Pharmacokinetic boosting of osimertinib in patients with non-small cell lung cancer.

Multiple recently developed targeted agents have the potential to deliver
benefit to cancer patients. However, the exorbitantly high prices of these new
drugs threaten the financial sustainability of cancer treatment. Osimertinib is
an example of such new anticancer agents. Like other new anticancer drugs,
osimertinib is no exception in terms of high costs with annual drug costs of
approximately ¤74,000 per patient.

In the pivotal randomized phase III study, osimertinib was significantly more
effective than standard chemotherapy in patients with advanced epidermal growth
factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC). The
median progression free survival (PFS) in patients with progressive disease
upon a first-line TKI was significantly longer with osimertinib than with a
platinum-based therapy (10,1 vs. 4,4 months, p < 0,001). Therefore, osimertinib
is registered as second-line treatment for these patients who progressed on
first-line treatment with EGFR targeted tyrosine kinase inhibitors (TKIs)
erlotinib, gefitinib or afatinib.
Osimertinib has also been studied as first-line treatment in patients with
EGFR-mutated NSCLC (exon 19 deletion or L858R). Osimertinib 80 mg was compared
to erlotinib 250 mg or gefitinib 150 mg. The PFS with osimertinib was
significantly longer than with erlotinib/gefitinib (18,9 vs. 10,2 months, p <
0,001). Because of this, osimertinib has also been registered as first-line
treatment for patients with EGFR-mutated NSCLC as mono therapy. The only
remaining issue in the Netherlands is the reimbursement of osimertinib as
first-line treatment for EGFR-mutated patients, which has not been approved
until now.

The pharmacokinetic characteristics of osimertinib have been extensively
studied. After multi-dose administration steady-state concentration is achieved
by day 15. During steady-state the ratio between the maximal and minimal
concentration osimertinib is 1.6 and the plasma-concentration curve is
relatively flat due to the long half-time of osimertinib and the ratio for the
minimal vs. maximal osimertinib concentration. Therefore, a low trough plasma
concentration is a good reflection of an overall low exposure to osimertinib.

Osimertinib is metabolized primarily by CYP3A4 and to a lesser extent by
CYP3A5. As combined administration of osimertinib with a strong CYP3A4
inhibitor resulted in increased osimertinib exposure [8], the underlying
mechanism of this drug-drug interaction may be used to boost osimertinib
exposure in patients with relative low trough plasma concentrations in steady
state (CminSS) without giving additional osimertinib.

Using this personalized treatment approach by implementing and combining the
concepts of therapeutic drug monitoring (TDM) and pharmacokinetic boosting,
osimertinib therapy could become much more cost-effective. By reducing the
necessary dose of osimertinib, this strategy will ultimately result in a
significant reduction in drug costs, as the additional expenditure for the
CYP3A4 inhibitor and blood sample analysis are negligible compared to the price
of osimertinib.
Cobicistat is a strong and selective CYP3A4 inhibitor. It is well known for its
boosting capacity of HIV-drugs and recently it was successfully used to boost
the exposure of axitinib, an anticancer TKI, in a patient with suboptimal
exposure after receiving the standard dose. Therefore, together with low costs
(¤1 per day) cobicistat is a suitable CYP3A4 inhibitor to investigate the
boosting concept of osimertinib. Cobicistat by itself is not known for causing
side-effects.

The main objective of this study is to evaluate if systemic exposure of
osimertinib (i.e. AUC) is enhanced when osimertinib is co-administered with
cobicistat in patients with relatively low blood concentrations while receiving
the standard osimertinib dose. Additionally the safety of combination therapy
will be evaluated.

This is a prospective pharmacokinetic, proof-of-concept pilot-study, to
evaluate to what extent cobicistat can increase the exposure to osimertinib.
During the study the patients will be asked to visit the hospital twice and in
between the two hospital-days the patient will use cobicistat for three weeks
additional to the treatment with osimertinib.

The study will be planned as follows:
- Day 1: hospital-day, four blood samples taken right before the ingestion of
osimertinib, and 0.5 - 1.5, 2.5 - 3.5 and 7-8 hours after ingestion of
osimertinib. The blood samples will be taken using a intravenous canula.
- Day 2 - 22: additional treatment with cobicistat (150, 300 or 600 milligram).
- Day 22: hospital-day, same program as on day 1.

This study will not include a controlgroup or a placebo. Due to the nature of
the study (proof-of-concept), the goal is that 20 patients will complete the
study on the selected dosage. To achieve this, and to complete the
dose-escalation part of cobicistat, and to compensate for withdrawal of
patients, the goal is to include 29 patients in this study.

Patient can opt to continue with cobicistat in consultation with their treating
physician, if the treatment was well tolerated during the first three weeks and
increasing the dosage of cobicistat has been deemed as inappropriate, due to
achieved effect and plasma concentrations of osimertinib. Patients that choose
to continue treatment with cobicistat, are asked to undergo blood sampling, one
more time to determine the plasma trough concentration of osimertinib to
evaluate whether the effect of cobicistat is constant over time.

The intervantion is the treatment with cobicistat 150/300/600 milligram
additional to the regulare treatment with osimertinib.

Patients who experience plasma trough concentration of osimertinib below 195
ng/mL during steady state will be eligible to take part in this study. This
plasma trough concentration is considerably lower than the mean measured in the
two centres (224 ng/mL), but higher than the mean plasma through concentration
reported in the literature (166 ng/ml). The discrepancy between the value
reported in the literature and seen in the two centres can possible be
explained: the results reported in the literature was from phase I and II
clinical studies of osimertinib. Since then instability of osimertinib at room
temperature and in the fridge was reported. To prevent degradation it is
necessary to take precautionary measures, such as storage at -80 degrees
Celsius and the use of dry-ice during transport. We believe that it is
plausible that not all precautionary measures were taken for transport and
storage of all blood samples in the phase I and II samples. Therefore, we
decided to relate the threshold value for the plasma through concentration of
osimertinib on the mean concentration in the two centres, in stead of the value
reported in the literature.

This low plasma trough concentration of osimertinib could possibly result in
suboptimal treatment-outcomes with osimertinib. Although such an relation
between exposure and effectiveness of the treatment with osimertinib, this
could lead to better treatment outcomes in those patients. A disadvantage of
the increase in osimertinib exposure is the possibility to experience adverse
events, which are common with osimertinib. Those adverse events could have been
absent prior to the start of the study. The estimation is that the adverse
events will be mild. In the registration study patients treated with
osimertinib experienced relatively few adverse events, which were mainly CTCAE
grade 2 or lower.

The main burden during the study will be the two days in the hospitals, for
which the amount of time spent in the hospital will be the primary burden.
During the two days in the hospital the patients will have to spend 7 - 8 hours
in the hospital, but will not be bedridden during those days. For research
purposes a intravenous cannula will be placed, which will be used to draw a
small amount of blood (four times) during the day. As a study-visit will be
combined with a routine-visit and therefore no additional punctures will be
needed to draw blood.

In conclusion, we think that the risk of this study is limited. The adverse
events which could be experienced by the participating patients are already
common for osimertinib and will be recognized by the treating physicians.
Besides, the patient will experience little physical discomfort for this study.