FLAURA/FLAURA2 Regimens as Treatment Options for NSCLC

Meet the experts

This Satellite Sessions program, hosted by CancerNetwork, focused specifically on non–small cell lung cancer (NSCLC). The discussion narrowed in on findings out of recent clinical trials, particularly involving a combination regimen of osimertinib (Tagrisso) and chemotherapy. The doctors delve into the pros and cons of the study, their criteria for patients for whom they recommend the treatment, and how they approach these conversations with their patients.

Angel Qin, MD, a clinical assistant professor at the University of Michigan Health, led the panel. She was joined by Fawzi Abu Rous, MD, a thoracic oncologist at Henry Ford Health; Zaid I. Al-Saheli, MD, a medical oncologist at Corewell Health; Rayli Pichardo, MD, a hematological oncologist at Henry Ford Health; Tareq Al Baghdadi, MD, a hematology/oncology specialist at Trinity Health IHA Medical Group; Ibrahim Azar, MD,a hematology/oncology specialist at Trinity Health IHA Medical Group; and Tarik Hadid, MD,a hematology/oncology and hospice/palliative care specialist at Karmanos Cancer Center.

FLAURA and FLAURA2 Discussion

Qin / I would love to hear thoughts from all of you about the phase 3 FLAURA [NCT02296125] trial and the phase 3 FLAURA2 [NCT04035486] trial.^1,2 Do you think it’s worth it? Have you all used the FLAURA2 regimen [of osimertinib/chemotherapy]? Have patients asked you for it? How are you counseling your patients about it?

Al-Saheli / I haven’t used it yet, but it’s worth having a discussion about the adverse effects [AEs] and [its usability] for patients with brain metastasis because the benefit is way clearer.

Qin / Have any of your patients asked for it?

Al-Saheli / No, not so far.

Pichardo / I haven’t used it either. [For patients] with a higher burden of disease, you can consider the FLAURA2 [regimen]. It’s hard to convince patients to add chemotherapy if you’re already offering a pill. Why not just offer [the pill]? There is [also] always the option to do chemotherapy as a next-line [treatment] when they [have disease progression]. It’s a challenging conversation to have with patients.

Al Baghdadi / I’ve used it in 1 patient who had brain metastasis at baseline and was young enough to tolerate 4 cycles of chemotherapy. I didn’t continue the pemetrexed for too long afterward. After the first 4 cycles, it was much easier, even with pemetrexed. When I stopped the pemetrexed, it was easy. The patient had brain metastasis at baseline, and that is my go-to regimen now. That’s how I counsel patients; brain metastasis can tolerate chemotherapy.

Al-Saheli / I agree. In the subgroup analysis, they showed that patients with brain metastasis would benefit more than those who do not have brain metastasis. The L858R mutation leveled the field between L858R and exon 19 deletion. They also had some data in [the European Society for Medical Oncology] that [Pasi A. Jänne, MD, PhD] presented, where they showed that those who had ctDNA [circulating tumor DNA] detected prior to initiation benefited more than those who did not have ctDNA detected.

The criteria that I have [to add chemotherapy to the treatment] is brain metastasis, positive ctDNA, which is like a reflection to the burden of disease, the patient’s fitness, to see [whether] they can tolerate chemotherapy, and then I counsel them about chemotherapy. I tell them that we can add chemotherapy to it. I agree with FLAURA, and I tried it for 2 patients, but then I didn’t continue the pemetrexed because, after they’re done with carboplatin, they’re super tired. Their [blood] counts start dropping and many complications arise. I eventually stopped the pemetrexed. I would only consider doing chemotherapy on a patient who is young, has brain metastasis, has positive ctDNA, and maybe the L858R [mutation].

Al Baghdadi / Do you stop it right away, or do you give the pemetrexed a try?

Al-Saheli / I give it a try. One of my patients was able to go through the 5 cycles of carboplatin plus pemetrexed and osimertinib and then go on pemetrexed plus osimertinib for a total of 8 cycles, so 4 or 5 more cycles. For 1 patient, I had to stop the third cycle. I stopped carboplatin early because of the drop in their [blood] counts, and they had to be on a blood thinner. You have to tweak it a little bit, but there is a benefit for patients with hypertension disease.

Al Baghdadi / I agree. I haven’t used it yet. I wish I used it for 1 patient. I wish they had designed the trial as just the induction, and that there was no maintenance part of the pemetrexed, because you’re telling [the patient] that you’re going to buy them 8 or 9 more months [of life] on this regimen, but then you’re asking them to come [for a visit] every 3 weeks.

You have to take the time toxicity in [consideration]. For the brain metastasis by itself, I don’t think that the pemetrexed or the carboplatin are crossing the blood-brain barrier a lot. It’s just a surrogate marker for high tumor burden. The 1 patient who I wish I used it on had both an EGFR and a KRAS mutation and didn’t respond to osimertinib, so she ended up passing away [quickly]. If I had used it, maybe I would have overrun the KRAS resistance.

Helping Patients Decide on a Treatment

Al-Saheli / It [has to be] a discussion with the patient. We don’t have overall survival [OS] [data] yet and there’s a lot more toxicity that comes with it too. I typically talk with the patient about what they want, and I’ll tell them there’s progression-free survival [PFS] improvement with some more toxicity. For patients who are young, fit, and healthy with other biomarkers, you could justify it. If somebody’s older and has a lot of comorbidities, things like single-agent osimertinib, it is probably OK for them.

Qin / It’s interesting because when FLAURA2 came out, I had 2 patients with EGFR [mutations] that I saw back-to-back, and they had 2 wildly different opinions about what I offered. They both had EGFR [mutations] and brain metastasis, so we discussed osimertinib alone vs osimertinib plus platinum-pemetrexed. I thought that 1 patient was going to go for osimertinib plus platinum-pemetrexed, and he did not. The patient had quite a bit of brain metastasis, and I told him I thought he would benefit from escalation therapy.

He was young [and] had no comorbidities, and his response to me was that the idea of coming every 3 weeks was a significant detriment [to] his life and what he wanted to do. He wanted to be there for life events, for his kids to travel. He didn’t want to be tied down to infusions. It’s not that osimertinib doesn’t have any central nervous system [CNS] penetrance; it has excellent CNS penetrance. It’s just that it can be more excellent. He said that if he had a survival curve, he’d rather live normally and then drop off a cliff when the time comes. He didn’t want to have a slow decline and slide into the bottom of the cliff, which is where he was headed anyway. I thought that was a very valid point.

I had another patient whose de novo presentation was CNS metastasis. She had seizures, [altered mental] status, a craniotomy, [and] postoperative radiation, and had no evidence of disease extracranially. I told her osimertinib alone is fine, but laid out her options because she did have brain metastasis that’s now been removed. [The patient] was adamant she needs to be alive for as long as she can be, no matter the cost. She has struggled through platinum-pemetrexed. I always ask her [whether] we can please stop the pemetrexed, and she will not.

It’s just interesting. We have these conceptions of what our patients value, but when they come and talk to us, I’m surprised by what I hear. [It changes] my presumptions about what might be important to them.

Abu Rous / It’s important to simplify the data and cite [them] to [the patient] in a very simple way, to get their perspective. We have our own [biased] perspectives; once we see a PFS benefit or an OS benefit, we’re sold. As [Dr Qin] said, sometimes a patient meets my criteria for using chemotherapy plus osimertinib, but then only wants to do [osimertinib] and see what happens. If things didn’t go well in 2 months or so, we decided that we’d add chemotherapy. That was fine by me. The patient was super tired [at that time] and had been admitted to the hospital for a long time. They didn’t need something else added to the infusion. The patients have a different perspective on the data than us.

How Metastasis Factors Into Treatment

Qin / One of my mentors, Greg Kalemkerian, MD—you have probably all seen at least 1 patient who’s seen him—always says the concept of a blood-brain barrier being intact is no longer true once they have brain metastasis. Technically, their blood-brain barrier is broken; that’s how brain metastasis develops.

That’s why, if you look at it in the chemotherapy immuno-
oncology world, so non–oncogene driven, where they look at the efficacy of immunotherapy intracranially, it tracks with what you see extracranially. It’s about a 30% to 40% response rate. That is what you expect to see extracranially. It isn’t the concept of penetrance anymore, once it’s penetrated. Like [Dr Abu Rous] said, when adding platinum-pemetrexed, it’s a reflection of the bad [disease] burden, but you are getting a cytotoxic benefit. You’re getting rid of your EGFR-addicted cells. [Dr Abu Rous’] patient who had the rapid progression had cells that couldn’t care less about EGFR inhibition. You’re just slamming both mechanisms.
I don’t know [whether] it’s CNS penetrance.

Abu Rous / I agree with you, but it’s also about how they reported the data. They decided to report the brain metastasis, but they did not report [staging details like] IVA and M1a, and they didn’t give us the complete details of the disease burden. They could have also reported liver metastasis. If you look at the liver metastasis, [patients with liver metastasis] had more benefit than those who did not. The way they reported the data, I don’t want to say masked some of the benefits, but led us in a different direction. I agree with [Dr Qin] because, even with our primary CNS lymphoma, we use rituximab [Rituxan].

I remember [Kyriakos P. Papadopoulos, MD, from START Center] always said that those antibodies don’t cross the blood-brain barrier, but here we use rituximab for CNS lymphoma.

Hadid / [Rituximab] is enough to change the survival. That’s a big change.… Maybe the biology of those patients is different from the biology of the patients who did not have brain metastasis. Maybe they’re not as responsive to EGFR as the other ones. That’s another thought.

Abu Rous / This is where the disease-persister cells come into play. They proliferate and become less responsive to tyrosine kinase inhibitors, and then you throw chemotherapy at them. Is it the brain metastasis? Is it the proliferation of the cancer? It’s hard to know.

Al Baghdadi / Would you ever think of adding chemotherapy if someone’s tumor progressed on osimertinib?

Qin / Before FLAURA2, if they progressed while on osimertinib, I would check to see [whether] they still had EGFR [mutations]. If they did, I gave them platinum-pemetrexed and kept the osimertinib.

Azar / We [added chemotherapy] to erlotinib [Tarceva] a lot back in the day. That was the normal way of managing erlotinib failure.

The difficult part is [figuring out] who does not do well on osimertinib. I’ve treated tons of patients. It’s not exon 19 vs exon 21, and it’s not CNS metastasis. There are some patients who it’s not even a burden for. There are some patients who just don’t do well on osimertinib for reasons I can’t explain. You salvage those patients by adding chemotherapy. Who are those patients? I don’t think we know. Where osimertinib works well, it works great. You can tell within 2 or 3 months [whether] a patient is going to do well on osimertinib.

Abu Rous / Correct. This is where comutations might add some value, like TP53 or a MET amplification. Some of these comutations or coalterations can help us. It was not even reported as far as I know.

Qin / We see this a lot with our oncogene-driven NSCLC. If you look at the PFS curve within the first 3 to 6 months, you see unanimously, whether you look at EGFR, ALK, or RET, there’s always about a 10% to 15% drop in patients in the first 3 to 6 months. Like [Dr Al Baghdadi] said, there is a cohort of patients who have aggressive disease.

I don’t see too much difference between exon 19 and L858R, but there’s something about patients who have this rapid progression. Perhaps where the benefit is, is if you look at the osimertinib plus platinum-pemetrexed, there may be a slight separation of that curve at 3 to 6 months, or maybe you’re salvaging some of those patients with more aggressive disease in the first 6 months. We don’t know who [those patients] are.

ctDNA Analysis and Additional Testing

Qin / I’d be curious to hear the rest of your practice. I haven’t been routinely getting ctDNA at a baseline level. I certainly won’t get it if I’m concerned about progression; I hate getting ctDNA if I have good scans, because, invariably, there’ll be a change in numbers. I don’t know about all of your patients, but my patients are highly anxious. I don’t want there to be a blip or a slight rise in ctDNA. They’ll wonder [whether] that means they have to escalate [treatment] and [whether] they’re progressing. I haven’t found that to be useful, but maybe I’m not doing it right.

Abu Rous / I don’t think there’s a right way to do it, honestly, unless [the phase 3 EA5182 trial (NCT04181060) testing osimertinib and bevacizumab (Avastin)] brings out positive [results]. Then that’s going to be a different story. I like to do [the ctDNA]. I got lucky [with my patients].

Hadid / Do you just do next-generation sequencing, like Guardant360, or do you do minimal residual disease [MRD] testing?

Abu Rous / MRD, just the ctDNA.

Hadid / That’s less sensitive. For example, if you [use] the Natera test, you’re much more likely to get a smaller percentage of tumor ctDNA, whereas if you do a generic ctDNA [test], you need a higher sensitivity. The problem with ctDNA is that it’s also a factor in the location of the disease.

Abu Rous / If it was not positive at the beginning, I don’t
check it again. If it was positive and high, maybe I’ll get a check at 3 months or with the first scan, but that’s it. I don’t do it with every scan, because as [Dr Qin] said, it’s going to be another layer of stress, [making the patient] wait for another test.

Al-Saheli / I’ve seen it used, and I’ve continued to use it on a patient with melanoma who has no evidence of disease. If [ctDNA] went up, you can order a PET scan and catch that 1 spot [of disease] early. In cases like this, where the patient usually has a high burden of disease, it’s just going to be positive. It’s telling the same story as the scan. I’ve heard of it being used in immunotherapy when sometimes you see the tumor grow a little bit. Then you can follow that with the ctDNA, but I haven’t used it [in immunotherapy]. I usually don’t. I usually continue immunotherapy, even if there’s a small increase.

Azar / That’s after 4 weeks. Guardant is developing their test to test for early response vs switching treatment. But that’s 4 weeks into treatment.

References

1. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137
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