Phase I trial of afatinib plus vinorelbine in Japanese patients with advanced solid tumors, including breast cancer
This phase I trial assessed afatinib, an irreversible ErbB family blocker, plus vinorelbine in Japanese patients with advanced solid tumors not amenable to standard treatment.
Primary objectives were evaluation of safety and the maximum tolerated dose (MTD) of once-daily (QD) afatinib plus weekly intravenous vinorelbine. Secondary objectives included pharmacokinetic assessments and preliminary efficacy. Dose finding utilized a 3 + 3 design, with a starting dose of afatinib 20 mg QD plus vinorelbine 25 mg/m2 weekly.
Seventeen patients were enrolled. Dose level 2 (afatinib 40 mg and vinorelbine 25 mg/m2) exceeded the MTD; dose-limiting toxicities (DLTs) were considered vinorelbine-related. Dose finding continued with modified dose levels; dose level 2a: afatinib 40 mg and a reduced dose of vinorelbine 20 mg/m2 and dose level 3: afatinib 40 mg and vinorelbine 25 mg/m2 allowing omission of vinorelbine for grade ≥2 neutropenia/thrombocytopenia and afatinib dose modification for adverse events (AEs). At dose level 3, 1/6 patients had a DLT (upper abdominal pain requiring afatinib dose reduction). Overall, the most frequent treatment-related AEs (any/grade 3 and 4) were: neutropenia (100/71 %), leukopenia (100/59 %), diarrhea (94/0 %), anemia (71/12 %) and stomatitis (65/0 %). Two patients with breast cancer achieved a partial response; eight patients (various cancer indications) had stable disease. Pharmacokinetic analyses suggested no relevant drug–drug interactions.
Afatinib 40 mg QD plus vinorelbine 25 mg/m2 weekly was tolerated in Japanese patients when dose modifications for known AEs for either compound were allowed. Tumor shrinkage was also observed. This dose schedule was recommended for phase II/III trials in Japanese patients.
KeywordsAfatinib Dose escalation Phase I Japanese Vinorelbine
The authors would like to acknowledge the support of all trial investigators, clinical trial support staff and participating patients and their families. This study was supported by Nippon Boehringer Ingelheim Co. Ltd. The authors were fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development and have approved the final version. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Christine Arris and Caroline Allinson of GeoMed, an Ashfield Company, part of UDG Healthcare plc, during the preparation of this article.
Compliance with ethical standards
Conflict of interest
Hirofumi Mukai has received funding from Boehringer Ingelheim. Akiko Sarashina, Martina Uttenreuther-Fischer and Aiko Watabe are employees of Boehringer Ingelheim. Yuichi Ando has received remuneration from Kyowa Hakko Kirin, Nippon Kayaku and Boehringer Ingelheim; has held a consultant/advisory role with Boehringer Ingelheim; and has received funding from Kyowa Hakko Kirin and Nippon Kayaku. All other authors declare no potential conflicts of interest.
- 3.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 27:4702–4711PubMedCentralCrossRefPubMedGoogle Scholar
- 5.Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M (2013) Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31:3327–3334CrossRefPubMedGoogle Scholar
- 6.Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee KY, Xu CR, Massey D, Kim M, Shi Y, Geater SL (2014) Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 15:213–222CrossRefPubMedGoogle Scholar
- 7.Yang JC-H, Sequist LV, Schuler MH, Mok T, Yamamoto N, O’Byrne KJ, Hirsh V, Geater SL, Zhou C, Massey D, Zazulina V, Wu Y-L (2014) Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): pooled analysis of two large open-label phase III studies [LUX-Lung 3 (LL3) and LUX-Lung 6 (LL6)] comparing afatinib with chemotherapy (CT). J Clin Oncol 32:[abstract 8004]Google Scholar
- 8.European Medicines Agency (2013) Afatinib—European Public Assessment Report (summary). http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002280/human_med_001698.jsp&mid=WC0b01ac058001d124. Accessed 7 April 2014
- 9.Boehringer Ingelheim (2013) Gilotrif® prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/201292s000lbl.pdf. Accessed 4 Feb 2013
- 10.Machiels JP, Haddad RI, Fayette J, Licitra LF, Tahara M, Vermorken JB, Clement PM, Gauler T, Cupissol D, Grau JJ, Guigay J, Caponigro F, de Castro G, Jr., de Souza Viana L, Keilholz U, Del Campo JM, Cong XJ, Ehrnrooth E, Cohen EE, LUX-H&N 1 investigators (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(5):583–594CrossRefPubMedGoogle Scholar
- 11.Goss GD, Felip E, Cobo M, Lu S, Syrigos KN, Lee KH, Göker, E., Georgoulias V, Li W, Isla D, Morabito A, Guclu SZ, Min YJ, Ardizzoni A, Gadgeel S, Love J, Chand V, Soria J (2014) A randomized, open-label, phase III trial of afatinib (A) vs erlotinib (E) as second-line treatment of patients (pts) with advanced squamous cell carcinoma (SCC) of the lung following first-line platinum-based chemotherapy: LUX-Lung 8 (LL8). Ann Oncol 25:[abstract iv426]Google Scholar
- 12.Lin NU, Winer EP, Wheatley D, Carey LA, Houston S, Mendelson D, Munster P, Frakes L, Kelly S, Garcia AA, Cleator S, Uttenreuther-Fischer M, Jones H, Wind S, Vinisko R, Hickish T (2012) A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab. Breast Cancer Res Treat 133:1057–1065PubMedCentralCrossRefPubMedGoogle Scholar
- 13.Bahleda R, Soria J, Berge Y, Massard C, Wind S, Uttenreuther-Fischer MM, Fleischer F, De-Montserrat H, Solca F, Tschoepe I, Delord J (2011) Phase I trial assessing safety and pharmacokinetics of afatinib (BIBW 2992) with intravenous weekly vinorelbine in advanced solid tumors. J Clin Oncol 29:[abstract 2585]Google Scholar
- 15.GlaxoSmithKline (2002) Navelbine® (vinorelbine tartrate) injection-prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20388s014lbl.pdf. Accessed 14 May 2014
- 16.MHRA (2010) Vinorelbine 10 mg/mL concentrate for solution for infusion UK Public Assessment Report. http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con099695.pdf. Accessed 19 Jan 2015
- 17.Pharmaceuticals and Medical Devices Agency J (2005) New drugs approved in FY 2005. http://www.pmda.go.jp/english/service/pdf/list/NewdrugsFY2005.pdf. Accessed 19 Jan 2015
- 18.Hollebecque A, Bahleda A, Bergé Y, Massard C, Uttenreuther-Fischer M, de Mont-Serrat H, Tschoepe I, Schnell D, Soria J-S, Delord J-P (2013) A phase I trial assessing the safety and pharmacokinetics of afatinib and weekly vinorelbine in patients with advanced solid tumours. Eur J Cancer 49:[abstract 892]Google Scholar
- 19.Harbeck N, Huang C-S, Hurvitz SA, Yeh D-C, Shao Z, Im SA, Jung KH, Shen K, Ro J, Jassem J, Zhang Q, Im YH, Wojtukiewicz M, Sun Q, Chen S, Goeldner RG, Lahogue A, Uttenreuther-Fischer M, Xu B, Piccart-Gebhart M (2014) Randomized Phase III trial of afatinib plus vinorelbine versus trastuzumab plus vinorelbine in patients with HER2-overexpressing metastatic breast cancer who had progressed on one prior trastuzumab treatment: LUX-Breast 1. Presented at San Antonio Breast Cancer Symposium, 9–13 Dec 2014. Abstract P5-19-01Google Scholar
- 20.European Medicines Agency (2014) Giotrif—European Public Assessment Report (product information). http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002280/WC500152392.pdf. Accessed 19 Nov 2014
- 21.Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRefPubMedGoogle Scholar
- 22.European Medicines Agency (2013) Giotrif—summary of product characteristics, annex 1. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002280/WC500152392.pdf. Accessed 19 Nov 2014
- 23.Hotta K, Kiura K, Takigawa N, Yoshioka H, Harita S, Kuyama S, Yonei T, Fujiwara K, Maeda T, Aoe K, Ueoka H, Kamei H, Umemura S, Moritaka T, Segawa Y, Kawai H, Bessho A, Kato K, Tabata M, Tanimoto M (2010) Comparison of the incidence and pattern of interstitial lung disease during erlotinib and gefitinib treatment in Japanese Patients with non-small cell lung cancer: the Okayama Lung Cancer Study Group experience. J Thorac Oncol 5:179–184CrossRefPubMedGoogle Scholar
- 24.Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, Ichinose Y, Koboyashi K, Takeda K, Kiura K, Nishio K, Seki Y, Ebisawa R, Shahidi M, Yamamoto N (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 31:3335–3341CrossRefPubMedGoogle Scholar