Abstract 1188TiP
Background
Osimertinib, a third-generation, irreversible epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits both EGFR-TKI sensitising (EGFRm) and EGFR T790M resistance mutations, with demonstrated efficacy in EGFRm NSCLC, including CNS metastases. Osimertinib is the preferred 1L treatment in EGFRm a NSCLC, with significant improvements in progression-free survival/overall survival vs comparators; however, pts may eventually develop disease progression. ORCHARD (NCT03944772) aims to identify mechanisms of resistance to 1L osimertinib and explore novel therapeutic options by allocating pts to biomarker/non-biomarker directed cohorts based on tumour molecular profile. Trophoblast cell-surface antigen 2 (TROP2) is a transmembrane glycoprotein that is overexpressed in NSCLC. Dato-DXd is a TROP2-directed antibody conjugated to a topoisomerase I inhibitor via a tumour-selective cleavable linker that has encouraging antitumour activity in a NSCLC. A new ORCHARD cohort will evaluate osimertinib + Dato-DXd in pts without identifiable, actionable resistance mechanisms.
Trial design
In the open-label, multicentre, multidrug, biomarker-directed, Phase II platform ORCHARD study, pts with EGFRm aNSCLC with progression on 1L osimertinib are allocated to treatment. Pts without a biomarker match (ALK, RET, BRAF) may enrol to receive oral osimertinib 80 mg once daily + intravenous Dato-DXd 4 mg/kg every 3 weeks (Q3W). If no dose-limiting toxicities occur in the first 3–4 pts, pts may enrol to receive osimertinib + 6mg/kg Dato-DXd. Safety/tolerability data will inform expansion of the 4 or 6 mg/kg Dato-DXd + osimertinib cohort to ∼16 pts. Tumour assessments (RECIST 1.1) will be performed Q6W for the first 24 weeks, then Q9W until disease progression. Primary outcome: investigator-assessed confirmed objective response rate. Secondary outcomes include safety/tolerability, duration of response, and pharmacokinetics; exploratory outcomes include change in tumour burden using circulating tumour DNA in plasma, and tumour/plasma biomarker analyses and their correlation with treatment effect.
Clinical trial identification
NCT03944772, 10 May 2019.
Editorial acknowledgement
The authors would like to acknowledge Bernadette Tynan, MSc, of Ashfield MedComms, Macclesfield, UK, part of UDG Healthcare for medical writing support that was funded by AstraZeneca.
Legal entity responsible for the study
AstraZeneca.
Funding
AstraZeneca.
Disclosure
J. De Langen: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Pfizer, Roche, Lilly, Merck Sharp & Dohme; Financial Interests, Personal, Research Grant: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme. B.C. Cho: Financial Interests, Advisory Board: Kanaph Therapeutic Inc, Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, Joseph BIO; Financial Interests, Member of the Board of Directors: Gencruix Inc, Interpark Bio Convergence Corp; Financial Interests, Full or part-time Employment: Yonsei University College of Medicine; Financial Interests, Stocks/Shares: TheraCanVac Inc, Gencruix Inc, Bridgebio, Kanaph Therapeutic Inc, Cyrus Therapeutics, Interpark Bio Convergence Corp; 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, GI Innovation, Eli Lilly, Blueprint Medicines, Interpark Bio Convergence Corp; Financial Interests, Other, Consulting fees: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Medpacto, Blueprint Medicines; Non-Financial Interests, Other: Daan; Non-Financial Interests, Other, Founder: Biotherapeutics. Z. Piotrowska: Financial Interests, Research Grant: Novartis, Takeda, Spectrum, AstraZeneca, Tesaro, Cullinan, Daiichi, AbbVie; Financial Interests, Other: AstraZeneca, Blueprint Medicines, Janssen, Takeda, Jazz Pharmaceuticals, C4 Therapeutics. X. Le: Financial Interests, Other, Consulting/advisory fees: EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Novartis, Eli Lilly, Boehringer Ingelheim, Hengrui Therapeutics, Janssen, AbbVie; Financial Interests, Sponsor/Funding, Consulting/advisory fees: Eli Lilly; Financial Interests, Sponsor/Funding: EMD Serono, Regeneron, Teligene, Boehringer Ingelheim. S.B. Goldberg: Financial Interests, Research Grant: AstraZeneca, Boehringer Ingelheim; Financial Interests, Advisory Board: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bristol-Myers Squibb, Genentech, Amgen, Spectrum, Blueprint Medicine, Sanofi Genzyme, Daiichi Sankyo, Regeneron, Takeda, Janssen. J.W. Goldman: Financial Interests, Research Grant: Advaxis, Array, AstraZeneca, BMS, Eli Lilly, Genentech/Roche, G1 Therapeutics, Merck, Pfizer; Financial Interests, Other, Honoraria: AstraZeneca, BMS, Genentech, Pfizer. I. Okamoto: Financial Interests, Research Grant: Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Ono Pharmaceutical, MSD Oncology, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharma, AbbVie; Financial Interests, Other: AstraZeneca, Taiho Pharmaceutical, Ono Pharmaceutical, MSD Oncology, Bristol-Myers Squibb, Chugai Pharma, Pfizer. N. Hewson, J. Maidment, J. Lau: Financial Interests, Full or part-time Employment: AstraZeneca. J. Cosaert: Financial Interests, Full or part-time Employment: AstraZeneca; Financial Interests, Project Lead: Orchard and Hudson; Financial Interests, Leadership Role: Orchard and Hudson. H. Ambrose: Financial Interests, Stocks/Shares: AstraZeneca. J.W. Riess: Financial Interests, Other: Blueprint, EcoR1, Medtronic, Spectrum, Loxo Oncology, Novartis, Boehringer Ingelheim, Genentech, Celgene. H.A. Yu: Financial Interests, Institutional, Sponsor/Funding: AstraZeneca, Cullinan, Novartis, Pfizer, ERASCA, Blueprint Medicine, Janssen; Financial Interests, Research Grant: AstraZeneca, Pfizer, Eli Lilly, Cullinan, Novartis, Daiichi; Financial Interests, Other, Consulting: AstraZeneca, Cullinan, Blueprint Medicine, Janssen, Black Diamond, C4 Therapeutics; Financial Interests, Other: AstraZeneca, Janssen, Blueprint Medicine, C4 Therapeutics, Daiichi. All other authors have declared no conflicts of interest.