Evaluation of Modified Osimertinib Dosing with Cobicistat for Pharmacokinetic Enhancement in Advanced EGFR-Mutated Non-Small Cell Lung Cancer

The primary objective of this study is to evaluate the clinical feasibility of a modified **osimertinib** dosing strategy in patients with advanced EGFR mutated Non-Small Cell Lung Cancer (NSCLC). This involves combining therapeutic drug monitoring, dose modification, and pharmacokinetic boosting to improve cost-effectiveness and reduce toxicity while maintaining clinical efficacy. The study aims to maintain **osimertinib** exposure within the clinically-proven therapeutic window of 125–259 ng/mL. Additionally, the study seeks to assess whether pharmacokinetic boosting can provide a viable therapeutic option for patients with asymptomatic central nervous system oligoprogression, offering a cost-effective alternative to off-label dose escalation.

Secondary objectives include:

• Evaluating the cost-effectiveness of the modified **osimertinib** treatment versus the standard-of-care.
• Assessing clinical efficacy in terms of progression-free survival and disease control rate at 12 weeks.
• Further evaluating the safety profile of **osimertinib**/**cobicistat** concomitant treatment.
• Evaluating pharmacokinetic parameters of **osimertinib**, **cobicistat**, and the active **osimertinib** metabolite AZ5104.
• Assessing the effect of CYP3A genotype on **osimertinib** exposure.

The clinical trial involves participants diagnosed with **Non-Small Cell Lung Cancer** (NSCLC) characterized by an EGFR driver mutation. The study population includes both male and female subjects aged 18 years and older, with a World Health Organisation Performance Status of 0-2, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The total number of participants is not provided by the sponsor. Participants were selected based on their current treatment with osimertinib 80 mg once daily as part of their standard care regimen. The trial does not include a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria require participants to be able and willing to sign informed consent and undergo additional blood sampling for therapeutic drug monitoring. The trial is designed to assess the clinical feasibility of a modified osimertinib dosing strategy and the potential for pharmacokinetic boosting in patients with advanced EGFR-mutated NSCLC.

The clinical trial is designed to evaluate the efficacy of modified **osimertinib** dosing, with or without **cobicistat** as a pharmacokinetic booster, in patients with advanced Non-Small Cell Lung Cancer (NSCLC) with an EGFR driver mutation. This trial is a Phase 4, low-intervention study, categorized as a randomized, double-blind, controlled trial. The trial is expected to commence recruitment on December 1, 2023, and conclude by June 1, 2026. The study comprises two sub-studies: OSIBOOST 2-A and OSIBOOST 2-B, each targeting different patient conditions within the NSCLC spectrum.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and current treatment regimen. The inclusion criteria require participants to be 18 years or older, with a WHO Performance Status of 0-2, and currently receiving osimertinib 80 mg once daily. Follow-up visits will be scheduled to monitor therapeutic drug levels, assess clinical feasibility, and evaluate CNS disease control. The end-of-study visit will conclude the participant's involvement, summarizing the outcomes and any adverse events experienced during the trial.

The expected duration of participant involvement varies depending on the sub-study. For OSIBOOST 2-A, the focus is on dose modification and pharmacokinetic boosting to maintain osimertinib exposure within a therapeutic range, while OSIBOOST 2-B aims to assess CNS disease control through pharmacokinetic boosting. Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or if their treating physician deems it necessary for their safety. The trial aims to improve the cost-effectiveness of osimertinib treatment while minimizing patient burden and maintaining clinical efficacy.

The clinical trial involves the administration of **Tybost** 150 mg film-coated tablets, which contain the active substance **cobicistat**. Cobicistat is a chemical compound used as a pharmacokinetic booster. The pharmaceutical form is a film-coated tablet, and the medication is administered orally. The maximum daily dose is 600 mg, with a total maximum dose of 164,400 mg over a treatment period of up to 36 months. The medication is manufactured by Gilead Sciences Ireland UC. The role of Tybost in the trial is auxiliary, serving to enhance the pharmacokinetic profile of the primary treatment.

**TAGRISSO** 80 mg film-coated tablets are also utilized in the trial, containing the active substance **osimertinib**. Osimertinib is a chemical compound used as a targeted therapy for advanced Non-Small Cell Lung Cancer (NSCLC) with EGFR mutations. The pharmaceutical form is a film-coated tablet, and the medication is administered orally. The maximum daily dose is 160 mg, with a total maximum dose of 14,640 mg over a treatment period of up to 6 months. The medication is produced by AstraZeneca AB. In this trial, TAGRISSO serves as the test product, with the objective of evaluating a modified dosing strategy to improve cost-effectiveness and reduce toxicity while maintaining clinical efficacy.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial. The study focuses on the potential benefits of pharmacokinetic boosting with cobicistat to enhance the therapeutic effects of osimertinib in patients with advanced EGFR mutated NSCLC. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy in the OSIBOOST 2 clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the effectiveness of modified **osimertinib** dosing strategies in patients with advanced EGFR-mutated Non-Small Cell Lung Cancer (NSCLC). The primary endpoints include the daily cumulative dose reduction achieved in individual patients while maintaining **osimertinib** exposure within the specified therapeutic range of 125 – 259 ng/mL for sub-study A, and the Central Nervous System (CNS) disease control rate (DCR) at 12 weeks for sub-study B.

Secondary endpoints will further assess efficacy by measuring **osimertinib** and AZ5104 trough concentrations in plasma during steady state, the number of (Serious) Adverse Events and Suspected Unexpected Serious Adverse Reaction events, and the average **osimertinib** intake reduction over time. Additionally, progression-free survival (PFS) during **osimertinib**/cobicistat concomitant treatment, CYP3A genotype, and trough concentration levels at steady state for **osimertinib** and AZ5104 in cerebrospinal fluid will be evaluated. The trial will also include ctDNA analysis of cerebrospinal fluid for sub-study B.