Relation of cetuximab-induced skin toxicity and early tumor shrinkage in metastatic colorectal cancer patients: results of the randomized phase 3 trial FIRE-3 (AIO KRK0306).

BACKGROUND: Cetuximab-induced skin toxicity (Cet-ST) is positively associated with outcome in metastatic colorectal cancer (mCRC). Besides its predictive relevance for targeted therapy, we investigated its prognostic impact with early tumor shrinkage (ETS) ≥20%, another on-treatment surrogate for clinical outcome in FIRE-3. PATIENTS AND METHODS: FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in mCRC patients with RAS-WT tumors (i.e. wild-type in KRAS and NRAS exons 2-4). Retrospective data on Cet-ST that occurred during cycles 1-3 of treatment were correlated with efficacy endpoints, including ETS. To control for guarantee-time bias, only patients who had completed three or more treatment cycles were considered. RESULTS: Of 199 patients treated with FOLFIRI/Cet, 181 (91.0%) completed three or more treatment cycles. A significant survival benefit of FOLFIRI/Cet over FOLFIRI/Bev was only evident in patients developing Cet-ST grade 2-3 [41.0 versus 26.6 months; hazard ratio (HR) = 0.73; 95% confidence interval (CI): 0.61-0.87; P < 0.001] compared with Cet-ST grade 0-1 (HR = 0.90; 95% CI: 0.67-1.20; P = 0.48). Regarding prognosis, Cet-ST grade 2-3 (n = 75; 41.4%), compared with Cet-ST grade 0-1 (n = 106; 58.6%), was associated with prolonged overall survival (OS; HR = 0.62; 95% CI: 0.42-0.91; P = 0.01). In multivariate analysis, both Cet-ST (HR = 0.66; 95% CI: 0.50-0.87; P = 0.003) and ETS (HR = 0.55; 95% CI: 0.41-0.74; P < 0.0001) were independently prognostic for OS. Absence of both Cet-ST grade ≥2 and ETS identified a subgroup of patients with very poor prognosis (median OS 15.1 months). CONCLUSIONS: In FIRE-3, the addition of cetuximab to FOLFIRI was associated with superior OS compared with FOLFIRI/Bev only in patients developing Cet-ST grade ≥2. Regarding prognostic relevance, both Cet-ST and ETS were independent and early predictors of survival. The present analysis supports that a combined evaluation of on-treatment parameters such as Cet-ST and ETS may help to guide treatment of mCRC.

Relevance of baseline carcinoembryonic antigen for first-line treatment against metastatic colorectal cancer with FOLFIRI plus cetuximab or bevacizumab (FIRE-3 trial).

PURPOSE: Increased baseline carcinoembryonic antigen (CEA) serum level is associated with inferior overall survival (OS) in metastatic colorectal cancer (mCRC). However, limited data exist on its predictive relevance for targeted therapies. Therefore, we analysed its relevance in FIRE-3, a randomised phase III study. EXPERIMENTAL DESIGN: FIRE-3 evaluated first-line FOLFIRI plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in mCRC patients with RAS-WT tumour (i.e. wild-type in KRAS and NRAS exons 2-4). Herein, the impact of CEA on patient outcome was investigated. RESULTS: Of 400 patients, 356 (89.0%) were evaluable for CEA. High CEA (>10 ng/ml; N = 237) compared to low CEA (≤10 ng/ml; N = 119) was associated with shorter OS in the FOLFIRI/Bev arm (hazard ratio [HR] = 1.50; P = 0.036), while no significant OS difference was observed in the FOLFIRI/Cet arm (HR = 1.07; P = 0.74). In patients with high CEA, FOLFIRI/Cet compared to FOLFIRI/Bev showed a greater OS benefit (HR = 0.56; P < 0.001) than in patients with low CEA (HR = 0.78; P = 0.30). Furthermore, FOLFIRI/Cet exhibited significantly superior objective response rate in patients with high CEA (odds ratio = 2.21; P = 0.006) in contrast to patients with low CEA (odds ratio = 0.90; P = 0.85). CONCLUSION: In patients with RAS-WT mCRC receiving first-line chemotherapy with FOLFIRI/Cet versus FOLFIRI/Bev, elevated CEA was associated with inferior survival in the bevacizumab arm, while this was not the case when cetuximab was applied. Comparison of OS and objective response rate according to treatment arms indicated that cetuximab was greatly superior to bevacizumab in patients with elevated CEA, while this effect was markedly lower and lost statistical significance in patients with low CEA.

Evaluation of survival across several treatment lines in metastatic colorectal cancer: Analysis of the FIRE-3 trial (AIO KRK0306).

BACKGROUND: We explored the impacts of sequential application of various treatment lines on survival kinetics. Therefore, differences in overall survival (OS) observed in FIRE-3 were investigated in the context of time and exposure to applied treatment. PATIENTS AND METHODS: OS analyses (stratified by treatment with FOLFIRI plus either cetuximab or bevacizumab) were performed according to time intervals as well as using a Cox model to define changes of hazard ratio (HR) over time. RESULTS: The fraction of patients with systemic treatment and time on treatment markedly decreases over treatment lines and time. OS evaluation by a Cox model indicated a trend towards a non-proportional hazard between treatment arms (P = 0.12/P = 0.09 for KRAS-intention-to-treat (ITT)/all-RAS wild-type populations, respectively). To improve the fit of the model, a change-point (point of curve separation) was estimated at 22.6 months (day 687) after randomisation. The HR between the two arms before 22.6 months was not significantly different from one. However, markedly different survival kinetics in favour of the cetuximab arm were apparent after the change-point (KRAS-ITT: P = 0.0018; HR, 0.60 [95% confidence interval [CI], 0.44-0.83] and RAS: P = 0.0006; HR, 0.51 [95% CI, 0.35-0.75]). CONCLUSION: The differences in OS favouring the cetuximab arm become apparent about 22.6 months after randomisation, indicating that only those patients who survive 22.6 months after randomisation benefit from the superiority of the cetuximab arm. When OS curves separate, only few patients receive active systemic treatment in short courses, suggesting that earlier treatment effects are responsible for later kinetics of survival curves.

Influence of mRNA expression of epiregulin and amphiregulin on outcome of patients with metastatic colorectal cancer treated with 5-FU/LV plus irinotecan or irinotecan plus oxaliplatin as first-line treatment (FIRE 1-trial).

Our aim was to investigate the impact of EREG and AREG mRNA expression (by RT-qPCR) in patients with metastatic colorectal cancer (mCRC). In addition, epidermal growth factor receptor (EGFR) expression (by immunohistochemistry) as well as RAS-and PIK3CA-mutations (by pyrosequencing) were assessed. Tumors of 208 mCRC patients receiving 5-fluorouracil/leucovorin plus irinotecan (FUFIRI) or irinotecan plus oxaliplatin (mIROX) within the FIRE-1 trial were analyzed for mutations. Molecular characteristics were correlated with response, progression-free survival (PFS), overall survival (OS). mRNA expression was evaluated using ROC-analysis in 192 tumors (AREG high n = 31 vs. low n = 161; EREG high n = 89 vs. low n = 103). High versus low AREG expression was associated with PFS of 10.0 versus 8.0 months (HR = 0.62, 95% CI: 0.402-0.940, p = 0.03) and OS of 24.6 versus 18.7 months (HR = 0.72, 95% CI: 0.476-1.078, p = 0.11). High versus low EREG expression correlated with prolonged PFS (9.4 vs. 6.8 months, HR = 0.62, 95% CI: 0.460-0.846, p = 0.002) and OS (25.8 vs. 15.5 months, HR = 0.48, 95% CI: 0.351-0.657, p < 0.001). The positive prognostic effect of high EREG expression was confirmed in a multivariate analysis and was neither affected by EGFR expression nor by mutations of RAS- and PIK3CA-genes. EREG expression appears as an independent prognostic marker in patients with mCRC receiving first-line irinotecan-based chemotherapy.

Left-sided primary tumors are associated with favorable prognosis in patients with KRAS codon 12/13 wild-type metastatic colorectal cancer treated with cetuximab plus chemotherapy: an analysis of the AIO KRK-0104 trial.

PURPOSE: AIO KRK-0104 investigated first-line therapy of metastatic colorectal cancer (mCRC) with cetuximab, capecitabine and irinotecan versus cetuximab, capecitabine and oxaliplatin. This analysis investigated the impact of primary tumor location on outcome of patients. PATIENTS AND METHODS: Left-sided primary tumors were defined as tumors from rectum to left flexure, while tumors in the remaining colon were regarded right sided. Overall survival (OS), progression-free survival (PFS) and response rate were correlated with primary tumor location. A Cox regression model was used to evaluate interaction between primary tumor location and KRAS mutation. RESULTS: Of 146 patients of the AIO KRK-0104 trial, 100 patients presented left-sided (of those 68 KRAS codon 12/13 wild-type) and 46 patients right-sided primary tumors (of those 27 KRAS codon 12/13 wild-type). Left-sided tumors were associated with significantly longer OS (p = 0.016, HR = 0.63) and PFS (p = 0.02, HR = 0.67) as compared to right-sided tumors. These effects were present in the KRAS codon 12/13 wild-type population (HR OS: 0.42; HR PFS: 0.54), while no impact of primary tumor location was evident in patients with KRAS codon 12/13 mutant tumors (HR OS: 1.3; HR PFS: 1.01). A significant interaction of KRAS status and primary tumor location concerning OS and PFS was observed. CONCLUSION: Our findings suggest that primary tumor location and KRAS codon 12/13 mutational status interact on the outcome of patients with mCRC receiving cetuximab-based first-line therapy. Left-sided primary tumor location might be a predictor of cetuximab efficacy.