centration in plasma was able to reach the brain implying
severe restriction of this agent for brain penetration.23
The variable ability of VEGF-TKIs to penetrate the CNS
may be dependent on reliance on active uptake through
drug transporters. For example, sorafenib and sunitinib
showed low-moderate affinity for the ATP-binding cassette
(ABC) transporter, ABCB1, where brain penetration
was increased 1.9-fold and 2.9-fold for sorafenib and sunitinib,
respectively, in knockout mice with the absence of
ABCB1 when compared to controls.24
Conclusion
Development of BM in patients with RCC comprises a
clinically relevant subgroup with high morbidity and
mortality. Although VEGFR TKIs have had success in extracranial
disease, the CNS response rates have been modest.
Mechanisms of differential response across agent
classes may be related to the ability of the agent to penetrate
the CNS and presence of molecular alterations
unique to RCC BM that are targetable by specific agents.
Further evaluation of cabozantinib in this setting is reasonable
and results with this TKI appear to be more promising
than with other agents in this class. There are
preliminary data that the use of checkpoint inhibitors
could yield potentially favorable results. There is an
unmet need for more studies where BM in mRCC patients
are not exclusionary criteria in clinical trials. These studies
will inform future investigations seeking to understand
the mechanisms of therapeutic resistance of RCC
BM and novel strategies to treat this population.
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