Presence and severity of skin rash in patients treated with erlotinib correlate with longer durations of progression-free survival, according to an article in the July 1 issue of Clinical Cancer Research.

Researchers from the drug’s developer, OSI Pharmaceuticals, analyzed data from phase III trials of patients with advanced non-small cell lung cancer or pancreatic cancer to confirm the finding. The current finding is not the first to show that a drug-related rash is associated with a survival advantage with epidermal growth factor receptor (EGFR) inhibitors ? a class of drugs which includes erlotinib, cetuximab, and panitumumab ? but it is the most detailed analysis to date.

In the current analysis, researchers found that patients taking erlotinib who developed a moderate to severe rash had durations of survival without progression of disease that were 245 percent longer than those seen in patients who had a mild rash or none at all. In fact, in the majority of cases, the more severe the rash, the longer the progression-free survival.

The rash, which often looks like acne, can be unpleasant enough for some people to consider discontinuing treatment, but “it is important for physicians and patients to understand that this a positive event because it means there is likely to be a better clinical outcome,” said lead author, Bret Wacker, MS, Director of Biostatistics at OSI Pharmaceuticals, Inc. “Further studies are needed to both identify patients most likely to develop rash and to determine if dose escalation to induce rash can improve efficacy.”

Although few patients dropped out of the large Phase III clinical trials testing the drug in patients with advanced non-small cell lung cancer or pancreatic cancer due to the rash, Wacker said that patients taking erlotinib or another EGFR inhibitor outside of a clinical trial may be likely to stop treatment.

According to the researchers, the rash can be controlled with mild steroids or antibiotics, and in most cases, improves with treatment. The authors speculate that the rash is due to an inflammatory response as a result of EGFR inhibition in skin tissue.

Researchers excluded patients who died in the first month after starting the study because they may not have had time to develop the rash or the rash may have been under-reported in these ill patients.

Of the 673 patients in the lung cancer study, called BR.21, and in the erlotinib-treated group, 81 percent developed a rash, the majority of which was grade 2 (The study graded rashes from 1, relatively mild, to 4, severe). The researchers found that the presence of any rash correlated with overall and progression-free survival and that these correlations increased with grade of rash.

Specifically, erlotinib-treated patients who did not develop a rash survived a median of 3.3 months compared with 7.1 months for those with a grade 1 rash and 11.1 months for patients with more severe, grade 2 rashes.

They also found, however, that 18 percent of patients treated with placebo also developed a rash, and that overall survival in these patients was also significantly longer (a median of 8.2 months compared with 4.7 months) compared with placebo patients who didn’t develop a rash. “We don’t know why some patients treated with a placebo developed a rash, but it could be due to the strength of their immune system, and that is why they survived longer,” Wacker said.

In the second clinical trial (known as PA.3) that tested erlotinib and gemcitabine against placebo and gemcitabine in 521 patients with advanced pancreatic cancer, 71 percent of patients using erlotinib/gemcitabine developed a rash compared with 30 percent of patients in the placebo group.

Unlike the BR.21 study, pancreatic cancer patients with rashes in the placebo group did not experience an increase in survival compared with placebo group patients without a rash.

In the erlotinib group, only a more severe rash of grade 2 or higher was associated with increased survival. Patients with a grade 2 rash survived a median of 10.8 months compared with treated patients with no rash (5.4 months) or a grade 1 rash (5.7 months).

“These different results may be associated with the addition of gemcitabine with erlotinib, or the lower dose of erlotinib in this study, but we just don’t know,” he said.

Wacker pointed out that lack of a rash doesn’t necessarily mean that patients will not benefit from erlotinib. “A small percentage of patients who didn’t develop a rash still had relatively long survival,” he said. “But, still, overall, patients who don’t develop a rash don’t do as well as those who do.”