University of Chicago Thought Process on First-line Treatment in EGFR NSCLC

Referring to the NCCN guidelines for the treatment of EGFR-mutated NSCLC will help clinicians determine which treatments are best recommended.

A panel of clinicians located at the University of Chicago convened to discuss the first-line use of first-line treatment options for patients with EGFR-mutated non–small cell lung cancer. The discussion focused on the phase 3 MARIPOSA study (NCT04487080), the phase 3 FLAURA (NCT02296125) trial, and the FLAURA2 (NCT04035486) trials.^1-3 The panelists focused on how each treatment regimen could play a role in their current clinical practice.

The discussion was led by Christine Bestvina, MD, associate professor of medicine. Additional panelists included James Wallace, MD, a geriatric oncologist; Shayan Rayani, MD, a clinical associate of medicine; and Aditya Juloori, MD, assistant professor of Radiation and Cellular Oncology.

The panel also highlighted the NCCN guidelines, efficacy results observed in each trial, and the toxicity observed for the patient population.

FLAURA Regimens

Bestvina: If you pulled up NCCN [guidelines] today in the clinic, which I know many of us do, what you would see is that the frontline treatment for EGFR mutations where that mutation is found prior to first-line systemic therapy.³ Right now, it’s category 1 osimertinib as preferred with other recommended osimertinib plus pemetrexed and cisplatin or carboplatin. If [the EGFR] mutation is discovered during first-line therapy, it is recommended to either finish that initial therapy or switch to osimertinib or amivantamab-vmjw [Rybrevant] plus lazertinib [Leclaza]. These are all the changes that have been made in the most recent NCCN updates. This is just to show how rapidly evolving this field is that in just a single NCCN update, we had 7 different modifications. It is an area where there is a ton of data flying out right now. A lot of room as far as interpretation and what regimen you’re going to use for which patient.

The ground stone that we’ve all been building off is the FLAURA trial. This is osimertinib in the frontline setting for patients with EGFR exon 19 or L858R randomly assigned to osimertinib vs a standard of care tyrosine kinase inhibitor [TKI]. At that time, it was gefitinib [Iressa] or erlotinib [Tarceva]. The median progression-free survival [PFS] of osimertinib is 19 months vs standard-of-care TKI is 10 months. This did translate to an overall survival [OS] benefit, although it was a little bit less impressive than many of us were hoping for: 31 months vs 38 months. As far as how osimertinib monotherapy goes for patients with central nervous system [CNS] metastasis, there was essentially an improvement regardless of baseline brain metastasis status.

About 18 months ago, we first saw the FLAURA2 results. This is osimertinib plus chemotherapy vs osimertinib [monotherapy]. The chemotherapy component was pemetrexed with either carboplatin or cisplatin with maintenance pemetrexed, as well as continuation of the osimertinib TKI. Patients could have baseline brain metastases if they were stable. We saw an improvement in the median PFS of about 8 months with the addition of chemotherapy. So, 25.5 months with the osimertinib chemotherapy vs 16 to 17 months with osimertinib monotherapy. The most striking improvement was for patients who had CNS metastasis at baseline. We saw an improvement in the median PFS: 14 months with osimertinib vs 25 months with osimertinib plus chemotherapy. For those patients who did not have baseline brain metastases, there was still an improvement, but it was not quite as impressive with a hazard ratio [HR] of 0.75. The adverse events were essentially what you would expect with chemotherapy plus osimertinib. We saw a combination of cytopenias from the chemotherapy as well as some diarrhea, likely from the TKI, but in general, this combination was tolerable. How do you feel about these PFS curves, and is this a regimen that you have used in your practice thus far or would think about using?

Rayani: I have started using it.

Bestvina: Are you using it for all patients with EGFR [mutations] at diagnosis? Are you using it for certain patients? How do you choose?

Rayani: [I use it] for patients who are in shape enough to tolerate chemotherapy; patients with very marginal performance status who are very elderly get osimertinib for now.

Wallace: I would agree with that. As a geriatric oncologist, I sometimes see patients who are less fit for the combination, but I’ve moved it to the top of my list in terms of what I think I should be using. It’s a direct comparator trial, so that’s what we need to see; that it should be used before monotherapy. I favor it, but I find that I’ve had 1 patient who strongly preferred just an oral tablet, even though there was a benefit to it. It’s also sometimes patient-specific, believe it or not, in terms of preference.

Bestvina: Out of curiosity, can you tell us a little bit about the patient? How old were they? Were they working?

Wallace: This was someone who’s holistically driven and had already been involved with our integrative provider. She was in her late 70s but fit. She had an ECOG [performance status] of 0 when I saw her. She had limited comorbidities, so there was no restriction. She did not want to do infusion chemotherapy.

Juloori: Do we have the OS data for [FLAURA2]?

Bestvina: Yes, but before I show you, would you be willing to give this regimen based on PFS alone, or do you think there needs to be a survival benefit before you want to give it to your patients?

Rampurwala: I struggle with just the PFS data because the osimertinib data is equally good. I would say yes; you have a PFS benefit here, and for a selected patient, it makes sense. [If they have] large disease burden, are young and have a very good functional state, it makes sense. I don’t know if I would, based on this data, give it to everybody as such.

Bestvina: Rampurwala is holding out for OS data. We’ve got 2 buy-ins and 1 holdout.

Garassino: If you have a patient who is EGFR exon 19 without other actionable alterations, and without brain metastases what do you do?

Rayani: The point is taken because the benefit is a lot greater for the brain--you can see a better benefit for the patients with brain metastases. There’s still a decent PFS benefit. I would give [osimertinib].

Garassino: You go with the chemotherapy in any case.

Rayani: Yes, if they’re fit and are willing to accept the toxicity.

Bestvina: After either the osimertinib or the osimertinib plus chemotherapy, what did patients get? Of the patients who got osimertinib upfront, a third of them got chemotherapy at the time of progression. It could be reasonable depending on what the length of time was between initial treatment and second-line therapy. Of patients who got osimertinib monotherapy upfront, 80% of them got platinum-based chemotherapy as their next line of treatment. What is not here, though, is the drop-off. Who never received a second-line therapy? That can enter the discussion here, and about 30% of patients with lung cancer, even in EGFR studies, never receive second-line therapy. This concept of saving a second-line therapy likely doesn’t hold up given that there’s such a huge drop off to second-line treatment.

Wallace: The other thing I also consider is sequencing. You’re starting to look forward, that’s where I’ve been struggling more recently for my patients who are on osimertinib. What is their next line? I recently got a denial for immunotherapy with platinum doublet, and I know the controversy in that region, but then I’ve used that routinely as my second-line [therapy] for other patients and had no problems with insurance approval.

Bestvina: We have the second interim OS [data]. At the first snapshot, we had 24 months where it looked like it was starting to trend to be a positive survival, but at 36 months, we’re now seeing a decent separation of the curves. At 36 months, 50% of patients are alive in the osimertinib monotherapy arm vs 64% in the osimertinib plus chemotherapy arm.

Wallace: Was the 1-year difference felt secondary to chemotherapy toxicity?

Bestvina: It was potentially just a statistical error, that would be my guess. It's about a 3% difference but certainly could be [secondary to chemotherapy toxicity]. Any other thoughts on FLAURA2? Rampurwala, are you changing your mind after this?

Rampurwala: No, I think it’s convincing enough, but it’s for select populations. The people who can tolerate [osimertinib] make sense. For somebody with a huge disease burden, brain metastases are still something [to be aware of]. It’s something important to take into account because that’s where the majority of the benefit was. I don’t know how much of that is skewing the survival as well. In those selected populations, for sure.

Juloori: It’s interesting to me, as a nonmedical oncologist, because there are not very many settings in which something has a survival benefit and people aren’t rushing to offer it. It does seem to me that this FLAURA2 regimen is too reticent to adopt. I don’t think I’ve seen the survival data until just now.

Garassino: They presented at the European Lung Cancer Conference, but it was a smaller conference, and I don’t think it got very widely presented.

Juloori: It’s very interesting because in most situations when something has a survival benefit, people are just like, "That’s the standard, let’s do it." This is a desire to avoid chemotherapy, which is natural.

Rampurwala: I don’t know how much of that is from the mindset as you describe. I think the osimertinib data when it came out was “Now you have an oral medicine for these patients” and you have the entire benefit that was sold. Instead of getting to intravenous chemotherapy, you can get an oral drug with more benefit. Now, we are going back to saying that adding chemotherapy to that will help. It’s just getting used to that.

Garassino: I think there’s also a lot of regional differences in who’s getting what. Being on different advisory boards, it seems the East Coast has completely bought into chemotherapy plus osimertinib and the West Coast is still using osimertinib monotherapy. Maybe that’s the holistic patients that Wallace is referring to. I have no idea if it’s provider-driven, or patient-driven, but the uptake has been all over the place.

MARIPOSA Trial

Bestvina: We are now going to transition to another first-line option for patients, which is amivantamab. Amivantamab is a bispecific antibody. It has activity against EGFR as well as MET. It acts through multiple different mechanisms, and it blocks ligand-induced activation, it causes receptor internalization and degradation. It also causes antibody dependence cellular trogocytosis. Which essentially means eating off parts of the membrane as well as cellular cytotoxicity.

This was a 3-arm trial called MARIPOSA. It looked at amivantamab and lazertinib. Lazertinib is an additional third-generation TKI. It is very similar to osimertinib. There are some minor differences in toxicity profile, but it is very similar to what we see with osimertinib. The primary goal of this trial was to look at arm A vs arm B. The FDA did mandate a large lazertinib arm as well so that we would essentially know whether osimertinib and lazertinib are truly equivalent. These are patients who were previously untreated, so they had not received any therapy before exon 19 deletion vs L858R, and brain metastases were allowed.

The median progression-free survival in the MARIPOSA trial.

At 16 months vs 24 months, the PFS had an HR of 0.7. The response rate is very hard to beat compared with osimertinib. The response rate of both arms was equivalent at 85% [for osimertinib and 86% for amivantamab plus lazertinib]. The duration of response was similar in this trial at 25.8 months vs 16.8 months. The intracranial PFS was 24.9 months vs 22.2 months [in the combination and monotherapy arms]. Does this regimen prevent CNS progression? Those [intracranial PFS] curves did separate further down the line.

The 3-year landmark was 18% vs 38% for intracranial PFS and time to second subsequent therapy. What did patients receive after that? It was a combination of doublet chemotherapy vs doublet chemotherapy plus immunotherapy and VEGF as the main drivers. At 3 years, [the survival was] 61% in the amivantamab plus lazertinib arm vs 53% in the Osimertinib arm. This is an analysis looking at some of those high-risk. Those with a history of brain metastases, liver metastases, detectable ctDNA, TP53 co-mutation, all showed a benefit of amivantamab plus lazertinib. What are your impressions looking at this efficacy data?

Rayani: It’s certainly compelling. The question is where does it fit? The problem I have with [the combination], is the infusion reactions and continuous IV treatment. If you’re looking for quality of life, that’s a big deal.

Bestvina: When you give carboplatin plus pemetrexed, how many cycles of the maintenance pemetrexed are you typically giving to your patients?

Rayani: You mean according to FLAUR2? Honestly, I wouldn’t necessarily keep it going after doublet if you’ve had a robust response.

Bestvina: Generally, with the chemotherapy and osimertinib, you’re dropping the pemetrexed off. A big concern here is continuing the IV component indefinitely.

Rampurwala: That would be my concern. Overall, the data looks compelling, at least from the efficacy perspective of safety.

Rayani: We can certainly see that osimertinib alone is falling out of favor, at least, unless you’re looking at a very specific population.

Bestvina: Rash does occur in over half of the patients. Almost a 15% occurrence of grade 3 rash or higher. Over half the patients experienced paronychia, and hypoalbuminemia came in at about 50% of patients with some stomatitis as well as peripheral edema. Most of these toxicities occur within the first few months. Although some of those toxicities do persist into the 5- to 8-month range.

Wallace: We haven’t fully adapted to bispecific antibodies simply because there’s some concern about the infrastructure, are you going to be able to manage the CRS? I think we’re the last of the community sites [that do not give amivantamab]. I think Orlin and Silver Cross are doing it. We’re starting to do it on trials.

Bestvina: We already heard of some hesitancy to add chemotherapy upfront to osimertinib for several reasons. How would you feel about the amivantamab/lazertinib combination in the frontline setting as an alternative to osimertinib? [MARIPOSA] is a positive trial as far as PFS goes. In the context of that, how do you feel about these toxicities? How would you counsel patients about this toxicity? Have you used this regimen, and would you consider it?

Rayani: The rashes are something that is bothersome to patients, like the paronychia. [Patients] just have to be educated on the AE profiles. It’s different than chemotherapy, and it’s not chemotherapy. If they want a chemotherapy-free regimen, this is certainly an option that’s better than osimertinib alone. They just have to understand that these toxicities are going to be persistent and may need further management by dermatology or additional medications.

Wallace: I also want to echo in a disease where we’re palliating it, and we’re not curing it and we’re trying to preserve the quality of life, it hasn’t excited me. Usually, within my notes, I try to put things one or two so I can remember them because that's what I'm doing for a second. I notably put this one at the bottom. I get it; it’s a positive trial. I’m just anxious about it, I’ve had such success with osimertinib. I think all of us have, and patients feel good on it. They’ve advanced it with chemotherapy enough that I’m willing to do that. I’m anxious about launching into this as my first treatment. I haven’t moved it higher in my pecking order, but I’m placing it as second-line because I think it was convincing there. You might convince me more tonight.

Bestvina: There is a 60% infusion reaction on the first day. It goes down to about 10% to 15% on the second day. Day 2, we will talk about some potential mitigation strategies for it, but for traditional IV, amivantamab given without mitigation strategy, is 60%. It’s just a bispecific antibody. It is all outpatient administration. You do have to split up the first dose, so it’s day 1, day 2, day 8, and day 15, and then it eventually goes on either a 2 or a 3-week cycle, depending on what context you're using it. It is given a lot up front, and they are long chairs. They’re 6-hour chairs.

Wallace: That may be something critical, especially when you start using out in the community, is IV therapy, availability, chair time, and all of those [considerations].

Bestvina: How readily available is a dermatologist to you?

Rayani: We just have to call them if need be.

Wallace: They are a 2- to 3-week wait. Do you have one that’s faster than that? I certainly don’t have one in the clinic, or we don’t have one approximate to the clinic. Do you [have a dermatologist rounding]?

Rayani: Not in the hospital, but we have several dermatology practices that are happy to help.

Bestvina: We have a few dermato-oncologists who will. We had 2 who would see [patients] within a week and would give us interim recommendations via email. Where I’m now struggling is they have gotten so busy that they’re going to other dermatologists, and it’s like an echo chamber. I can’t get the same degree of help that I had before. We’re feeling very much like now it’s our job to manage these. A safety net does make a big difference in my level of comfort with some of the skin [toxicities].

Rayani: Are there any prophylaxis for skin like we do for cetuximab [Erbitux] with doxycycline and hydrocortisone?

Wallace: You’re getting to what I was [saying]. I didn’t feel like it was mature enough in terms of the mitigation strategies. That made me comfortable with these AEs. If those have been evolved, then maybe I’ll become more approximate to this regimen. I haven’t started using them.

Bestvina: We will talk about some of the mitigation strategies that are being proposed. This is the impact of dose interruptions. If patients do require a dose interruption because of any of those toxicities that we just discussed, it did not seem to affect efficacy. The only other thing I will comment about the toxicity before we move on it’s a bispecific that has met activity as well. These patients do get the MET TKIs and significant peripheral edema as well as hypoalbuminemia. I don't know what experience people at the table have with MET TKIs, but from the MET TKI perspective, I found those to be quite difficult to manage as well. It has been an issue for my patients on this drug as well. What I heard from the group is that even though this is an FDA-approved frontline regimen, there’s a bit of hesitancy given the toxicity profile. As far as using this or implementing this in a frontline strategy, how would you compare this to the Osimertinib/chemotherapy that we saw? Both from an efficacy as well as a toxicity perspective.

Wallace: You’re permitting us to do a cross-trial comparison? I still think the osimertinib/chemotherapy trial is somewhat favored in terms of outcome. That’s how I interpreted the data, but it’s cross-trial, and I’m not supposed to do that.

Rayani: It’s skewed because we’re so comfortable with chemotherapy and osimertinib. It’s hard to make a new change. Especially a drug you’re not used to giving. It’s a hard sell.

Rampurwala: It’s an infusion that nurses and clinic nurses are used to it. We can all argue about the toxicities from a patient perspective, but from a comfort level, as James mentioned, chemotherapy/osimertinib is much easier to pick up compared with a whole new drug with infusion reactions, a host of different AEs that physicians and staff are not comfortable with.

Rayani: It’s worth a discussion with the patients, especially those who don’t want chemotherapy, that it is better than osimertinib alone. There’s going to be much more chair time and different toxicities [with amivantamab]. If that’s something they’re interested in over chemotherapy, it might be a reasonable option.

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. Ramalingam SS, 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
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. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 11.24. Accessed December 12, 2024. https://shorturl.at/34kWd