Ramalingam SS, et al. ESMO 2017:LBA2_PR

Osimertinib versus standard of care EGFR TKIs as first-line treatment in patients with EGFR M+ advanced NSCLC: FLAURA


Osimertinib, a central nervous system (CNS)-active epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), has shown promising preclinical and early clinical trial data for the first-line treatment of EGFR mutation-positive (M+) advanced non-small cell lung cancer (NSCLC).1–4 Osimertinib was studied in the first-line setting in a phase III trial compared against standard of care (SoC) in patients with EGFR M+ advanced NSCLC. Efficacy and safety results from this study were presented at the ESMO 2017 Congress.5

Study design

  • The FLAURA study is a phase III, double-blind, randomized study assessing the efficacy and safety of osimertinib versus an SoC EGFR TKI (gefitinib or erlotinib) in first-line therapy for patients with advanced EGFR M+ NSCLC.
  • The primary endpoint of the study was progression-free survival (PFS) according to investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
    • This study had a 90% power to detect a hazard ratio (HR) of 0.71 (representing an improvement in median PFS from 10 months to 14.1 months) at a two-sided alpha level of 5%.
  • Secondary endpoints included:
    • Objective response rate (ORR);
    • Duration of response (DOR);
    • Disease control rate;
    • Depth of response;
    • Overall survival (OS);
    • Patient-reported outcomes; and
    • Safety.
  • Patients in the SoC arm could cross over and receive open-label osimertinib upon central confirmation of progression and exon 20 T790M resistance mutation positivity.

Study Design

Key findings

  • Globally, 556 patients were randomized to treatment (osimertinib, n = 279; SoC, n = 277 [with 66% of patients receiving gefitinib and 34% receiving erlotinib]).
  • Baseline characteristics were balanced across treatment arms.
  • In the osimertinib and SoC arms, respectively, 64% and 62% of patients were female, and 19% and 23% of patients had CNS metastases at study entry.
  • In both treatment arms, median age was 64 years, 62% of patients were of Asian race, 63% of patients had an EGFR exon 19 deletion, and 37% of patients had an EGFR exon 21 L858R point mutation.


  • At data cutoff (June 12, 2017), 342 events had occurred in 556 patients (62% maturity; osimertinib = 136 events [49%], SoC = 206 events [74%]).
  • Osimertinib significantly prolonged PFS compared to SoC with an HR of 0.46 (95% CI: 0.37–0.57; p <0.0001). (Figure 1)
    • The median PFS was 18.9 months in the osimertinib arm and 10.2 months in the SoC arm.
  • PFS outcomes favoured the osimertinib arm in all subgroups analyzed (sex, age, race, smoking history, CNS metastases, World Health Organization performance status, and EGFR mutation).
    • In particular, for patients with CNS metastases (n = 116) and without CNS metastases (n = 440), osimertinib significantly prolonged PFS compared to SoC (HR = 0.47 and 0.46, respectively). (Figure 2)
    • In all patients, CNS progression events occurred in 17 patients (6%) receiving osimertinib versus 42 patients (15%) receiving SoC.
  • There was not a significant difference in ORR between treatment arms (osimertinib: 80% vs. SoC: 76%, odds ratio = 1.28, 95% CI: 0.85–1.93; p = 0.2335).
  • The estimated percentage of patients remaining in response at 12 months was 64% (95% CI: 58–71) and 37% (95% CI: 31–44) for the osimertinib arm versus SoC arm, and at 18 months was 49% (95% CI: 41–56) versus 19% (95% CI: 13–26), respectively.
  • The DOR was more than 2-fold higher in the osimertinib arm versus SoC arm, with non-overlapping CIs (17.2 months, 95% CI: 13.8–22.0 vs. 8.5 months, 95% CI: 7.3–9.8, respectively).
  • At data cutoff, 141 deaths occurred in 556 patients (25% maturity; osimertinib = 58 deaths [21%]; SoC = 83 deaths [30%]).
  • A trend towards an OS benefit for osimertinib over SoC was observed (HR = 0.63, 95% CI: 0.45–0.88; p = 0.0068); however, the p-value did not reach what was required (p <0.0015) for statistical significance at the current maturity. (Figure 3)

Figure 1. PFS by investigator assessment

Figure 2. PFS* in patients by CNS metastases at study entry

Figure 3. Overall survival interim analysis


  • The median duration of exposure was 16.2 months for osimertinib (range: 0.1–27.4) and 11.5 months (range: 0–26.2) for SoC.
  • Compared to SoC, patients treated with osimertinib had a lower incidence of grade ≥3 adverse events (AEs) of any cause (34% vs. 45%) and of grade ≥3 treatment-related AEs (18% vs. 28%).
  • The incidence of gastrointestinal toxicity was similar between treatment arms; however, the incidence of stomatitis was higher with osimertinib versus SoC (29% vs. 20%). (Table 1)
  • Compared to SoC, the incidence of the following AEs of any grade were lower in the osimertinib arm:
    • Dermatitis acneiform (25% vs. 48%);
    • Aspartate aminotransferase (9% vs. 25%); and
    • Alanine aminotransferase (6% vs. 27%).

Table 1. All-causality adverse events (≥15% of patients)

Key conclusions

  • Osimertinib resulted in a significant improvement in PFS over SoC, with a 54% reduction in the risk of progression or death relative to SoC (HR = 0.46 and an early separation of Kaplan-Meier curves).
    • There was a consistent PFS benefit in patients with and without CNS metastases at study entry.
  • The duration of response was doubled in the osimertinib versus SoC arm (median: 17.2 months vs. 8.5 months).
  • The interim OS results showed promising survival favouring osimertinib versus SoC; however, data is not yet significant at 25% maturity (HR = 0.63, 95% CI: 0.45–0.88; p = 0.0068).
  • The safety profile of osimertinib was comparable to SoC, although with lower rates of grade ≥3 AEs and a lower discontinuation rate.
  • Osimertinib may be a new SoC as first-line therapy in patients with EGFR M+ advanced NSCLC.

References: 1. Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014;4(9):1046–61. 2. Yang JC, Ahn MJ, Kim DW, et al. Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study phase II extension component. J Clin Oncol 2017;35(12):1288–96. 3. Eberlein CA, Stetson D, Markovets AA, et al. Acquired resistance to the mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling in preclinical models. Cancer Res 2015;75(12):2489–500. 4. Meador CB, Jin H, de Stanchina E, et al. Optimizing the sequence of anti-EGFR-targeted therapy in EGFR-mutant lung cancer. Mol Cancer Ther 2015;14(2):542–52. 5. Ramalingam SS, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard-of-care EGFR-TKI as first-line treatment in patients with EGFRm advanced NSCLC: FLAURA. ESMO Annual Congress Abstracts 2017:LBA2_PR.