446PD - Phase I study of afatinib (BIBW 2992), an ErbB family blocker plus nintedanib (BIBF 1120), a triple angiokinase inhibitor, in patients (pts) with ad...
|Date||30 September 2012|
|Event||ESMO Congress 2012|
|Topics|| Drug Development
J. Soria1, A. Hollebecque1, C. Massard2, E. Deutsch3, A. Varga1, N. Morsli4, M. Ould Kaci4, H. Staines4, K. Marzin5, R. Bahleda1
Inhibiting multiple signalling pathways with the combination of afatinib, an oral irreversible ErbB Family Blocker, and nintedanib, an oral triple angiokinase inhibitor of VEGFR, PDGFR and FGFR, may lead to better efficacy.Methods
This Phase I study used a modified 3 + 3 design to determine the maximum tolerated dose (MTD) of afatinib, with dose escalating from 10 to 40 mg qd given in 2 schedules: continuous (C) or intermittent (I) (every other week), in combination with fixed-dose nintedanib (200 mg bid reduced to 150 mg bid after protocol amendment) in a 28-day cycle. Secondary endpoints were safety, efficacy, pharmacokinetics (PK), and circulating tumour cells (CTC) analysis. Treatment continued until disease progression or intolerability.Results
45 pts with heavily pretreated advanced solid tumours were included: 26 men; median age 56 years (range 37–73); main cancer types: lung (NSCLC), colorectal, breast, melanoma and ovary. Main adverse events were diarrhoea, asthenia, nausea, vomiting and transaminase elevation. Two MTDs were established: afatinib 40 mg qd (I) plus nintedanib 150 mg bid and afatinib 30 mg qd (C) plus nintedanib 150 mg bid (Table). Efficacy data showed evidence of antitumour activity with partial responses (RECIST) observed in 2 pts (HER2-negative breast cancer, and head & neck squamous cell carcinoma) and stable disease in 27 pts (lasting >3 months in 8 pts). Preliminary PK data showed no drug–drug interaction. CTC analysis will be presented.
|Afatinib (C or I) (mg qd)||Nintedanib (mg bid)||Evaluable pts/dose-limiting toxicity (DLT)||DLT/Grade (G)|
|30 C||200||7/2||diarrhoea G3, transaminase elevation G3|
|40 C||200||3/3||diarrhoea G3, transaminase elevation G3; creatinine increase G2|
|30 I||200||6/2||diarrhoea G3, transaminase elevation G3, creatinine increase G2|
|40 I||200||6/2||dehydration G3, transaminase elevation G4|
|40 C||150||3/2||diarrhoea G3, renal failure G3|
At MTD, the combination of afatinib with nintedanib showed a manageable safety profile and evidence of activity in different heavily pretreated tumour types.Disclosure
J. Soria: Honoraria from Boehringer Ingelheim and Roche.
N. Morsli: Employee of Boehringer Ingelheim.
M. Ould Kaci: Employee of Boehringer Ingelheim.
H. Staines: Employee of Boehringer Ingelheim.
K. Marzin: Employee of Boehringer Ingelheim.
All other authors have declared no conflicts of interest.