Increasing the dosing interval of osimertinib in patients with EGFR mutated locally advanced or meta-static non-small cell lung cancer - OSI-SAVE

The primary objective is to assess the non-inferiority of an extended dosing interval of osimertinib compared to the standard dosage in patients with EGFR mutated locally advanced or metastatic non-small cell lung cancer. This evaluation is clinically relevant as it may determine whether alternate-day dosing maintains therapeutic efficacy while potentially reducing treatment burden and costs.

The secondary objectives include:

• To assess the efficacy of osimertinib 80 mg every other day (QOD) compared with osimertinib 80 mg once daily (QD).

• To assess the safety of osimertinib 80 mg QOD compared with osimertinib 80 mg QD.

• To assess disease-related symptoms and health-related quality of life in patients treated with osimertinib 80 mg QOD compared to osimertinib 80 mg QD.

• To assess cost-effectiveness for patients treated with osimertinib 80 mg QOD compared with osimertinib 80 mg QD.

• To evaluate the effect of osimertinib 80 mg QOD compared with osimertinib 80 mg QD on the risk of developing central nervous system (CNS) metastases over time.

• To assess the feasibility and patient adherence to osimertinib 80 mg QOD compared with osimertinib 80 mg QD.

The sponsor did not provide information regarding the total number of participants for this clinical trial. The study population includes **adult** participants aged 18 years and older, with both **male** and **female** subjects eligible for enrollment. Participants are patients diagnosed with **locally advanced or metastatic non-small cell lung cancer** harboring specific **EGFR mutations**, including **exon 19 deletions** or **exon 21 L858R mutations**, who are not candidates for curative intent therapy. The trial population is selected from individuals who have been receiving first-line **osimertinib** 80 mg once daily, with or without **chemotherapy**, for a minimum of three months as part of standard care and who have demonstrated a radiological response to treatment. Eligible participants must possess sufficient understanding of the local language to complete study questionnaires and must be capable of providing informed consent. No vulnerable populations are included in this trial.

This is a randomized, open-label, non-inferiority clinical trial evaluating an extended dosing interval of **osimertinib** compared to the standard daily dosing regimen in patients with **EGFR mutated** locally advanced or **metastatic non-small cell lung cancer**. The study is classified as a **low-intervention clinical trial** as the investigational medicinal product is authorized and used within the terms of its marketing authorization. The trial is designed as a **Phase IV** study with the primary objective of assessing the non-inferiority of an extended dosing interval of osimertinib compared to the standard dosage. The investigational product is **TAGRISSO 80 mg film-coated tablets** containing osimertinib as the active substance, administered via the **oral** route. The maximum daily dose is **80 mg**, with a maximum treatment period of **104 weeks**.

Eligible participants must be at least 18 years of age with locally advanced or metastatic non-small cell lung cancer harboring **EGFR exon 19 deletions** or **exon 21 L858R mutations** not eligible for curative intent therapy. Participants must have been treated with first-line osimertinib 80 mg once daily with or without **chemotherapy** for at least three months according to standard of care and must demonstrate a radiologic response defined as complete or partial response according to **RECIST 1.1** criteria or a radiological response according to the treating physician. Participants must be able to understand written information, provide informed consent, and have sufficient knowledge of the local language to answer questionnaires.

The primary endpoint of the study is **progression-free survival**. Secondary endpoints include **overall survival**, patient reported toxicity of any grade excluding laboratory abnormalities, economic assessment, **quality of life**, cumulative incidence of **central nervous system metastases**, and feasibility or medication adherence. The trial duration extends from the estimated recruitment start date in October 2025 to the estimated end date in October 2031, representing an overall trial duration of approximately six years.

Participants will undergo a screening visit to assess eligibility criteria, followed by regular follow-up visits throughout the treatment period to monitor disease status, assess safety and tolerability, evaluate quality of life, and ensure medication adherence. The end-of-study visit will be conducted to perform final assessments and document study completion. The expected length of participant involvement may extend up to 104 weeks of treatment, with additional follow-up for survival assessment. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or other circumstances as determined by the treating physician or protocol requirements.

The experimental medication under investigation in this clinical trial is **Tagrisso** (**osimertinib**), also known by the synonym AZD9291. The active substance is osimertinib, a chemical compound with the European substance number SUB176340. The medicinal product is manufactured by AstraZeneca AB and holds the marketing authorization number EU/1/16/1086/002 under the European Medicines Agency reference EMEA/H/C/004124. The product is classified under ATC code L01EB04.

Tagrisso is supplied as **film-coated tablets** containing **80 mg** of osimertinib. The route of administration is **oral**. The **maximum daily dose** is **80 mg**, which corresponds to one tablet administered per day. The **maximum total dose** per administration is also 80 mg. The **maximum treatment period** is **104 weeks**. The primary objective of this trial is to assess the non-inferiority of an extended dosing interval of osimertinib compared to the standard dosage regimen in patients with **EGFR-mutated locally advanced or metastatic non-small cell lung cancer**. The trial investigates modifications to the dosing schedule while maintaining therapeutic efficacy.

Efficacy will be assessed using progression-free survival (PFS) as the primary endpoint to evaluate the non-inferiority of an extended dosing interval of osimertinib compared to the standard dosage in patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer. Secondary endpoints include overall survival (OS), patient-reported toxicity of any grade excluding laboratory abnormalities, economic assessment, quality of life, cumulative incidence of central nervous system (CNS) metastases, and feasibility or medication adherence. Radiologic assessment will be utilized to determine response according to RECIST 1.1 criteria as evaluated by the treating physician. Patients must demonstrate a radiological response, defined as complete or partial response per RECIST 1.1 or a radiological response as determined by the treating physician that does not meet partial response criteria, following at least three months of first-line osimertinib treatment at 80 mg once daily with or without chemotherapy.