Aktueller Stellenwert von Erlotinib und Gefitinib in der palliativen Therapie des NSCLC – welche Bedeutung hat der EGF-R-Mutationsstatus?

Zusammenfassung

Die Prognose des metastasierten nichtkleinzelligen Lungenkarzinoms (NSCLC) ist trotz intensiver Forschung und ungezählter Chemotherapiestudien nach wie vor sehr schlecht, sodass zunehmend auch Therapieformen mit innovativen Wirkmechanismen eingesetzt werden. Mit Erlotinib und Gefitinib sind zwei Tyrosinkinase-Inhibitoren (TKI) zugelassen, die gezielt gegen den EGF-Rezeptor (EGF-R) gerichtet sind. Aktivierende Mutationen in der Tyrosinkinase-Domäne führen zu einer besseren Wirksamkeit der Substanzen. Welche klinische Bedeutung hat daher die EGF-R-Mutationsbestimmung im Tumor? Wie ist der Stellenwert der TKI in der Erst-, Zweit- und Drittlinientherapie? Welche Therapieoptionen gibt es nach Versagen der TKI-Erstlinientherapie? Diese und andere in der Praxis relevante Fragen im Zusammenhang mit TKI werden in diesem Übersichtsartikel diskutiert.

Abstract

In spite of intensive research and a huge amount of chemotherapy trials, the prognosis of metastastic non-small cell lung cancer (NSCLC) is still poor. Erlotinib and Gefitinb are tyrosine kinase inhibitors (TKIs) which act against the EGF receptor (EGF-R). Activation of mutations in the tyrosine kinase domain leads to an increase in effectiveness. What is the clinical impact of EGF-R mutation screening? What value do TKIs in 1^st, 2^nd and 3^rd line have in therapy for metastatic NSCLC? Which treatment options exist after failure of TKI in the 1^st line? These and other clinically relevant questions in the context of TKIs are discussed in the present comprehensive review.

Literatur

• 1 Goeckenjan G, Sitter H, Thomas M. et al . Prävention, Diagnostik, Therapie und Nachsorge des Lungenkarzinoms. Interdisziplinäre S3-Leitlinie der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin und der Deutschen Krebsgesellschaft.  Pneumologie. 2010;  64 e1-e124
• 2 Jackman D M, Johnson B E. Small-cell lung cancer.  Lancet. 2005;  366 1385-1396
• 3 Jemal A, Siegel R, Ward E. et al . Cancer statistics, 2009.  CA Cancer J Clin. 2009;  59 225-249
• 4 Maeda R, Yoshida J, Ishii G. et al . Long-term survival and risk factors for recurrence in stage I non-small cell lung cancer patients with tumors up to 3 cm in maximum dimension.  Chest. 2010;  , Online-Publikation DOI: DOI: 10.1378/chest.09-3046]
• 5 Butts C A, Ding K, Seymour L. et al . Randomized phase III trial of vinorelbine plus cisplatin compared with observation in completely resected stage IB and II non-small-cell lung cancer: updated survival analysis of JBR-10.  J Clin Oncol. 2010;  28 29-34
• 6 Zirlik S, Lampert S, Hahn E G. et al . An approach to individualised therapy of non-small cell lung carcinoma (NSCLC) – relevance of molecular predictive and prognostic factors.  Pneumologie. 2007;  61 731-738
• 7 Cecere F, Bria E, Rosell R. DNA repair by ERCC1 in non-small-cell lung cancer.  N Engl J Med. 2006;  355 2590-2591; author reply 2591
• 8 Dabholkar M, Vionnet J, Bostick-Bruton F. et al . Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy.  J Clin Invest. 1994;  94 703-708
• 9 Metzger R, Leichman C G, Danenberg K D. et al . ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy.  J Clin Oncol. 1998;  16 309-316
• 10 Olaussen K A, Dunant A, Fouret P. et al . DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy.  N Engl J Med. 2006;  355 983-991
• 11 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
• 12 Pirker R, Pereira J R, Szczesna A. et al . Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial.  Lancet. 2009;  373 1525-1531
• 13 Gridelli C, Ardizzoni A, Douillard J Y. et al . Recent issues in first-line treatment of advanced non-small-cell lung cancer: Results of an International Expert Panel Meeting of the Italian Association of Thoracic Oncology.  Lung Cancer. 2010;  68 319-331
• 14 Scagliotti G V, Parikh P, Pawel J von. et al . Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.  J Clin Oncol. 2008;  26 3543-3551
• 15 Sandler A, Gray R, Perry M C. et al . Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.  N Engl J Med. 2006;  355 2542-2550
• 16 Gridelli C. The ELVIS trial: a phase III study of single-agent vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer. Elderly Lung Cancer Vinorelbine Italian Study.  Oncologist. 2001;  6 Suppl 1 4-7
• 17 Reck M, Pawel J von, Zatloukal P. et al . Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil.  J Clin Oncol. 2009;  27 1227-1234
• 18 Wells A. EGF receptor.  Int J Biochem Cell Biol. 1999;  31 637-643
• 19 Brueckl W M, Schoeberl A, Wirtz R M. et al . Increased vascular-endothelial growth factor (VEGF) tumor expression and response to epidermal growth factor receptor (EGF-R) inhibitor erlotinib in non-small cell lung cancer (NSCLC).  J Thorac Oncol. 2008;  3 314-316
• 20 Gamou S, Hunts J, Harigai H. et al . Molecular evidence for the lack of epidermal growth factor receptor gene expression in small cell lung carcinoma cells.  Cancer Res. 1987;  47 2668-2673
• 21 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
• 22 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
• 23 Paez J G, Janne P A, Lee J C. et al . EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.  Science. 2004;  304 1497-1500
• 24 Kosaka T, Yatabe Y, Endoh H. et al . Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications.  Cancer Res. 2004;  64 8919-8923
• 25 Marchetti A, Martella C, Felicioni L. et al . EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment.  J Clin Oncol. 2005;  23 857-865
• 26 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
• 27 Tomida S, Koshikawa K, Yatabe Y. et al . Gene expression-based, individualized outcome prediction for surgically treated lung cancer patients.  Oncogene. 2004;  23 5360-5370
• 28 Gazdar A F. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors.  Oncogene. 2009;  28 Suppl 1 S24-S31
• 29 Jackman D M, Miller V A, Cioffredi L A. et al . Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials.  Clin Cancer Res. 2009;  15 5267-5273
• 30 Rosell R, Moran T, Queralt C. et al . Screening for epidermal growth factor receptor mutations in lung cancer.  N Engl J Med. 2009;  361 958-967
• 31 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
• 32 Inukai M, Toyooka S, Ito S. et al . Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer.  Cancer Res. 2006;  66 7854-7858
• 33 Maheswaran S, Sequist L V, Nagrath S. et al . Detection of mutations in EGFR in circulating lung-cancer cells.  N Engl J Med. 2008;  359 366-377
• 34 Hammerman P S, Janne P A, Johnson B E. Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer.  Clin Cancer Res. 2009;  15 7502-7509
• 35 Engelman J A, Janne P A. Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer.  Clin Cancer Res. 2008;  14 2895-2899
• 36 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 1545-1552
• 37 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
• 38 Herbst R S, Giaccone G, Schiller J H. et al . Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial – INTACT 2.  J Clin Oncol. 2004;  22 785-794
• 39 Herbst R S, 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. 2005;  23 5892-5899
• 40 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
• 41 Chou T Y, Chiu C H, Li L H. et al . Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer.  Clin Cancer Res. 2005;  11 3750-3757
• 42 Cortes-Funes H, Gomez C, Rosell R. et al . Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small-cell lung cancer patients.  Ann Oncol. 2005;  16 1081-1086
• 43 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
• 44 Takano T, Ohe Y, Sakamoto H. et al . Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer.  J Clin Oncol. 2005;  23 6829-6837
• 45 Taron M, Ichinose Y, Rosell R. et al . Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas.  Clin Cancer Res. 2005;  11 5878-5885
• 46 Zhang X T, Li L Y, Mu X L. et al . The EGFR mutation and its correlation with response of gefitinib in previously treated Chinese patients with advanced non-small-cell lung cancer.  Ann Oncol. 2005;  16 1334-1342
• 47 Mok T S, Wu Y L, Thongprasert S. et al . Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.  N Engl J Med. 2009;  361 947-957
• 48 Kobayashi K, Inoue A, Maemondo M. et al . First-line gefitinib versus first-line chemotherapy by carboplatin (CBDCA) plus paclitaxel (TXL) in non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations: A phase III study (002) by North East Japan Gefitinib Study Group.  Proc Am Soc Clin Oncol. 2009;  27 [abstr8016]
• 49 Tsurutani J, Mitsudomi T, Mori S. et al . A phase III, first-line trial of gefitinib versus cisplatin plusdocetaxel for patients with advanced or recurrent non-small cell lungcancer (NSCLC) harboring activating mutation of the epidermal growthfactor receptor (EGFR) gene.  ECCO/ESMO. 2009;  7 abstr 505
• 50 Sequist L V, Bell D W, Lynch T J. et al . Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer.  J Clin Oncol. 2007;  25 587-595
• 51 Inoue A, Kobayashi K, Usui K. et al . First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy.  J Clin Oncol. 2009;  27 1394-1400
• 52 Cappuzzo F, Ciuleanu T, Stelmakh L. et al . SATURN: A double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC.  Proc Am Soc Clin Oncol. 2009;  27 [abstr 8001]
• 53 Miller V A, O'Connor P, Soh C. et al . A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC).  Proc Am Soc Clin Oncol. 2009;  27 [abstr LBA8002]
• 54 Fidias P M, Dakhil S R, Lyss A P. et al . Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer.  J Clin Oncol. 2009;  27 591-598
• 55 Weiss G J, Rosell R, Fossella F. et al . The impact of induction chemotherapy on the outcome of second-line therapy with pemetrexed or docetaxel in patients with advanced non-small-cell lung cancer.  Ann Oncol. 2007;  18 453-460
• 56 Brugger W, Kim J, Hansen O. Molecular markers and clinical outcome with erlotinib: results from the phase III placebo-controlled SATURN study of maintenance therapy for advanced NSCLC.  J Thorac Oncol. 2009;  4 S348
• 57 Cappuzzo F, Ciuleanu T, Steimakh L. et al . Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study.  Lancet Oncol. 2010;  11 521-529
• 58 Shepherd F A, Rodrigues Pereira J, Ciuleanu T. et al . Erlotinib in previously treated non-small-cell lung cancer.  N Engl J Med. 2005;  353 123-132
• 59 Thatcher N, Chang A, Parikh P. et al . Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer).  Lancet. 2005;  366 1527-1537
• 60 Bezjak A, Tu D, Seymour L. et al . Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21.  J Clin Oncol. 2006;  24 3831-3837
• 61 Clark G M, Zborowski D M, Culbertson J L. et al . Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib.  J Thorac Oncol. 2006;  1 837-846
• 62 Zhu C Q, da Cunha Santos G, Ding K. et al . Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21.  J Clin Oncol. 2008;  26 4268-4275
• 63 Cufer T, Vrdoljak E, Gaafar R. et al . Phase II, open-label, randomized study (SIGN) of single-agent gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage IIIb or IV) non-small-cell lung cancer.  Anticancer Drugs. 2006;  17 401-409
• 64 Kim E S, Hirsh V, Mok T. et al . Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial.  Lancet. 2008;  372 1809-1818
• 65 Niho S, Ichinose Y, Tamura T. et al . Results of a randomized Phase III study to compare the overall survival of gefitinib (IRESSA) versus docetaxel in Japanese patients with non-small-cell lung cancer who failed one or two chemotherapy regimens.  Proc Am Soc Clin Oncol. 2007;  25 [abstract LBA 7509]
• 66 Schneider C P, Heigener D, Schott-von-Romer K. et al . Epidermal growth factor receptor-related tumor markers and clinical outcomes with erlotinib in non-small cell lung cancer: an analysis of patients from german centers in the TRUST study.  J Thorac Oncol. 2008;  3 1446-1453
• 67 Schumann C, Heigener D, Dittrich I. et al . Long term benefit from Erlotinib treatment is independent of prognostic factors and therapeutic response.  ECCO/ESMO. 2009;  15 P 9146
• 68 Hughes A N, O'Brien M E, Petty W J. et al . Overcoming CYP1A1/1A2 mediated induction of metabolism by escalating erlotinib dose in current smokers.  J Clin Oncol. 2009;  27 1220-1226
• 69 Uhm J E, Sun J M, Lee S H. et al . Comparison of Erlotinib (TarcevaTM) versus Gefitinib (Iressa^®) as the Second Line Therapy for the Treatment of Advanced Non-Small Cell Lung Cancer Patients: A Randomized Phase II Trial.  WCLC. 2009;  13 A2.6
• 70 Costa D B, Schumer S T, Tenen D G. et al . Differential responses to erlotinib in epidermal growth factor receptor (EGFR)-mutated lung cancers with acquired resistance to gefitinib carrying the L747S or T790M secondary mutations.  J Clin Oncol. 2008;  26 1182-1184; author reply 1184 – 1186
• 71 Wu J Y, Shih J Y, Yang C H. et al . Second-line treatments after first-line gefitinib therapy in advanced nonsmall cell lung cancer.  Int J Cancer. 2010;  126 247-255
• 72 Shukuya T, Takahashi T, Tamiya A. et al . Gefitinib plus paclitaxel after failure of gefitinib in non-small cell lung cancer initially responding to gefitinib.  Anticancer Res. 2009;  29 2747-2751
• 73 Kurata T, Tamura K, Kaneda H. et al . Effect of re-treatment with gefitinib (“Iressa”, ZD1839) after acquisition of resistance.  Ann Oncol. 2004;  15 173-174
• 74 Yano S, Nakataki E, Ohtsuka S. et al . Retreatment of lung adenocarcinoma patients with gefitinib who had experienced favorable results from their initial treatment with this selective epidermal growth factor receptor inhibitor: a report of three cases.  Oncol Res. 2005;  15 107-111
• 75 Yokouchi H, Yamazaki K, Kinoshita I. et al . Clinical benefit of readministration of gefitinib for initial gefitinib-responders with non-small cell lung cancer.  BMC Cancer. 2007;  7 51
• 76 Yoshimoto A, Inuzuka K, Kita T. et al . Remarkable effect of gefitinib retreatment in a patient with nonsmall cell lung cancer who had a complete response to initial gefitinib.  American Journal of the Medical Sciences. 2007;  333 221-225
• 77 Kwak E L, Sordella R, Bell D W. et al . Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib.  Proc Natl Acad Sci U S A. 2005;  102 7665-7670
• 78 Li D, Ambrogio L, Shimamura T. et al . BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.  Oncogene. 2008;  27 4702-4711
• 79 Wong K K. HKI-272 in non small cell lung cancer.  Clin Cancer Res. 2007;  13 s4593-s4596
• 80 Kwak E L, Camridge D R, Clark G. et al . Clinical activity observed in a phase I dose escalation trial of an oral c-met and ALK inhibitor, PF-02341066.  J Clin Oncol. 2009;  27 abstr 3509
• 81 Richardson F, Richardson G, Sennello G. et al . Biomarker analysis from completely resected NSCLC patients enrolled in an adjuvant erlotinib clinical trial (RADIANT).  Proc Am Soc Clin Oncol. 2009;  25 abstr 7520