OSI-SAVE is a randomized-controlled multicenter non-inferiority trial comparing standard treatment with osimertinib 80 mg QD to treatment with osimertinib 80 mg QOD. A total of 383 patients will be enrolled in the study. Follow-up will be 24 months.

Patients receiving 80 mg of osimertinib QD with or without platinum-pemetrexed chemotherapy as first-line treatment option will be randomized 1:1, three months after treatment initiation to:

• The intervention arm where osimertinib 80 mg is administered QOD with or without chemotherapy;
• The control arm where osimertinib 80 mg is administered QD with or without chemotherapy.

Main trial endpoint

• Progression-free survival (PFS)

Secondary trial endpoints

• Overall survival (OS)
• Patient reported toxicity of any grade (laboratory abnormalities excluded)
• Quality of life
• Economic assessment
• Cumulative incidence of central nervous system (CNS) metastases
• Feasibility / medication adherence

Translational endpoints

• Osimertinib pharmacokinetic outcomes

Optional

• Detection of the primary EGFR mutation or resistance mutation(s) in circulating tumor DNA (ctDNA)
• Pharmacogenetic analysis

In order to be eligible to participate in this study, a patient must meet all of the following criteria

• Locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or exon 21 L858R mutation, not eligible for curative intent therapy;
• Treatment with first-line osimertinib 80 mg QD with or without chemotherapy for at least three months according to standard of care;
• A response on radiologic assessment

A potential patient who meets any of the following criteria will be excluded from participation in this study:

• Patients with known CNS metastases at baseline;
• Usage of strong CYP3A4 inducers
• Treatment related toxicity for which a dose reduction of osimertinib is indicated