A phase I/II, open-label, randomised study of nintedanib plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 in first-line metastatic colorectal cancer patients

Van Cutsem, E.; Prenen, H.; D'Haens, G.; Bennouna, J.; Carrato, A.; Ducreux, M.; Bouché, O.; Sobrero, A.; Latini, L.; Staines, H.; Oum'Hamed, Z.; Dressler, H.; Studeny, M.; Capdevila, J.

doi:10.1093/ANNONC/MDV286

Title

A phase I/II, open-label, randomised study of nintedanib plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 in first-line metastatic colorectal cancer patients

Author

Van Cutsem, E.

Prenen, H.

D'Haens, G.

Bennouna, J.

Carrato, A.

Ducreux, M.

Bouché, O.

Sobrero, A.

Latini, L.

Staines, H.

Oum'Hamed, Z.

Dressler, H.

Studeny, M.

Capdevila, J.

Abstract

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). Patients and 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/m2, l-leucovorin 200 mg/m2 or d,l-leucovorin 400 mg/m2, 5-fluoruracil bolus 400 mg/m2 followed by 2400 mg/m2, 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.

Language

English

Source (journal)

Annals of oncology / European Society for Medical Oncology. - Amsterdam

Publication

Amsterdam : 2015

ISSN

0923-7534

DOI

10.1093/ANNONC/MDV286

Volume/pages

26 :10 (2015) , p. 2085-2091