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

Autor: Jones RL; University of Washington and Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, 98109, USA. robin.Jones@rmh.nhs.uk.; Royal Marsden Hospital and Institute of Cancer Research, London, UK. robin.Jones@rmh.nhs.uk., Mo G; Eli Lilly and Company, Lilly Corporate Center, 46285, Indianapolis, IN, USA., Baldwin JR; Eli Lilly and Company, Lilly Corporate Center, 46285, Indianapolis, IN, USA., Peterson PM; Eli Lilly and Company, Lilly Corporate Center, 46285, Indianapolis, IN, USA., Ilaria RL Jr; Eli Lilly and Company, Lilly Corporate Center, 46285, Indianapolis, IN, USA.; Celgene, Summit, NJ, USA., Conti I; Eli Lilly and Company, Lilly Corporate Center, 46285, Indianapolis, IN, USA.; EMD Serono Research & Development Institute, Billerica, MA, USA., Cronier DM; Eli Lilly and Company, Lilly Research Centre, Erl Wood Manor Sunninghill Road, Windlesham, Surrey, GU20 6PH, UK.; Merck Serono Ltd, Feltham, UK., Tap WD; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, 1275 York Ave, New York, NY, 10065, USA.
Jazyk: angličtina
Zdroj: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2019 Jan; Vol. 83 (1), pp. 191-199. Date of Electronic Publication: 2018 Nov 08.
DOI: 10.1007/s00280-018-3723-4
Abstrakt: 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.
Databáze: MEDLINE
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