As pointed out by the authors, progress in the metastatic setting has been mixed. The negative phase III data for bevacizumab (Avastin)- and cetuximab (Erbitux)-containing regimens is particularly disappointing given their demonstrated efficacy in other gastrointestinal cancers and the strong rationale for their use in pancreatic ductal adenocarcinoma.[6,7] As outlined by the authors, cytotoxic combinations of gemcitabine with capecitabine (Xeloda) and platinum agents do appear to offer a small benefit, particularly in patients with good performance status.
What is one to make of the recently published study by Moore et al? In this study, 569 patients with untreated locally advanced or metastatic pancreatic cancer were randomized to receive gemcitabine with either erlotinib or placebo. The investigators observed a very modest but statistically significant improvement in progression-free survival (hazard ratio [HR] = 0.77, 95% confidence interval [CI] = 0.64–0.92; P = .004), 1-year survival (23% vs 17%; P = .023), and median overall survival (6.24 vs 5.91 months, HR = 0.82, 95% CI = 0.69–0.99; P = .038) favoring the erlotinib arm. This was the first trial to show a survival benefit for any combination therapy in pancreatic cancer and led to US Food and Drug Administration approval of this combination in front-line therapy for pancreatic cancer in 2005.
As has been the experience with epidermal growth factor receptor (EGFR) inhibitors in colorectal cancer and lung cancer, the occurrence of a rash in the study by Moore et al was associated with improved survival after controlling for other prognostic factors (P = .037; HR = 0.74; 95% CI = 0.56–0.98). The median survival rates for patients with grade 0, 1, and 2+ rash were 5.3, 5.8, and 10.5 months, respectively; and the 1-year survival rates were 16%, 9%, and 43% (P < .001). These data suggest that although the benefit for the entire cohort is small, a specific subpopulation of patients do benefit significantly from the addition of erlotinib.
The molecular basis for sensitivity/resistance to erlotinib in pancreatic cancer is unclear. Unlike the case in non–small-cell lung cancer, no predictive EGFR mutations have been discovered. Likewise, the relationship between K-ras mutations and response to tyrosine kinase inhibition (a well established inverse relationship in lung cancer and probably colon cancer) has not been elucidated for pancreatic cancer.[10,11]
Future priorities in pancreatic cancer include the following: (1) Given the negative phase III data involving regimens that had appeared promising at the phase II level, an increased consideration should be given to the incorporation of a randomized phase II trial design in order to strengthen the signal prior to committing to phase III development. (2) We need a renewed focus on conducting clinical trials in the significant population of patients who proceed to second-line therapy.
In parallel with these efforts, a major emphasis on tissue procurement may assist in furthering an understanding of the fundamentals of pancreatic cancer tumor biology when new strategies work, and perhaps even more importantly, when and why they do not. Although concrete progress in this field has been limited, we believe the future holds promise—not the least of which is a reflection of the interest of clinical investigators, society at large, and major and minor pharma in this disease.
—Austin Duffy, MD
—Eileen M. O'Reilly, MD
1. Schenk M, Schwartz AG, O'Neal E, et al: Familial risk of pancreatic cancer. J Natl Cancer Inst 93:640-644, 2001.
2. Ghadirian P, Liu G, Gallinger S, et al: Risk of pancreatic cancer among individuals with a family history of cancer of the pancreas. Int J Cancer 97:807-810, 2002.
3. Del Chiaro M, Zerbi A, Falconi M, et al: Cancer risk among the relatives of patients with pancreatic ductal adenocarcinoma. Pancreatology 7:459-469, 2007.
4. Huguet F, Andre T, Hammel P, et al: Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J Clin Oncol 25:326-331, 2007.
5. Duffy A, Kortmansky J, Schwartz GK, et al: A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma. Ann Oncol Sept 17, 2007 [epub ahead of print].
6. Kindler HL, Niedzwiecki D, Hollis D, et al: A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis of Cancer and Leukemia Group B (CALGB) (abstract 4508). J Clin Oncol 25:199s, 2007.
7. Philip PA, Benedetti J, Fenoglio-Preiser C, et al: Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study (abstract LBA4509). J Clin Oncol 25:199s, 2007.
8. Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960-1966, 2007.
9. Kwak EL, Jankowski J, Thayer SP, et al: Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clin Cancer Res 12:4283-4287, 2006.
10. Moore MJ, da Cunha Santos G, Kamel-Reid S, et al: The relationship of K-ras mutations and EGFR gene copy number to outcome in patients treated with erlotinib on National Cancer Institute of Canada Clinical Trials Group trial study PA.3 (abstract 4521). J Clin Oncol 25(18S):202s, 2007.
11. Pao W, Wang TY, Riely GJ, et al: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Medicine 2:e17, 2005.