TORONTO, CANADA-Adding erlotinib (Tarceva) to gemcitabine(Drug information on gemcitabine) (Gemzar) increased 1-year survival by 40% for patients with advanced pancreatic cancer in a phase III international study (abstract 1). "This is the first trial to show a survival benefit for a targeted therapy in ad- vanced pancreatic cancer. And this trial has shown that gemcitabine plus erlotinib is superior to single-agent gemcitabine," according to Malcolm Moore, MD, the study's lead investigator and Director of the New Drug Development Program at Princess Margaret Hospital in Toronto. "This is also the first demonstration of the benefit of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor in combination with chemotherapy in any disease," he added. Patients Totaled 569 The double-blind placebo-controlled phase III study, conducted by the National Cancer Institute of Canada, Clinical Trials Group at Queens University in collaboration with OSI Pharmaceuticals, enrolled a total of 569 patients with locally advanced or metastatic pancreatic cancer. Patients were balanced in terms of known prognostic factors-performance status, locally advanced vs metastatic disease, and the presence of pain. Most patients had measurable disease. Patients were randomized to receive gemcitabine (1,000 mg/m2 IV weekly for 7 of 8 weeks and then 3 of 4 weeks) plus daily oral placebo (n = 284) or erlotinib (n = 285). The erlotinib dose was 100 mg throughout most of the trial, but an additional, smaller cohort of patients receiving 150 mg was later added to the study. All analyses are based on the entire study group. Primary Endpoint Met The study met its primary endpoint of overall survival. "The hazard rate of survival is 0.81, which translates into a 24% improvement in survival from the use of erlotinib with gemcitabine," Dr. Moore said. The median survival for patients in the erlotinib arm was 6.4 months, vs 5.9 months in the placebo arm. "The 1-year survival was improved from 17% to 24%, which is an approximate improvement of 40%," he reported. Progression-free survival for patients treated with erlotinib was 3.75 months, compared with 3.55 months for those receiving placebo. Tumor response occurred in 57.5% of patients receiving erlotinib, vs 49.2% of patients receiving placebo. Rash Linked to Better Response "Whatever subset we looked at, the hazard ratio was always less than 1, which indicates a positive effect in favor of erlotinib," Dr. Moore reported. "In some particular subsets, the effect of erlotinib seems more pronounced, particularly in the performance status 2 patients and in those with metastatic disease. However, as these are subset analyses, these are really just hypotheses generating." Expected adverse events included rash, diarrhea, infection, and stomatitis and were generally tolerable and manageable. As seen before with erlotinib, patients who developed a rash responded better to treatment. Grade 3 and 4 toxicities "were relatively low in both arms," Dr. Moore said, and there were "no differences in hematologic, in renal, or in hepatic toxicities between the arms." Quality-of-life assessments showed "no detrimental effects on quality of life from the addition of erlotinib to gemcitabine." Further Refinement Needed to Identify Which Patients Will Benefit "The small improvement in survival afforded to erlotinib-treated patients was accompanied by increased toxicity, challenging us to think carefully about the therapeutic index, when an unselected population of patients with pancreatic cancer is exposed to the combination of gemcitabine and erlotinib," James L. Abbruzzese, MD, of M. D. Anderson Cancer Center in Houston, noted. Understanding the reason for the relationship between the erlotinib-induced skin rash and improved outcome "will be a critical first step in identifying patients most likely to benefit from EGFR antagonists," he said. He also said that "a detailed pharmacoeconomic analysis to include the costs of drug treatment as well as the costs of managing incremental toxicity encountered with this combination would be highly instructive." "Based on these considerations, at this time, I do not feel that the results clearly alter the standard of care for patients treated with advanced pancreatic cancer and continued refinement of the patient population most likely to benefit from this combination will be needed," Dr. Abbruzzese said. Exploit Molecular Biology "For me, the disappointment of this trial is not as much the magnitude of the statistical benefit or the uncertainty surrounding the clinical benefit, but that the trial used a pathologic classification developed in the 19th century, a drug development strategy from the 20th century, in an effort to develop a 21st century targeted agent," Dr Abbruzzese said. "In particular, inadequate assessment of the patient population likely to respond to target agents during preclinical and clinical development of erlotinib and other targeted therapeutics has not allowed us to prospectively define which patients will benefit from these drugs," he continued. "In the end, I think this trial's greatest contribution may be to focus us, the oncology community, to increase our efforts to therapeutically exploit the molecular biology of complex malignancies like pancreatic cancer, to look for opportunities to intervene earlier in the process of pancreatic carcinogenesis, and finally to continue the hard work of identifying which patients are likely to benefit from targeted therapy."