Funding

The study was funded by a research grant by Astrazeneca (grant number ESR-16-12212), as well as access to the study medication osimertinib. Guardant Health financed the costs of the analysis of 34/54 samples (UMCG-LCR-nr 138118). Both AstraZeneca and Guardant Health had no role in study design, data collection, data interpretation, and writing of the manuscript.

Conflicts of Interest

The authors F.Z., P.R., and P.L. declare no potential conflicts of interest. B.M. received travel grants from the American Association of Cancer Research-Bristol Myers Squibb, and the Netherlands Respiratory Society. A.J.L. reports grants from AstraZeneca, BMS, MSD, Boehringer Ingelheim, and non-financial support from Merck Serono and Roche, all outside the submitted work. L.H. reports grants for research funding from Roche Genentech, AstraZeneca, Boehringer Ingelheim, Takeda, Merck, Pfizer, Novartis, and Gilead (all payments were paid to the institution); payments for speaker educationals/webinars from AstraZeneca, Bayer, Lilly, MSD, high5oncology, Takeda, Janssen, GSK, Sanofi, Pfizer (Inst), Medtalks, Benecke, VJOncology, and Medimix (self); participation on advisory boards for Abbvie, Amgen, Anhearth, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi, GSK, Janssen, Lilly, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Summit Therapeutics, and Takeda; has a leadership or fiduciary role in the secretary NVALT studies foundation, subchair EORTC metastatic NSCLC systemic therapy, vice-chair scientific committee Dutch Thoracic Group; local PI of clinical trials from AstraZeneca, GSK, Novartis, Merck, Roche, Takeda, Blueprint, Mirati, Abbvie, Gilead, MSD, Merck, Amgen, Boehringer Ingelheim, and Pfizer (all payments to the institution). M.H. reports research funding from Roche Genentech, AstraZeneca, BMS,Boehringer Ingelheim, Merck, Novartis, Pamgene, Pfizer, Roche diagnostics, Stichting Treatmeds, and Takeda (all payments were paid to the institution); received speaker educationals/webinars from Amgen, Astrazeneca, BMS, Janssen Pharmaceutica, Merck, MSD, Novartis, Pfizer, and Roche (all inst); participation on advisory boards: Abbvie, Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Janssen, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Sanofi, and Takeda; chair NVALT studies foundation, chair section oncology NVALT; local PI of clinical trials from AstraZeneca, BMS, GSK, Novartis, Merck, Roche, Takeda, Mirati, Abbvie, MSD, Merck, Amgen, Boehringer Ingelheim, and Pfizer (all payments to the institution). C.L. reports advisory roles in AstraZeneca, BMS, MSD (all payments to the institution). S.H. reports research grants and/or advisory roles in AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Janssen, GSK, MSD, Novartis, Roche and Takeda; J.H. received grants or contracts from AstraZeneca, BMS and Roche. E.S. received unrestricted grants (all paid to UMCG institution) from Abbott, Biocartis, AstraZeneca, Invitae/Archer, Bayer, Bio-Rad, Roche, Agena Bioscience, CC Diagnostics, MSD/MERCK, and Boehringer Ingelheim; has received consulting fees (all paid to UMCG institution) from MSD/Merck, AstraZeneca, Roche, Novartis, Bayer, BMS, Lilly, Amgen, llumina, Agena Bioscience, CC Diagnostics, Janssen Cilag (Johnson & Johnson), Astellas Pharma, GSK, Sinnovisionlab, and Sysmex; has received payments or honoraria (all paid to UMCG institution) from Bio-Rad, Seracare, Roche, Biocartis, Lilly, Agena Bioscience, and Illumina; has received support for attending meetings and/or travel from BioRad, Biocartis, Ageno Sciences, and Illumina; is a board member for the Dutch Society of Pathology (unpaid), European Society of Pathology (unpaid), European Liquid Biopsy Society (unpaid), is a secretary/member of the advisory committee for assessment of molecular diagnostics (cieBOD) (honoraria paid to UMCG institution), and is committee member of national guideline advisory (honoraria paid to UMCG institution). A.W. has received grants or contracts from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche, and Takeda; has received consulting fees from AstraZeneca, Janssen, Lilly, Roche, and Takeda; has received payments or honoraria from AstraZeneca, BMS, Lilly, Pfizer, and Roche; has a leadership or fiduciary role in the oncology section NVALT, guideline committee NSCLC and CUP, dure geneesmiddelen committee NVALT and FMS.

Ethics Approval

The study was approved by all medical research ethics committees at each site.

Consent to Participate

All patients gave their written informed consent prior to the study.

Consent for Publication

Not applicable.

Availability of Data and Material

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

Code Availability

Not applicable.

Authors’ Contributions

Conceptualization: F.Z., B.M., P.R., P.L., E.S., and A.W. Data curation: F.Z. and B.M. Formal analysis: F.Z. Validation: B.M. Supervision: E.S. and A.W. Funding acquisition: E.S. and A.W. Investigation: A.L., L.H., M.H., C.L., J.H., and A.W. Visualization: F.Z. and B.M. Methodology: F.Z., B.M., E.S., and A.W. Writing—original draft: F.Z. and B.M. Project administration: F.Z., B.M., and P.R. Writing—review and editing: P.R., A.L., L.H., M.H., C.L., P.L., J.H., E.S., and A.W.