FLAURA Trial Update: Osimertinib Outperforms Other TKIs for OS in Advanced NSCLC

Suresh S. Ramalingam, MD

Suresh S. Ramalingam, MDS

New results from the FLAURA trial have shown that patients with treatment-naïve,EGFRmutation—positive advanced non–small-cell lung cancer (NSCLC) who received first-line osimertinib (Tagrisso) experienced improved overall survival (OS) compared with patients who received either gefitinib (Iressa) or erlotinib (Tarceva).¹

The phase III data, which were recently published inThe New England Journal of Medicine,showed that the median OS in the osimertinib group was 38.6 months (95% confidence interval [CI], 34.5 to 41.8). OS in the comparator group, which included patients who received either gefitinib or erlotinib, was 31.8 months (95% CI, 26.6 to 36.0). The hazard ratio [HR] for death was 0.80 (95.05% CI, 0.64 to 1.00;P=0.046).

“With an opportunity to conduct at least 43 months of follow-up in the two groups, the median overall survival was longer by 6.8 months in the osimertinib group than in the comparator group, with a 20% lower risk of death, even in the presence of crossover from the comparator group to the osimertinib group,” wrote the authors, led by Suresh S. Ramalingam, MD, Winship Cancer Institute, Emory University School of Medicine, Atlanta. “Furthermore, at 36 months, three times as many patients were continuing to receive the assigned trial drug in the osimertinib group as in the comparator group.”

The FLAURA trial randomized a total of 556 patients, with 279 assigned to the osimertinib group and 277 assigned to the comparator group. Of these, 183 patients (66%) received gefitinib and 94 patients (34%) received erlotinib. All patients were adults with either locally advanced or metastatic NSCLC with anEGFRmutation who had not previously been treated.

Patients were stratified according toEGFRmutational status (exon 19 deletion or L858R allele) and race (Asian or non-Asian). They were randomized to receive either oral osimertinib (80 mg once daily) or gefitinib (250 mg once daily) or erlotinib (150 mg once daily) until disease progression, unacceptable toxicity, or withdrawal of consent. The trial design permitted comparator group patients to cross over to receive osimertinib following independently confirmed disease progression. Post-progression documentation of the presence of a T790M resistance mutation was required for these patients.

At the time of the data cutoff, the osimertinib group had a median treatment duration of 20.7 months (range, 0.1 to 49.8). This compares with 11.5 months (range, 0.0 to 50.6) in the comparator group. Nearly one-quarter of patients in the osimertinib group (n = 61, 22%) were still on therapy at data cutoff, while only 5% of the comparator group (n = 13) were still taking their originally assigned drug.

At data cutoff, the osimertinib group had reached a median OS follow-up of 35.8 months, while the comparator group’s median OS follow-up was 27.0 months. The median OS in the osimertinib group was 38.6 months (95% CI, 34.5 to 41.8), while the comparator group’s was 31.8 months (95% CI, 26.6 to 36.0) in the comparator group. The HR for death was 0.80 (95.05% CI, 0.64 to 1.00;P=0.046).

Overall, 98% of the patients in the two trial groups had at least one adverse event (AE). About one-quarter of patients in each group (27%) experienced serious AEs, while 42% of osimertinib patients and 47% of comparator patients experienced an AE of grade 3 or higher. Ejection fraction decrease was seen in 14 patients (5%) in the osimertinib group and in 5 (2%) in the comparator group. QT prolongation on electrocardiography was reported in 40 patients (14%) in the osimertinib group and in 14 patients (5%) in the comparator group.

Nine patients (3%) in the osimertinib group experienced fatal AEs, while 10 comparator group patients (4%) did. None of these deaths in the osimertinib group were found to be treatment-related, but 2 were in the comparator group.

The authors noted that osimertinib is more effective in pretreated patients in whom theEGFRT790M resistance mutation develops than are other earlier-generation EGFR-TKIs. “Therefore, crossover from the comparator group to the osimertinib group probably contributed to the duration of overall survival in the comparator group (31.8 months),” they wrote. “In the real-world setting, it has been reported that 25 to 39% of patients who receive first- or second-generation EGFR-TKIs go on to receive osimertinib as a second-line therapy, in line with the crossover rate of 31% (in 85 of 277 patients) observed in all the patients who were assigned to the comparator group in FLAURA (i.e., 85 of 180 patients [47%] who discontinued the comparator EGFR-TKI and received osimertinib as the first subsequent therapy).”

Ramalingam et al had reported in their previous analysis of data from the FLAURA trial that osimertinib also had activity in patients with central nervous system (CNS) metastases.²In the current study, they found 18-month progression-free survival (PFS) among patients with CNS metastases to be 58% in the osimertinib group (95% CI, 40 to 72) and 40% in the comparator group (95% CI, 25 to 55). The HR for disease progression or death was 0.48 (95% CI, 0.26 to 0.86).

Finally, the authors emphasized the importance of understanding resistance mechanisms after first-line treatment and determining appropriate therapies on the basis of molecular-resistance profiles. “Preliminary data suggest that first-line osimertinib resistance mechanisms are similar to those observed in patients with the T790M mutation who are receiving osimertinib as a second-line therapy,: they wrote. “Such resistance mechanisms are also similar to those associated with less frequent mutations (i.e., other than T790M) that are seen in patients who have resistance to other first- and second-generation EGFR-TKIs.”

They referred colleagues to two ongoing phase 2 studies: the ORCHARD trial (NCT03944772) and the SAVANNAH trial (NCT03778229) as research continues into determining the most effective treatment on the basis of resistance patterns after disease progression while patients are receiving first-line osimertinib therapy.^3,4

References

1. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med. Published online November 21, 2019. DOI: 10.1056/NEJMoa1913662.
2. Reungwetwattana T, Nakagawa K, Cho BC, et al. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. 2018;36:JCO2018783118.
3. Phase 2 Platform Study in Patients With Advanced Non-Small Lung Cancer Who Progressed on First-Line Osimertinib Therapy (ORCHARD). Clinical Trials.gov. Accessed December 4, 2019.https://clinicaltrials.gov/ct2/show/NCT03944772.
4. Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib (SAVANNAH). Clinical Trials.gov. Accessed December 4, 2019.https://clinicaltrials.gov/ct2/show/NCT03778229.