OBJECTIVES

Most anticancer drugs cannot achieve adequate CNS exposure due to being P-gp substrates, a key efflux transporter of the blood–brain barrier. Entrectinib is a weak P-gp substrate and achieves CNS therapeutic levels. Crizotinib and larotrectinib (inhibitors of the same class) are strong P-gp substrates with poor CNS exposure. Therefore, the potential economic and patient quality of life value of entrectinib in targeting and resolving CNS metastases is patient and healthcare system relevant.

METHODS

Entrectinib is a potent and selective inhibitor of ROS1/TRK/ALK tyrosine kinase activity in vitro with systemic and CNS activity. Intracranial ORRs of 79.2% and 62.5% were observed in adult patients with ROS1 fusion positive NSCLC and NTRK fusion positive solid tumours, respectively, who had measurable baseline CNS metastases. For ROS1-positive NSCLC, the median intracranial PFS was 12.0 months, while for NTRK it was 10.1 months.

Published costs incurred by patients with early brain metastases vs. patients without were applied to the average duration in which the cohort was free of CNS metastases (ie. in the CNS Progression Free state). Similarly, the QALY benefit was estimated by applying literature EQ-5D utility estimates for patients with CNS metastases vs. the utilities derived from the entrectinib trials for patients without CNS metastases; again, informed by the average duration of the CNS Progression Free state.

RESULTS

The CNS effect of entrectinib could result in significant cost savings of $62K and $58K USD per patient with baseline CNS metastases and ROS1-positive NSCLC or NTRK solid tumours respectively. Similarly, resolving CNS metastases with entrectinib would contribute additional QALYs of 0.24 and 0.28 per patient for ROS1-positive and NTRK solid tumours respectively.

CONCLUSIONS

Entrectinib has demonstrated important CNS clinical benefit relative to other available treatments, which could lead to significant healthcare system cost savings and substantial quality of life improvements for patients.