FLAURA Data Provides Insight on Sequencing Therapy for EGFR+ NSCLC

Martin F. Dietrich, MD, PhD

Targeted OncologyTM: What was the significance of the FLAURA study (NCT02296125) in the EGFR-mutated non–small cell lung cancer (NSCLC) setting?

DIETRICH: The current standard-of-care [comes from] the FLAURA study, which was first-line osimertinib [Tagrisso] vs standard of care [at the time of the study]. Erlotinib [Gilotrif] was the United States standard and gefitinib [Iressa] was the international standard for [patients with EGFR-mutant lung cancer. This was a study enrolling patients with stage IV NSCLC with EGFR exon 19 and 21 mutations. Patients with symptomatic central nervous system metastases that were untreated were allowed, and there was a crossover option. Patients who progressed on erlotinib or gefitinib with an EGFR T790 [resistance] mutation were allowed to cross over to osimertinib, and treatment [was given] until disease progression or unacceptable toxicity with a PFS [progression-free survival] endpoint. In 2017, this was reported as positive, so this is not new.¹

The median OS [overall survival] was 38.6 months [for osimertinib] and 31.8 months for erlotinib and gefitinib, and the question was, which sequence is better?² I think ‘best therapy first’ proved to be right yet again. [There should be] no holding back better agents, especially here when toxicity is even better with osimertinib.

The OS landmarks across the board were better for [patients on] osimertinib [at 89% vs 83% at 12 months, 74% vs 59% at 24 months, 54% vs 44% at 36 months, for osimertinib vs comparators, respectively]. In my opinion, this has been the better agent in all subsets for the long and short run. About half of the patients [85 out of 180; 47%] progressed with an EGFR T790M mutation and were able to cross over in the study. This is truly a sequencing study in the comparator arm for osimertinib [as a next-line therapy].

What was found about patients receiving subsequent therapy in FLAURA?

It is depressing when in many of our trials, we capture in a systematic manner how many patients progress in a way that they will not be eligible for next-line therapy. Here…the longer a patient is on the study, [the more] they don’t have a chance [median time to first subsequent therapy, 25.5 months for osimertinib vs 13.7 months for comparator].² It’s not surprising that we see a drug that leads to earlier progression would also be leading to a concern about not able to proceed to second line, and [osimertinib vs erlotinib/gefitinib] have similar percentages, but with a much right-shifted curve [favoring osimertinib].

[Giving] the best therapies first is always true. There are a few examples where this is not the case where toxicity is higher in the second line: [stem cell] transplant in lymphoma or chimeric antigen receptor T-cell therapy. But in lung cancer, going ‘all in’ in the first line has always been the way to go. That’s [true] with immunotherapy approaches, and I think we’ll also see this happening with the antibody-drug conjugates [when] they’ll be moving to the first-line standard of care.

What stood out about subgroups benefiting from osimertinib in the FLAURA trial?

Looking at the subgroup analysis there are a couple interesting features. Some of the confidence intervals [for hazard ratios cross 1.0]. The patients with central nervous system [CNS] metastases [favor osimertinib with] the absolute number of relative benefit, [nearly] the same [as in patients without CNS metastases], but the confidence interval is overlapping here, and I think this is simply a matter of statistics; that number is too small. I wouldn’t have a good explanation why, [if they had] good performance status, they wouldn’t be benefiting the same way they possibly have. [The HR for] OS was [0.80], so they would have a better chance of progressing on second line therapy.

[For patients with EGFR mutations in] ctDNA [circulating tumor DNA] detected by blood, this was not mandatory, but collected in the overwhelming majority of patients with the Cobas® test. [OS outcomes appeared] in a very similar way, even if they didn’t have a shed fraction [of EGFR-positive ctDNA]. Then for the Asian population, [in the] pattern of serial EGFR inhibitors…[the benefit was not as] massive as the non-Asian population [with a HR of] 0.54 [favoring osimertinib].

What did FLAURA show about the use of subsequent therapies?

If you look at the subsequent lines of therapies, I think this is still one of those big questions. What do you do with a patient who progresses on the third-line therapy? The answer is that I don’t know. [For] a patient who progresses on first-line osimertinib; [what is] the second-line standard? We’ve seen those data [from KEYNOTE-789; NCT03820986]—randomized chemotherapy vs chemotherapy plus immunotherapy—at the American Society of Clinical Oncology Annual Meeting and showed clearly no benefit for the addition of immunotherapy.³

Some of the original signal that were [EGFR-mutated] subgroups analyzed from the IMpower150 study [NCT02366143] didn’t seem to be holding up.^4,5 Carboplatin/pemetrexed is my current standard if I don’t have a clinical trial, so anything we could do to extend first-line utility of osimertinib would certainly be highly welcome. Anti-VEGF [therapy] didn’t pan out as positively as we had hoped. Maybe chemotherapy is it, or maybe an antibody in combination. I think those data are [maturing] as well.

What is the safety profile of osimertinib based on FLAURA and FLAURA2?

We’re all familiar with osimertinib’s relatively tolerable AE profile, with very few grade 3/4 toxicities.² The one that I want to point out is interstitial lung disease [ILD]/pneumonitis, especially in the post-immunotherapy setting. We do see ILD/pneumonitis with virtually all small molecule inhibitors but the rate goes up exponentially if it’s given post immunotherapy. We’ll have that in patients post immunotherapy, when given appropriately in the post radiation setting, and when we have it inappropriately given in the context of immunotherapy in the metastatic setting.

[Concerning] FLAURA2, the baseline demographics [include] the typical EGFR mutation population, predominantly with exon 19, predominantly metastatic disease, about a fifth of patients here with CNS metastases. To accommodate the international nature, cisplatin and carboplatin arms were provided here.

[It showed] the typical AEs. I don’t think there was anything new. If there’s a choice in your in your institution, [although] right now, availability has flattened here, cisplatin has a different AE profile, different cytopenias, different renal function impairments, but otherwise, there was not a big difference [from the use of carboplatin].

_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. 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. Yang JC, Lee DH, Lee J, et al. Pemetrexed and platinum with or without pembrolizumab for tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutant, metastatic nonsquamous NSCLC: Phase 3 KEYNOTE-789 study. J Clin Oncol. 2023;41(suppl_17):LBA9000. doi:10.1200/JCO.2023.41.17_suppl.LBA9000}

_{4. Reck M, Mok TSK, Nishio M, et al. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med. 2019;7(5):387-401. doi:10.1016/S2213-2600(19)30084-0}

_{5. Nogami N, Barlesi F, Socinski MA, et al. IMpower150 final exploratory analyses for atezolizumab plus bevacizumab and chemotherapy in key NSCLC patient subgroups with EGFR mutations or metastases in the liver or brain. J Thorac Oncol. 2022;17(2):309-323. doi:10.1016/j.jtho.2021.09.014}

_{6. Planchard D, Feng PH, Karaseva N, et al. Osimertinib plus platinum-pemetrexed in newly diagnosed epidermal growth factor receptor mutation-positive advanced/metastatic non-small-cell lung cancer: safety run-in results from the FLAURA2 study. ESMO Open. 2021;6(5):100271. doi:10.1016/j.esmoop.2021.100271}