hase III FLAURA trial shows MET-amplification and EGFR C797S mutation among most frequent resistance mechanisms to Tagrissoin NSCLC patients. AstraZeneca

AstraZeneca presented new data on the mechanisms of acquired resistance from the Tagrisso (osimertinib) pivotal Phase III FLAURA trial during an oral late-breaker abstract session at the ESMO 2018 Congress (European Society of Medical Oncology) in Munich, Germany. MET-amplification and the epidermal growth factor receptor (EGFR) C797S mutation were among the most frequent resistance mechanisms observed after treatment with 1st-line Tagrisso in patients with previously-untreated EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) who experienced disease progression during the trial period. As expected, there was no evidence of the acquired EGFR T790M mutation in the 1st-line Tagrisso arm.

Based on those findings, AstraZeneca announced the initiation of a new clinical trial, Osimertinib Resistance CoHorts, Addressing 1L Relapse Drivers (ORCHARD), an open-label, multi-centre, multi-drug Phase II platform trial in patients with advanced NSCLC who have experienced disease progression following 1st-line therapy with Tagrisso.

Results from the preliminary FLAURA subgroup analysis showed that following treatment with Tagrisso in the 1st-line setting, the most frequent acquired resistance mechanisms detected in patient plasma were MET-amplification (15%) and the EGFR C797S mutation (7%), followed by HER2-amplification and the PIK3CA and RAS mutations (2-7%). For the comparator EGFR-TKI arm, the most frequent acquired resistance mechanism to erlotinib or gefitinib was the EGFR T790M mutation (47%). Data from the Phase III AURA3 trial, also presented at the congress, were consistent with the FLAURA findings. The most frequent mutations detected in patient plasma after progression with 2nd-line Tagrisso included EGFR C797 mutations (15%; C797S n=10; C797G n=1), MET-amplification (19%), HER2-amplification (5%) and the PIK3CA mutation (5%).