Biomarkers Predicting Clinical Outcome of Epidermal Growth Factor Receptor–Targeted Therapy in Metastatic Colorectal Cancer

Salvatore Siena; Andrea Sartore-Bianchi; Federica Di Nicolantonio; Julia Balfour; Alberto Bardelli

Disclosures

J Natl Cancer Inst. 2009;101(19):1308-24. 

In This Article

Early Response Evaluation

The characteristic "acneiform" skin rash observed in most patients who are treated with EGFR inhibitors has been studied as a potential marker of efficacy. This adverse effect is usually apparent after approximately 1 week of treatment and reaches maximum severity after 2–3 weeks. As with the tyrosine kinase inhibitor erlotinib in patients with lung cancer,[24,119] skin toxicity has been consistently linked with higher response rates and longer survival among patients with metastatic colorectal cancer who have been treated with panitumumab[13,120] or cetuximab,[7,11,12] whereas patients without rash appear to have a poor outcome. Figure 4 illustrates the relationship between survival and worst grade of rash among patients treated with panitumumab[13] or cetuximab[12] monotherapy in two phase III studies. A landmark analysis (including only patients who were progression free for ≥28 days to allow time for onset) of progression-free interval data from the panitumumab study (n = 231) showed a statistically significant benefit for patients with grade 2–4 skin toxicity compared with those with grade 1 skin toxicity (HR = 0.62, 95% CI = 0.44 to 0.88).[13]

Figure 4.

Probability of survival by worst grade of skin toxicity in patients with metastatic colorectal cancer who were treated with EGFR-targeted monoclonal antibodies in two randomized phase III studies. A) Patients treated with panitumumab. Data are from a landmark analysis that was limited to patients with progression-free interval of at least 28 days[13] (with permission from the American Society of Clinical Oncology. B) Patients treated with cetuximab.[12] Reproduced with permission from the New England Journal of Medicine. Copyright 2007 Massachusetts Medical Society. All rights reserved. CI = confidence interval; HR = hazard ratio.

Rash might indicate receptor saturation, and "dose-to-rash" strategies are being studied with the aim of optimizing response to EGFR-targeted treatment. Preliminary data from the phase I–II Evaluation of Various Erbitux Regimens by means of Skin and Tumour biopsies (ie, EVEREST) study suggest that among patients receiving cetuximab-based treatment, cetuximab dose escalation to 500 mg/m2 per week may improve response rates in those with no or slight skin reactions,[121] but the difference was not statistically significant and results require confirmation in a larger study. Subsequent analysis of results by KRAS status showed that cetuximab dose escalation did not increase response in patients with tumors carrying a mutant KRAS gene. However, among those with tumors carrying wild-type KRAS, this strategy improved the response rate from four (21%) of 19 patients to 13 (46%) of 28 patients.[122] It is important to note that the panitumumab regimen of 6 mg/kg every 2 weeks, which is approved for treatment of metastatic colorectal cancer, achieves similar drug exposure to a regimen of 2.5 mg/kg per week, which was studied in early phase trials and was found to be associated with a 100% incidence of rash.[123]

There are several limitations to the use of rash as an early physical marker of efficacy. As highlighted by De Roock et al.,[57] there are no criteria for toxic effects involving skin that are specifically tailored to the activity of EGFR-targeted treatment. Rash often occurs in patients without apparent benefit from anti-EGFR treatment, and conversely, clinical benefit has also been seen in patients without rash.[124] Because EGFR is expressed in the skin, skin rash may indicate local receptor saturation, but other factors, such as their immune status, might alter an individual's susceptibility to rash. An association has been observed between tumor and normal tissue with regard to high-affinity EGFR. This finding might provide an explanation for the link observed between skin toxicity and clinical outcome of patients treated with EGFR-targeted treatment.[81] Moreover, the relationship between rash and clinical benefit is inconsistent for the tyrosine kinase inhibitor gefitinib[124] and, intriguingly, rash is not observed in patients treated with the humanized anti-EGFR monoclonal antibody nimotuzumab,[125,126] although it should be noted that efficacy data for this drug are currently limited.

Anti-EGFR monoclonal antibody treatment may compromise renal magnesium retention capacity, leading to hypomagnesemia in some patients with colorectal cancer.[127] Vincenzi et al.[128] recently suggested that reduction in serum magnesium levels might potentially provide an early marker of efficacy of combined treatment with cetuximab and irinotecan. It has also been suggested that treatment with cetuximab may induce a sudden and lasting modulation of circulating VEGF levels,[129] although the association between this finding and clinical efficacy was not reported.

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