Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD)

Abstract

Introduction: Osimertinib, a third-generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations and has demonstrated efficacy in non-small cell lung cancer (NSCLC) CNS metastases. Most patients with EGFRm NSCLC treated with osimertinib will eventually develop resistance. ORCHARD (NCT03944772) is a phase II study aiming to characterize first-line osimertinib resistance and identify post-progression treatments.

Methods: Adults aged ≥ 18 years (Japan ≥ 20 years), with EGFRm locally advanced/metastatic NSCLC will be allocated to one of three groups after first-line osimertinib progression, based on molecular profiling from a post-progression tumor biopsy. Group A will evaluate patients with protocol-determined biomarkers of resistance treated with novel osimertinib combination therapies, Group B will evaluate patients without a detectable protocol-determined biomarker treated with non-biomarker selected therapies that are chemotherapy- or EGFR-TKI-based, and Group C (observational) includes patients with histologically transformed disease, and/or a biomarker with an available therapy not investigated in ORCHARD. Group C patients will be treated as per local practice and followed to assess overall survival. The study's platform design allows for adaptability to include emerging treatments related to novel resistance mechanisms. The primary endpoint is confirmed objective response rate (investigator assessed). Other endpoints are progression-free survival, duration of response, overall survival, pharmacokinetics and safety.

Conclusions: ORCHARD aims to characterize mechanisms of resistance to first-line osimertinib and explore treatments to overcome acquired resistance. The modular design allows for additional biomarker-directed cohorts and treatment options as understanding of osimertinib resistance mechanisms evolves.

Keywords: Acquired resistance; EGFR-TKI; EGFRm; NSCLC; post-progression.

Figure 1

ORCHARD Study Design *Following a protocol amendment, all newly enrolled patients with MET alterations will receive savolitinib 300 mg qd, replacing the previous weight-based dosing regimen (300 mg for patients weighing ≤55 kg at screening, or 600 mg once daily for patients >55 kg at screening). ^†On days 1 and 8 of each 3-week cycle. Group A: Patients who are positive for protocol-determined biomarker; Group B: patients without an available protocol-determined biomarker match, allocated sequentially, once first cohort cap has been reached, the next cohort allocation will begin; Group C: observational cohort, treated in accordance with local practice. Most treatments will be provided by the sponsor. In some participating countries, pemetrexed and carboplatin are sourced locally. Abbreviations: ALK = anaplastic lymphoma kinase; AUC= area under curve; BID = twice daily; EGFR = epidermal growth factor; EGFRm = EGFR-tyrosine kinase inhibitor sensitizing mutation-positive; IV = intravenous; NGS = next-generation sequencing; NSCLC = non-small cell lung cancer; PO = orally; q3(4)w = once every 3(4)-week cycle; QD = once daily; SCLC = small cell lung cancer.