Clinical significance
- Daily dosing of savolitinib will be more effective in the clinic than
intermittent dosing.
- This modelling framework may be useful to translate tumour growth
inhibition in mice to humans.
Abstract
Background and purpose: Savolitinib (AZD6094, HMPL-504,
volitinib) is an oral, potent, and highly selective MET receptor
tyrosine kinase inhibitor. This series of studies aimed to develop a
pharmacokinetic-pharmacodynamic (PK/PD) model to link inhibition of MET
phosphorylation (pMET) by savolitinib with anti-tumour activity.
Experimental approach: Cell line-derived xenograft (CDX)
experiments using human lung cancer (EBC-1) and gastric cancer (MKN-45)
cells were conducted in athymic nude mice using a variety of doses and
schedules of savolitinib. Tumour pMET changes and growth inhibition were
calculated after 28 days. Population PK/PD techniques were used to
construct a PK/PD model for savolitinib.
Key results: Savolitinib showed dose- and schedule-dependent
anti-tumour activity in the CDX models, with more frequent, lower dosing
schedules (e.g. twice daily) being more effective than intermittent,
higher dosing schedules (e.g. 4 days on/3 days off or 2 days on/5 days
off). There was a clear exposure–response relationship, with maximal
suppression of pMET of >90%. Data from additional CDX and
patient-derived xenograft (PDX) models overlapped, allowing the
calculation of a single EC50 of 0.38 ng/mL. Tumour
growth modelling demonstrated that prolonged, high levels of pMET
inhibition (>90%) were required for tumour stasis and
regression in the models.
Conclusion and implications: High and durable levels of MET
inhibition by savolitinib are needed for optimal monotherapy anti-tumour
activity in preclinical models. The modelling framework developed here
can be used to translate tumour growth inhibition from the mouse to
human, and thus guide choice of clinical dose and schedule.