The OSIBOOST-2 project is designed with the intention to improve the cost-effectiveness of osimertinib treatment for all patients treated with osimertinib 80 mg QD for advanced EGFRm NSCLC. Therefore, based on disease status (≥ stable disease or CNS oligoprogression), patients may be enrolled in one of two sub studies (OSIBOOST 2-A and OSIBOOST 2-B, respectively).

OSIBOOST 2-A: During this sub-study, participants in cohort 1 and 2 will receive cobicistat 150 mg QD, and an adjusted osimertinib treatment schedule, if possible according to their osimertinib Cmin,SS,ave (see trial design). Participants will undergo blood sampling for TDM at trial initiation, each three to four weeks during the period of finding the optimal cost-effective osimertinib dosing schedule including concomitant cobicistat (if needed), and during the continuation phase every 4 – 12 weeks. This implies 2 – 4 visits during the first three months of the trial. The patients will be asked to adhere to a medication regimen, as recorded in a medication diary, in which they will also record any toxicity or non-serious adverse event.

OSIBOOST 2-B: During this sub-study, participants will receive cobicistat 150 mg QD concurrent with regular osimertinib 80 mg QD as an alternative intervention strategy for regular osimertinib dose escalation to 160 mg QD, and undergo additional blood sampling for TDM. The frequency of MRI cerebral imaging will be similar to which is regularly applied when osimertinib 160 mg QD is considered. Optionally, participants may optionally undergo a lumbar puncture before (visit 1) and during (either visit 2 or 3) concurrent use of osimertinib and cobicistat.

OSIBOOST 2-A: The main endpoint will be the osimertinib cumulative dose reduction accomplished in individual patients, while retaining osimertinib exposure (i.e. osimertinib trough (Cmin,SS) levels within the specified provisional therapeutic range (125 – 259 ng/mL).

OSIBOOST 2-B: The main trial endpoint will be CNS disease control rate (DCR) at twelve weeks.

In order to be eligible to participate in this OSIBOOST 2-A, a participant must meet all of the following
criteria:

• The patient receives osimertinib 80 mg QD as part of their standard treatment plan.
• The patient has a World Health Organization (WHO) Performance Status (PS) of 0-2.
• 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 additional blood sampling for e.g. TDM.
• 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.
• The patient is willing to use adequate contraception.

In order to be eligible to participate in OSIBOOST 2-B, a participant must meet all of the following
criteria:

• The patient is receives osimertinib 80 mg QD as part of their standard treatment plan.
• The patient has a World Health Organization (WHO) Performance Status (PS) of 0-2.
• 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 additional blood sampling for e.g. TDM.
• The patient has non-squamous EGFR-mutated NSCLC with radiologically confirmed progressive (RANO-BM/RANO-LM), but asymptomatic intracranial metastasis, not in aneloquent area (to be discussed with neurologist). Furthermore, the disease is controlled extracranially (no RECIST v1.1 progression).
• The patient is willing to use adequate contraception.

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

• The patient is taking any other drug which is known to strongly inhibit CYP3A4/CYP3A5, P-gp
  or BCRP activity (as described in 8.1.2).
• The patient is taking any other drug which is primarily metabolized by CYP3A4/CYP3A5, P-GP
  or BCRP and which has a small therapeutic window (as described in 8.1.2).
• The patient is taking any drug or (food or herb, such as St. John’s Wort) product which may
  otherwise affect CYP3A4/CYP3A5, P-gp or BCRP metabolic activity (as described in 8.1.2).
• The patient has impaired gastrointestinal function that may alter the absorption of
  osimertinib or cobicistat (e.g. ulcerative disease, uncontrolled nausea or vomiting,
  malabsorption syndrome, small bowel resection).
• The patient has Child-Pugh score class C or chronic liver disease.
• The patient has any condition which is contra-indicated for treatment with osimertinib (e.g.
  hypersensitivity to the active substance (osimertinib (as mesylate)) or to any of the excipients
  and/or QTc-prolongation (i.e. QTc interval greater than 481 msec on at least 2 separate
  electrocardiograms (ECGs)).
• The patient is either pregnant, breastfeeding, or actively trying to conceive.