First-line Treatment with Osimertinib Associated with Longer OS in EGFR Mutation–positive Advanced NSCLC

Osimertinib provides longer overall survival than a comparator EGFR tyrosine kinase inhibitor in EGFR mutation–positive, advanced non-small cell lung cancer

FLAURA investigators led by Prof. Suresh S. Ramalingam of the Winship Cancer Institute, Emory University School of Medicine, Atlanta, US reported on 21 November 2019 in The New England Journal of Medicine (NEJM) that among patients with previously untreated locally advanced or metastatic non-small cell lung cancer (NSCLC) with an EGFR mutation, those patients who received osimertinib had longer overall survival (OS) than those who received a comparator EGFR tyrosine kinase inhibitor (TKI). The safety profile for osimertinib was similar to that of the comparator EGFR TKIs, despite a longer duration of exposure in the osimertinib group.

The study findings were simultaneously published in NEJM along presentation by Prof. Byoung Chul Cho of the Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea at ESMO Asia Congress 2019 in Singapore. The abstract LBA16 was presented during proffered papers session on thoracic cancers.

Osimertinib is a third-generation, irreversible, oral EGFR TKI that selectively inhibits both EGFR TKI–sensitising and EGFR T790M resistance mutations and has shown efficacy in patients with NSCLC who have central nervous system (CNS) metastases.

The FLAURA trial is a double-blind, phase III trial involving patients with previously untreated advanced NSCLC with EGFR mutations that compared the efficacy and safety of osimertinib with that of two other EGFR-TKIs, gefitinib or erlotinib (both drugs, gefitinib and erlotinib were included in the comparator group).

The primary analysis with data cut-off on 12 June 2017 showed significantly longer progression-free survival (PFS) with the osimertinib regimen than with the comparator regimen, median duration, 18.9 months vs. 10.2 months (hazard ratio for disease progression or death, 0.46; p < 0.001).

At the time of the primary analysis, OS data were immature (data maturity, 25%) but showed a trend toward longer OS with osimertinib (hazard ratio for death, 0.63; p = 0.007).

The safety profile of osimertinib was similar to that of the comparator EGFR TKIs, and the rates of serious adverse events were lower with osimertinib. On the basis of these efficacy and safety data, the indication for osimertinib was extended to include first-line treatment in patients with advanced NSCLC whose tumours have sensitising EGFR mutations.

In the latest NEJM publication and during the ESMO Asia Congress 2019, the FLAURA team reported the results of the planned final analysis of OS data.

Patients eligible for the study were ≥18 years (in Japan ≥20), treatment-naïve with WHO performance status 0–1. Patients with stable CNS metastases not requiring steroids for ≥2 weeks were allowed. FLAURA investigators randomly assigned 556 patients with previously untreated advanced NSCLC with an EGFR mutation (exon 19 deletion or L858R allele) in a 1:1 ratio to receive either osimertinib 80 mg once daily or one of two other EGFR TKIs, gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily (patients receiving gefitinib or erlotinib combined in a single comparator group). Crossover was allowed for patients in the comparator EGFR TKI arm upon central confirmation of progression and T790M positivity.

The OS was a secondary endpoint. The median OS was 38.6 months (95% confidence interval [CI], 34.5 to 41.8) in the osimertinib group and 31.8 months (95% CI, 26.6 to 36.0) in the comparator group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; p = 0.046).

At 3 years, 79 of 279 patients (28%) in the osimertinib group and 26 of 277 (9%) in the comparator group were continuing to receive a trial regimen; the median exposure was 20.7 months and 11.5 months, respectively.

Adverse events of grade 3 or higher were reported in 42% of the patients in the osimertinib group and in 47% of those in the comparator group.

The authors concluded that first-line treatment with osimertinib is associated with significantly longer OS than treatment with comparator EGFR TKIs in patients with EGFR mutation–positive, locally advanced or metastatic NSCLC and had a similar safety profile.

Osimertinib is the first EGFR TKI monotherapy to show a statistically significant OS benefit versus another EGFR TKI. The final OS analysis of FLAURA reinforces osimertinib as the standard of care for first-line treatment in patients with EGFR mutated advanced NSCLC.

In another abstract presented at ESMO Asia Congress 2019 (LBA17), the FLAURA investigators showed that longitudinal circulating tumour DNA monitoring may allow for earlier identification of patients who progress on first-line EGFR TKI therapy and the detection of EGFR-mediated resistance mechanisms.

The authors wrote in NEJM that understanding resistance mechanisms after first-line treatment and determining appropriate therapies on the basis of molecular-resistance profiles remain important considerations. 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. Such resistance mechanisms are also similar to those associated with less frequent mutations that are seen in patients who have resistance to other first- and second-generation EGFR TKIs. Further research is ongoing in the phase II ELIOS trial. Research to understand the most effective treatment on the basis of resistance patterns after disease progression while patients are receiving first-line osimertinib therapy is also ongoing in two phase II studies, the ORCHARD and the SAVANNAH trial.

 

Disclosure

The study was funded by AstraZeneca. 

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