Published in:
Open Access 01-01-2019 | Original Article
Exposure–response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma
Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2019
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Purpose
Olaratumab is a recombinant human IgG1 monoclonal antibody against PGDFRα. Olaratumab plus doxorubicin improved survivalversus doxorubicin in an open-label, randomised phase 2 soft tissue sarcoma (STS) trial. We characterised the olaratumab exposure–response relationship for progression-free survival (PFS), overall survival (OS), and safety.
Methods
PFS and OS data from the 133 patients enrolled in the phase 2 study were analysed using time-to-event modelling. The effect of olaratumab on PFS/OS was explored using the trough serum concentration after cycle 1 (Cmin1) and the average concentration throughout treatment (Cavg). The rate of treatment-emergent adverse events (TEAEs) was compared across olaratumab exposure quartiles.
Results
PFS and OS were described by models with an exponential hazard function and inhibitory EMAX functions to describe the effect of olaratumab, regardless of the PK endpoint. The olaratumab EC50s for PFS (ECmin150 = 82.0 µg/mL, ECavg50 = 179 µg/mL) and OS (ECmin150 = 66.1 µg/mL, ECavg50 = 134 µg/mL) corresponded to the median and 25th percentile of Cmin1/Cavg in the study, respectively. Maximum predicted improvement in the hazard ratio for OS and PFS was approximately 75% and 60%, respectively. There was no change in the rate of TEAEs with increasing olaratumab serum levels.
Conclusions
PFS/OS benefits occurred without a rate change in TEAEs across quartiles. Maximum benefit in OS was achieved in the upper three quartiles and a potential of early disease progression in the lower quartile of olaratumab serum exposure. These results prompted a loading dose strategy in the ongoing phase 3 STS trial.