Pharmacodynamic study of soluble FAS (sFAS) and FASL (sFASL), in patients (pts) with advanced colorectal cancer (ACRC) after irinotecan and cetuximab treatment in third-line therapy: Results of HCB-05–01 trial

Abstract

22046 Background: No predictive markers of cetuximab efficacy in ACRC, have been validated prospectively fulfilling REMARK criteria. We have previously observed in ACRC pre-treated pts a decrement of sFAS (sFAS/sFASL) ratio (Nadal et al, Clin Cancer Res., 2005) and in a pharmacodynamic study an increment of sFAS ratio between 24–72 h, after first-line therapy (Carcereny et al Proc. ASCOGI, 2006). We hypothesize that changes of sFAS ratio could be an early biological predictor marker to cetuximab-irinotecan efficacy in third-line therapy. Methods: Pts with ACRC and progressive disease (PD) to oxaliplatin and irinotecan, with WHO PS 0–2 were eligible on a multicenter study. Pts received cetuximab (400 mg/m2 initial dose then 250 mg/m2 (w) plus irinotecan 180 mg/m2 q 2w. Serum analysis of sFAS and sFASL were done by ELISA basally and at 48 hours. Spiral computed tomography were done basally, every 2 months until six months, and every 3 months thereafter until PD. Response was assessed q 4 cycles. Primary end point was progression free survival (PFS). 76 pts were needed assuming α and β errors of 0.05 and 0.2 respectively to detect ≥40% of pts without PD at 4 months in the group of sFAS ratio increment above the median (A) compared with ≤10% of pts with PD in the group with sFAS ratio below the median (B). Results: 93 pts were recruited between May 2005 and July 2007. Median age was 63 (range 38–84) years. PFS was 3.3 (95% CI 1.9–4.8) months in the group B and 3.1 (95% CI 2.5–3.6) months (p=0.86) in the group A. Univariate analysis identified the following variables associated with PFS: PS 1 (HR 1.67, 95% CI 1.01–2.76), PS 2 (HR 2.92, 95% CI 1.16–7.34), LDH (0.02% increase of risk, 95% CI 0.002–0.05) and CEA (0.02% increase of risk, 95% CI 0.002–0.04). Multivariate analysis identified LDH as a prognostic factor for survival. Conclusions: Variation of sFAS ratio after treatment with cetuximab and irinotecan in ACRC, is not predictor of PFS. sFAS ratio ≤ 0.03 sFAS ratio > 0.03 p PFS (95% CI) 3.3 (1.9-4.8) 3.1 (2.5-3.6) 0.864 OS (95% CI) 9.66 (5.65-13.67) 7.66 (6.58-8.73) 0.192 Response rate (%) 6 (15) 5 (11.6) 0.641 No significant financial relationships to disclose.