1188TiP ORCHARD platform study: Osimertinib + datopotamab deruxtecan (Dato-DXd) cohort in patients (pts) with advanced NSCLC (aNSCLC) who have progressed on first-line (1L) osimertinib

Abstract

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. 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. NCT03944772, 10 May 2019. 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. AstraZeneca.