Combination chemotherapy with intermittent erlotinib and pemetrexed for pretreated patients with advanced non-small cell lung cancer: a phase I dose-finding study

BMC Cancer

Seigo Minami¹  Takashi Kijima²  Ryo Takahashi²  Hiroshi Kida²  Takeshi Nakatani¹  Masanari Hamaguchi¹  Yoshiko Takeuchi¹  Izumi Nagatomo²  Suguru Yamamoto¹  Isao Tachibana²  Kiyoshi Komuta¹  Ichiro Kawase³ 

[1] Department of Respiratory Medicine, Osaka Police Hospital, 10-31 Kitayama-cho, Tennoji-ku, Osaka 543-0035, Japan

[2] Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan

[3] Present Affiliation: Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, 3-7-1 Habikino, Habikino, Osaka 583-8588, Japan

关键词: Phase I;    NSCLC;    Pemetrexed;    Erlotinib;    Combination;   

Others  :  1080311
DOI  :  10.1186/1471-2407-12-296

 received in 2012-01-11, accepted in 2012-06-20,  发布年份 2012

【 摘 要 】

Background

Erlotinib and pemetrexed have been approved for the second-line treatment of non-small cell lung cancer (NSCLC). These two agents have different mechanisms of action. Combined treatment with erlotinib and pemetrexed could potentially augment the antitumor activity of either agent alone. In the present study, we investigated the safety profile of combined administration of the two agents in pretreated NSCLC patients.

Methods

A phase I dose-finding study (Trial registration: UMIN000002900) was performed in patients with stage III/IV nonsquamous NSCLC whose disease had progressed on or after receiving first-line chemotherapy. Patients received 500 mg/m² of pemetrexed intravenously every 21 days and erlotinib (100 mg at Level 1 and 150 mg at Level 2) orally on days 2–16.

Results

Twelve patients, nine males and three females, were recruited. Patient characteristics included a median age of 66 years (range, 48–78 years), stage IV disease (nine cases), adenocarcinoma (seven cases) and activating mutation-positives in the epidermal growth factor receptor gene (two cases). Treatment was well-tolerated, and the recommended dose of erlotinib was fixed at 150 mg. Dose-limiting toxicities were experienced in three patients and included: grade 3 elevation of serum alanine aminotransferase, repetitive grade 4 neutropenia that required reduction of the second dose of pemetrexed and grade 3 diarrhea. No patient experienced drug-induced interstitial lung disease. Three patients achieved a partial response and stable disease was maintained in five patients.

Conclusions

Combination chemotherapy of intermittent erlotinib with pemetrexed was well-tolerated, with promising efficacy against pretreated advanced nonsquamous NSCLC.

【 授权许可】

   
2012 Minami et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin 2010, 60(5):277-300.
• [2]Azzoli CG, Baker S, Temin S, Pao W, Aliff T, Brahmer J, Johnson DH, Laskin JL, Masters G, Milton D, et al.: American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2009, 27(36):6251-6266.
• [3]Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, 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(8):1227-1234.
• [4]Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006, 355(24):2542-2550.
• [5]Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, 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(21):3543-3551.
• [6]Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, et al.: Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004, 22(9):1589-1597.
• [7]Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O'Rourke M, Levitan N, Gressot L, Vincent M, Burkes R, et al.: Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000, 18(10):2095-2103.
• [8]Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, et al.: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005, 353(2):123-132.
• [9]Hanauske AR, Chen V, Paoletti P, Niyikiza C: Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors. Oncologist 2001, 6(4):363-373.
• [10]Cullen MH, Zatloukal P, Sorenson S, Novello S, Fischer JR, Joy AA, Zereu M, Peterson P, Visseren-Grul CM, Iscoe N: A randomized phase III trial comparing standard and high-dose pemetrexed as second-line treatment in patients with locally advanced or metastatic non-small-cell lung cancer. Ann Oncol 2008, 19(5):939-945.
• [11]Ohe Y, Ichinose Y, Nakagawa K, Tamura T, Kubota K, Yamamoto N, Adachi S, Nambu Y, Fujimoto T, Nishiwaki Y, et al.: Efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in previously treated patients with non-small cell lung cancer. Clin Cancer Res 2008, 14(13):4206-4212.
• [12]Dancey J, Sausville EA: Issues and progress with protein kinase inhibitors for cancer treatment. Nat Rev Drug Discov 2003, 2(4):296-313.
• [13]Giovannetti E, Lemos C, Tekle C, Smid K, Nannizzi S, Rodriguez JA, Ricciardi S, Danesi R, Giaccone G, Peters GJ: Molecular mechanisms underlying the synergistic interaction of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, with the multitargeted antifolate pemetrexed in non-small-cell lung cancer cells. Mol Pharmacol 2008, 73(4):1290-1300.
• [14]Li T, Ling YH, Goldman ID, Perez-Soler R: Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in human non-small cell lung cancer cells. Clin Cancer Res 2007, 13(11):3413-3422.
• [15]Furugaki K, Iwai T, Shirane M, Kondoh K, Moriya Y, Mori K: Schedule-dependent antitumor activity of the combination with erlotinib and docetaxel in human non-small cell lung cancer cells with EGFR mutation, KRAS mutation or both wild-type EGFR and KRAS. Oncol Rep 2010, 24(5):1141-1146.
• [16]Yoshimura M, Nakamura S, Imamura F, Ueno K, Yamamoto S, Igarashi T: Severe myelotoxicity in a combination of gefitinib and vinorelbine. Lung Cancer 2004, 45(1):121-123.
• [17]Ranson M, Reck M, Anthoney A, Hanauske AR, Dean E, Melezinek I, Klingelschmitt G, Kletzl H, Blatter J, Twelves C: Erlotinib in combination with pemetrexed for patients with advanced non-small-cell lung cancer (NSCLC): a phase I dose-finding study. Ann Oncol 2010, 21(11):2233-2239.
• [18]Davies AM, Ho C, Beckett L, Lau D, Scudder SA, Lara PN, Perkins N, Gandara DR: Intermittent erlotinib in combination with pemetrexed: phase I schedules designed to achieve pharmacodynamic separation. J Thorac Oncol 2009, 4(7):862-868.
• [19]Kubota K, Nishiwaki Y, Tamura T, Nakagawa K, Matsui K, Watanabe K, Hida T, Kawahara M, Katakami N, Takeda K, et al.: Efficacy and safety of erlotinib monotherapy for Japanese patients with advanced non-small cell lung cancer: a phase II study. J Thorac Oncol 2008, 3(12):1439-1445.
• [20]Takahashi T, Yamamoto N, Nukiwa T, Mori K, Tsuboi M, Horai T, Masuda N, Eguchi K, Mitsudomi T, Yokota S, et al.: Phase II study of erlotinib in Japanese patients with advanced non-small cell lung cancer. Anticancer Res 2010, 30(2):557-563.
• [21]von Pawel J, Papai-Szekely Z, Vinolas N, Sederholm C, Klima M, Desaiah D, Leschinger MI, Dittrich C: A randomized phase II study of pemetrexed versus pemetrexed plus erlotinib in second-line treatment for locally advanced or metastatic, nonsquamous NSCLC [abstract]. J Clin Oncol 2011, 29:s7526.
• [22]Mitsudomi T, Yatabe Y: Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci 2007, 98(12):1817-1824.
• [23]Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczesna A, Juhasz E, Esteban E, Molinier O, Brugger W, Melezinek I, 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(6):521-529.
• [24]Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova V, et al.: Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009, 374(9699):1432-1440.