Patients Should Welcome The Rash Caused By EGFR Inhibitors, Say Researchers

Main Category: Cancer / Oncology
Also Included In: Pharma Industry / Biotech Industry;  Clinical Trials / Drug Trials;  Dermatology
Article Date: 28 Aug 2007 - 16:00 PST

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Development of an itchy pustular rash over the torso, head, and face of patients treated with inhibitors of the epidermal growth factor receptor (EGFR)---a type of targeted drug that is increasingly used to treat several types of cancer---may actually indicate the treatment is working well, according to an analysis of two phase III trials published in Clinical Cancer Research last month (Clinical Cancer Research 3913 2007;13(13) July 1, 2007).

According to the study, the worse the rash is the more likely patients are to survive their cancers or at least maintain good control of the disease. Researchers from OSI Pharmaceuticals, the company which manufactures the EGFR inhibitor erlotinib, analysed side-effect data and outcomes from two phase III studies that showed a positive result after treatment with their drug, which is just one of many similar agents currently being prescribed by oncologists.

Both trials from which the researchers drew their data had made a special note of a rash among patients who had received the drug and those that had not---and it is this information the researchers used to asses a link between severity of the rash and effectiveness of the treatment. The first trial compared treatment with 150 mg erlotinib daily with placebo in 731 patients with stage IIIB/IV non - small-cell lung cancer who had failed at least one prior chemotherapy regimen. Overall survival, tumor response, progression-free survival, and time to symptom deterioration were all improved in the group taking erlotinib. The second study evaluated erlotinib plus gemcitabine compared with placebo plus gemcitabine for the treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer. Erlotinib again improved survival.

Most of the patients taking erlotinib in both studies developed a post-treatment rash, which was graded for severity by the clinical trial teams. The OSI investigators excluded from their analysis all patients who had died within 28 days of therapy, because they reasoned that that time frame was not sufficient for a rash associated with outcome to have developed. This specific cut-off was chosen because there was a large difference in the incidence of rash among those who died within four weeks and those who survived for longer (less than 20% versus greater than 70%).

In the first study, 81% of the 444 erlotinib-treated patients experienced a rash. Patients who developed grade 1 rash survived 144% longer than patients who did not develop rash and patients with grade 2 rash survived 245% longer than patients who did not develop rash. In the other study, among the 254 patients in the erlotinib plus gemcitabine group rhe incidence of rash was 71%. But in this second study the incidence of rash among the placebo group was, at 30%, lmost double that in the first trial. As a result, there were no statistically significant differences in outcomes between the patients with rash and those without. The authors explain the discrepancy between the two studies by explaining that their analysis of the correlation of rash with outcomes in the second study was potentially confounded because rash is an adverse event associated with both erlotinib and gemcitabine treatment.

Concluding that "the patient who does not develop a characteristic rash within 2 to 4 weeks is less likely to benefit from erlotinib," the researchers note that physicians and patients should view the development of rash as a desirable outcome---perhaps as a sign of erlotinib-induced biological effect. They emphasise the need to develop methods for managing the rash without interfering with the improvement in outcomes it brings. "Optimal management of rash in patients on EGFR inhibitors remains somewhat controversial, but aggressive treatment of the side effects may allow patients to continue receiving therapy without dose interruption or drug discontinuation," they wrote. Part of clinical management of this side effect, patients should also be counseled to help them regard the development of the rash as a positive step, the researchers suggest.

Correlation between Development of Rash and Efficacy in Patients Treated with the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib in Two Large Phase III Studies.
B Wacker, T Nagrani, J Weinberg, K Witt, G Clark, PJ Cagnoni.
Clinical Cancer Research 2007;13(13) July 1, 2007

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