Abstract
Non-small-cell lung cancer (NSCLC) and pancreatic cancer represent two major causes of cancer-related morbidity and mortality worldwide. Conventional cytotoxic agents seem to have reached a therapeutic plateau in the last decade but prognosis remains dismal for both tumour types.
Recent advances in molecular biology have allowed the development of novel molecular agents that target specific pathways implicated in the process of neoplastic transformation. Epidermal growth factor receptor (EGFR) represents an appealing therapeutic target in both malignancies and a number of EGFR-targeting agents have recently been approved for the first- or second-line treatment of locally advanced, recurrent or metastatic disease.
Erlotinib, an orally administered EGFR tyrosine kinase inhibitor has recently received approval by both the US FDA and the European Medicines Agency (EMA) for the treatment of advanced NSCLC after chemotherapy failure and in combination with gemcitabine for the treatment of advanced pancreatic cancer, on the basis of large, randomized, phase III trials that demonstrated survival benefit over standard therapy or best supportive care. Erlotinib toxicity, as reported in these trials, seems to be modest, with the most prevalent adverse events being fatigue, acneiform rash and diarrhoea. However, recent pharmacovigilance reports, as well as sporadic case reports from the literature, raise concern of some serious adverse events, including pulmonary toxicity, sepsis and some rare cases of treatment-related deaths.
In the current review, we present an evidence-based summary of the benefits and risks associated with erlotinib treatment in both advanced NSCLC and pancreatic cancer. Evidence for survival benefit in each of the drug’s indications is provided, and treatment-related risks and costs are discussed. Finally, synthetic evaluation of the benefit-risk equilibrium is attempted, in order to help clinicians put this drug into perspective.
Similar content being viewed by others
References
Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin 2009; 59: 225–49
Owonikoko TK, Ragin CC, Belani CP, et al. Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database. J Clin Oncol 2007; 25: 5570–7
Subramanian J, Govindan R. Lung cancer in never smokers: a review. J Clin Oncol 2007; 25: 561–70
Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin 2010; 60(5): 277–300
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; 25: 1960–6
Shepherd FA, Rodrigues PJ, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: 123–32
Stepanski EJ, Houts AC, Schwartzberg LS, et al. Second-and third-line treatment of patients with non-small-cell lung cancer with erlotinib in the community setting: retrospective study of patient healthcare utilization and symptom burden. Clin Lung Cancer 2009; 10: 426–32
Ailawadhi S, Derby L, Natarajan R, et al. Erlotinib for metastatic non-small-cell lung cancer: first-, second- or third-line setting — does it matter? A single-institution experience. Oncology 2009; 76: 85–90
Ricciardi S, Tomao S, de Marinis F. Toxicity of targeted therapy in non-small-cell lung cancer management. Clin Lung Cancer 2009; 10: 28–35
Capdevila J, Elez E, Macarulla T, et al. Anti-epidermal growth factor receptor monoclonal antibodies in cancer treatment. Cancer Treat Rev 2009; 35: 354–63
Mountzios G, Dimopoulos MA, Soria JC, et al. Histo-pathologic and genetic alterations as predictors of response to treatment and survival in lung cancer: a review of published data. Crit Rev Oncol Hematol 2010; 75(2): 94–109
Gridelli C, Maione P, Rossi A, et al. Potential treatment options after first-line chemotherapy for advanced NSCLC: maintenance treatment or early second-line? Oncologist 2009; 14: 137–47
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947–57
De Luca A, Normanno N. Predictive biomarkers to tyrosine kinase inhibitors for the epidermal growth factor receptor in non-small-cell lung cancer. Curr Drug Targets 2010; II(7): 851–64
Modjtahedi H, Essapen S. Epidermal growth factor receptor inhibitors in cancer treatment: advances, challenges and opportunities. Anticancer Drugs 2009; 20(10): 851–5
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 2001; 19: 3267–79
Perez-Soler R, Chachoua A, Hammond LA, et al. Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 2004; 22: 3238–47
Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer: molecular and clinical predictors of outcome. N Engl J Med 2005; 353: 133–44
Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304: 1497–500
Spanish Lung Cancer Group. Phase III study (Tarceva®) vs chemotherapy to treat advanced non-small cell lung cancer (NSCLC) in patients with mutations in the TK domain of EGFR [ClinicalTrials.gov identifier NCT00446225]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clinicaltrials.gov/ct2/show/NCT00446225 [Accessed 2010 Sep 9]
Hoffmann-La Roche. A study of first or second line treatment with Tarceva (erlotinib) in patients with advanced non-small cell lung cancer [ClinicalTrials.gov identifier NCT01066884]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov/ct2/show/NCT01066884?term=erlotinib+AND+monotherapy&rank=12 [Accessed 2010 Sep 9]
Gatzemeier U, Pluzanska A, Szczesna A, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 2007; 25: 1545–52
Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined 185 with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005; 23: 5892–9
Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355: 2542–50
Cappuzzo F, Coudert B, Wierzbicki R, et al. Efficacy and safety of erlotinib as first-line maintenance in NSCLC following non-progression with chemotherapy: results from the phase III SATURN study [abstract no. A2.1]. 13th World Conference on Lung Cancer IASCL 2009; 2009 Jul 31–Aug 4; San Francisco (CA)
Milller V, O’Connor P, Soh CH, et al. A randomized, double blind, placebo controlled, phase IIIb trial (ATLAS) comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy with bevacizumab for 1st-line treatment of locally-advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC) [abstract no. LBA8002]. J Clin Oncol 2009; 27: 18s
Pennell NA, Lynch Jr TJ. Combined inhibition of the VEGFR and EGFR signaling pathways in the treatment of NSCLC. Oncologist 2009; 14: 399–411
Herbst RS, Sandler A. Bevacizumab and erlotinib: a promising new approach to the treatment of advanced NSCLC. Oncologist 2008; 13: 1166–76
Herbst RS, O’Neill VJ, Fehrenbacher L, et al. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. J Clin Oncol 2007; 25: 4743–50
Hainsworth J, Lin M, O’Connor P, et al. A phase III, multicenter, placebo-controlled, double-blind, randomized, clinical trial to evaluate the efficacy of bevacizumab (Avastin) in combination with erlotinib (Tarceva) compared with erlotinib alone for treatment of advanced non-small cell lung cancer (NSCLC) after failure of standard first line chemotherapy (BETA). J Thorac Oncol 2008; 3 (Suppl. 4): S302
Wacker B, Nagrani T, Weinberg J, et al. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Can Res 2007; 13: 3913–21
Chou CL, Ko HW, Wang CW, et al. Erlotinib-associated near-fatal interstitial pneumonitis in a patient with relapsed lung adenocarcinoma. Chang Gung Med J 2010; 33: 100–5
Nishimura T, Tada H, Fukushima M. Lessons from gefitinib-induced interstitial lung disease: pharmacovigilance for erlotinib in Japan. Int J Risk Saf Med 2009; 21(4): 237–8
Lee S, Rudd R, Khan I, et al. TOPICAL: randomized phase III trial of erlotinib compared with placebo in chemotherapy-naive patients with advanced non-small cell lung cancer (NSCLC) and unsuitable for first-line chemotherapy [abstract]. J Clin Oncol 2010; 28 (15 Suppl.): 7504
Lynch Jr TJ, Kim ES, Eaby B, et al. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist 2007; 12: 610–21
Burris III HA, 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 1997; 15: 2403–13
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 2002; 20: 3270–5
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 2004; 22: 3776–83
Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005; 23: 3509–16
Oettle H, Richards D, Ramanathan RK, et al. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 2005; 16: 1639–45
Abou-Alfa GK, Letourneau R, Harker G, et al. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J Clin Oncol 2006; 24: 4441–7
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 2004; 22: 1430–8
Bramhall SR, Schulz J, Nemunaitis J, et al. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002; 87: 161–7
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 2000; 60: 2926–35
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 2002; 1: 777–83
Kulke MH, Blaszkowsky LS, Ryan DP, et al. Capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer. J Clin Oncol 2007; 25: 4787–92
Boeck S, Vehling-Kaiser U, Waldschmidt D, et al. Erlotinib 150 mg daily plus chemotherapy in advanced pancreatic cancer: an interim safety analysis of a multicenter, randomized, cross-over phase III trial of the ‘Arbeitsgemeinschaft Internistische Onkologie’. Anticancer Drugs 2010; 21: 94–100
Chinnaiyan P, Huang S, Vallabhaneni G, et al. Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res 2005; 65: 3328–35
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 2005; 28: 570–5
Danson S, Blackhall F, Hulse P, et al. Interstitial lung disease in lung cancer: separating disease progression from treatment effects. Drug Saf 2005; 28: 103–13
Lyseng-Williamson KA. Erlotinib: a pharmacoeconomic review of its use in advanced non-small cell lung cancer. Pharmacoeconomics 2010; 28: 75–92
Hartmann JT, Haap M, Kopp HG, et al. Tyrosine kinase inhibitors: a review on pharmacology, metabolism and side effects. Curr Drug Metab 2009; 10: 470–81
Bradbury PA, Tu D, Seymour L, et al. Economic analysis: randomized placebo-controlled clinical trial of erlotinib in advanced non-small cell lung cancer. J Natl Cancer Inst 2010; 102: 298–306
Reck M, van Zandwijk N, Gridelli C, et al. Erlotinib in advanced non-small cell lung cancer: efficacy and safety findings of the global phase IV Tarceva Lung Cancer Survival Treatment Study. J Thorac Oncol 2010; 5(10): 1616–22
Mok T, Wu YL, Au JS, et al. Efficacy and safety of erlotinib in 1242 East/South-East Asian patients with advanced non-small cell lung cancer. J Thorac Oncol 2010; 5(10): 1609–15
Miksad RA, Schnipper L, Goldstein M. Does a statistically significant survival benefit of erlotinib plus gemcitabine for advanced pancreatic cancer translate into clinical significance and value? J Clin Oncol 2007; 25: 4506–7
Van Cutsem E, Verslype C, Grusenmeyer PA. Lessons learned in the management of advanced pancreatic cancer. J Clin Oncol 2007; 25: 1949–52
Siena S, Sartore-Bianchi A, Di NF, et al. Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J Natl Cancer Inst 2009; 101: 1308–24
Acknowledgements
No funding was received for the preparation of this review. G. Mountzios and K.N. Syrigos have no conflicts of interest to declare.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Mountzios, G., Syrigos, K.N. A Benefit-Risk Assessment of Erlotinib in Non-Small-Cell Lung Cancer and Pancreatic Cancer. Drug-Safety 34, 175–186 (2011). https://doi.org/10.2165/11586540-000000000-00000
Published:
Issue Date:
DOI: https://doi.org/10.2165/11586540-000000000-00000