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
Session Developmental therapeutics
Topics Clinical Research
Basic Scientific Principles
Presenter Jean-Charles Soria
Authors J. Soria1, A. Hollebecque1, C. Massard2, E. Deutsch3, A. Varga1, N. Morsli4, M. Ould Kaci4, H. Staines4, K. Marzin5, R. Bahleda1
  • 1Dept. Of Medicine, Institut Gustave Roussy, FR-94805 - Villejuif CEDEX/FR
  • 2Sitep, Institut Gustave Roussy, FR-94805 - Villejuif CEDEX/FR
  • 3Radiation Oncology, Institut Gustave Roussy, FR-94805 - Villejuif CEDEX/FR
  • 4Medical Affairs, Boehringer Ingelheim, Paris/FR
  • 5Pharmacokinetics, Boehringer Ingelheim, Biberach/DE



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.


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.


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)
10 C 200 3/0
20 C 200 3/0
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
40 I 150 6/0 MTD
30 C 150 6/0 MTD


At MTD, the combination of afatinib with nintedanib showed a manageable safety profile and evidence of activity in different heavily pretreated tumour types.


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.