Mature results of the FLAURA trial

James Fleck: Anticancerweb 12(21), 2019

Lung cancer still leads the overall incidence (ASR = 22.5) and mortality (ASR = 23.1) of malignant diseases. Most patients (85%) are diagnosed with non-small cell lung cancer (NSCLC) and even the most common histological subtype (adenocarcinoma) usually includes a wide range of molecular phenotypes. In the era of lung cancer whole-genome sequencing, the presence of cancer predisposition genes seems to be less frequent and clinically relevant than somatic mutation. Since it was first described in 2004, EGFR somatic mutation turned to be the most important target driver-mutation in lung adenocarcinoma. Currently, EGFR somatic mutation is a prognostic and a predictive factor for lung adenocarcinoma. The wild-type EGFR-kinase domain is intrinsically distorted and only becomes active upon its dimerization. EGFR mutation causes a spontaneous kinase activation or decreases the threshold for dimerization-mediated activation. The most frequent mutated subtypes are the exon 19 deletion and the L858R point mutation in exon 21, respectively accounting for 45 and 35% of all EGFR-mutated NSCLC. Mutations located between exon 18 and 21 usually confer sensitivity to EGFR TKI, except those located in exon 20, including T790M and exon 20 insertions. Osimertinib is a third-generation EGFR-TKI able to overcome T790M resistance mutation, also showing efficacy in CNS metastases. This was the main rationale to design the FLAURA phase 3 clinical trial. Previously untreated EGFR-mutated advanced NSCLC patients were randomly assigned (1:1) to an experimental arm treated with osimertinib or to a standard arm treated with either gefitinib or erlotinib. Primary analysis, published in 2018, showed a significant longer progression-free survival favoring patients treated with osimertinib (HR=0.46 P<0.001). Safety analysis revealed a lower incidence of serious adverse events, also favoring osimertinib.

On December 2019, the New England Journal of Medicine published the FLAURA trial mature date. Patients were stratified according EGFR mutation status and race. Patients in the comparator group, defined as a combination of those who received either gefitinib or erlotinib were eligible for crossover to osimertinib after disease progression. Based on a 95% confidence interval, the median overall survival was 38.5 months for the osimertinib arm and 31.8 months for the comparator group (HR=0.80 P=0.046). Safety profile was very similar in the two arms, except for cardiac events. Decrease in ejection fraction was reported in 5% of the patients treated with osimertinib versus 2% observed in the comparator group. QT prolongation on electrocardiography was described in 10% on the osimertinib arm versus 4% in the comparator group. Use of osimertinib conducted to a 20% reduction in the risk of death, even in the presence of crossover from the comparator group to osimertinib. Three time as many patients were continuing to receive osimertinib as in the comparator group, which might explain the higher incidence of cardiac events. Osimertinib also has activity in patients with CNS metastases. As previously described, 50% of EGFR-mutated NSCLC will have CNS metastases within three years of diagnosis, further encouraging the use of osimertinib as a new treatment standard.

ASR = Age-standardized rate per 100 000, EGFR = Epidermal growth factor receptor, CNS = Central nervous system  

References:

1.     S.S. Ramalingam, J. Vansteenkiste, D. Planchard, et al: Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC, N Engl J Med, Nov 21, 2019 DOI: 10.1056/NEJMoa1913662 

2.     Yue I. Cheng, Yun Cui Gan, Dan Liu, et al: Potential genetic modifiers for somatic EGFR mutation in lung cancer: a meta- analysis and literature review, BMC Cancer 19:1068, 2019