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)
Authors: J.W. Holch, S. Held, S. Stintzing, L. Fischer von Weikersthal, T. Decker, A. Kiani, F. Kaiser, T. Heintges, C. Kahl, F. Kullmann, W. Scheithauer, M. Moehler, J.C. von Einem, M. Michl, V. Heinemann
Journal: Annals of Oncology (2020)

•Cetuximab-induced skin toxicity positively correlated with survival in patients with metastatic colorectal cancer.•Cetuximab-induced skin toxicity predicted benefit from FOLFIRI plus cetuximab over FOLFIRI plus bevacizumab.•Cetuximab-induced skin toxicity and early tumor shrinkage predicted survival independently in multivariate analysis.•A combined evaluation of Cet-ST and ETS may help to guide treatment of metastatic colorectal cancer. BackgroundCetuximab-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 methodsFIRE-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.ResultsOf 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).ConclusionsIn 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. 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. 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. 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). 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.