Early clearance of plasma EGFR mutations as a predictor of response to osimertinib in the AURA3 trial
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AbstractBackground: In the Phase III AURA3 trial (NCT02151981), osimertinib, a third-generation EGFR-TKI, had significantly greater efficacy than platinum-pemetrexed in patients (pts) with advanced NSCLC and T790M-mediated acquired resistance to first-line EGFR-TKI. We investigate whether the presence of plasma EGFR mutations at 3 and 6 wks post-osimertinib treatment (80 mg, once daily) is associated with clinical outcomes, and identify pre-existing genomic aberrations that may impact outcomes. Methods: EGFR mutation analysis (Ex19del/L858R/T790M) was conducted at baseline, wks 3 and 6, by droplet digital (dd)PCR (Biodesix). Next generation sequencing (NGS, Guardant Health; 73 genes) was conducted on baseline plasma samples to explore mechanisms of innate resistance. Clinical outcomes (median progression-free survival [mPFS], objective response rate [ORR]) were investigator assessed, per RECIST 1.1. Results: Of 207 pts with a valid plasma ddPCR result at baseline (all T790M+), 150 had detectable EGFR-TKI sensitizing mutations (EGFRm; Ex19del/L858R) and 57 did not. mPFS was 14.0 mo (95% CI 12.4, not calculable) in pts without detectable baseline EGFRm vs 8.3 mo (95% CI 6.9, 10.9) in pts with detectable baseline EGFRm; EGFRm allelic fraction in baseline plasma was not related to ORR or mPFS. Of the 129 pts with baseline EGFRm and evaluable plasma samples at wk 3, 48 had detectable EGFRm (EGFRm+) and 81 had undetectable EGFRm (EGFRm-). mPFS was 5.7 mo (95% CI 4.1, 9.7) in pts EGFRm+ vs 10.9 mo (95% CI 8.3, 12.7) in pts EGFRm-; hazard ratio (HR) 2.0 (95% CI 1.3, 3.2), p = 0.001; HR > 1 favors pts EGFRm-. ORR was 50% vs 82%, respectively. A similar trend was observed at wk 6 (n = 132): PFS, HR 2.8 (95% CI 1.8, 4.3), p < 0.0001. NGS of baseline plasma showed no association between pre-existing genomic aberrations (TP53, BRAF, KRAS, MET/HER2 amp) and clinical outcome; additional analyses are ongoing. Conclusions: In pts with tissue T790M+ NSCLC and detectable baseline plasma EGFRm, continued presence of EGFRm at wks 3 and 6 was associated with less favorable outcomes with osimertinib. Early dynamic changes of plasma EGFR mutations may predict clinical outcome in pts receiving osimertinib for T790M+ NSCLC. Clinical trial information: NCT02151981
All Author(s) ListFrances A. Shepherd, Vassiliki Papadimitrakopoulou, Tony Mok, Yi-Long Wu, Ji-Youn Han, Myung-Ju Ahn, Suresh S. Ramalingam, Tom John, Martin Sebastian, Willemijn Theelen, Gianluca Laus, Barbara Collins, Aleksandra Markovets, Kenneth S. Thress, Geoffrey R. Oxnard
Name of ConferenceASCO Annual Meeting 2018
Start Date of Conference01/06/2018
End Date of Conference05/06/2018
Place of ConferenceChicago, IL
Country/Region of ConferenceUnited States of America
Proceedings TitleJournal of Clinical Oncology
Series TitleLung Cancer—Non-Small Cell Metastatic
Number in SeriesPoster Session (Board #350); suppl; abstr 9027
Volume Number36
Issue Number15 suppl
LanguagesEnglish-United Kingdom

Last updated on 2020-14-07 at 01:18