Lin CC, et al. - Osimertinib is approved for the treatment of non-small-cell lung cancer in patients who develop the EGFR Thr790Met mutation after treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). In this study, researchers assessed the impact of osimertinib, a third-generation EGFR TKI, on outcomes in patients with non-small-cell lung cancer and the EGFR Thr790Met mutation, after previous treatment failure with one or more other EGFR TKIs. Findings demonstrated the development of heterogeneous resistance mechanisms in patients receiving osimertinib.

Methods

• Eligible patients had been enrolled at 1 centre in the AURA study.
• The included participants had displayed resistance to a previous EGFR TKI, and had EGFR-activating mutations and acquired Thr790Met mutation detectable in tumour tissue or plasma.
• Per day 20–240 mg osimertinib was consumed by patients until disease progression or development of intolerable side-effects.
• Every 6 weeks, plasma samples were collected.
• Tumour tissue biopsy was done at study entry and was optional after disease progression.
• Researchers tested samples for resistance mechanisms, including EGFR-activating, Thr790Met, and Cys797Ser mutations.
• They assessed associations with overall survival, progression-free survival, and survival after disease progression.

Results

• A total of 53 of 71 patients enrolled in AURA, were eligible for this analysis.
• Data reported that median progression-free survival was 11·1 months (95% CI 8·4–13·9) and overall survival was 16·9 months (11·7–29·1).
• Disease progression was noted in 47 patients.
• Median overall survival after osimertinib progression was 5·4 months (95% CI 4·1–10·0).
• Data showed that plasma samples were available for 40 patients after disease progression and 12 (30%) of these had the Thr790Met mutation (four of whom also had Cys797Ser mutations).
• The best overall and post-progression survival was reported in patients without detectable EGFR-activating mutations in plasma before treatment (22·4 months, 95% CI 15·6–not reached, and 10·8 months, 7·2–not reached, respectively).
• Findings demonstrated that loss of the Thr790Met mutation but presence of EGFR-activating mutations in plasma were associated with the shortest progression-free survival (median 2·6 months, 95% CI 1·3–not reached).
• One squamous cell and two small-cell transformations were found in 22 post-progression tumour samples.
• Researchers detected Thr790Met in 9 (50%) of 18 samples, Cys797Ser in 2 (17%) of 12, cMET amplification in 5 (50%) of 10, BRAF mutation in 1 (8%) of 13, and KRAS mutation in 1 (8%) of 13.