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. 2024 Dec:198:107972.
doi: 10.1016/j.lungcan.2024.107972. Epub 2024 Sep 28.

Combined analysis of circulating tumor DNA and tumor tissue to overcome osimertinib resistance (OSIRIS); the second line osimertinib cohort

J W T van der Wel  1 , M Jebbink  1 , D van den Broek  2 , L C Steinbusch  3 , W S M E Theelen  1 , G Ruiter  1 , W Buikhuisen  1 , J A Burgers  1 , P Baas  1 , M Vermeulen  4 , V van der Noort  4 , S M S Hashemi  5 , L J W Bosch  6 , K Monkhorst  6 , E F Smit  3 , M C Boelens  6 , A J de Langen  7
Affiliations

Combined analysis of circulating tumor DNA and tumor tissue to overcome osimertinib resistance (OSIRIS); the second line osimertinib cohort

J W T van der Wel et al. Lung Cancer. 2024 Dec.

Abstract

Introduction: Osimertinib resistance inevitably occurs in EGFR mutated NSCLC. We aimed to identify resistance mechanisms (RM) using paired plasma and tumor samples in patients that progressed on 2nd/3rd line osimertinib.

Methods: From 09 - 2019 to 02 - 2021, 51 patients were enrolled. Plasma sequencing used AVENIO Expanded Panel (research use only), tumor biopsies underwent DNA and RNA sequencing and histological evaluation. Sequencing was regarded successful when the driver mutation was confirmed with a variant allele frequency of ≥0.10%. Concordance between modalities was calculated for the driver mutation and RMs covered in both modalities. The Molecular Tumor Board formulated a treatment advice.

Results: The driver mutation was detected in 42/51 plasma samples (82%) and in 50/51 tumor samples (98%), concordance rate was 80%. In 41/51 (80%) patients ≥1 RM was identified. Thirty-two RMs covered in both modalities were found in plasma (61.5%), 39 in tumor (75%), nineteen in both. RM concordance rate was 36.5%.

Conclusion: Combined analysis of plasma and tumor samples post 2nd/3rd line osimertinib identifies additional RMs regardless of the comparative approach used. Plasma sequencing identified 61.5% of RMs, tumor analysis identified 75%. Combined, they provide a superior overview of osimertinib resistance, enabling more tailored treatment options.

Keywords: Biopsy; Drug resistance; EGFR; NSCLC; Osimertinib; ctDNA.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Baas reports a grant from BMS, unrestricted to the hospital, as well as consulting fees paid to the hospital by BMS, MSD, AMheart, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events to the hospital from BMS. Burgers reports a grant from MSD as support for an investigator initiated study, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events to the hospital from MSD, participation on a data safety monitoring board or advisory board with Roche, paid to the hospital, and receipt of free drugs for an investigator initiated study from MSD. Hashemi reports grants from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Janssen, GSK, MSD, Novartis, Roche and Takeda, all to the institution. De Langen reports grants from BMS, grants from MSD, grants from Boehringer, non-financial support from Merck Serono, grants from AstraZeneca, non-financial support from Roche, outside the submitted work. Monkhorst reports consulting fees from Lilly, Bayer and Amgen, all paid to the institution. Smit reports consulting fees from Eli Lilly, AstraZeneca, MSD, Merck, BMS, DSI, Takeda and Boehringer Ingelheim, all paid to the institution, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board with DSI. Theelen reports grants from Sanofi/Regeneron and MSD to the institution. Boelens, Bosch, Buikhuisen, van den Broek, Jebbink, van der Noort, Steinbusch, Ruiter, Vermeulen, van der Wel declare no potential conflict of interest.

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