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

Date

10 Oct 2016

Session

Sarcoma

Presenters

Robin Jones

Citation

Annals of Oncology (2016) 27 (6): 483-492. 10.1093/annonc/mdw388

Authors

R. Jones1, G. Mo2, J.R. Baldwin2, R.D. Nichols2, R.L. Ilaria2, I. Conti2, D.M. Cronier3, W.D. Tap4

Author affiliations

  • 1 Oncology, Fred Hutchinson Cancer Research Center, 98109 - Seattle/US
  • 2 Oncology, Eli Lilly and Company, Indianapolis/US
  • 3 Oncology, Eli Lilly and Company, Windlesham/GB
  • 4 Oncology, Memorial Sloan-Kettering Cancer Center, New York/US
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Background

Olaratumab (Olara), a recombinant human IgG1 monoclonal antibody, selectively binds human PGDFRα. Olara plus doxorubicin (Dox) improved survival vs Dox in a Phase 2 sarcoma trial (NCT01185964). We characterized the exposure-response relationship of Olara for progression free survival (PFS), overall survival (OS) and safety.

Methods

PFS/ OS, pharmacokinetic (PK) and safety data from the 66 patients who received Olara on the phase 2 study were analyzed. The effect of Olara serum levels was explored using average serum concentration (Cavg) and trough serum concentration after cycle 1 (Cmin1). The PFS/OS data were analyzed using a matched case-control (MCC) analysis across quartiles of Olara serum levels and a time-to-event (survival) model with a constant baseline hazard and a Hill function to describe the effect of Olara. The rate of treatment-emergent adverse events (TEAEs) was compared across quartiles of Olara exposure.

Results

The MCC analysis using both Cavg and Cmin1 showed a benefit in PFS above the median Olara exposure (Cavg ≥ 175.2 µg/mL; Cmin1 ≥86.9 µg/mL), with patients progressing earlier in the lowest quartile (Cavg 

Conclusions

Cmin1 and Cavg showed a similar predictive role for Olara effect. PFS/OS benefits occurred without a rate change in TEAEs across quartiles. The MCC and modeling analyses showed consistent results with maximum apparent/predicted benefit in OS achieved in the upper 3 quartiles and a risk of early progression in the lower quartile of Olara serum exposure. These results prompted a loading dose strategy in the ongoing phase 3 STS trial.

Clinical trial identification

NCT01185964

Legal entity responsible for the study

Eli Lilly and Company

Funding

Eli Lilly and Company

Disclosure

R. Jones, R.L. Ilaria: IMClone- Grant Consulting role with Eisai, Pharmamar, Merck, Adaptimmune, Immune design, Immodulon, Daiichi, Lilly, and Pfizer. G. Mo, J.R. Baldwin, R.D. Nichols, D.M. Cronier: Lilly – Employee. I. Conti: Lilly - Employee, Shareholder, Honorarium. W.D. Tap: Honorarium - Lilly, Plexxikon, Advaxis, Ariad, Boehringer Ingelheim, EMD Serono, Daiichi Sankyo, and Morphotek.

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