Exposure-response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma

PurposeOlaratumab is a recombinant human IgG1 monoclonal antibody against PGDFR. 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.MethodsPFS 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.ResultsPFS 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 mu g/mL, EC(avg)50=179 mu g/mL) and OS (EC(min1)50=66.1 mu g/mL, EC(avg)50=134 mu g/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.ConclusionsPFS/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.