LBA53 - ELIOS: A multicentre, molecular profiling study of patients (pts) with epidermal growth factor receptor-mutated (EGFRm) advanced NSCLC treated with first-line (1L) osimertinib

Background

Osimertinib – a 3^rd-generation EGFR-TKI – is the preferred 1L treatment for EGFRm advanced NSCLC; however, pts can eventually develop progressive disease (PD). ELIOS (NCT03239340) characterised resistance mechanisms to 1L osimertinib. To our knowledge, this is the first prospective study with a primary objective comparing paired baseline and post-PD tumour tissue biopsies.

Methods

Pts with EGFR-TKI naïve advanced NSCLC with an EGFR-TKI-sensitising mutation received osimertinib 80 mg QD. Mandatory tumour biopsies were taken pre-treatment and post-PD; samples were analysed by next-generation sequencing. 1º endpoint: proportion of pts with a given tumour genetic and proteomic marker (including, but not limited to, EGFR mutations, HER2 and MET expression and/or amplification [amp]) at PD. 2º endpoints included investigator-assessed PFS (RECIST 1.1) and safety.

Results

154 pts were enrolled (full analysis set; FAS): median age 62 yrs (range 35–87), 77% Asian, Ex19Del/L858R/atypical EGFR mutations 55/38/7%. At data cutoff, 119 pts had PD (24 not progressed; 11 censored for other reasons); of these, 46 (39%) had evaluable paired biopsies. Median PFS (FAS) was 16.4 months (95% CI, 12.7, 20.3). AEs/SAEs occurred in 97/31% of pts. Key genetic alterations (Table) included acquired amp in MET (17%) and NKX2.1 (11%) and acquired EGFR C797S (15%). High frequency mutations at baseline (CDKN2A loss, EGFR amp, EGFR and TP53 mutations) did not differ significantly at PD.

Conclusions

Efficacy and safety of 1L osimertinib were consistent with FLAURA. MET amp was the main acquired resistance mechanism to osimertinib, consistent with previous data. NKX2.1 amp was identified as a potential new resistance marker. Paired biopsies were obtained in only 39% of pts, highlighting the challenges of obtaining post-PD tissue biopsies and the need for more comprehensive non-invasive testing methods. See table. Table: 000LBA53

*Defined as mutations detectable at PD that were not detectable at baseline (for an individual patient) Genetic alterations shown were selected based on high-frequency of detection and/or prior knowledge of involvement in osimertinib resistance.

Clinical trial identification

NCT03239340.

Editorial acknowledgement

The authors would like to acknowledge Caroline Allinson, BSc, of Ashfield MedComms, an Inizio Company, for medical writing support that was funded by AstraZeneca in accordance with Good Publications Practice (GPP3) guidelines.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

Z. Piotrowska: Financial Interests, Personal, Advisory Board: Janssen, Takeda, Cullinan, C4 Therapeutics, Blueprint, AstraZeneca, EliLilly; Financial Interests, Institutional, Research Grant: Novartis, Takeda, Spectrum, AstraZeneca, Tesaro/GSK, Cullinan, Daiichi, Janssen, Blueprint; Financial Interests, Institutional, Invited Speaker: AbbVie; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Non-Financial Interests, Institutional, Principal Investigator: Cullinan; Financial Interests, Personal, Advisory Role: Eli Lilly, Janssen, Daiichi. M. Ahn: Financial Interests, Advisory Board: AstraZeneca, Bristol-Myers Squibb, MSD, Ono Pharmaceutical, Roche, Takeda, Alpha Pharmaceutical; Financial Interests, Other: AstraZeneca, Bristol-Myers Squibb, MSD, Ono Pharmaceutical, Roche. Y.K. Pang: Other, Personal, Principal Investigator: FLAURA and ELIOS trials. S.H. How: Financial Interests, Invited Speaker: AstraZeneca, MSD, Boehringer Ingelheim; Financial Interests, Advisory Board: AstraZeneca, Pfizer, Novartis, Roche, MSD, Boehringer Ingelheim, Takeda; Financial Interests, Research Grant: AstraZeneca, Pfizer, Novartis, Roche, MSD, Boehringer Ingelheim. S. Kim: Financial Interests, Research Grant: AstraZeneca, Boehringer Ingelheim, Novartis, Eli Lilly, Yuhan; Financial Interests, Other: AstraZeneca, Boehringer Ingelheim, Novartis, Eli Lilly, Roche, BMS. P.J. Voon: Financial Interests, Advisory Board: AstraZeneca, Novartis, MSD, Ipsen, Pfizer. D.L. Cortinovis: Financial Interests, Advisory Board: MSD, BMS, Novartis, Boehringer Ingelheim, Amgen, Roche, Sanofi Genzyme, Takeda; Financial Interests, Invited Speaker: AstraZeneca, Roche. J. De Castro Carpeno: Financial Interests, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Gilead, Hoffmann- La Roche, Merck Sharp and Dohme, Pfizer, Takeda; Financial Interests, Advisory Board: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, GSK, Janssen, Lilly, Merck Sharp and Dohme, Novartis, Pfizer, Hoffmann- La Roche, Sanofi, Takeda. M. Tiseo: Financial Interests, Speaker’s Bureau: AstraZeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre, Amgen, Merck, Sanofi; Financial Interests, Research Grant: AstraZeneca, Boehringer Ingelheim. D. Rodriguez Abreu: Financial Interests, Speaker’s Bureau: Roche, AstraZeneca, Bristol-Myers Squibb, MSD, Eli Lilly, Pfizer, Novartis; Financial Interests, Other: Roche, Bristol-Myers Squibb, MSD, Novartis. S.S. Ramalingam: Financial Interests, Research Grant: Amgen, Advaxis, AstraZeneca, BMS, Merck, Tesaro, Takeda, Genmab; Financial Interests, Other: Amgen, BMS, Genentech, Merck, Tesaro, Takeda, GlaxoSmithKline, AstraZeneca. J. Li: Financial Interests, Full or part-time Employment: AstraZeneca; Financial Interests, Stocks/Shares: AstraZeneca. L. Servidio: Financial Interests, Full or part-time Employment: AstraZeneca; Financial Interests, Stocks/Shares: AstraZeneca. S. Sadow: Financial Interests, Research Grant: Novartis, Takeda, Spectrum, AstraZeneca, Tesaro, Cullinan, Daiichi, AbbVie; Financial Interests, Other: AstraZeneca, Blueprint, Medicine, Janssen, Takeda, Jazz Pharmaceuticals, C4 Therapeutics. R.J. Hartmaier: Financial Interests, Full or part-time Employment: AstraZeneca; Financial Interests, Stocks/Shares: AstraZeneca; Other, Other: Genetech and Foundation Medicine. B.C. Cho: Financial Interests, Advisory Board: Kanaph Therapeutic Inc., Bridgebio therapeutics, Cyrus therapeutics, Guardant Health, Oscotec Inc.; Financial Interests, Member of the Board of Directors: Interpark Bio Convergence Corp., J Ints Bio; Financial Interests, Stocks/Shares: TheraCanCac Inc., Gencurix Inc., Bridgebio Therapeutics, Kanaph Therapeutic Inc., Cyrus therapeutics, Interpark Bio Convergence Corp., J INTS BIO; Financial Interests, Royalties: Champions Oncology; Financial Interests, Research Grant: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, AbbVie, Medpacto, GIInnovation, Eli Lilly, Blueprint medicines, Interpark Bio Convergence Corp.; Financial Interests, Advisory Role: Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Janssen, Medpacto, Blueprint medicines; Financial Interests, Other: DAAN Biotherapeutics.