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

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.