Factors Predicting Response to EGFR Tyrosine Kinase Inhibitors

ABSTRACT

Over the past few years, two epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) and erlotinib (Tarceva), have been developed for the treatment of patients with cancer. In patients with non-small cell lung cancer (NSCLC), these therapies occasionally demonstrate remarkable and durable activity. However, EGFR TKIs are active in only a small subset of patients. Responders are more often nonsmokers, of East Asian descent, and female, and have tumors with adenocarcinoma histology. In April 2004, two groups reported that a cluster of somatic mutations in the kinase domain of the EGFR are observed in the majority of NSCLCs that demonstrate remarkable responses to EGFR TKIs. These findings have been validated by other investigators and have revolutionized the manner in which clinicians are thinking about their utilization for the treatment of NSCLC. This review focuses on the clinical experience with EGFR TKIs, the present knowledge regarding the biology of EGFR mutations, the limitations of using EGFR mutational status to predict who will respond to EGFR TKIs, and the implications of this information on the use of these agents for the treatment of advanced NSCLC.

KEYWORDS

Epidermal growth factor receptor (EGFR) - non-small cell lung cancer (NSCLC) - gefitinib - erlotinib

REFERENCES

• 1 Jemal A, Tiwari R C, Murray T et al.. Cancer statistics, 2004.  CA Cancer J Clin. 2004;  54 8-29
• 2 Breathnach O S, Freidlin B, Conley B et al.. Twenty-two years of phase III trials for patients with advanced non-small-cell lung cancer: sobering results.  J Clin Oncol. 2001;  19 1734-1742
• 3 Schiller J H, Harrington D, Belani C P et al.. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.  N Engl J Med. 2002;  346 92-98
• 4 Laskin J J, Sandler A B. Epidermal growth factor receptor: a promising target in solid tumours.  Cancer Treat Rev. 2004;  30 1-17
• 5 Brabender J, Danenberg K D, Metzger R et al.. Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer is correlated with survival.  Clin Cancer Res. 2001;  7 1850-1855
• 6 Fontanini G, De Laurentiis M, Vignati S et al.. Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non-small-cell lung cancer: amphiregulin and microvessel count are independent prognostic indicators of survival.  Clin Cancer Res. 1998;  4 241-249
• 7 Ohsaki Y, Tanno S, Fujita Y et al.. Epidermal growth factor receptor expression correlates with poor prognosis in non-small cell lung cancer patients with p53 overexpression.  Oncol Rep. 2000;  7 603-607
• 8 Rusch V, Baselga J, Cordon-Cardo C et al.. Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung.  Cancer Res. 1993;  53(10 Suppl) 2379-2385
• 9 Rusch V, Klimstra D, Venkatraman E, Pisters P W, Langenfeld J, Dmitrovsky E. Overexpression of the epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but does not predict tumor progression.  Clin Cancer Res. 1997;  3 515-522
• 10 Volm M, Rittgen W, Drings P. Prognostic value of ERBB-1, VEGF, cyclin A, FOS, JUN and MYC in patients with squamous cell lung carcinomas.  Br J Cancer. 1998;  77 663-669
• 11 Carraway III K L, Cantley L C. A neu acquaintance for erbB3 and erbB4: a role for receptor heterodimerization in growth signaling.  Cell. 1994;  78 5-8
• 12 Riese II D J, Stern D F. Specificity within the EGF family/ErbB receptor family signaling network.  Bioessays. 1998;  20 41-48
• 13 Roskoski Jr R. The ErbB/HER receptor protein-tyrosine kinases and cancer.  Biochem Biophys Res Commun. 2004;  319 1-11
• 14 Kawamoto T, Sato J D, Le A, Polikoff J, Sato G H, Mendelsohn J. Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody.  Proc Natl Acad Sci USA. 1983;  80 1337-1341
• 15 Cunningham D, Humblet Y, Siena S et al.. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.  N Engl J Med. 2004;  351 337-345
• 16 Sirotnak F M. Studies with ZD1839 in preclinical models.  Semin Oncol. 2003;  30(1, Suppl 1) 12-20
• 17 Baselga J, Rischin D, Ranson M et al.. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types.  J Clin Oncol. 2002;  20 4292-4302
• 18 Herbst R S, Maddox A M, Rothenberg M L et al.. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial.  J Clin Oncol. 2002;  20 3815-3825
• 19 Ranson M, Hammond L A, Ferry D et al.. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial.  J Clin Oncol. 2002;  20 2240-2250
• 20 Nakagawa K, Tamura T, Negoro S et al.. Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (“Iressa,” ZD1839) in Japanese patients with solid malignant tumors.  Ann Oncol. 2003;  14 922-930
• 21 Fukuoka M, Yano S, Giaccone G et al.. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer.  J Clin Oncol. 2003;  21 2237-2246
• 22 Kris M G, Natale R B, Herbst R S et al.. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial.  JAMA. 2003;  290 2149-2158
• 23 Bailey R, Kris M, Wolf M et al.. Gefitinib (“Iressa”; ZD1839) monotherapy for pretreated advanced non-small cell lung cancer in IDEAL 1 and 2: tumor response is not clinically relevantly predictable from tumor EGFR membrane staining alone.  Lung Cancer. 2003;  41 (2 Suppl) 71
• 24 Giaccone G, Herbst R S, Manegold C et al.. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial-INTACT 1.  J Clin Oncol. 2004;  22 777-784
• 25 Shepherd F A, Pereira J, Ciuleanu T E et al.. A randomized placebo-controlled trial of erlotinib in patients with advanced non-small cell lung cancer (NSCLC) following failure of first-line or second-line chemotherapy: a National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial [abstract 7022].  Proc Am Soc Clin Oncol. 2004;  23
• 26 Thatcher N, Chang A, Parikh P, Pemberton K, Archer V. Results of the Phase III placebo-controlled study (ISEL) of gefitinib (IRESSA) plus best supportive care (BSC) in patients with advanced non-small-cell lung cancer (NSCLC) who received 1 or 2 prior chemotherapy regimens. Paper presented at AACR 2005 Anaheim, California;
• 27 Miller V A, Kris M G, Shah N et al.. Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer.  J Clin Oncol. 2004;  22 1103-1109
• 28 Janne P A, Gurubhagavatula S, Yeap B Y et al.. Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, “Iressa”) on an expanded access study.  Lung Cancer. 2004;  44 221-230
• 29 Haringhuizen A, van Tinteren H, Vaessen H F, Baas P, van Zandwijk N. Gefitinib as a last treatment option for non-small-cell lung cancer: durable disease control in a subset of patients.  Ann Oncol. 2004;  15 786-792
• 30 Simon G R, Ruckdeschel J C, Williams C et al.. Gefitinib (ZD1839) in previously treated advanced non-small-cell lung cancer: experience from a single institution.  Cancer Control. 2003;  10 388-395
• 31 Argiris A, Mittal N. Gefitinib as first-line, compassionate use therapy in patients with advanced non-small-cell lung cancer.  Lung Cancer. 2004;  43 317-322
• 32 Park J, Park B B, Kim J Y et al.. Gefitinib (ZD1839) monotherapy as a salvage regimen for previously treated advanced non-small cell lung cancer.  Clin Cancer Res. 2004;  10 4383-4388
• 33 Lynch T J, Bell D W, 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. 2004;  350 2129-2139
• 34 Paez J G, Jänne P A, Lee J C et al.. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.  Science. 2004;  304 1497-1500
• 35 Pao W, Miller V, Zakowski M et al.. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib.  Proc Natl Acad Sci USA. 2004;  101 13306-13311
• 36 Han S W, Kim T Y, Hwang P G et al.. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib.  J Clin Oncol. 2005;  23 2493-2501
• 37 Mitsudomi T, Kosaka T, Endoh H et al.. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence.  J Clin Oncol. 2005;  23 2513-2520
• 38 Pao W, Wang T Y, Riely G J et al.. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib.  PLoS Med.. 2005;  2 e17
• 39 Heinrich M C, Corless C L, Demetri G D et al.. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor.  J Clin Oncol. 2003;  21 4342-4349
• 40 Gilliland D G, Griffin J D. The roles of FLT3 in hematopoiesis and leukemia.  Blood. 2002;  100 1532-1542
• 41 Arao T, Fukumoto H, Takeda M, Tamura T, Saijo N, Nishio K. Small in-frame deletion in the epidermal growth factor receptor as a target for ZD6474.  Cancer Res. 2004;  64 9101-9104
• 42 Amann J, Kalyankrishna S, Massion P P et al.. Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer.  Cancer Res. 2005;  65 226-235
• 43 Tracy S, Mukohara T, Hansen M, Meyerson M, Johnson B E, Jänne P A. Gefitinib induces apoptosis in the EGFRL858R non-small cell lung cancer cell line H3255.  Cancer Res. 2004;  64 7241-7244
• 44 Sordella R, Bell D W, Haber D A, Settleman J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways.  Science. 2004;  305 1163-1167
• 45 Johnson B. Preliminary results from a phase II study of the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in patients > 70 years of age with previously untreated advanced non-small cell lung carcinoma [abstract 7080].  Proc Am Soc Clin Oncol. 2004;  22
• 46 Ahrendt S A, Decker P A, Alawi E A et al.. Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung.  Cancer. 2001;  92 1525-1530
• 47 Nelson H H, Christiani D C, Mark E J, Wiencke J K, Wain J C, Kelsey K T. Implications and prognostic value of K-ras mutation for early-stage lung cancer in women.  J Natl Cancer Inst. 1999;  91 2032-2038
• 48 Kosaka T, Yatabe Y, Endoh H, Kuwano H, Takahashi T, Mitsudomi T. Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications.  Cancer Res. 2004;  64 8919-8923
• 49 Pao W, Miller V A, Politi K A et al.. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain.  PLoS Med.. 2005;  2 e17
• 50 Eberhard D A, Johnson B E, Amler L C et al.. Mutations in the epidermal growth factor receptor and K-ras are predictive and prognostic indicators in non-small cell lung cancers treated with chemotherapy alone and in combination with erlotinib.  J Clin Oncol. 2005;  , In press
• 50a Cappuzzo F, Hirsch F R, Rossi E et al.. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer.  J Natl Cancer Inst. 2005;  97 643-655
• 51 Engelman J A, Janne P A, Mermel C et al.. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines.  Proc Natl Acad Sci USA. 2005;  102 3788-3793
• 52 Cappuzzo F, Magrini E, Ceresoli G L et al.. Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer.  J Natl Cancer Inst. 2004;  96 1133-1141
• 53 Kobayashi S, Boggon T J, Dayaram T et al.. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib.  N Engl J Med. 2005;  352 786-792
• 54 Gorre M E, Mohammed M, Ellwood K et al.. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.  Science. 2001;  293 876-880
• 55 Tamborini E, Bonadiman L, Greco A et al.. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient.  Gastroenterology. 2004;  127 294-299
• 56 Cools J, DeAngelo D J, Gotlib J et al.. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.  N Engl J Med. 2003;  348 1201-1214
• 57 Shigematsu H, Lin L, Takahashi T et al.. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers.  J Natl Cancer Inst. 2005;  97 339-346
• 58 Huang S F, Liu H P, Li L H et al.. High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan.  Clin Cancer Res. 2004;  10 8195-8203