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Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 4, pp 891–899 | Cite as

Phase I study of continuous afatinib (BIBW 2992) in patients with advanced non-small cell lung cancer after prior chemotherapy/erlotinib/gefitinib (LUX-Lung 4)

  • H. Murakami
  • T. Tamura
  • T. Takahashi
  • H. Nokihara
  • T. Naito
  • Y. Nakamura
  • K. Nishio
  • Y. Seki
  • A. Sarashina
  • M. Shahidi
  • N. YamamotoEmail author
Original Article

Abstract

Purpose

This Phase I study determined the maximum-tolerated dose (MTD) of afatinib (Afatinib is an investigational compound and its safety and efficacy have not yet been established) (BIBW 2992; trade name not yet approved by FDA), an irreversible inhibitor of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor (HER)1 and 2, up to a dose of 50 mg/day in advanced non-small cell lung cancer (NSCLC), to establish the recommended dose for Phase II.

Methods

Patients with advanced NSCLC who had received prior platinum-doublet chemotherapy and/or erlotinib/gefitinib therapy, or who were ineligible for, or not amenable to, treatment with established therapies, received oral afatinib once daily. The MTD was determined based on dose-limiting toxicities (DLTs); other assessments included safety, pharmacokinetic profile, antitumour activity according to response evaluation criteria in solid tumours and EGFR/HER1 mutation analysis where possible.

Results

Twelve evaluable patients were treated at doses of 20–50 mg/day. One DLT was observed at 50 mg/day in Course 1 (Grade 3 mucositis). The most frequent drug-related adverse events were diarrhoea, dry skin, stomatitis, rash, paronychia and anorexia; most were Grade 1 or 2. Six out of 12 patients had tumour size reductions; durable stable disease was achieved in three patients including one with EGFR/HER1 exon 19 and T790 M mutations. Peak plasma concentrations of afatinib were reached 3–4 h after administration and declined with a half-life of 30–40 h. Afatinib 50 mg/day was well tolerated with an acceptable safety profile during Phase I.

Conclusion

Recommended dose for Phase II was defined as 50 mg/day for Japanese patients; the same as for non-Japanese patients.

Keywords

Phase I Afatinib BIBW 2992 Epidermal growth factor receptor Tyrosine kinase inhibitor Non-small cell lung cancer 

Notes

Acknowledgments

This study was supported by Boehringer Ingelheim. The authors acknowledge the editorial assistance of Ogilvy Healthworld. Boehringer Ingelheim provided financial support for this assistance.

Conflict of interest

Haruyasu Murakami, Tomohide Tamura, Toshiaki Takahashi, Hiroshi Nokihara, Tateaki Naito, Yukiko Nakamura, Kazuto Nishio, Nobuyuki Yamamoto: nothing to disclose. Yoko Seki, Akiko Sarashina, Mehdi Shahidi: employee of Boehringer Ingelheim.

References

  1. 1.
    Winer E, Gralow J, Diller L, Karlan B, Loehrer P, Pierce L, Demetri G, Ganz P, Kramer B, Kris M, Markman M, Mayer R, Pfister D, Raghavan D, Ramsey S, Reaman G, Sandler H, Sawaya R, Schuchter L, Sweetenham J, Vahdat L, Schilsky R, Blayney D, Lichter A (2008) Clinical cancer advances 2008: major research advances in cancer treatment, prevention, and screening–a report from the American Society of Clinical Oncology. J Clin Oncol 27(5):812–826. doi: 10.1200/JCO.2008.21.2134 PubMedCrossRefGoogle Scholar
  2. 2.
    Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5(5):341–354. doi: 10.1038/nrc1609 PubMedCrossRefGoogle Scholar
  3. 3.
    Salomon DS, Brandt R, Ciardiello F, Normanno N (1995) Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19(3):183–232. doi: 104084289400144I PubMedCrossRefGoogle Scholar
  4. 4.
    Arteaga CL (2002) Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist 7(Suppl 4):31–39PubMedCrossRefGoogle Scholar
  5. 5.
    Johnson BE, Jackman D, Janne PA (2006) Impact of EGFR mutations on treatment of non-small cell lung cancer. Cancer Chemother Pharmacol 58(Suppl 7):5–9CrossRefGoogle Scholar
  6. 6.
    Doroshow JH (2005) Targeting EGFR in non-small-cell lung cancer. N Engl J Med 353(2):200–202. doi: 10.1056/NEJMe058113 PubMedCrossRefGoogle Scholar
  7. 7.
    Giaccone G, Rodriguez JA (2005) EGFR inhibitors: what have we learned from the treatment of lung cancer? Nat Clin Pract Oncol 2(11):554–561PubMedCrossRefGoogle Scholar
  8. 8.
    Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D, Eek R, Horai T, Noda K, Takata I, Smit E, Averbuch S, Macleod A, Feyereislova A, Dong RP, Baselga J (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial). J Clin Oncol 21(12):2237–2246PubMedCrossRefGoogle Scholar
  9. 9.
    Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304(5676):1497–1500PubMedCrossRefGoogle Scholar
  10. 10.
    Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabarbara P, Seymour L (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353(2):123–132. doi: 10.1056/NEJMoa050753 PubMedCrossRefGoogle Scholar
  11. 11.
    Engelman JA, Janne PA (2008) Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 14(10):2895–2899. doi: 10.1158/1078-0432.CCR-07-2248 PubMedCrossRefGoogle Scholar
  12. 12.
    Turke AB, Zejnullahu K, Wu YL, Song Y, Dias-Santagata D, Lifshits E, Toschi L, Rogers A, Mok T, Sequist L, Lindeman NI, Murphy C, Akhavanfard S, Yeap BY, Xiao Y, Capelletti M, Iafrate AJ, Lee C, Christensen JG, Engelman JA, Janne PA (2010) Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17(1):77–88. doi:  10.1016/j.ccr.2009.11.022
  13. 13.
    Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, Inserra E, Diederichs S, Iafrate AJ, Bell DW, Digumarthy S, Muzikansky A, Irimia D, Settleman J, Tompkins RG, Lynch TJ, Toner M, Haber DA (2008) Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 359(4):366–377. doi: 10.1056/NEJMoa0800668 PubMedCrossRefGoogle Scholar
  14. 14.
    Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, Padera RF, Shapiro GI, Baum A, Himmelsbach F, Rettig WJ, Meyerson M, Solca F, Greulich H, Wong KK (2008) BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27(34):4702–4711. doi: 10.1038/onc.2008.109 PubMedCrossRefGoogle Scholar
  15. 15.
    Plummer R, Vidal L, Li L, Shaw H, Perrett R, Shahidi M, Amelsberg A, Temple G, Calvert H, de Bono J (2006) Phase I study of BIBW 2992, an oral irreversible dual EGFR/HER2 inhibitor, showing activity in tumours with mutated EGFR. Eur J Cancer Suppl 4(12):174Google Scholar
  16. 16.
    Yang C-H, Shih J, Su W, Hsia T, Sequist LV, Chang G, Calvo R, Cong XJ, Shahidi M, Miller VA (2010) A phase II study of BIBW 2992 in patients with adenocarcinoma of the lung and activating EGFR/HER1 mutations (LUX-LUNG2). Ann Oncol 21(Suppl8):viii122–viii161 (abstract 367PD)Google Scholar
  17. 17.
    Agus DB, Terlizzi E, Stopfer P, Amelsberg A, Gordon MS (2006) A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in a continuous schedule in patients with advanced solid tumours. J Clin Oncol 24(18S):2074Google Scholar
  18. 18.
    Eskens FA, Mom CH, Planting AS, Gietema JA, Amelsberg A, Huisman H, van Doorn L, Burger H, Stopfer P, Verweij J, de Vries EG (2008) A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours. Br J Cancer 98(1):80–85. doi: 10.1038/sj.bjc.6604108 PubMedCrossRefGoogle Scholar
  19. 19.
    Lewis N, Marshall J, Amelsberg A, Cohen RB, Stopfer P, Hwang J, Malik S (2006) A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in a 3 week on 1 week off schedule in patients with advanced solid tumors. ASCO Meet Abstr 24 (18_suppl):3091Google Scholar
  20. 20.
    Yap TA, Vidal L, Adam J, Stephens P, Spicer J, Shaw H, Ang J, Temple G, Bell S, Shahidi M, Uttenreuther-Fischer M, Stopfer P, Futreal A, Calvert H, de Bono J, Plummer R (2010) Phase I trial of the irrevisible ErbB1 (EGFR) and ErbB2 (HER2) kinase inhibitor BIBW 2992 in patients with advanced solid tumours. J Clin Oncol 28(25):3965–3972PubMedCrossRefGoogle Scholar
  21. 21.
    Plummer R, Vidal L, Perrett R, Spicer J, Stopfer P, Shahidi M, Temple G, Futreal A, Calvert H, de Bono J (2007) A Phase I and pharmacokinetic (PK) study of BIBW 2992, an oral irreversible dual EGFR/HER2 inhibitor. Eur J Cancer Suppl 5(4):108CrossRefGoogle Scholar
  22. 22.
    Spicer J, Calvert H, Vidal L, Azribi F, Perrett R, Shahidi M, Temple G, Futreal A, De Bono J, Plummer R (2007) Activity of BIBW2992, an oral irreversible dual EGFR/HER2 inhibitor, in non-small cell lung cancer (NSCLC) with mutated EGFR. J Thorac Oncol 2(8):S410CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • H. Murakami
    • 1
  • T. Tamura
    • 2
  • T. Takahashi
    • 1
  • H. Nokihara
    • 2
  • T. Naito
    • 1
  • Y. Nakamura
    • 1
  • K. Nishio
    • 3
  • Y. Seki
    • 4
  • A. Sarashina
    • 5
  • M. Shahidi
    • 6
  • N. Yamamoto
    • 1
    Email author
  1. 1.Division of Thoracic OncologyShizuoka Cancer CenterShizuokaJapan
  2. 2.National Cancer Center HospitalTokyoJapan
  3. 3.Kinki University School of MedicineOsakaJapan
  4. 4.Nippon Boehringer IngelheimTokyoJapan
  5. 5.Nippon Boehringer IngelheimKobeJapan
  6. 6.Boehringer IngelheimBracknellUK

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