495PTracking of activating EGFR mutations predicts progression-free survival in advanced EGFR-mutated NSCLC patients treated with osimertinib. (24th November 2019) - Buder, A
Abstract: Background: Osimertinib has been established as standard treatment for patients with advanced EGFR-mutated NSCLC. We assessed the clinical relevance of EGFR mutation tracking in plasma circulating tumor DNA (ctDNA) after initiation of osimertinib therapy in patients who were pre-treated with EGFR-tyrosine kinase inhibitors (TKIs). Methods: Plasma samples of 106 patients with advanced EGFR-mutated NSCLC who received second-line osimertinib after detection of T790M mutation in plasma ctDNA and/or tissue re-biopsy were collected under osimertinib therapy. Plasma ctDNA was tested for EGFR deletions in exon 19, L858R, L861Q, S768I, T790M and C797S mutations using droplet digital PCR (ddPCR). Primary endpoint was progression-free survival (PFS). Univariate and multivariable Cox proportional hazard models were used to evaluate the risk of progression. Results: In 57 out of 106 patients plasma samples were available within the first 8 weeks after osimertinib therapy initiation. Within this time frame, the activating mutation remained detectable in plasma of 19/57 patients (33%) and the T790M mutation in 8/57 patients (14%). The C797S mutation was not detectable within 8 weeks after osimertinib start. Patients with persistence of the activating EGFR mutation in plasma ctDNA within 8 weeks after osimertinib initiation had a shorter PFS compared to patients who had lost the activating EGFR mutation (median PFS 3.4 versus 26.9 months; hazard ratio [HR] 6.17, 95% confidence interval [CI] 3.03-12.56, p < 0.0001). Similarly, detection of T790M in plasma ctDNA was also associated with shorter PFS (median PFS 7.0 versus 19.0 months; HR 2.32, 95% CI 1.00-5.37, p = 0.05). Multivariable analysis using a stepwise backward elimination model demonstrated that persistence of activating EGFR mutations and T790M in plasma ctDNA remained significant predictors of shorter PFS after adjusting for clinical parameters and T790M. Conclusions: Our results show that tracking of activating EGFR mutations during osimertinib therapy is clinically relevant. Detection of activating EGFR mutations in plasma ctDNA 8 weeks after osimertinib initiation predicts shorter PFS of second-line treatment with osimertinib. Legal entity responsible for the study: The authors. Funding: AstraZeneca. Disclosure: A. Buder: Honoraria (self): AstraZeneca. M.J. Hochmair: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. M. Filipits: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim. All other authors have declared no conflicts of interest.