Skip to main content

Advertisement

SpringerLink
Log in

A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors

  • PHASE I STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Introduction Afatinib, an irreversible ErbB family blocker, demonstrated synergistic inhibition of epidermal growth factor receptor-mutant cell growth with pemetrexed. This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of afatinib plus pemetrexed in patients with advanced solid tumors. Methods In a 3 + 3 dose-escalation design, patients were given intravenous pemetrexed (500 mg/m2) on day 1 of a 21-day cycle (maximum 6 cycles), combined with continuous daily oral afatinib (schedule A [SA]; starting dose 30 mg, escalation to 50 mg) or pulsed-dose daily oral afatinib (schedule B [SB]; starting dose 50 mg, escalation to 70 mg) on days 1–6 of each 21-day cycle. Primary endpoint was determination of MTD based on dose-limiting toxicities (DLTs) in cycle 1. Results Fifty-three patients were treated (SA: n = 23; SB: n = 30). Eight patients had DLTs in SA, 11 patients in SB; diarrhea and fatigue were the most common. MTD of afatinib was 30 mg in SA and 50 mg in SB. Six patients in SA and eight in SB completed 6 treatment cycles. One patient in each schedule had confirmed objective response; 18/53 patients had disease control (SA: n = 7; SB: n = 11). Most frequent drug-related adverse events were diarrhea, rash, fatigue, and stomatitis. No relevant pharmacokinetic interactions were observed. Conclusions Continuous- or pulsed-dose afatinib combined with pemetrexed exhibited a manageable safety profile. Pulsed dosing conferred no apparent safety or dose advantage. Continuous-dose afatinib 30 mg/day with pemetrexed is recommended for phase II studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Wong KK (2008) Searching for a magic bullet in NSCLC: the role of epidermal growth factor receptor mutations and tyrosine kinase inhibitors. Lung Cancer 60(Suppl 2):S10–S18

    Article  PubMed  Google Scholar 

  2. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E et al (2012) Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13:239–246

    Article  CAS  PubMed  Google Scholar 

  3. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N et al (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947–957

    Article  CAS  PubMed  Google Scholar 

  4. Hrustanovic G, Lee BJ, Bivona TG (2013) Mechanisms of resistance to EGFR targeted therapies. Cancer Biol Ther 14:304–314

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF et al (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73

    Article  PubMed Central  PubMed  Google Scholar 

  6. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P et al (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3:75ra26

    Article  PubMed Central  PubMed  Google Scholar 

  7. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M et al (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786–792

    Article  CAS  PubMed  Google Scholar 

  8. Goldberg SB, Oxnard GR, Digumarthy S, Muzikansky A, Jackman DM, Lennes IT et al (2013) Chemotherapy with erlotinib or chemotherapy alone in advanced non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitors. Oncologist 18:1214–1220

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Yoshimura N, Okishio K, Mitsuoka S, Kimura T, Kawaguchi T, Kobayashi M et al (2013) Prospective assessment of continuation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of pemetrexed. J Thorac Oncol 8:96–101

    Article  CAS  PubMed  Google Scholar 

  10. Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR et al (2008) BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27:4702–4711

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Solca F, Dahl G, Zoephel A, Bader G, Sanderson M, Klein C et al (2012) Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther 343:342–350

    Article  CAS  PubMed  Google Scholar 

  12. Ioannou N, Dalgleish AG, Seddon AM, Mackintosh D, Guertler U, Solca F et al (2011) Anti-tumour activity of afatinib, an irreversible ErbB family blocker, in human pancreatic tumour cells. Br J Cancer 105:1554–1562

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Yang JC, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SH et al (2012) Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol 13:539–548

    Article  CAS  PubMed  Google Scholar 

  14. Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T et al (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31:3327–3334

    Article  CAS  PubMed  Google Scholar 

  15. Wu YL, Zhou C, Hu CP, Feng JF, Lu S, Huang Y, et al (2013) LUX-Lung 6: a randomized, open-label, phase III study of afatinib (A) versus gemcitabine/cisplatin (GC) as first-line treatment for Asian patients (pts) with EGFR mutation-positive (EGFR M+) advanced adenocarcinoma of the lung. ASCO Meeting Abstracts 31:8016

  16. Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW et al (2012) Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 13:528–538

    Article  CAS  PubMed  Google Scholar 

  17. Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A et al (2013) LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol 31:3335–3341

    Article  CAS  PubMed  Google Scholar 

  18. Adjei AA (2004) Pemetrexed (ALIMTA), a novel multitargeted antineoplastic agent. Clin Cancer Res 10:4276s–4280s

    Article  CAS  PubMed  Google Scholar 

  19. Genova C, Rijavec E, Truini A, Coco S, Sini C, Barletta G et al (2013) Pemetrexed for the treatment of non-small cell lung cancer. Expert Opin Pharmacother 14:1545–1558

    Article  CAS  PubMed  Google Scholar 

  20. Takezawa K, Okamoto I, Tanizaki J, Kuwata K, Yamaguchi H, Fukuoka M et al (2010) Enhanced anticancer effect of the combination of BIBW2992 and thymidylate synthase-targeted agents in non-small cell lung cancer with the T790M mutation of epidermal growth factor receptor. Mol Cancer Ther 9:1647–1656

    Article  CAS  PubMed  Google Scholar 

  21. Li T, Ling YH, Goldman ID, Perez-Soler R (2007) Schedule-dependent cytotoxic synergism of pemetrexed and erlotinib in human non-small cell lung cancer cells. Clin Cancer Res 13:3413–3422

    Article  CAS  PubMed  Google Scholar 

  22. Giovannetti E, Lemos C, Tekle C, Smid K, Nannizzi S, Rodriguez JA et al (2008) 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 73:1290–1300

    Article  CAS  PubMed  Google Scholar 

  23. Sangha R, Davies AM, Lara PN Jr, Mack PC, Beckett LA, Hesketh PJ et al (2011) Intercalated erlotinib-docetaxel dosing schedules designed to achieve pharmacodynamic separation: results of a phase I/II trial. J Thorac Oncol 6:2112–2119

    Article  PubMed Central  PubMed  Google Scholar 

  24. Hata A, Fujita S, Kaji R, Nanjo S, Katakami N (2013) Dose reduction or intermittent administration of erlotinib: which is better for patients suffering from intolerable toxicities? Intern Med 52:599–603

    Article  PubMed  Google Scholar 

  25. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247

    Article  CAS  PubMed  Google Scholar 

  26. Eskens FA, Mom CH, Planting AS, Gietema JA, Amelsberg A, Huisman H et al (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 98:80–85

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Wind S, Schmid M, Erhardt J, Goeldner RG, Stopfer P (2013) Pharmacokinetics of afatinib, a selective irreversible ErbB family blocker, in patients with advanced solid tumours. Clin Pharmacokinet 52:1101–1109

    Article  CAS  PubMed  Google Scholar 

  28. Yap TA, Vidal L, Adam J, Stephens P, Spicer J, Shaw H et al (2010) Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J Clin Oncol 28:3965–3972

    Article  CAS  PubMed  Google Scholar 

  29. Lacouture ME, Schadendorf D, Chu CY, Uttenreuther-Fischer M, Stammberger U, O’Brien D et al (2013) Dermatologic adverse events associated with afatinib: an oral ErbB family blocker. Expert Rev Anticancer Ther 13:721–728

    Article  CAS  PubMed  Google Scholar 

  30. Yang JC, Reguart N, Barinoff J, Kohler J, Uttenreuther-Fischer M, Stammberger U et al (2013) Diarrhea associated with afatinib: an oral ErbB family blocker. Expert Rev Anticancer Ther 13:729–736

    Article  CAS  PubMed  Google Scholar 

  31. Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E et al (2009) 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 374:1432–1440

    Article  CAS  PubMed  Google Scholar 

  32. Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V et al (2004) Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 1. J Clin Oncol 22:777–784

    Article  CAS  PubMed  Google Scholar 

  33. Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C et al (2004) Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial–INTACT 2. J Clin Oncol 22:785–794

    Article  CAS  PubMed  Google Scholar 

  34. Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A et al (2005) 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 23:5892–5899

    Article  CAS  PubMed  Google Scholar 

  35. Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F et al (2007) 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 25:1545–1552

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge the support of all trial investigators and clinical trial support staff, and of all patients and their families participating in this study. The authors would also like to thank Roxana Sufan and Yu Gu, previously employed by Boehringer Ingelheim, for their contributions to the study and article development.

The authors were fully responsible for all content and editorial decisions, were involved at all stages of article development, and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Gill McFeat of Ogilvy Healthworld and Katie McClendon of GeoMed, part of KnowledgePoint360, an Ashfield Company, during the preparation of this article.

Financial support

This clinical research is supported by the sponsor, Boehringer Ingelheim. Medical writing assistance was supported financially by Boehringer Ingelheim.

Ethics statement

The study was conducted in accordance with the Declaration of Helsinki and guidelines on Good Clinical Practice, and the protocol was approved by a local ethics committee at each participating center. Written informed consent consistent with the International Conference on Harmonization Good Clinical Practice guidelines was obtained.

Conflict of interest

Q. S. Chu has served on advisory boards for Boehringer Ingelheim. R. Sangha has served on advisory boards and has received educational sponsorship from Boehringer Ingelheim. V. K. Chand and D. Schnell are full-time employees of Boehringer Ingelheim Pharmaceuticals Inc. G. Sergenson, S. J. Hotte, and H. W. Hirte declare no potential conflicts of interest.

Author information

Authors and Affiliations

  1. Cross Cancer Centre, 11560 University Ave NW, Edmonton, Alberta, T6G 1Z2, Canada

    Quincy S. Chu, Randeep Sangha & Gwen Sergenson

  2. Juravinski Cancer Centre, Hamilton, Ontario, Canada

    Sebastien J. Hotte & Hal W. Hirte

  3. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany

    David Schnell

  4. Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA

    Vikram K. Chand

Authors
  1. Quincy S. Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Randeep Sangha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sebastien J. Hotte
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gwen Sergenson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Schnell
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Vikram K. Chand
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hal W. Hirte
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Quincy S. Chu.

Additional information

Trial Registration

NCT01169675 (ClinicalTrials.gov).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chu, Q.S., Sangha, R., Hotte, S.J. et al. A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors. Invest New Drugs 32, 1226–1235 (2014). https://doi.org/10.1007/s10637-014-0139-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-014-0139-9

Keywords

Search

Navigation