Circulating Biomarkers in Pazopanib Phase III Trial

Yuan Liu of GlaxoSmithKline presented a poster with the results of a retrospective study of biomarkers for baseline tumor size and response to the TKI (tyrosine kinase inhibitor) pazopanib (Votrient). Molecular markers could correlate with mRCC disease prognosis and treatment outcomes, which could aid individualized treatment decisions. 

Earlier trials identified plasma cytokine and angiogenic factors (CAFs) including IL6, IL8, HGF, OPN, TIMP1, VEGF, and E-Selectin that significantly correlated with progression-free survival (PFS) in patients treated with pazopanib.  This randomized, placebo-controlled study was used to retrospectively determine relationships of baseline levels of these CAFs with primary tumor burden at diagnosis and with treatment tumor response, ultimately identifying a CAF signature predictive of PFS.  A total of 344 patients were included in the biomarker population, 225 of whom were treated with pazopanib and 119 of whom were treated with placebo. 

The trial found that circulating baseline IL6, IL8, HGF, OPN, TIMP1 and VEGF correlated with baseline tumor size, while E-Selectin did not.  Higher levels of IL6, HGF and OPN were associated with reduced tumor shrinkage after pazopanib treatment.   

The researchers combined the 7 angiogenic factors into a single 7-CAF signature profile. Patients  with a Higher signature profile  experienced significantly shorter PFS in both the placebo and the pazopanib arms, suggesting that patients with higher levels of these proteins have poorer clinical outcomes in both cases. 

This signature was prognostic in RCC.  The hazard ratio measures the difference between two variables so a hazard ratio of 0.42 means that patients with low signature taking pazopanib were 58% more likely to have a longer PFS than patients with low signature. Protein profiling may pave the way for prognostic evaluation and may help determine potential response to VEGF inhibitors in advanced RCC patients. 

This study is enlightening especially due to the overall lack of confirmed biomarkers in RCC.