EGFR mutation tracking predicts survival in advanced EGFR -mutated non-small cell lung cancer patients treated with osimertinib.

Background: Osimertinib has become standard therapy of advanced epidermal growth factor receptor ( EGFR )-mutated non-small cell lung cancer (NSCLC) patients and T790M-mediated resistance. We investigated the clinical utility of EGFR mutation tracking in plasma-based circulating tumor DNA (ctDNA) after start of osimertinib therapy in metastatic, EGFR -mutant NSCLC patients who had progressed on prior therapy with EGFR tyrosine kinase inhibitors (TKIs).
Methods: We enrolled 141 patients with advanced EGFR -mutated NSCLC who underwent second-line osimertinib treatment for T790M-positive disease. After initiation of osimertinib, we obtained plasma samples from 108 patients. Plasma ctDNA was tested for EGFR mutations by means of droplet digital PCR and was termed positive if any EGFR mutation was detected.
Results: Plasma ctDNA was detected in 58 of 108 (54%) patients after osimertinib initiation and was associated with poor progression-free survival (PFS) [hazard ratio (HR) 4.26, 95% confidence interval (CI): 2.55-7.10, P<0.0001] and overall survival (OS) (HR 3.23, 95% CI: 1.80-5.78, P<0.0001). In multivariable analysis, ctDNA status remained significantly associated with PFS and OS (HR 4.87, 95% CI: 2.81-8.44, P<0.0001; HR 3.49, 95% CI: 1.88-6.50, P<0.0001). Patients with persistence of activating EGFR mutations within eight weeks had shorter durations of PFS (HR 6.17, 95% CI: 3.03-12.56, P<0.0001) and OS (HR 4.83, 95% CI: 2.25-10.36, P<0.0001) than patients with total clearance of the activating EGFR mutation. Persistence of activating EGFR mutations in plasma ctDNA remained an independent predictor of poor PFS and OS in multivariable analyses.
Conclusions: Patients with persistence of activating EGFR mutations in plasma ctDNA within eight weeks after osimertinib initiation have worse prognosis and may require the addition of chemotherapy or other treatments in order to achieve better outcome.
Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr.2020.03.02). AB reports personal fees from AstraZeneca, outside the submitted work; MJH reports personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from Merck Sharp & Dohme, personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, outside the submitted work; RP reports personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Gedeon Richter, personal fees from Genmab, personal fees from Merck Sharp & Dohme, personal fees from Regeneron, personal fees from Roche, outside the submitted work; RP serves as the unpaid editorial board member of Translational Lung Cancer Research from Dec 2019 to Nov 2020. MF reports personal fees from AstraZeneca, personal fees from Bayer, personal fees from Biomedica, personal fees from Boehringer Ingelheim, personal fees from Eli Lilly, personal fees from Merck Sharp & Dohme, personal fees from Myriad Genetics Inc., personal fees from Pfizer, personal fees from Roche, outside the submitted work; US has no conflicts of interest to declare.
(2020 Translational Lung Cancer Research. All rights reserved.)