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Phase I trial of dacomitinib, a pan-human epidermal growth factor receptor (HER) inhibitor, with concurrent radiotherapy and cisplatin in patients with locoregionally advanced squamous cell carcinoma of the head and neck (XDC-001)

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Summary

Background Curative-intent, non-surgical treatment options for locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) include radiotherapy with/without chemotherapy or radiotherapy with cetuximab. This single institution phase I dose escalation trial tested the pan-human epidermal growth factor receptor (HER) oral tyrosine kinase inhibitor, dacomitinib, in combination with standard cisplatin-based chemoradiotherapy. Methods Patients received oral dacomitinib once daily at 3 protocol-defined dose levels (15 mg, 30 mg, and 45 mg). Cisplatin was given intravenously at 100 mg/m2 every 3 weeks. Radiotherapy was delivered using intensity modulated radiation therapy (IMRT) to a dose of 70Gy in 35 daily fractions to the primary and nodal disease. Dose escalation was performed using a standard 3 + 3 design. Results Twelve patients with LA-SCCHN were enrolled between January 2013 and August 2014. No dose limiting toxicities (DLTs) were observed in the 15 mg and 30 mg dose levels. In the 45 mg dose level, one of four evaluable patients developed a DLT with intolerable grade 2 diarrhea requiring discontinuation of therapy. Adverse events (AEs) attributed to dacomitinib alone include diarrhea, hypertension, and acneiform and maculopapular rash. The most common non-hematological AEs include weight loss, diarrhea, dry mouth, mucositis, nausea, hypoalbuminemia, and hyponatremia. Frequency and severity of AEs did not increase with increasing dose levels of dacomitinib. All patients completed the full course of radiotherapy on schedule and the median dose of cisplatin was 200 mg/m2, which is comparable to historical standards. Of the 10 patients evaluable for response, 1 patient relapsed with metastatic disease. Conclusions The triple combination has a tolerable side effect profile and dose levels 15 mg and 30 mg were cleared safely. The addition of dacomitinib did not preclude delivery of standard chemoradiotherapy. Studies testing the addition of other HER-targeted therapies to platinum-based concurrent chemo-radiotherapy in LA-SCCHN have failed to demonstrate improved patient outcomes and have reported trends towards excessive toxicities. These results generated uncertainty regarding the future of these agents in combination with chemo-radiation for the treatment of LA-SCCHN, which ultimately led to the early termination of this study.

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References

  1. Blanchard P, Baujat B, Holostenco V, et al. (2011) Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol J Eur Soc Ther Radiol Oncol 100:33–40

    Article  Google Scholar 

  2. Huang SH, Xu W, Waldron J, et al. (2015) Refining American joint committee on cancer/Union for International Cancer Control TNM stage and prognostic groups for human papillomavirus-related oropharyngeal carcinomas. J Clin Oncol Off J Am Soc Clin Oncol 33:836–845

    Article  Google Scholar 

  3. Cancer Genome Atlas N (2015) Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517:576–582

    Article  Google Scholar 

  4. Bonner JA, Harari PM, Giralt J, et al. (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567–578

    Article  CAS  PubMed  Google Scholar 

  5. Kruser TJ, Wheeler DL (2010) Mechanisms of resistance to HER family targeting antibodies. Exp Cell Res 316:1083–1100

    Article  CAS  PubMed  Google Scholar 

  6. Wong TW, Lee FY, Yu C, et al. (2006) Preclinical antitumor activity of BMS-599626, a pan-HER kinase inhibitor that inhibits HER1/HER2 homodimer and heterodimer signaling. Clin Cancer Res Off J Am Assoc Cancer Res 12:6186–6193

    Article  CAS  Google Scholar 

  7. Abdul Razak AR, Soulieres D, Laurie SA, et al. (2013) A phase II trial of dacomitinib, an oral pan-human EGF receptor (HER) inhibitor, as first-line treatment in recurrent and/or metastatic squamous-cell carcinoma of the head and neck. Ann Oncol Off J Euro Soc Med Oncol / ESMO 24:761–769

    Article  CAS  Google Scholar 

  8. Williams JP, Kim I, Ito E, et al. (2014) Pre-clinical characterization of dacomitinib (PF-00299804), an irreversible pan-ErbB inhibitor, combined with ionizing radiation for head and neck squamous cell carcinoma. PLoS One 9:e98557

    Article  PubMed  PubMed Central  Google Scholar 

  9. Shi W, Kato H, Perez-Ordonez B, et al. (2009) Comparative prognostic value of HPV16 E6 mRNA compared with in situ hybridization for human oropharyngeal squamous carcinoma. J Clin Oncol Off J Am Soc Clin Oncol 27:6213–6221

    Article  Google Scholar 

  10. Takahashi T, Boku N, Murakami H, et al. (2012) Phase I and pharmacokinetic study of dacomitinib (PF-00299804), an oral irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, −2, and −4 tyrosine kinases, in Japanese patients with advanced solid tumors. Investig New Drugs 30:2352–2363

    Article  CAS  Google Scholar 

  11. Eisenhauer EA, Therasse P, Bogaerts J, 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 

  12. Janne PA, Boss DS, Camidge DR, et al. (2011) Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin Cancer Res Off J Am Assoc Cancer Res 17:1131–1139

    Article  CAS  Google Scholar 

  13. Ang KK, Zhang Q, Rosenthal DI, et al. (2014) Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol Off J Am Soc Clin Oncol 32:2940–2950

    Article  CAS  Google Scholar 

  14. Harari PM, Harris J, Kies MS, et al. (2014) Postoperative chemoradiotherapy and cetuximab for high-risk squamous cell carcinoma of the head and neck: radiation therapy oncology group RTOG-0234. J Clin Oncol Off J Am Soc Clin Oncol 32:2486–2495

    Article  CAS  Google Scholar 

  15. Mesia R, Henke M, Fortin A, et al. (2015) Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial. The Lancet Oncology 16:208–220

    Article  CAS  PubMed  Google Scholar 

  16. Harrington K, Berrier A, Robinson M, et al. (2013) Randomised phase II study of oral lapatinib combined with chemoradiotherapy in patients with advanced squamous cell carcinoma of the head and neck: rationale for future randomised trials in human papilloma virus-negative disease. Eur J Cancer 49:1609–1618

    Article  CAS  PubMed  Google Scholar 

  17. Martins RG, Parvathaneni U, Bauman JE, et al. (2013) Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: a randomized phase II trial. J Clin Oncol Off J Am Soc Clin Oncol 31:1415–1421

    Article  CAS  Google Scholar 

  18. Cohen EE, Haraf DJ, Kunnavakkam R, et al. (2010) Epidermal growth factor receptor inhibitor gefitinib added to chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol Off J Am Soc Clin Oncol 28:3336–3343

    Article  CAS  Google Scholar 

  19. Knecht R, Peters S, Solbach C, Baghi M, Gstottner W, Hambek M (2003) EGFR antibody-supplemented TPE-chemotherapy. Preclinical investigations to a novel approach for head and neck cancer induction treatment. Anticancer Res 23:4789–4795

    CAS  PubMed  Google Scholar 

  20. Sartor CI (2004) Mechanisms of disease: radiosensitization by epidermal growth factor receptor inhibitors. Nat Clin Pract Oncol 1:80–87

    Article  CAS  PubMed  Google Scholar 

  21. Vokes EE, Weichselbaum RR (1990) Concomitant chemoradiotherapy: rationale and clinical experience in patients with solid tumors. J Clin Oncol Off J Am Soc Clin Oncol 8:911–934

    CAS  Google Scholar 

  22. Del Campo JM, Hitt R, Sebastian P, et al. (2011) Effects of lapatinib monotherapy: results of a randomised phase II study in therapy-naive patients with locally advanced squamous cell carcinoma of the head and neck. Br J Cancer 105:618–627

    Article  PubMed  PubMed Central  Google Scholar 

  23. Machiels JP, Haddad RI, Fayette J, et al. (2015) Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 16:583–594

    Article  CAS  PubMed  Google Scholar 

  24. Kim HS, Kwon HJ, Jung I, et al. (2015) Phase II clinical and exploratory biomarker study of dacomitinib in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Clinical Cancer Res J Am Assoc Cancer Res 21:544–552

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada

    Amy Prawira, Irene Brana-Garcia, Anna Spreafico, Albiruni R. Abdul Razak, Eric X Chen, Raymond Jang, Lisa Wang, Lillian L. Siu & Aaron R Hansen

  2. Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada

    Andrew Hope, John Waldron, Brian O’Sullivan, Meredith Giuliani, Andrew Bayley & John Cho

  3. Department of Pathology, University Health Network, Toronto, ON, Canada

    Bayardo Perez-Ordonez & Ilan Weinreb

  4. Drug Development Program, Princess Margaret Cancer Centre, 620 University Avenue, Suite 7-706, Room 702, Toronto, ON, M5G 2M9, Canada

    Aaron R Hansen

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  1. Amy Prawira
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Correspondence to Aaron R Hansen.

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Disclosures

Dr. Lillian L. Siu received research funding from Pfizer to conduct clinical trials.

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Prawira, A., Brana-Garcia, I., Spreafico, A. et al. Phase I trial of dacomitinib, a pan-human epidermal growth factor receptor (HER) inhibitor, with concurrent radiotherapy and cisplatin in patients with locoregionally advanced squamous cell carcinoma of the head and neck (XDC-001). Invest New Drugs 34, 575–583 (2016). https://doi.org/10.1007/s10637-016-0367-2

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  • DOI: https://doi.org/10.1007/s10637-016-0367-2

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