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With Cetuximab and Erlotinib,Rash Correlates With Survival

With Cetuximab and Erlotinib,Rash Correlates With Survival

CHICAGO-Separate reviews of data from multiple phase II trials with novel agents cetuximab (Erbitux) and erlotinib (OSI-774, Tarceva) have concluded that patients who developed an acne-like rash lived longer than those who did not, and that patients with more severe rash lived longer than patients with mild rash. In presenting their analyses at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO) (ASCO abstracts 786 and 817), the investigators suggested that rash could be a biomarker for response to HER1/ epidermal growth factor receptor inhibitors (HER1/EGFR). A recent journal article also identified rash as a predictor of response to gefitinib (ZD1839, Iressa), a third agent that targets EGFR (Cohen et al: J Clin Oncol May 15; 21(10):1980-1987, 2003). The big question is whether the observation will prove clinically useful. Both sets of researchers presenting data speculated that the optimal dose of HER1/EGFR inhibitors could be linked to an optimal degree of rash in each patient. They cautioned, however, that the rash might be a surrogate for another factor involved in the response. "It could mean that a strategy for improving the effectiveness of the drug could be to dose to a certain level of rash; that some people may need more drug and be able to tolerate more drug in order to escalate to a degree of side effect that will be commensurate with a higher degree of activity," Leonard B. Saltz, MD, of Memorial Sloan-Kettering Cancer Center, told ONI. Alternative Hypothesis
"An alternative hypothesis would be that patients have particular polymorphisms of the epidermal growth factor receptor that make them more vulnerable to toxicity and their tumors more vulnerable to the attack by this particular drug," Dr. Saltz continued. "We really don't know if this observation will have a therapeutic meaning or not," Dr. Saltz said. Gary M. Clark, PhD, senior director of biostatistics and data management of OSI Pharmaceuticals, Inc., compared the rash to tumor flares experienced by breast cancer patients treated with tamoxifen in the early 1980s. Some women asked to be taken off the new drug because of pain and vaginal dryness, but it turned out to be a sign the drug was working, Dr. Clark said. He is the lead investigator of the erlotinib analysis. "The question, of course, is can we do anything about this? Can we take advantage of it?" he said to ONI. "Is it possible to increase the dose in some patients and achieve a better clinical outcome?" He said that OSI has already started a dose-to-rash study. Review of Previous Trials
Dr. Saltz and Dr. Clark each mined data from previously reported phase II trials. ImClone Systems Incorporated of Somerville, New Jersey, develop- er of cetuximab with Bristol-Myers Squibb Oncology, participated in the cetuximab study. Dr. Saltz reviewed trials evaluating cetuximab:

  • with irinotecan (CPT-11, Camptosar) in 120 patients with colorectal cancer;

  • alone in 57 colorectal cancer patients;

  • with cisplatin in 79 squamous cell cancer of the head and neck patients; and

  • with gemcitabine (Gemzar) in 41 pancreatic cancer patients.
About 75% of patients developed a rash. In all four studies, patients with no rash had the shortest median survival, while patients with grade 3 rash lived longest (see Figure 1). In patients with pancreatic cancer, for example, the range for length of survival went from 2.3 months with no rash to 13.9 months with grade 3 rash. So far the rash has been treatable as well as controllable with dose adjustment, Dr. Saltz said. He voiced a concern, however, that the finding "implies a relatively modest therapeutic window whereby we're going to have to accept the skin toxicity to get what we want out of the drug." Relationship to Outcome Dr. Clark reviewed three erlotinib studies.
  • Among 57 patients with refractory non-small-cell lung cancer (NSCLC), 75% developed rash.

  • Among 115 patients with advanced squamous cell cancer of the head and neck, 70% developed rash.

  • Among 34 patients with advanced ovarian cancer, 82% developed rash.
No patient without a rash responded to therapy. Pooled data from all three studies showed median survival of 44 days without rash, 67 days with grade 1 rash, and 95 days with grades 2/3 rash. "I looked at every possible pretreatment characteristic I could find. Some of them correlated with outcomes, but none of them changed the relationship between rash and outcomes," Dr. Clark said. A co-author of the erlotinib analysis, Roman Perez-Soler, MD, of Montefiore Medical Center, Albert Einstein College of Medicine, New York, raised the rash issue at "Targeting Critical Pathways in Oncology" a post- ASCO, industry-sponsored satellite symposium. Nine studies with several hundred patients have shown a strong relationship between rash and survival with agents targeting HER1/EGFR, according to Dr. Perez-Soler. And there is a consistant trend between higher grades of rash and longer survival. "Should we adjust doses to grade 1/2 rash?" he asked rhetorically. "We don't have the answer today; but obviously we should pay attention to this."
 
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