Advanced Pancreatic Cancer

ORLANDO, FL—For patients with advanced pancreatic cancer, combination therapy with gemcitabine, the standard of care, plus erlotinib, an epidermal growth factor (EGFR) inhibitor, significantly increased one-year and progression-free survival compared with gemcitabine alone in patients with advanced pancreatic cancer, according to the results of a study presented as Abstract #1 at the ASCO Annual Meeting. One-year survival was increased by about 40% for patients who received the combination. Although these are encouraging results, further study is needed, experts said, and it is not clear whether this combination will become the standard of care.Figure: Malcolm J. Moore, MD, noted that further studies of this combination for pancreatic cancer are ongoing, including a Phase III trial to explore the combination of gemcitabine + erlotinib + bevacizumab and other studies combining biologic therapies.This is the first trial to show a benefit for targeted therapy in pancreatic cancer, and it is the first demonstration of the survival benefit of an EGFR inhibitor plus cytotoxic chemotherapy, said lead investigator Malcolm J. Moore, MD, Director of the New Drug Development Program at Princess Margaret Hospital and Professor of Medicine and Pharmacology at the University of Toronto. This is also the first gemcitabine-based combination to show a survival benefit, he noted. Gemcitabine has been the standard of care for the past decade. Previous studies of gemcitabine in combination with other agents failed to show a benefit over that observed with gemcitabine alone. Combinations that have been studied include gemcitabine and fluorouracil, gemcitabine and oxaliplatin, gemcitabine and irinotecan, and gemcitabine and pemetrexed. 17 Countries, 140 Centers The study, results of which were also presented earlier this year at ASCO's Gastrointestinal Cancers Symposium, was conducted in 17 countries and 140 centers; 40% of patients were from the United States, 20% from Canada, and 40% from the rest of the world. A total of 569 patients with locally advanced or metastatic pancreatic cancer were enrolled, who were randomized to receive either standard-dose gemcitabine or gemcitabine plus erlotinib. Due to safety concerns about combining these agents, the first 521 patients were treated with erlotinib at 100 mg/day, and after it became clear that the combination was safe, a cohort of 48 patients received erlotinib at 150 mg/day. The analysis Dr. Moore presented was based on all 569 patients enrolled in the trial: 285 randomized to gemcitabine/erlotinib and 284 to gemcitabine/placebo. The demographics for age, gender, and performance status were similar in both treatment groups, and approximately one quarter of both groups of patients had locally advanced disease. Both median and progression-free survival were significantly increased with the addition of erlotinib, Dr. Moore reported. Median survival was 6.37 months in the combination therapy group compared with 5.9 months in the monotherapy group; one-year survival was 24% vs 17%, respectively. A consistent, beneficial effect of erlotinib on survival and progression-free survival was observed in all subsets analyzed. A more pronounced effect was observed in those with metastatic disease and in Performance Status 2 patients, “but this was not a preplanned analysis and should be considered hypothesis-generating,” Dr. Moore said. Overall, 50% of patients had rapid disease progression within the first four months. The survival curves were similar for the two groups at a median of four months, diverged thereafter, and the differences grew more pronounced over time. Stable disease was seen in 57% of patients in the combination-therapy group and 49% of those in the gemcitabine/placebo group. Toxicities More Frequent in Erlotinib Group Grade 1 and 2 toxicities (rash, diarrhea, stomatitis) were more frequent in the patients receiving erlotinib. The frequency of Grade 3 and 4 adverse events was relatively low and comparable between groups. There were no differences observed between treatment groups for renal, hepatic, and hematologic toxicities, and quality-of-life analysis showed that erlotinib was not associated with any deterioration in quality of life. The only difference favoring the placebo group was related to diarrhea. EGFR status (analysis of which was performed in only 30% of patients) did not appear to influence outcome, and survival in both EGFR-positive and EGFR-negative groups favored erlotinib.Figure: Discussant James Abbruzzese, MD: “It is uncertain whether this study should alter the standard of care for all patients with pancreatic cancer. We need to weigh the efficacy and toxicity of the treatment, and we need a detailed pharmacokinetic analysis to explore the cost of treatment as well as the cost of managing associated toxicity. We also need continued refinement patient selection for this treatment. Not all patients should receive it.”Rash and Survival The presence of Grade 2 or higher rash was associated with increased survival—an effect that has been reported in other trials of EGFR inhibitors. Median survival was 10.51 months in those with that level of rash and the one-year survival rate was 43% for these patients. “Rash is an interesting phenomenon,” Dr. Moore commented in an interview. “It could be an artifact of patients living longer and having time to develop rash, but this is unlikely. Fifty percent of patients who developed rash lived for one year compared with 20% who did not develop rash.” The Discussant for the paper, James Abbruzzese, MD, Chairman of the Department of GI Medical Oncology of the University of Texas M. D. Anderson Cancer Center, said that identifying the reasons skin rash is associated with increased survival will be a critical step in understanding how EGFR inhibitors exert their action. “These results are not a home run, and we need to build on them in the future,” he said. “Evidence suggests that combining these therapies will improve outcome over gemcitabine alone.” Dr. Moore said that further studies are ongoing in pancreatic cancer, including a Phase III trial to explore the combination of gemcitabine + erlotinib + bevacizumab and other studies combining biologic therapies. Whither Progress? Progress depends on understanding the molecular properties of advanced pancreatic cancer and developing new strategies based on that information, Dr. Abbruzzese noted. He told the audience that EGFR is an appropriate target in pancreatic cancer since it is present and functionally abnormal in tumor tissue. Survival with gemcitabine alone was similar to what has been reported in other randomized controlled trials, which further validates the results, he said, noting that the 8% increase in median survival in the group receiving combination therapy was lower than the 33% hypothesized by the authors of the study. “The median survival advantage [of gemcitabine/erlotinib] is small and marginally significant,” he said. “On average, the treatment provided approximately one month of additional life. “It is uncertain whether this study should alter the standard of care for all patients with pancreatic cancer. We need to weigh the efficacy and toxicity of the treatment, and we need a detailed pharmacokinetic analysis to explore the cost of treatment as well as the cost of managing associated toxicity. “We also need continued refinement of patient selection for this treatment. Not all patients should receive it.”

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