Abstract
PurposeOlaratumab 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.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 (Cmin1) and the average concentration throughout treatment (Cavg). 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 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.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.
Highlights
Soft tissue sarcomas (STS) are a group of rare tumours of mesenchymal origin, accounting for approximately 1% of all adult cancers [1,2,3]
Cmin1 and Cavg had a similar predictive role for drug effect, so that the half-maximum effective Cmin1 and Cavg (ECmin150 and ECavg50) estimates corresponded to the 25th percentile of Cmin1 and Cavg in the study, respectively
The exposure–response relationship of olaratumab for progression-free survival (PFS) and overall survival (OS) are best described by time-to-event models with exponential hazard functions, and the effects of olaratumab on PFS and OS were well-characterized by inhibitory E MAX functions with Hill coefficients
Summary
Soft tissue sarcomas (STS) are a group of rare tumours of mesenchymal origin, accounting for approximately 1% of all adult cancers [1,2,3]. High-risk patients will develop recurrent locally advanced inoperable or metastatic disease. The outcome for patients with advanced inoperable/metastatic STS is poor with a median overall survival (OS) in the range of 12–18 months [4,5,6,7,8]. There are few treatment options available, and these have historically included doxorubicin with or without ifosfamide. Over the last few years, a number of other drugs have emerged including gemcitabine/docetaxel, trabectedin, pazopanib, and eribulin [6, 9–12]
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