Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic...

Area of Science:

• Oncology
• Pharmacology

Background:

• Osimertinib is a third-generation EGFR-TKI effective against EGFRm NSCLC, including CNS metastases.
• Acquired resistance to osimertinib is a significant clinical challenge in EGFR-mutated NSCLC.
• Understanding resistance mechanisms is crucial for developing effective post-progression strategies.

Purpose of the Study:

• To characterize resistance mechanisms to first-line osimertinib in EGFR-mutated NSCLC.
• To identify and evaluate novel post-progression treatment strategies.
• To explore the efficacy of biomarker-directed therapies.

Main Methods:

• Phase II, multi-cohort study (ORCHARD, NCT03944772) in adult patients with EGFRm advanced/metastatic NSCLC.
• Patients are allocated to treatment groups based on molecular profiling after first-line osimertinib progression.
• Investigates novel osimertinib combinations, chemotherapy/EGFR-TKI based therapies, and observational cohorts for transformed disease.

Main Results:

• Primary endpoint: confirmed objective response rate (investigator assessed).
• Secondary endpoints include progression-free survival, duration of response, and overall survival.
• Pharmacokinetics and safety will also be assessed.

Conclusions:

• The ORCHARD study aims to elucidate mechanisms of osimertinib resistance.
• It seeks to establish effective treatment options for patients progressing on first-line osimertinib.
• The adaptive platform design facilitates the inclusion of emerging therapies for evolving resistance patterns.