We read with interest the recent article by Stintzing et al. entitled “Prognostic value of cetuximab-related skin toxicity in metastatic colorectal cancer patients and its correlation with parameters of the epidermal growth factor receptor signal transduction pathway: Results from a randomized trial of the GERMAN AIO CRC Study Group.”1 This very interesting report—based on a previously published randomized phase II study2—explores the relationship between KRAS status and the development of skin toxicity in patients receiving cetuximab therapy for colorectal cancer.
Surprisingly, this retrospective report demonstrated that within the KRAS-mutated subgroup patients who developed grade 2–3 cetuximab-related skin toxicity had a markedly longer progression-free survival (PFS; 8.5 vs. 4.8 months) and overall survival (OS; 28.7 vs. 12.4 months) than patients with grade 0–1 skin toxicity. While the authors do acknowledge that this cannot speak to a cetuximab benefit—as all patients received cetuximab—they nonetheless do include a statement in their discussion which we believe to be erroneous and potentially misleading. They state that “a comparable observation was also reported from the PRIME study investigating the combination of panitumumab and FOLFOX4. In that trial, patients with KRAS-mutated tumors who developed skin toxicity grade 2–4 had a longer PFS (8.8 vs. 7.3 months) and OS (19.3 vs. 15.5 months) than patients who presented with grade 0–1 toxicity.”
The PRIME study was a randomized phase III study evaluating the potential benefit (or not) of panitumumab in combination with FOLFOX4 chemotherapy in advanced untreated colorectal cancer.3 Its main conclusion was to confirm the small benefit previously shown for anti-EGFR therapy in patients with KRAS-wild type colorectal cancer. However, it is important to emphasize that in the PRIME study not only was there no benefit for the addition of panitumumab in KRAS-mutant patients but in fact this was detrimental, associated with an inferior PFS (7.3 vs. 8.8 months) and OS (15.5 vs. 19.3 months). Contrary to the statement by Stintzing et al., there was no reported benefit in the subset of patients with KRAS-mutated tumors who developed skin toxicity and we noticed that the figures they quote from the PRIME study ostensibly showing benefit with the occurrence of skin toxicity—PFS (8.8 vs. 7.3 months) and OS (19.3 vs. 15.5 months)—are identical to those figures which in fact demonstrate inferiority of outcome in the KRAS-mutated subset.
This is a very important point for a number of reasons. First of all, there are increasing reports of potential benefit for anti-EGFR therapy in codon 13 mutated KRAS colon cancer, data which await prospective confirmation.4, 5 Second, Stintzing et al. provide very useful information relating to the kinetics of cetuximab-related skin toxicity. A combination of these factors may lead a reader to the conclusion that treating a patient with KRAS-mutated colorectal cancer—perhaps to see if they develop a rash after 1–2 months—would be a reasonable thing to do, whereas in fact we know—from the PRIME study, amongst other data—that this would not be reasonable and would be harmful. We would, therefore, ask the authors to clarify or correct.