A phase I/II, open-label, randomised study of nintedanib plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 in first-line metastatic colorectal cancer patients.
BACKGROUND
This randomised, open-label, phase I/II study evaluated the efficacy and safety of nintedanib, an oral, triple angiokinase inhibitor, combined with chemotherapy, relative to bevacizumab plus chemotherapy as first-line therapy in patients with metastatic colorectal cancer (mCRC).


METHODS
Patients with histologically confirmed mCRC (adenocarcinoma), an Eastern Cooperative Oncology Group performance status ≤ 2 and adequate organ function were included. Patients were randomised 2:1 to receive nintedanib 150 mg or 200 mg b.i.d. plus mFOLFOX6 (oxaliplatin 85 mg/m(2), l-leucovorin 200 mg/m(2) or d,l-leucovorin 400 mg/m(2), 5-fluoruracil bolus 400 mg/m(2) followed by 2400 mg/m(2), every 2 weeks) or bevacizumab (5 mg/kg every 2 weeks) plus mFOLFOX6. During phase I, patients underwent a 3 + 3 dose-escalation schema to determine the maximum tolerated dose (MTD) of nintedanib in combination with mFOLFOX6. The primary end point was progression-free survival (PFS) rate at 9 months. Objective response (OR) was a secondary end point.


RESULTS
The nintedanib recommended phase II dose was 200 mg b.i.d. plus mFOLFOX6 based on safety data from phase I (n = 12). Of 128 patients randomised in the phase II part, 126 received treatment (nintedanib plus mFOLFOX6, n = 85; bevacizumab plus mFOLFOX6, n = 41). PFS at 9 months was 62.1% with nintedanib and 70.2% with bevacizumab [difference: -8.1% (95% confidence interval -27.8 to 11.5)]. Confirmed ORs were recorded in 63.5% and 56.1% of patients in the nintedanib and bevacizumab groups, respectively. The incidence of adverse events (AEs) considered related to treatment was 98.8% with nintedanib and 97.6% with bevacizumab; the incidence of serious AEs was 37.6% with nintedanib and 53.7% with bevacizumab. The pharmacokinetics of nintedanib and the components of mFOLFOX6 were unaffected by their combination.


CONCLUSIONS
Nintedanib in combination with mFOLFOX6 showed efficacy as first-line therapy in patients with mCRC with a manageable safety profile and further studies in this population are warranted.
Digestive Oncology, University Hospitals Leuven and KULeuven, Leuven, Belgium eric.vancutsem@uzleuven.be.
E
E
Van Cutsem
Digestive Oncology, University Hospitals Leuven and KULeuven, Leuven, Belgium.
H
H
Prenen
Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands Imelda GI Clinical Research Centre, Bonheiden, Belgium.
G
G
D'Haens
Department of Medical Oncology, Centre René Gauducheau, Nantes, France.
J
J
Bennouna
Department of Medical Oncology, Ramon y Cajal University Hospital, Madrid, Spain.
A
A
Carrato
Gustave-Roussy Cancer Campus, Institut Gustave Roussy, Paris University of Paris-Sud, Le Kremlin Bicêtre, Paris.
M
M
Ducreux
Department of Digestive Oncology, CHU Reims, Reims, France.
O
O
Bouché
Department of Medical Oncology, San Martino Hospital, Genoa.
A
A
Sobrero
Oncology Unit, Macerata Hospital, Macerata, Italy.
L
L
Latini
Medical and Drug Regulatory Affairs, Boehringer Ingelheim France S.A.S., Reims, France.
H
H
Staines
Medical and Drug Regulatory Affairs, Boehringer Ingelheim France S.A.S., Reims, France.
Z
Z
Oum'Hamed
Global Pharmacovigilance, Boehringer Ingelheim, Ingelheim, Germany.
H
H
Dressler
Division of Medicine/Department of Clinical Development, Boehringer Ingelheim, Vienna, Austria.
M
M
Studeny
Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
J
J
Capdevila
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D015996:Survival Rate
D007211:Indoles; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000068258:Bevacizumab; C530716:nintedanib; D002955:Leucovorin; D005472:Fluorouracil
CRC; FOLFOX; VEGF; angiogenesis; nintedanib