Critical updates in non–small cell lung cancer (NSCLC) occurred during the 2025 World Conference on Lung Cancer (WCLC). Two teams of qualified clinicians met to debate and “face off” on these key areas of interest. The teams competed in 3 key areas: clinical updates, hot topics, and applying data in practice.

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 the winner.

Round 1: Clinical Updates

Team Blue on the MARIPOSA Study

Presented by Eric K. Singhi, MD

The phase 3 MARIPOSA trial (NCT04487080) randomly assigned patients 2:2:1 to either the amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze) arm (n = 429), osimertinib (Tagrisso) monotherapy arm (n = 429), or the lazertinib monotherapy arm (n = 216).¹ For all patients, serial brain MRIs were required, and crossover was not allowed. The presentation of this study at WCLC focused on the doublet arm and the osimertinib monotherapy arm.

The median age was 64 years vs 63 years, 64% vs 59% were women, 58% vs 59% were Asian, and 67% vs 65% had an ECOG performance status of 1 in the combination arm and the osimertinib arm, respectively. Additionally, 30% vs 31% of patients had a history of smoking, 41% vs 40% had a history of brain metastases, and 97% vs 97% had an adenocarcinoma history.

At the median follow-up of 37.7 months, the median overall survival (OS) in the amivantamab/lazertinib arm was not reached (NR; 95% CI, 42.9-NR) vs 36.7 months (95% CI, 33.4-41.0) in the osimertinib arm (HR, 0.75; 95% CI, 0.61-0.92; P <.005). At 24 months, the OS rates were 75% vs 70%, 60% vs 51% at 36 months, and 56% vs 44% at 42 months.

The median progression-free survival (PFS) was 23.7 months (95% CI, 19.1-27.7) in the combination 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). The 18-month PFS rates were 60% vs 48%, and at 24 months, they were 48% vs 34%.

The objective response rates (ORRs) were 86% (95% CI, 83%-89%) in the amivantamab/lazertinib arm and 85% (95% CI, 81%-88%) in the osimertinib arm. The complete response rates were 7% vs 4%, respectively, partial response rates were 79% vs 81%, stable disease rates were 7% vs 10%, and disease progression rates were 2% vs 3%.

The intracranial PFS was 25.4 months (95% CI, 20.1-29.5) vs 22.2 months (18.4-26.9) between either arm, respectively (HR, 0.79; 95% CI, 0.62-1.02; P = .07). The intracranial ORRs were 78% (95% CI, 71%-84%) vs 77% (95% CI, 71%-83%). The intracranial duration of response (DOR) was 35.7 months (95% CI, 25.8-NR) vs 29.6 months (95% CI, 23.9-34.1).

Any-grade adverse effects (AEs) were observed in 100% of patients in the combination arm vs 99% in the monotherapy arm, grade 3 or higher were noted in 75% vs 43%, serious AEs in 49% vs 33%, AEs leading to death in 8% vs 7%, events leading to interruption of any trial agent in 83% vs 39%, events leading to dose reductions in 59% vs 5%, and events leading to discontinuation in 35% vs 14%.

Team Purple’s Rebuttal

Devarakonda / One of the challenges, if you think about it, is that it’s an effective regimen. The survival curve speaks for itself. [This is a treatment] that comes with a learning curve when it comes to supportive care, and you talk about how there are dose interruptions, but it doesn’t truly impact survival in the first 4 months. [However, there are toxicities] that lead to dose interruptions and a quality-of-life challenge for many of our patients. For me, when I think about the challenges associated with that regimen, that’s the one thing that truly stands out.

Sabari / You like the trial, you like the design, you like the survival data, but you’re worried about the toxicity. Team Blue, your response.

Husain / Those are fair responses and questions, but I think now in 2025 and in lung cancer, it’s incumbent upon us as oncologists to come up with structured supportive recommendations for patients, and this applies across medicines. There are several medicines in which now we’re coming into the arena in lung cancer where skin toxicity may be an issue. So how we set up the multidisciplinary teams, how we counsel patients early and up front about supportive measures and prophylactic measures that can be helpful for patients, and how we educate in an up-front, transparent, and fully transparent [manner] to the whole family of a patient so that there can be and ensure as much [adherence] as possible with the supportive care. That’s where we’re at.

Rotow / You brought up toxicity. It’s a great point. We think about all forms of toxicity in our patients’ day-to-day life, both AEs of therapy, chronic long-term risks, as well as time toxicity and the quality-of-life implications from day-to-day care. I’m going to rebut your comment and bring up that we’re here in Europe, where subcutaneous amivantamab is also approved. So, we’re looking at now potentially short-term injections for patients, maybe in the future, as [infrequently] as once a month. I’ll contrast that with every-3-week intravenous chemotherapy infusions, sitting for [laboratory testing], sitting through clinic, sitting through premeds, and I’d argue that there may be an advantage in time toxicity with this regimen compared with FLAURA2.

Kareff / I might just rebut the rebuttal, right? These ideals that you all are planting are important and certainly necessary in a multidisciplinary fashion. As the designated community hybrid voice here, I’ll push back on that a little bit. We deliver this education to patients, and this can be tough for an 80-year-old or older patient, making sure they get the moisturizer right, take antibiotics for an extended period, and [they experience] lots of diarrhea from that alone. This is a tough regimen to sell to patients. I’m anxiously awaiting the subcutaneous form as well. It’s not here for us in the US yet.

Qin / There’s also a cost. A lot of the supportive care is not going to be paid for: venous thromboembolism prophylaxis, creams, sun moisturizer, chlorhexidine, and antibiotics. We’re asking the patients to pay a lot in addition to what they’re already paying for their therapy. While trials such as the phase 2 COCOON trial (NCT06120140) cover a lot of the dermatologic toxicity and the phase 2 PALOMA-2 trial (NCT05498428) covers the infusion-related reactions, no one is yet talking about the toxicities related to MET inhibition, and they’re not insignificant. The lower extremity edema, we have all seen it in the clinic. It is not subtle, and it is not easy to manage. I haven’t found compression stockings or Lasix to be effective there. We haven’t come up with a strategy to hit all the AEs.

Team Purple on the FLAURA2 Trial

Presented by Siddhartha Devarakonda, MD

The phase 3 FLAURA2 trial (NCT04035486) assessed osimertinib plus platinum pemetrexed vs osimertinib monotherapy.² The median age was 61 years vs 62 years, 62% vs 61% were women, and 64% vs 63% were Asian between the combination and monotherapy arms. Additionally, 33% vs 35% of patients had a history of smoking, 42% vs 40% had a history of brain metastases, and 99% vs 99% had adenocarcinoma histology.

The median follow-up for the combination arm was 31.7 months, and the median OS was NR (95% CI, 38.0-not calculable [NC]). The median follow-up for the monotherapy arm was 30.5 months, and the median OS was 36.7 months (95% CI, 33.2-NC). The 12-month OS rates were 92% vs 89%, 80% vs 72% at 24 months, and 64% vs 50% at 36 months (HR, 0.75; 95% CI, 0.57-0.97; P = .0280).

The PFS by [blinded independent central review] was 29.4 months (95% CI, 25.1-NC) in the osimertinib plus chemotherapy arm vs 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). The disease control rates were 95% (95% CI, 92%-98%) vs 93% (95% CI, 90%-96%), and the median duration of response was 28.3 months (95% CI, 23.7-NC) vs 21.0 (95% CI, 17.8-NC).

The overall response rates were 92% (95% CI, 88%-95%) in the osimertinib plus chemotherapy arm vs 83% (95% CI, 78%-87%) in the osimertinib monotherapy arm. The complete response rates were 1% vs less than 1%, partial response rates were 91% vs 82%, stable disease rates for 35 days or more were 4% vs 10%, and disease progression rates were 1% vs 4%.

In the central nervous system (CNS) full analysis set, 24% of patients in the osimertinib plus chemotherapy arm had CNS progression vs 30% in the osimertinib monotherapy arm. The median CNS PFS was 30.2 months (95% CI, 28.4-NC) vs 27.6 (95% CI, 22.1-NC; HR, 0.58; 95% CI, 0.33-1.01; P = .0548), respectively; the CNS ORRs were 73% (95% CI, 64%-81%) vs 69% (95% CI, 59%-78%; OR, 1.19; 95% CI, 0.67-2.14; P = .5492), and the median CNS DOR was NR (95% CI, 23.8-NC) vs 26.2 months (95% CI, 19.4-NC).

The CNS evaluable for response set had 28% of patients in the osimertinib plus chemotherapy arm vs 47% in the osimertinib monotherapy arm [who] had CNS progression. The median CNS PFS was NR in the combination arm (95% CI, 23.0-NC) vs 17.3 months (95% CI, 13.9-NC) in the monotherapy arm (HR, 0.40; 95% CI, 0.19-0.84; P = .0157). The CNS ORRs were 88% (95% CI, 73%-96%) vs 87% (95% CI, 72%-96%; OR, 1.06; 95% CI, 0.28-4.00). The median CNS DOR was NR (95% CI, 21.6-NC) vs 20.9 months (95% CI, 12.6-NC).

Regarding safety, any event was observed in 100% of patients in the combination arm vs 97% in the monotherapy arm; grade 3 or higher AEs in 64% vs 27%, respectively; serious AEs in 38% vs 19%; AEs leading to death in 7% vs 3%; and any event leading to discontinuation of any trial agent in 48% vs 6%.

Team Blue on the Defensive

Singhi / This answers the question for both of us that combination therapy seems to be preferred for most patients as opposed to a single agent. That has changed that mindset for me. Maybe if you asked me a year and a half ago, 2 years ago, I was thinking, “Who needs the combination strategy?” Now I think, “Who doesn’t?” I acknowledge that, and that’s because of the data that you presented.… Our patients are often young, they’ve never smoked, and they are very motivated to have meaningful outcomes. This is the time to be proactive, to be novel, to introduce new concepts, to mitigate and prevent the required mechanisms of resistance. We need to think a little bit more outside of the box here and not lean on the familiar, not lean on the comfortable, but push ourselves.

Sabari / Low blow from Eric there. What are your thoughts on this concept of familiarity vs novel mechanism of action? It’s an interesting thing to think about.

Qin / I don’t think that newer means better. Things persist because they work, and there is some advantage to familiarity because we are expected to deliver this care equitably across all settings. For oncologists who don’t have the benefit of only seeing lung cancer, being familiar with their regimen and knowing how to manage toxicities are going to play out better for the patient than someone who doesn’t know what to do with all the prophylactic things that are required with the MARIPOSA study. I would argue that newer is not better, and we’ll see what the OS shows, but the news release would suggest that perhaps the HRs are quite similar.

Kareff / My colleagues have said it quite well. All that glitters is not gold.… Acknowledging that we do have patients who, unfortunately, have severe life-threatening toxicities, I feel in real-life practice, it’s a lot less unpredictable.

Round 2: Hot Topics

Striking an Optimal Balance Between Long-Term Efficacy and Tolerability

Team Blue on MARIPOSA/PALOMA-3

Presented by Hatim Husain, MD

We have to think about novel agents and where the field is heading. When we do PALOMA-3 in the integration of subcutaneous amivantamab into the story here, it is a very important setup. When we talk about MARIPOSA, we understand and can gather the OS benefit, we can gather the tail of the curve, and how that also can be further pursued. We can understand, as I had mentioned before, how the drug is working through its mechanism and intended effects. We understand the safety profile, and now, when we think about the other studies that will be in this space to further guide the management, PALOMA-3, COCOON, all of these will help tailor our approach to be more precise, more effective, and safer for patients with a more tolerable strategy once those are integrated.

Team Purple on FLAURA2

Presented by Angel Qin, MD

I agree that we certainly are always looking for novel therapies. However, that is not the topic of this debate. The topic of this debate is not about novelty; it’s about [the tolerability] and long-term efficacy of these 2 regimens. First, it’s a little unfair to FLAURA2 since we do not know what the OS data will show for FLAURA2. [Editor’s note: This filming occurred prior to the data presentation of FLAURA2.] Based on the news release and what we know about the HR, it shows that this OS benefit is probably like MARIPOSA. On an efficacy standpoint, there’s a draw. When it comes to tolerability, though, let us think about what we are asking of our patients on MARIPOSA. MARIPOSA has had to do the COCOON and PALOMA-3 studies just to support this regimen. There were no other studies needed to support FLAURA2. We know how to manage chemotherapy. Chemotherapy AEs are also self-limiting. We all tell our patients for a couple of days, “You may feel more fatigued, or monitor your blood counts. You take folic acid every day.” Simple as that. With the MARIPOSA regimen, this is a daily proactive treatment. I’m going to ask the gentleman in this room: How many times a day do you put lotion on your face? None of you gentlemen has done that. Now, if you’re asking your patient to go on MARIPOSA, this is what they’re doing every single day. From a tolerability standpoint, tolerating something for a few days and then for the rest of the days you feel relatively like your normal self, vs every single day for this regimen, I would say the FLAURA2 wins for tolerability.

Singhi / I want to commend the fact that we’ve leaned into supportive measures for our patients. We’re trying to be proactive, not just reactive. There are good strategies, there are continued strategies that are developing, but it’s been blown out of proportion, to be honest. We shouldn’t underestimate our patients. We should empower them. This is an opportunity for it.

Qin / Are you going to help them pay for that? All the creams?

Singhi / We as a community can develop resources to help.

Qin / We have not. As it currently stands in this debate, if you’re saying that we should empower them, we have not given them the tools to empower themselves. We are merely saying, “Do it.”

Husain / I will also say the patient decision here is a core concept. Patients should be offered all [parts of] the regimen, and if the OS benefit that’s seen justifies to them how they view the additional work that they’ll have to do, that is truly their decision. It’s not our decision to tell them that. The other thing I will just mention is that in PALOMA-3, we saw that OS was a little bit better with the subcutaneous than the intravenous. If we’re seeing the MARIPOSA intravenous OS, I would just raise the possibility that in a subcutaneous world, we may see a slightly better HR. How would that look in comparison with an alternative regimen?

Rotow / I’d also bring up that a lot of these prophylactic agents that we’ve been highlighting as challenging for patients are short-term. It’s a few months of anticoagulant prophylaxis, a few months of oral antibiotics, and you are then left with a topical moisturizer and maybe topical nail treatments. That feels feasible. And there are many different ceramide moisturizers, but you don’t have to choose the Cadillac of these fancy moisturizers. You can choose other ceramide moisturizers to make this more cost-effective as well. It’d be part of troubleshooting and problem-solving with patients. If we think about efficacy or tolerability as well, I’d highlight that pemetrexed is tolerable, but people are getting an average of only 8 months of therapy. This is our fittest, most motivated, highly selected, and most supported clinical trial patient population, with only 8 months of therapy. That’s short, and it suggests that tolerability is not all that we think it is.

Round 3: Apply Data in Practice

Team Purple and Finding the Optimal Treatment Strategies After FLAURA/FLAURA2

Presented by Siddartha Devarakonda, MD

There is a population of patients with lung cancer that you see for whom I acknowledge single-agent osimertinib is still going to be quite relevant. Quality of life is a thing. There is the beauty of an oral regimen that you can take with very little toxicity. I’m going to acknowledge up front that there is still that group of patients that you will be seeing in your clinic. This is where the field has become quite murky right now, and, full disclosure,nobody has a secret formula or one way of doing things here. The beauty of FLAURA2 or an osimertinib plus chemotherapy approach for me is that when you think of the FLAURA2 design, the OS benefit and the PFS benefit still hold despite the median exposure to chemotherapy being only 8 months. You can almost make an argument that you need that induction chemotherapy, probably, and then you’re free to alter the regimen as you go forward based on tolerability. We have done this with chemotherapy and immunotherapy. As your responses start to falter, there’s probably a role for bringing that chemotherapy back in. When you talk about the OS benefit on either regimen, you have to keep in mind that OS is heavily influenced by the subsequent treatment that patients get. With FLAURA2, it’s a pragmatic design in the sense that, despite being a global trial, everyone has exposure to platinum and pemetrexed. Everyone has access to that. The second-line percentage of patients who did not receive second-line treatment, they wouldn’t have seen second-line treatment anywhere, because it’s not a question of drug access.

When it comes to MARIPOSA, the one criticism I have of the trial design and of my partners here is that amivantamab plus lazertinib is an effective regimen. Nobody’s contesting that. Amivantamab is extremely active. It has good biology behind it. It has good CNS activity, but the trial did not have a crossover. When I have access to amivantamab, a standard of care in the second-line setting, in a real sense, is the OS benefit still going to hold? Am I doing that much of a disservice by punting this to the second line? Would my strongest rebuttal be against the MARIPOSA trial and my Blue Team counterparts here when it comes to the sequencing of treatment? Subsequently, you have a host of ADCs [antibody-drug conjugates] that you can select from. This field is active; it’s evolving. We have more treatment options we can look at now. If you do have MET dysregulation on FLAURA or FLAURA2, there’s also the beauty that you can sometimes bring in a MET TKI [tyrosine kinase inhibitor]. We have seen some data from ASCO [American Society of Clinical Oncology] around that with savolitinib, and we have been doing this off-label for a while, too. Starting with FLAURA and FLAURA2 still gives you that flexibility of adjusting down the lane with regard to how the clinical course evolves.

Team Blue on Optimal Sequencing After MARIPOSA

Presented by Julia Rotow, MD

How do you think about the impact of first-line choices in sequencing vs FLAURA, vs FLAURA2, and then about the impact on the resistance profile? First, when I think about when I’m treating my patients, we know that everyone goes on to get second-line therapy, and it’s been the strongest argument for giving a combination. I agree there will always be patients who are appropriate for FLAURA, who prefer a more tolerable regimen, prefer quality-of-life focus care over a quantity-of-life focus care. That’s a patient preference that’s very valid, and [it’s] appropriate to have that conversation. We are all saying here and agreeing that for the majority of patients today with EGFR-
mutant lung cancer, likely a combination is more the default standard. That puts FLAURA at a disadvantage when it comes to sequencing. Some of those patients will never go on to get a second-line regimen and therefore don’t get to benefit from novel therapeutic modalities that become available.

Thinking about sequencing post FLAURA2 vs post MARIPOSA, I always think about how I can make sure my patients get access to all effective modalities of treatment. That’s an EGFR TKI third generation, that’s a platinum doublet chemotherapy, that’s amivantamab, and it’s an [ADC]. If you give a patient MARIPOSA, you’ve given the amivantamab, you’ve given lazertinib. You have space now to give your platinum doublet, probably with a TKI-based combination. We know that’s an effective regimen. We maintain CNS control, and we get the platinum doublet on board. Later, in a more polyclonal scenario,you have ADCs to come next. You’ve gotten multiple lines of effective therapy. We have emerging data with other, more exciting, potentially chemotherapy-based combinations such as the HARMONY data coming out at ASCO, and at World Lung coming up soon. We’re going to see maybe alternative strategies to utilize our platinum doublet in a second line or later, as opposed to the front line. Now you give FLAURA2 front line, you’ve done your chemotherapy, you’ve done your TKI, you can give an ADC next. Datopotamab deruxtecan will be our standard at that point, given the new approvals in that space. You don’t have a way to access amivantamab as a class of therapy driven by data that are randomized with confidence regarding insurance coverage. We don’t have MARIPOSA-2 data after FLAURA2, and we don’t have approvals for amivantamab or osimertinib in the previously treated setting. It’s not a guarantee that patients will have coverage. If you want to optimize access to all different modalities, MARIPOSA gives you some advantages there.

References

1. Rybrevant (amivantamab-vmjw) plus Lazcluze (lazertinib) prevents acquired resistance versus osimertinib in first-line EGFR-mutated non-small cell lung cancer. News release. Johnson & Johnson. September 6, 2025. Accessed November 6, 2025. https://tinyurl.com/33heay6r
2. Final FLAURA2 OS data show osimertinib plus chemo offers benefit compared with monotherapy. IASLC Lung Cancer News. September 7, 2025. Accessed November 6, 2025. https://tinyurl.com/5n8ubu5t