The multicenter, single-arm, phase II trial (Simon's two stage design) evaluated the efficacy of mFOLFOX6 + cetuximab (500 mg/m2) q2w as 1st line therapy in KRAS wt mCRC. Final extended molecular and subgroup analyses are presented.
Primary endpoint was response rate (ORR) per RECIST 1.0. In stage 1 and 2, 13 and 25 responders were needed in 37 and 53 pts, respectively, to further evaluate this therapy (H1 p > 0.55). Secondary endpoints were PFS, OS, safety, metastasectomy and quality of life (QoL). Extended molecular profiling was performed using NGS-based panel sequencing including NRAS, KRAS, BRAF, PIK3CA and TP53. Clinical parameters included: tumor location (left-sided LCRC), early tumor-shrinkage (ETS), depth of response (DPR), metastasectomy and inflammation markers (neutrophil/lymphocyte ratio-NLR). Differences in ORR, PFS and OS were calculated using chi-square and log rank tests. Hazard ratios were calculated by Cox regression analysis.
The primary endpoint was met with 57 pts enrolled (ITT) and 53 pts evaluable for response. There were 26 responders in stage 1 (70%) and 38 responders in the ITT (ORR of 67%). Median PFS and OS were 9.6 (7.4-11.7) and 29.4 (19.3-39.5) months, respectively. Secondary metastasectomy was achieved in 31.7%. Grade 3/4 AEs occurred in 52%, including leukocytopenia, rash and GI-toxicity. Molecular profiling could be performed in 44 pts (77%). Additional RAS or BRAF mutations were detected in 17.8% and 10.6%, respectively, with a negative impact on outcomes. TP53 mutations were detected in 62.5% without impact on outcomes. Pts with LCRC, ETS or metastasectomy had significantly prolonged OS, whereas pts with high NLR (>5) had inferior OS (all p-values
This study supports the efficacy and safety of q2w cetuximab given in combination with mFOLFOX6. Extended mutational analyses of key oncogenes and routinely assessed clinical parameters may help to identify patients with maximum likelihood of benefit from cetuximab-based chemotherapy.
Clinical trial identification
Clinical trial information: NCT01051167
Legal entity responsible for the study
University Hospital Essen
S. Kasper: Merck: Research grant Merck, Sanofi, Amgen, Lilly: scientific talks Merck, Sanofi, Amgen, Lilly, BMS, MSD, Roche, Bayer: Adboards. J. Meiler: Sanofi, Amgen:Scientific talk Lilly, Pfizer, BMS, Sanofi: Adboard Bayer: Meeting invitation. M. Schuler: AstraZeneca,, Alexion, Boehringer Ingelheim, BMS, Celgene, GSK, IQWig, Lilly, Novartis Pfizer: Advisory Boards, Honoraria, Research Funding, Travel University Duisburg-Essen: Patent T. Trarbach: Merck, Sanofi und Amgen: Advisory Boards, travel grants, research grants. All other authors have declared no conflicts of interest.