PULSE, a phase 2 study of mFOLFOX6-panitumumab (P) with biomarker stratification as first-line chemotherapy (CT), in patients (pts) with KRAS (exon 2) metastatic colorectal cancer (mCRC). A GEMCAD 09-03 study

Matrilysin (MMP7) can activate phospho-insulin growth factor receptor-1 (pIGF-1R) through IGFBP-3 degradation, releasing IGF-1. Co-expression of MMP7 and pIGF-1R (double positivity, DP) correlates with poor prognosis in WT KRAS pts treated with anti-EGFR in second-third line therapy. We performed a prospective clinical trial in WT KRAS (exon 2) pts, treated with FOLFOX6-P in first-line CT to validate those findings. A non-planned sub-analysis in the RAS/BRAF WT subset of pts is now presented. Positive cases were defined by immunohistochemistry as those with moderate or strong intensity (++ / + ++ ) and >70% expression for both MMP7 and pIGF-1R (antibody anti-pY1316). The primary end-point was progression-free survival (PFS). Seventy-eight pts and 56 events were required to have an 80% power to detect a difference in median PFS of 6 months (m) (two-sided p < 0.05). We screened 196 mCRC pts in 24 centers between Nov/2010 and Apr/2013 and 60/78 pts were RAS/BRAF WT (31 non-DP and 29 DP). Median follow-up was 23m. Response rate was 81.7%, mPFS 9.6m (95%CI 7.1-14.1) and median overall survival (OS) 30.4m (95%CI 18.2-39.1).There were no differences in baseline characteristics (age, sex, liver metastases, lactate dehydrogenase (LDH) levels and performance status between both groups). There were no differences in the number of CT cycles received and second-line therapies between both groups. Response rate was 86.2% in non-DP and 77.4% in DP pts (p = 0.74). Median PFS (95% CI) was 9.2m (95%CI 5.2-15.2) in non-DP and 10.5m (95% CI 7.8-18.2, p = 0.16) in DP pts. Median OS was 18.2m (11.2-37.9) in non-DP pts and 39.1m (30-NE, p = 0.11) in DP pts. Adjusted HR for PFS was 0.60 (95% CI 0.31-1.14). Adjusted HR for OS was 0.51 (95% CI 0.27-0.98). Our study suggest that unexpectedly, co-expression of MMP7 and pIGF-1R, could be a novel strong prognostic biomarker of survival benefit, in mCRC RAS/BRAF WT pts treated in first-line with FOLFOX6-P.