LBA20_PR - Nintedanib plus best supportive care (BSC) versus placebo plus BSC for the treatment of patients (pts) with colorectal cancer (CRC) refractory to s...

Date 09 October 2016
Event ESMO 2016 Congress
Session Gastrointestinal tumours, colorectal 1
Topics Cytotoxic agents
Colon and Rectal Cancer
Biological therapy
Presenter Eric Van Cutsem
Citation Annals of Oncology (2016) 27 (6): 1-36. 10.1093/annonc/mdw435
Authors E. Van Cutsem1, T. Yoshino2, H. Lenz3, S. Lonardi4, A. Falcone5, M.L. Limon6, M.P. Saunders7, A. Sobrero8, E. Maiello9, Y.S. Park10, R. Ferreiro Monteagudo11, Y.S. Hong12, J. Tomasek13, H. Taniguchi14, F. Ciardiello15, J. Hocke16, Z. Oum’hamed17, S. Vlassak18, M. Studeny19, J. Tabernero20
  • 1Digestive Oncology, University Hospitals Leuven - Campus Gasthuisberg, 3000 - Leuven/BE
  • 2Department Of Gi Oncology, National Cancer Center Hospital East, Kashiwa/JP
  • 3Department Of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles/US
  • 4Oncologia Medica 1, Istituto Oncologico Veneto IRCCS, Padova/IT
  • 5Oncologia Medica, Azienda Ospedaliera Universitaria S.Chiara, Pisa/IT
  • 6Medical Oncology, Hospital Universitario Virgen del Rocio, Sevilla/ES
  • 7Clinical Oncology, The Christie NHS Foundation Trust, M20 4BX - Manchester/GB
  • 8Department Of Medical Oncology, Ospedale S. Martino, 16132 - Genoa/IT
  • 9Onco-hematology, Ospedale Casa Sollievo della Sofferenza, 71013 - San Giovanni Rotondo/IT
  • 10Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul/KR
  • 11Medical Oncology, Hospital Universitario Ramon y Cajal, 28031 - Madrid/ES
  • 12Department Of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul/KR
  • 13Medical Communications, InVentiv Health, WC1A 2SL - London/GB
  • 14Department Of Clinical Oncology, Aichi Cancer Center Hospital, 464-8681 - Nagoya/JP
  • 15Medical Oncology, AOU Seconda Università degli Studi di Napoli (AOU-SUN), 81130 - Napoli/IT
  • 16Statistics, Boehringer Ingelheim Pharma GmbH & Co. KG, Tübingen/DE
  • 17Clinical Trials, Boehringer Ingelheim B.V. France S.A.S, Reims/FR
  • 18Medical Affairs, SCS Boehringer Ingelheim Comm. V., Brussels/BE
  • 19Division Of Medicine/clinical Development Department, Boehringer Ingelheim, Vienna/AT
  • 20Oncologia Médica, Vall d`Hebron University Hospital Institut d'Oncologia, 08035 - Barcelona/ES



Angiogenesis is critical to CRC tumour growth and metastasis. Nintedanib (N) is a multiple angiokinase signalling pathway inhibitor (including VEGFR, PDGFR and FGFR). N demonstrated similar efficacy to bevacizumab when combined with mFOLFOX6 as 1st-line therapy in a Phase I/II study. These findings and a manageable safety profile provided the rationale to examine N in refractory CRC. We conducted a global, randomised Phase III study (NCT02149108) to evaluate the efficacy and safety of N in pts with mCRC after failure of standard therapies.


Eligible pts (aged ≥18 years; ECOG PS 0–1; mCRC adenocarcinoma refractory to standard treatments, including oxaliplatin, irinotecan, fluoropyrimidines, anti-VEGF and anti-EGFR in RAS wt) were randomised 1:1 to receive either N (200 mg bid) + BSC or placebo (P; bid) + BSC. The co-primary endpoints were PFS by central review and OS, evaluated by log-rank test to determine the effect of N independently at the two-sided alpha level of 0.05.


768 mCRC patients (37% pretreated with regorafenib) were randomised to N (n = 386) or P (n = 382). Baseline characteristics were similar between the groups. A statistically significant improvement in PFS was observed (HR [95% CI] 0.58 [0.49, 0.69]; p < 0.0001; median PFS 1.5 months with N vs 1.4 months with P), but no difference in OS (HR [95% CI]: 1.01 [0.86, 1.19]; p = 0.8659; median OS 6.4 months with N vs 6.1 months with P). Disease control by central review was 26% with N vs 11% with P (OR [95% CI]: 2.96 [2.00, 4.4]; p < 0.0001). 14% of patients in the N arm discontinued due to AEs, vs 11% with P. Serious AEs occurred in 39% vs 35% of patients in the N and P arms, respectively. The most frequent ≥Grade 3 AEs (in the N arm, by medical concept) occurring in N vs P patients were liver related investigations (16% vs 8%) and fatigue (9% vs 6%).


N was well tolerated and demonstrated clinical activity, with a significant increase in PFS (HR 0.58). However, improvement in PFS did not translate to an improvement in OS. Additional analyses are ongoing to further interrogate the efficacy findings.

Clinical trial identification


Legal entity responsible for the study

Boehringer Ingelheim GmbH & Co. KG


Boehringer Ingelheim GmbH & Co. KG


E. Van Cutsem: Research funding paid to his institute from Amgen; Bayer; Boehringer Ingelheim; Lilly; Merck Serono; Novartis; Roche and Sanofi. T. Yoshino: Research funding from GlaxoSmithKline K.K. and Boehringer Ingelheim. H-J. Lenz: Honoraria and research funding from Boehringer Ingelheim. A. Falcone: Reports grants and personal fees from Amgen, Bayer, Roche, Servier, Lilly, Merck, outside the submitted work. A. Sobrero: Reports personal fees from Roche, Merck, BMS, Sanofi, Bayer, Servier, Amgen, outside the submitted work. F. Ciardiello: Advisory Board Role: Bayer, Boerhinger, Merck Serono, Roche, Lilly, AstraZeneca. Research grants: Roche, Bayer, Merck Serono. J. Hocke, Z. Oum'hamed, S. Vlassak, M. Studeny: Employee of Boehringer Ingelheim. J. Tabernero: Consulting or advisory services for Amgen; Boehringer Ingelheim, Celgene; Chugai Pharma; ImClone Systems; Lilly; Merck KGaA; Millennium Takeda; Novartis; Roche/Genentech; Sanofi and Taiho Pharmaceutical. All other authors have declared no conflicts of interest.