P76.27 ORCHARD: A Biomarker-Directed Phase 2 Platform Study in pts with Advanced EGFRm NSCLC Progressing on First-Line Osimertinib

Abstract

Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations, and has demonstrated efficacy in EGFRm advanced NSCLC, including central nervous system metastases. Most patients’ (pts) tumors develop resistance to osimertinib through secondary EGFR mutations (including C797S, G724S and L718V/Q) and off-target genomic alterations (including MET amplification and gene fusions). Data suggest that off-target alterations such as ALK and RET fusions may be resistance mechanisms to first-line osimertinib in some pts (each <5%). The ORCHARD study (NCT03944772) aims to better characterize resistance mechanisms to first-line osimertinib, and evaluate post-progression treatments. The flexible, platform-based design allows for new cohorts and treatment arms, for broader exploration of targeting resistance mechanisms. Previously presented: WCLC 2019 (Yu H, et al. J Thorac Oncol;14[10 suppl]:S647). In this open-label, multicenter, multidrug, biomarker-directed Phase 2 platform-based study (Figure), adult pts with locally advanced/metastatic EGFRm NSCLC whose disease progressed on first-line osimertinib are eligible. Treatment is assigned per molecular characterization of a mandatory tissue biopsy from a progressing lesion, analyzed by next-generation sequencing (Foundation Medicine Inc.). The protocol has recently been amended: Group A now includes treatment arms for pts with ALK/RET rearrangements, who will receive osimertinib plus alectinib/selpercatinib, respectively. The ‘MET alterations’ arm has been expanded from MET-amplification to also include MET exon 14 skipping, and the ‘EGFR alterations’ arm has been expanded from EGFR-amplification to also include mutations at the EGFR L718/G724 residue, or insertion in EGFR exon 20. Group B encompasses pts with no identifiable resistance mechanism; Group C is observational, for pts whose tumors harbor resistance mechanisms not currently addressed within the study. Tumor assessments (RECIST 1.1) will be performed every 6 weeks for 24 weeks, and every 9 weeks thereafter until disease progression or treatment discontinuation. Interim analyses will be performed on the first 16 pts in each cohort who have had the opportunity for two post-baseline RECIST assessments; individual cohorts may be stopped (if there is <10% probability for objective response rate [ORR] to be above target value [45%, equaling ≤4 of the 16 pts with confirmed responses]), or expanded to 30–40 pts for further evaluation. Primary endpoint: confirmed ORR (investigator assessed); secondary endpoints include: progression-free survival, duration of response, overall survival, and pharmacokinetics. Safety will also be reported. A summary of the observed genomic landscape during enrolment will be presented. osimertinib, non-small cell lung cancer, resistance