Cetuximab-related skin toxicity and efficacy: do we understand the mechanisms?

The article by Holch and coworkers1Holch J.W. Held S. Stintzing S. et al.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).Ann Oncol. 2020; 31: 72-78Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar is a retrospective analysis of the FIRE-3 trial, focusing on parameters potentially linked to treatment outcome. In this analysis, the conclusions were based on the already-known link between cetuximab-related skin toxicity (ST) and treatment efficacy reported in advanced colorectal cancer (CRC). Surprisingly, there was only a low relationship (P = 0.096) in favor of the expected higher objective response rate in patients with marked ST, while there was a strong prognostic impact of ST with significantly longer progression-free survival (PFS) [hazard ratio (HR) = 0.63) and overall survival (OS) (HR = 0.62) in patients with ST. To describe correlations, but avoiding any attempt to propose underlying mechanisms, markedly limits the claim by the authors that ST may help guide treatment in advanced CRC. Take, for instance, variability in both the drug and its target. For example, one can consider the well-known link between drug exposure and treatment pharmacodynamics. However, published data are not convincing regarding the existence of such a relationship for cetuximab.2Le Louedec F. Alix-Panabières C. Lafont T. et al.Cetuximab pharmacokinetic/pharmacodynamics relationships in advanced head and neck carcinoma patients.Br J Clin Pharmacol. 2019; 85: 1357-1366Crossref PubMed Scopus (14) Google Scholar A proposed mechanism convincingly supporting the link between ST and treatment efficacy of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (McAb) lies in the existence of a polymorphism in the intron 1 of the EGFR gene impacting EGFR gene expression and leading to a partitioning between low and high EGFR expressers.3Amador M.L. Oppenheimer D. Perea S. et al.An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors.Cancer Res. 2004; 64: 9139-9143Crossref PubMed Scopus (241) Google Scholar The consequence of this is that high EGFR expression may confer more sensitivity to both tumors and to normal skin tissue with anti-EGFR McAb, while the reverse is true with low EGFR expression.4Graziano F. Ruzzo A. Loupakis F. et al.Pharmacogenetic profiling for cetuximab plus irinotecan therapy in patients with refractory advanced colorectal cancer.J Clin Oncol. 2008; 26: 1427-1434Crossref PubMed Scopus (111) Google Scholar It would be of interest, therefore, to genotype patient cohorts for this EGFR gene polymorphism in order to examine more specifically the link between EGFR genotypes, ST, and treatment efficacy, especially in such a retrospective setting. In contrast, explanations regarding the observed link between ST and disease evolution are more difficult to understand. Immediately evident in the present study, but not grasped by the authors, is the fact that BRAF-mutated tumors, known to have a poor prognosis, were more frequent in the low ST group compared with the high ST group (14.2% versus 5.3%), thus providing one plausible explanation for the prognostic impact of ST in the study. Another working hypothesis could be related to antibody-directed cell toxicity (ADCC), a component of cetuximab cytotoxic activity.5Ferris R.L. Lenz H.J. Trotta A.M. et al.Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation.Cancer Treat Rev. 2018; 63: 48-60Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar Of note, ADCC can trigger patient immunity through T-cell priming5Ferris R.L. Lenz H.J. Trotta A.M. et al.Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation.Cancer Treat Rev. 2018; 63: 48-60Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar with a consequent long-term positive impact on disease evolution. Hence, variable individual ability to develop ADCC could contribute to both antitumor and normal cell toxicity and play a role in achieving better treatment outcomes in CRC patients. None declared.