Soluble factors (SF) associated with efficacy and toxicity of pazopanib (PZB) in advanced soft tissue sarcoma (STS) patients (pts): An EORTC-STBSG study.

Abstract

10040 Background: PZB has interesting activity in relapsed non-adipocytic STS in a phase II (EORTC 62043; JCO 27(19):3126-32). We explored whether SF levels were related to outcome and toxicity. Methods: By a multiplex assay, 25 different serum SF were measured at baseline in 85 pts and also sVEGFR2 and PlGF at week 12 in 32 pts. Primary objectives were to explore associations between baseline SF levels and progression-free survival at week 12 (PFS12wks) (study primary endpoint) and between sVEGFR2 decrease and PlGF increase at week 12, both indicating VEGFR inhibition, and the PZB-specific toxicities hypertension and hypopigmentation. Secondary objectives were correlations with other efficacy end points and toxicities. Standard statistical tests were used. Results: At baseline, positive correlations were found for IL12p40 and MPC3 with PFS12wks, bNGF and HGF with PFS, and ICAM1 and IL2ra with overall survival (OS) (all p<.05). However, due to repetitive testing, false discovery rates were high (±20% for PFS and OS, 50% for PFS12wks). At 12 weeks, sVEGFR2 had decreased (1.1-2.7x) and PlGF increased (1-43x), both factors were strongly interrelated (p<.0001). Low sVEGFR2 and high PlGF levels at week 12 were associated with higher grade hypertension (p<.0005 and p<.002, respectively), but not with hypopigmentation. Associations were also observed with TSH elevations and poorer PFS12wks, and OS (all p<.05). Conclusions: Several baseline SF were related to outcome parameters, but these exploratory results should be interpreted with caution given high false discovery rates. Consistent with VEGFR inhibition, PZB decreases sVEGFR2 and increases PlGF levels, both are associated with the PZB-specific toxicities hypertension and TSH elevations. The association of these changes with poorer efficacy is unexpected and may point out alternative mechanisms of action of PZB in addition to VEGFR inhibition. Findings of this study will be validated in the currently ongoing phase III study of PZB in non-adipocytic STS. If confirmed, these factors may be used as early markers for response to PZB enabling further individualization of STS treatment. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline