| Abstract: |
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 (C min1 ) and the average concentration throughout treatment (C avg ). 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 E MAX functions to describe the effect of olaratumab, regardless of the PK endpoint. The olaratumab EC50s for PFS (EC min1 50 = 82.0 μg/mL, EC avg 50 = 179 μg/mL) and OS (EC min1 50 = 66.1 μg/mL, EC avg 50 = 134 μg/mL) corresponded to the median and 25th percentile of C min1 /C avg 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. © 2018, The Author(s). |
