Erlotinib: success of a molecularly targeted agent for the treatment of advanced pancreatic cancer
Abstract
Epidermal growth factor receptor (EGFR) is overexpressed by several solid tumors, including pancreatic cancer, and has become an important target for novel anticancer pharmacotherapy. Erlotinib (Tarceva®, OSI-774) is an orally available small-molecule inhibitor of the EGFR tyrosine kinase. The addition of erlotinib to gemcitabine has been shown to prolong survival of patients treated for advanced pancreatic cancer in the National Cancer Institute of Canada PA.3 trial. This survival advantage is small yet noteworthy, in that numerous gemcitabine-containing combinations have failed to show a statistically significant survival advantage over gemcitabine alone. The most frequent toxicities associated with the addition of erlotinib are diarrhea and rash. Erlotinib-induced rash appears to be predictive of outcome. Further clinical studies of erlotinib in the treatment of pancreatic cancer are ongoing.
Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.
Bibliography
- 1 Sener SF, Fremgen A, Menck HR et al.: Pancreatic cancer: a report of treatment and survival trends for 100,313 patients diagnosed from 1985–1995, using the National Cancer Database. J. Am. Coll. Surg.189,1–7 (1999).
- 2 Neoptolemos JP, Stocken DD, Friess H et al.: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N. Engl. J. Med.350,1200–1210 (2004).
- 3 Burris HA, 3rd, Moore MJ, Andersen J et al.: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol.15,2403–2413 (1997).
- 4 Berlin JD, Catalano P, Thomas JP et al.: Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J. Clin. Oncol.20,3270–3275 (2002).
- 5 Louvet C, Labianca R, Hammel P et al.: GemOx (gemcitabine + oxaliplatin) versus Gem (gemcitabine) in nonresectable pancreatic adenocarcinoma: Final results of the GERCOR/GISCAD Intergroup Phase III. J. Clin. Oncol.22 (2004) (Abstract 4008).
- 6 Rocha Lima CM, Green MR, Rotche R et al.: Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J. Clin. Oncol.22,3776–3783 (2004).
- 7 Richards D, Kindler H, Oettle H et al.: A randomized Phase III study comparing gemcitabine + pemetrexed versus gemcitabine in patients with locally advanced and metastatic pancreas cancer. J. Clin. Oncol.22 (2004) (Abstract 4007).
- 8 Van Cutsem E, van de Velde H, Karasek P et al.: Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J. Clin. Oncol.22,1430–1438 (2004).
- 9 Herrmann R, Bodoky G, Ruhstaller T et al.: Gemcitabine plus capecitabine versus gemcitabine alone in locally advanced or metastatic pancreatic cancer. A randomized phase III study of the Swiss Group for Clinical Cancer Res. earch (SAKK) and the Central European Cooperative Oncology Group (CECOG). J. Clin. Oncol.23 (2005) (Abstract 4010).
- 10 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. (2007) (Epub ahead of print).•• Pivotal Phase III trial leading to approval of erlotinib in combination with gemcitabine for advanced pancreatic cancer.
- 11 Cunningham D, Chau I, Stocken D et al.: Phase III randomised comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer. Eur. J. Cancer3,4 (2005).
- 12 Prenzel N, Fischer OM, Streit S et al.: The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr. Relat. Cancer8,11–31 (2001).
- 13 Yamanaka Y, Friess H, Kobrin MS et al.: Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. AntiCancer Res..13,565–569 (1993).
- 14 Tobita K, Kijima H, Dowaki S et al.: Epidermal growth factor receptor expression in human pancreatic cancer: Significance for liver metastasis. Int. J. Mol. Med.11,305–309 (2003).
- 15 Dong M, Nio Y, Guo KJ et al.: Epidermal growth factor and its receptor as prognostic indicators in Chinese patients with pancreatic cancer. AntiCancer Res..18,4613–4619 (1998).
- 16 Ueda S, Ogata S, Tsuda H et al.: The correlation between cytoplasmic overexpression of epidermal growth factor receptor and tumor aggressiveness: poor prognosis in patients with pancreatic ductal adenocarcinoma. Pancreas29,E1–E8 (2004).
- 17 Hidalgo M, Bloedow D: Pharmacokinetics and pharmacodynamics: maximizing the clinical potential of erlotinib (Tarceva). Semin. Oncol.30,25–33 (2003).• Excellent review of preclinical and early clinical development of erlotinib.
- 18 Moyer JD, Barbacci EG, Iwata KK et al.: Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res.57,4838–4848 (1997).
- 19 Pollack VA, Savage DM, Baker DA et al.: Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J. Pharmacol. Exp. Ther.291,739–748 (1999).
- 20 Durkin AJ, Bloomston PM, Rosemurgy AS et al.: Defining the role of the epidermal growth factor receptor in pancreatic cancer grown in vitro.Am. J. Surg.186,431–436 (2003).
- 21 Ng SS, Tsao MS, Nicklee T et al.: Effects of the epidermal growth factor receptor inhibitor OSI-774, Tarceva, on downstream signaling pathways and apoptosis in human pancreatic adenocarcinoma. Mol. Cancer Ther.1,777–783 (2002).
- 22 Bruns CJ, Solorzano CC, Harbison MT et al.: Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res.60,2926–2935 (2000).
- 23 Perez-Soler R, Saltz L: Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J. Clin. Oncol.23,5235–5246 (2005).•• Excellent review of the etiology, relevance and management of epidermal growth factor receptor (EGFR)-inhibitor-related skin rash.
- 24 Hidalgo M, Siu LL, Nemunaitis J et al.: Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J. Clin. Oncol.19,3267–3279 (2001).• Important Phase I trial defining the maximally tolerated dose of erlotinib.
- 25 Clark G, Perez-Soler R, Siu LL et al.: Rash severity is predictive of increased survival with erlotinib HCl. J. Clin. Oncol.22 (2003) (Abstract 786).
- 26 Soulieres D, Senzer NN, Vokes EE et al.: Multicenter Phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J. Clin. Oncol.22,77–85 (2004).
- 27 Herbst RS, Prager D, Hermann R et al.: TRIBUTE: a Phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J. Clin. Oncol.23,5892–5899 (2005).
- 28 Chen EX, Zhang W, Pond GR et al.: Correlation between erlotinib concentrations and severity of skin rash. Presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. Philadelphia, PA, USA, 14–18 November 2005.
- 29 Ali S, El-Rayes BF, Sarkar FH et al.: Simultaneous targeting of the epidermal growth factor receptor and cyclooxygenase-2 pathways for pancreatic cancer therapy. Mol. Cancer Ther.4,1943–1951 (2005).
- 30 Hess V, Salzberg M, Borner M et al.: Combining capecitabine and gemcitabine in patients with advanced pancreatic carcinoma: a Phase I/II trial. J. Clin. Oncol.21,66–68 (2003).
- 31 Scheithauer W, Schull B, Ulrich-Pur H et al.: Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized Phase II trial. Ann. Oncol.14,97–104 (2003).
- 32 Kindler HL, Friberg G, Singh DA et al.: Phase II Trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J. Clin. Oncol.23,8033–8040 (2005).
- 33 Xiong HQ, Rosenberg A, LoBuglio A et al.: Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter Phase II trial. J. Clin. Oncol.22,2610–2616 (2004).
- 34 Kindler HL, Niedzwiecki D, Hollis D et al.: A double-blind, placebo-controlled, randomiozed phase III trial of gemcitabine plus bevacizumab verus gemcitabine plus placebo in patients with advanced pancreatic cancer: a preliminary analysis of Cancer and Leukemia Group B (CALGB) 80303. Presented at: ASCO Gastrointestinal Cancers Symposium. Orlando, FL, USA, 19–21 January 2007.
- 35 Blaszkowsky LS, Kulke KH, Ryan DP et al.: A Phase II study of erlotinib in combination with capecitabine in previously treated patients with metastatic pancreatic cancer. J. Clin. Oncol.23 (2005) (Abstract 4099).• Interesting Phase II trial exploring the role of erlotinib with capecitabine in refractory pancreatic cancer.
- 36 Iannitti D, Dipetrillo T, Akerman P et al.: Erlotinib and chemoradiation followed by maintenance erlotinib for locally advanced pancreatic cancer: a Phase I study. Am J. Clin. Oncol.28,570–575 (2005).
- 37 Kortmansky JS, O'Reilly EMO, Minsky BD et al.: A Phase I trial of erlotinib, gemcitabine and radiation for patients with locally-advanced, unresectable pancreatic cancer. J. Clin. Oncol.23 (2005) (Abstract 4107).
- 38 Gordon AN, Finkler N, Edwards RP et al.: Efficacy and safety of erlotinib HCl, an epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, in patients with advanced ovarian carcinoma: results from a Phase II multicenter study. Int. J. Gynecol. Cancer15,785–792 (2005).
- 39 Gatzemeier U, Pluzanska A, Szczesna A et al.: Results of a Phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC). J. Clin. Oncol.22 (2004) (Abstract 7010).
- 40 Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al.: Erlotinib in previously treated non-small-cell lung cancer. N. Engl. J. Med.353,123–132 (2005).
- 41 Tsao MS, Sakurada A, Cutz JC et al.: Erlotinib in lung cancer - molecular and clinical predictors of outcome. N. Engl. J. Med.353,133–144 (2005).•• Analysis of patients on the National Cancer Institute of Canada BR.21 trial of erlotinib versus placebo in non-small-cell lung cancer (NSCLC) to determine putative biomarkers predictive of outcome and response.
- 42 Lynch TJ, Bell DW, Sordella R et al.: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med.350,2129–2139 (2004).
- 43 Immervoll H, Hoem D, Kugarajh K et al.: Molecular analysis of the EGFR-RAS-RAF pathway in pancreatic ductal adenocarcinomas: lack of mutations in the BRAF and EGFR genes. Virchows Arch.448,788–796 (2006).
- 44 Ebershard DA, Johnson BE, Amler LC et al.: Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J. Clin. Oncol.23,5900–5909 (2005).• Analysis of patients on the TRIBUTE trial (Tarceva responses in conjunction with paclitaxel and carboplatin) suggesting mutational status of EGFR and K-ras as predictors of outcome.

