Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials
The Lancet Oncology, 07/05/2012
Tran HT et al. – CAF profiles could provide prognostic information beyond that of standard clinical classification and identify markers predictive of pazopanib benefit in patients with metastatic renal-cell carcinoma.Methods
- We used a three-step approach for screening, confirmation, and validation of prospective CAF biomarkers.
- We screened 17 CAFs in 129 patients who had the greatest or least tumour shrinkage in a phase 2 trial of 215 patients treated with pazopanib.
- We confirmed associations of candidate CAFs (those identified in the screening and from previous studies) with tumour response and progression-free survival (PFS) in 215 patients from this phase 2 trial with an independent analytical platform.
- We validated confirmed markers in 344 patients from a randomised, placebo-controlled, phase 3 clinical study of pazopanib.
- Five candidate markers emerged from initial screening—interleukin 6, interleukin 8, hepatocyte growth factor (HGF), tissue inhibitor of metalloproteinases (TIMP)-1, and E-selectin.
- Confirmatory analyses identified associations of interleukin 6, interleukin 8, VEGF, osteopontin, E-selectin, and HGF with continuous tumour shrinkage or PFS in patients treated with pazopanib.
- In the validation set of samples from the phase 3 trial, patients treated with pazopanib who had high concentrations (relative to median) of interleukin 8 (p=0·006), osteopontin (p=0·0004), HGF (p=0·010), and TIMP-1 (p=0·006) had shorter PFS than did those with low concentrations.
- In the placebo group, high concentrations of interleukin 6 (p<0·0001), interleukin 8 (p=0·002), and osteopontin (p<0·0001) were all prognostically associated with shorter PFS.
- These factors were stronger prognostic markers than were standard clinical classifications (Eastern Cooperative Oncology Group, Memorial Sloan-Kettering Cancer Center, and Heng criteria).
- High concentrations of interleukin 6 were predictive of improved relative PFS benefit from pazopanib compared with placebo (pinteraction=0·009); standard clinical classifications were not predictive of PFS benefit.