Clinical trial NCT05748093: Improving Osimertinib Exposure and Cost-effectiveness Using Pharmacokinetic Boosting With Cobicistat
Official title: Improving Osimertinib Exposure and Cost-effectiveness Using Pharmacokinetic Boosting With Cobicistat (OSIBOOST 2)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Non-small Cell Lung Cancer
Keywords: Osimertinib
Cobicistat
Pharmacokinetics
Boosting
Non-small Cell Lung Cancer
CNS metastases
Lead sponsor: Maastricht University Medical Center
Sponsor class: OTHER
First posted: 2023-02-28
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study will involve two cohorts, which will both receive PK-boosting, but for different purposes, and with different primary outcomes. The cohorts will not be compared, and there will be no cross-over between cohorts.
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to assess the feasibility of pharmacokinetically boosting osimertinib using cobicistat in order to improve osimertinib exposure in individual patients with advanced NSCLC (Non-Small Cell Lung Cancer) with mutated EGFR (Epidermal Growth Factor Receptor). The main questions it aims to answer are:

* Cohort 1: Does concurrent use of osimertinib and cobicistat allow for osimertinib weekly intake reductions? If so, how much can the intake be reduced while retaining clinically effective exposure?
* Cohort 2: Does concurrent use of osimertinib and cobicistat allow for improved penetration of osimertinib in the central nervous system, in patients with CNS (central nervous system) oligoprogression?

Participants who are taking osimertinib in regular care will receive cobicistat in addition to their other medication. They will undergo blood sampling to measure the amount of osimertinib in blood, and measure the effect of boosting. Additionally, in cohort 1 patients will be dose-reduced if their exposure levels allow.

Detailed description: In 2016 Osimertinib was registered for the treatment of patients with metastatic Non-Small Cell Lung Cancer (NSCLC) with an activating Epidermal Growth Factor Receptor (EGFR) mutation, initially only for patients with the T790M resistance mutation, but since 2018 also in the first line treatment. Use of osimertinib in the first line provides improved overall survival and progression-free survival, more potent efficacy against brain metastases, and better tolerability compared to older generation EGFR tyrosine kinase inhibitors (EGFR-TKIs). The downside of osimertinib is that -like many new anticancer agents- it is highly expensive (over €70 000 per patient per year in the Netherlands). In a period of five years, healthcare costs associated with expensive medication have risen from €1.71 billion to €2.46 billion per year in the Netherlands. The Dutch Cancer Society has warned that this astronomical cost increase will start to suffocate the national health care budget. In order to safeguard sustained affordability and accessibility of oncological healthcare, improving cost-effectiveness of available drugs is of paramount importance. In a previous study, we have demonstrated that osimertinib exposure may be boosted, through concomitant use of cobicistat, as a result of CYP3A4 inhibition. We now aim to apply pharmacokinetic (PK) boosting in order to improve osimertinib exposure and cost-effectiveness, without impacting treatment efficacy and safety.

This trial is designed to study whether pharmacokinetic boosting may alleviate these issues. In the first cohort, we will assess whether PK-boosting is able to reduce the amount of osimertinib which a patient needs to take. In order to assess this, the patient will receive cobicistat (the booster drug) and we will measure the amount of osimertinib and its metabolite in blood. Afterwards, the researchers and physicians may calculate how much osimertinib a patient actually needs. Ideally this will both reduce the amount of osimertinib that a patient needs to take, as well as reduce the price-tag of the overall treatment. In the second cohort, we will assess whether PK-boosting is a viable alternative to dose-doubling osimertinib. Some patients with NSCLC develop progressive CNS metastases despite osimertinib therapy. There is an indication that increasing the osimertinib dosage to double the standard therapy might provide longer/better treatment efficacy in these patients. Because of the tremendous cost associated with double-dosing osimertinib, most health care insurance providers in the Netherlands do not cover this therapy. In cohort 2 we look to find out whether PK-boosting might provide a similar effect to increasing the dosage, for a far more affordable price-tag.

Eligibility criteria: Inclusion Criteria:

In order to be eligible to participate in this cohort 1, a subject must meet all of the following criteria:

* The patient is set to receive osimertinib 80 mg QD as part of their standard treatment plan
* The patient has a World Health Organization (WHO) Performance Status (PS) of ≤2.
* The patient is 18 years or older
* The patient is able and willing to sign informed consent
* The patient is able and willing to undergo blood sampling
* The patient has non-squamous advanced EGFR-mutated NSCLC with no signs of imminent progression (CT confirmed). If the patient does have signs of progression, they are only eligible if their treating physician deems the treatment to be appropriate beyond progression.
* The patient consents to their blood being analysed for CYP3A-genotype

In order to be eligible to participate in this cohort 2, a subject must meet all of the following criteria:

* The patient is set to receive osimertinib 80 mg QD as part of their standard treatment plan
* The patient has a World Health Organization (WHO) Performance Status (PS) of ≤2.
* The patient is 18 years or older
* The patient is able and willing to sign informed consent
* The patient is able and willing to undergo blood sampling
* The patient has non-squamous EGFR-mutated NSCLC with radiologically confirmed progressive (RECIST v1.1), but asymptomatic intracranial metastasis, not in an eloquent area (to be discussed with neurologist). Furthermore, the disease is controlled extracranially (no RECIST v1.1 progression).

Exclusion Criteria:

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

* The patient does not take any other drug which is known to strongly inhibit CYP3A4/CYP3A5 activity
* The patient does not take any other drug which is metabolized by CYP3A4/CYP3A5 and which has a small therapeutic window
* The patient does not take any drug or product which may otherwise affect CYP3A4/CYP3A5 metabolic activity
* The patient does not have impaired gastrointestinal function
* The patient is neither pregnant nor breastfeeding
* The patient does not have any contra-indication for cobicistat prescription, as listed in the summary of product characteristics for cobicistat

Primary outcomes:
measure: Cohort 1 primary end-point: Dose modification feasibility
timeFrame: 2-18 months after intervention initiation
measure: Cohort 2 primary end-point: Disease Control Rate at 12 weeks
timeFrame: 12 weeks after intervention initiation
Secondary outcomes:
measure: Cohort 1 secondary end-point: plasma concentrations of osimertinib and AZ5104
timeFrame: 2-18 months after intervention initiation
measure: Cohort 1 secondary end-point: safety set
timeFrame: 2-18 months after intervention initiation
measure: Cohort 1 secondary end-point: Cost-effectiveness analysis
timeFrame: 2-18 months after intervention initiation
measure: Cohort 1 secondary end-point: CYP3A predictiveness for osimertinib exposure
timeFrame: 2-18 months after intervention initiation
measure: Cohort 2 secondary end-point: plasma concentrations of osimertinib and AZ5104
timeFrame: 12 weeks after intervention initiation
measure: Cohort 2 secondary end-point: safety set
timeFrame: 12 weeks after intervention initiation
Other outcomes:
measure: Cohort 1 exploratory end-point: Comparison of progression-free survival to historical data
timeFrame: 2-18 months after intervention initiation
measure: Cohort 2 exploratory end-point: Comparison of Progression-free Survival to historical data
timeFrame: 12 weeks after intervention initiation
measure: Cohort 2 exploratory end-point: Extracranial disease control
timeFrame: 12 weeks after intervention initiation
measure: Cohort 2 exploratory end-point: Osimertinib and AZ5104 concentrations in cerebrospinal fluid.
timeFrame: 12 weeks after intervention initiation
measure: Cohort 2 exploratory end-point: Liquid biopsy measurements of resistance mutations in cerebrospinal fluid
timeFrame: 12 weeks after intervention initiation
Locations:
city: Maastricht
country: Netherlands
facility: MaastrichtUMC
state: Limburg
Study officials:
affiliation: Maastricht University Medical Centre+
name: Lizza Hendriks, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: van Veelen A, Gulikers J, Hendriks LEL, Dursun S, Ippel J, Smit EF, Dingemans AC, van Geel R, Croes S. Pharmacokinetic boosting of osimertinib with cobicistat in patients with non-small cell lung cancer: The OSIBOOST trial. Lung Cancer. 2022 Sep;171:97-102. doi: 10.1016/j.lungcan.2022.07.012. Epub 2022 Jul 25.
citation: Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. doi: 10.1056/NEJMoa1713137. Epub 2017 Nov 18.