Osimertinib With or Without Chemo is Top Choice for Frontline NSCLC

The NCCN guidelines have stated that osimertinib is the preferred category 1 treatment for patients with EGFR-mutated NSCLC discovered before the first line of therapy.

A panel of clinicians located at the University of Chicago convened to discuss the first-line use of osimertinib (Tagrisso) for patients with EGFR-mutated non–small cell lung cancer. The discussion focused on the phase 3 FLAURA (NCT02296125) and FLAURA2 (NCT04035486) trials and how those results can play into their clinical practice.^1,2

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, and how osimertinib is a category 1 recommendation for patients in the aforementioned population. While leading the discussion, Bestvina asked probing questions regarding the preferred patient population for osimertinib, and if there needs to be a survival benefit presented before treatment.

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.

References

1. 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
2. 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
3. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 11.24. Accessed December 12, 2024. https://shorturl.at/34kWd