases

Presented by Hatim Husain, MD

As it has been discussed before, one of the key subgroups that was analyzed was those patients who had brain metastasis. We can see a significant improvement in CNS response, and we’re waiting on full maturity regarding DOR. This is, in my opinion, clinically important, partly because the improvement in the brain can improve symptomatology.

When the original FLAURA2 CNS data were presented, one thing that particularly motivated me was the fact that it was presented in a waterfall fashion, showing complete responses as well. When I articulate with patients and show them data about how a regimen may be applicable in the brain, being able to reference a waterfall plot to show those data, even in real time in the clinic room, patients can internalize that and actually see it. Personally, that has a certain amount of resonance, rather than quoting CNS PFS or CNS DOR, especially with some of the complexity that has been mentioned around a clinically valuable data set vs a full analysis set. The presentation of the CNS data from FLAURA2 has benefited from the fact that a waterfall plot has been presented, and I think that has some value, too.

Team Purple Reign on MARIPOSA-Based Intensification

Presented by Misako Nagasaka, MD, PhD

In MARIPOSA, we can not only evaluate for CNS efficacy in regard to response rate and DOR, but also for intracranial PFS. We’re seeing the improvement or lack of progression of the CNS in patients who already had CNS metastases at baseline and those who did not. [In] the full study for amivantamab and lazertinib, we have the intracranial PFS outcomes from all 429 patients; unfortunately, in FLAURA2, that was not possible. How they presented their CNS data was that they focused on the patients who had baseline CNS metastasis, and for the patients who were measurable, they only had fewer than 80 in the total study. So in regard to the robustness of the data, I feel that MARIPOSA has an advantage in evaluating for CNS efficacy outcomes, including intracranial PFS.

Team Thriller Vs Team Purple Reign

Do COPERNICUS-level safety improvements make subcutaneous amivantamab/lazertinib a first-line standard for all-comers?

Fidler: Between COPERNICUS and the arrival of subcutaneous amivantamab, I definitely think it would be hard to argue against great improvement for our patients. But with the subcutaneous amivantamab/lazertinib combination, there still is quite an extensive amount of prophylaxis to do. It was brought up that patients [may] feel more like a patient by having everything lined up in the day where they’re doing things because of their cancer almost all day long. That’s a bit of a cost, too. Certainly, the AEs have improved, but I wouldn’t say that they’ve gone away.

I think that the work involved in the amivantamab/lazertinib regimen with the COCOON protocol is going to be an important part for patients: to keep them on study and active [without] having to change their life because of an AE and a bad rash. [It is] improvement, but still not perfect.

Rodriguez: I’m glad we can agree that the subcutaneous formulation is definitely progress and a better way to deliver this drug, and it’s been very well received in our practices. Actually, in our cancer center, we no longer use the intravenous formulation, mainly because for the infusion-related reactions, the rate now is almost nonexistent.

On the toxicity there are improvements, but I do take your point that even with those improvements, you still require a lot of patient-driven care. Sometimes, we overcomplicate what that is because I tell patients there’s this option, “It’s not chemotherapy, but you’re going to be in charge of 3 drugs: lazertinib, an antibiotic, and an anticoagulant.” I don’t try to make it more complicated than that because it’s 3 pills that patients can manage, unless you have a contraindication for anticoagulation.

We’re going to see more data coming up for COPERNICUS; I would imagine they will have fewer interruptions with the proper regimen but still some. I think we’re getting better at managing the toxicities and starting earlier. The COPERNICUS data inform an amivantamab part B, or how we can do it better. Hopefully, we’ll see a survival advantage or a difference that comes with that.

Round 3: Patient Cases

Team Purple Reign on TP53-Comutated NSCLC With Brain Metastases

Presented by Estelamari Rodriguez, MD, MPH

A 58-year-old woman who has never smoked presented with new-onset headaches, cough, and nausea in the past month. She had imaging of the chest that revealed a large right upper lobe lung mass with mediastinal adenopathy and bilateral pulmonary nodules plus an MRI of the brain that showed 3 small asymptomatic metastases. The PET-CT revealed no extrathoracic disease in the liver, adrenal, and bone. The molecular testing showed an EGFR L858R mutation, and a comutation of TP53. The performance status of the patient is 1. The patient has a flexible schedule.

When weighing the efficacy and convenience of what can be considered for this patient who’s young, flexible in her schedule, and has asymptomatic or minimally symptomatic brain metastases and EGFR-positive lung cancer with some high-risk features, what factors would guide your treatment decision?

Raez: We have to present the options and see how motivated the patient is. Maybe the prophylaxis is a little bit burdensome, but if it’s not a big deal to the patient and the patient wants to still do it, we can give them both options. In our cancer center, we sometimes don’t make the decision right away. We give the patient a couple of days because patients like to be well informed now.

Rodriguez: The TP53 [mutation] data that were discussed here are useful, and we have data to support the use of both the MARIPOSA and the FLAURA2 regimen. However, when you bring in the CNS metastases and the consistency of those data, I do gravitate to discussing amivantamab with a patient who’s willing to deal with the toxicity.

Riess: I would push for a treatment-intensified regimen with some high-risk factors, such as TP53 comutation and brain metastasis. I would discuss both FLAURA2 and MARIPOSA with the patient. Again, I don’t see any real-world difference between the 2—both are active in the CNS—and I would go through the pros and cons of both regimens. In shared decision-making, [I would] choose one of those.

Team Thriller on Prioritizing Convenience in the Clinic

Presented by Mary Jo Fidler, MD

The patient is a 52-year-old man who recently retired; he is very active. The patient’s preference was to continue to be a runner. He had no smoking history, was newly diagnosed, had some mild dyspnea on exertion, and a cough over the past 6 weeks. A right lower lobe primary mass was noted with bilateral lung nodules. The brain MRI showed no brain metastases. The liquid biopsy showed no detectable ctDNA, with no evidence of the EGFR exon 19 insertion mutation. The performance status was 0, and the patient’s preferences were for the longest survival possible with good quality of life. How would you consider treating this patient? What factors would guide the decision?

Riess: I wanted to hone in on his preference: longest survival possible with good quality of life. Representing Team Thriller, I would argue that FLAURA2 checks both those boxes. It has an OS benefit and a PFS benefit. There’s not as intensive skin prophylaxis. He has an active lifestyle; if he bikes, bungee jumps, or skydives, he doesn’t have to be on apixaban. I would stipulate that, per his preferences, chemotherapy/osimertinib, [per] FLAURA2, would be the best choice.

Raez: I think quality of life is defined by every person who has the definition. You’re assuming that the patient is going to ruin his quality of life because he’s going to do skin prophylaxis, but maybe you should ask the patient first. The patient may say, “No, that’s okay.”

Rodriguez: From my experience, a lot of this investment is in the first 4 months, and patients do get better, and get doses that they tolerate better and continue to have great quality of life. If [the patient] came and said, “I don’t want to do anything, even in the first 4 months,” then I think it’s a clear decision that he wants the least involved treatment. But we have plenty of patients who are willing to do that work, and they see the benefit for themselves. We can’t assume what patients are willing to do.

Nagasaka: I would ask the patient to define what good quality of life would look like for them. I’ve had pretty active patients that do sports—it was more like pickleball and not running—some people like that, they have to play every other day. They cannot have an every-3-week feeling of being fatigued or nauseous for 3 days in a row. We really need patients to let us know what they’re able to tolerate, what they think they can do, and guide us toward what we would be able to offer as a team.

WINNER: Team Thriller

References

1. 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
2. Data on file. Janssen Biotech, Inc. NCT06667076.
3. 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
4. Jänne PA, Planchard D, Kobayashi K, et al. Survival with osimertinib plus chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2026;394(1):27-38. doi:10.1056/NEJMoa2510308
5. Yang Y, Zhou T, Gao F, et al. Osimertinib with or without chemotherapy as first-line treatment in EGFR-mutant advanced NSCLC with concurrent TP53 mutations (TOP study). Presented at: 2026 European Lung Cancer Congress; March 25-28, 2026; Copenhagen, Denmark. Abstract 2O.