LBA12 - Tumour genomics in patients (pts) with epidermal growth factor receptor-mutated (EGFRm) advanced NSCLC treated with first-line (1L) osimertinib in the phase II ELIOS study

Background

Osimertinib, a 3^rd-generation EGFR-TKI, is the preferred 1L treatment for EGFRm advanced NSCLC; however, resistance eventually develops. ELIOS (NCT03239340) characterised resistance mechanisms to 1L osimertinib with a primary objective comparing paired tumour tissue biopsies from baseline (BL) and after PD. We report exploratory analyses of concordance between tissue and plasma testing from BL and post-PD samples and PFS by detected plasma EGFRm at BL and by plasma EGFRm clearance at 8 wks post-treatment.

Methods

Pts with EGFR-TKI naïve advanced NSCLC with an EGFR-TKI-sensitising mutation received osimertinib 80 mg QD in 28-day cycles. Mandatory tumour biopsies were obtained pre-treatment and after PD. Concordance between tissue and plasma tumour testing was assessed via NGS at BL and post-PD. Plasma EGFRm (Ex19del/L858R only) analysis was conducted at BL and wk 8 by ddPCR. Clearance was defined as undetected EGFRm ctDNA at wk 8, where it was detected at BL.

Results

154 pts were enrolled: 77% Asian, Ex19del/L858R/atypical EGFR mutations 55/38/7%. Concordance was high between tissue and plasma NGS at BL (n=118) and PD (n=50) for point mutations, e.g., sensitising EGFRm (BL: 109 samples, 80% concordance; PD: 45 samples, 87% concordance). Amplifications were detected more frequently in tissue than plasma at PD, e.g., MET (PD: 12 samples, 33% concordance). Plasma better captured tumour heterogeneity at PD, including point mutations (EGFR C797S; RAS) and fusions (RET). Of 136 pts with evaluable ctDNA at BL, 111 had detected plasma EGFRm. Median (95% CI) PFS in pts with vs without detectable BL EGFRm was 15.7 (11.3–20.2) vs 36.8 (9.1–not calculable) months. Of 104 pts with evaluable ctDNA at BL and wk 8, 94 had plasma EGFRm clearance at wk 8. Median (95% CI) PFS in pts with clearance was 19.6 (14.3–23.8) months and not calculated in pts without clearance due to the low number of events (9 events in 10 pts).

Conclusions

Concordance between tissue and plasma NGS at BL and PD was high for point mutations but lower for amplifications which were detected more frequently in tissue. Our data support the prognostic importance of plasma EGFRm detection at BL and its early clearance during treatment.

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 (http://www.ismpp.org/gpp3).

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

M. Ahn: Financial Interests, Personal, Advisory Role: AstraZeneca, Lilly, MSD, Merck, ONO, Takeda, Yuhan, Amgen , Pfizer, Novartis, Roche, Alpha-pharmaceuticals; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Lilly, MSD, Merck, Ono, Takeda, Yuhan, Amgen, Pfizer, Novartis, Roche. B.C. Cho: Financial Interests, Personal, Advisory Role: AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, BridgeBio Therapeutics, Bristol Myers Squibb, Cyrus Therapeutics, Eli Lilly and Company, Guardant Health, Janssen, KANAPH Therapeutics, Inc., MedPacto, Merck Sharp & Dohme, Novartis, Ono Pharmaceuticals Co., Ltd., Oscotec, Inc., Pfizer, Roche, Takeda, Yuhan Corporation; Financial Interests, Personal, Member of the Board of Directors: Interpark Bio. Convergence Corp., J INTS BIO.; Financial Interests, Personal, Other: DAAN Biotherapeutics; Financial Interests, Personal, Research Grant: AbbVie Inc., AstraZeneca, Bayer, Blueprint Medicines, Champions Oncology, Dizal Pharma, Dong-A ST, Eli Lilly and Company, GI Innovation, Inc., Interpark Bio. Convergence Corp., Janssen, MedPacto, MOGAM Biotechnology Research Institute, Merck Sharp & Dohme, Novartis, Ono Pharmaceuticals Co., Ltd., Yuhan Corporation; Financial Interests, Personal, Royalties: Champions Oncology; Financial Interests, Personal, Stocks/Shares: BridgeBio Therapeutics, Cyrus Therapeutics, Gencurix, Inc., Interpark Bio. Convergence Corp., J INTS BIO., KANAPH Therapeutics, Inc., TheraCanVac, Inc. Y.K. Pang: Financial Interests, Personal, Principal Investigator: AstraZeneca. P.J. Voon: Financial Interests, Personal, Advisory Role: AstraZeneca, Ipsen, Merck Sharp & Dohme, Novartis, Pfizer. S. Kim: Financial Interests, Personal, Other: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Novartis, Roche; Financial Interests, Personal, Research Grant: AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Novartis, Yuhan Corporation. J. De Castro Carpeno: Financial Interests, Personal, Advisory Role: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi, Takeda, TESARO, Inc.; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Gilead, Merck Sharp & Dohme, Pfizer, Roche, Takeda. M. Tiseo: Financial Interests, Personal, Research Grant: AstraZeneca, Boehringer Ingelheim; Financial Interests, Personal, Speaker’s Bureau: Amgen Inc., AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Laboratoires Pierre Fabre, Merck-Serono, Merck Sharp & Dohme, Novartis, Otsuka Pharmaceutical, Pfizer, Roche, Sanofi, Takeda. J. Li: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. L. Servidio: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. S. Sadow: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. A. Markovets: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. K.H. Tang: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. Z. Piotrowska: Financial Interests, Personal, Advisory Role: AstraZeneca, Blueprint Medicines, C4 Therapeutics, Cullinan Oncology, Daiichi Sankyo, Eli Lilly and Company, Janssen, Takeda; Financial Interests, Personal, Principal Investigator: AstraZeneca, Cullinan Oncology; Financial Interests, Personal, Research Grant: AbbVie Inc., AstraZeneca, Blueprint Medicines, Cullinan Oncology, Daiichi Sankyo, Janssen, Novartis, Spectrum Pharmaceuticals, Inc., Takeda, Tesaro, Inc.