Anti-VEGF agents in combination with chemotherapy improve PFS of patients with mCRC in the 1st- and 2nd-line-setting. During anti-VEGF treatment tumour angiogenesis is driven by other factors but VEGF. Nintedanib is a triple angiokinase inhibitor of human VEGFR-1-3, FGFR-1/-3 and PDGFR-α/-β thereby additionally targets angiogenic escape mechanisms upon resistance to anti-VEGF treatment. The TRICC-C trial evaluates the combination of mFOLFOX6 plus Nintedanib. Final results of the randomized phase II trial are presented.
Patients with mCRC having received one line of non-oxaliplatin containing palliative chemotherapy, with an ECOG-PS of 0 or 1 were randomized 1:1 in a double-blind design to receive: mFOLFOX6 plus Nintedanib (2 x 200 mg p.o./d, d1-d14) or placebo, respectively, repeated every 14 days. Primary endpoint was PFS. Secondary endpoints were ORR, OS and safety. Patients who received at least one dose of trial medication were included in the efficacy and safety analyses.
From 12/2012 to 5/2016 53 patients (scheduled n = 180) were randomized. The trial was terminated prematurely due to slow accrual. Compared to mFOLFOX6 plus placebo (F+P), the combination of mFOLFOX6 plus Nintedanib (F+N) improved mPFS (F+P: 4.6 vs F+N: 8.1 mo.; HR 0.65; 95% CI 0.32-1.30; p = 0.2156), mOS (F+P: 9.9 vs. F+N: 17.1 mo.; HR 1.03, 95% CI 0.48-2.23; p = 0.9387) and DCR (F+P: 50 vs. F+N: 66,7%; p = 0.2709). ORR was comparable in both arms (F+N: 3.8 vs. F+P: 3.7%). Toxicity was low to moderate without major differences between both arms except G 3/4 neutropenia (F+N: 19%, F+P: 12%) and GI disorders (F+N: 23%, F+P: 15%).
Final results suggest a PFS, OS and DCR benefit for mFOLFOX6 + Nintedanib vs. mFOLFOX6 + placebo in the 2nd-line therapy of mCRC. Due to the premature termination of the trial there was no statistical significance demonstrable. Showing no clinically significant PFS-benefit in the 1st-line situation (mFOLFOX6 plus Nintedanib/Bevacizumab, Ann Oncol. 2015) or the last line as single agent, respectively (ESMO 2016) the TRICC-C results suggests that Nintedanib could be an interesting therapeutic option for the 2nd-line situation in combination with mFOLFOX6.
Clinical trial identification
Legal entity responsible for the study
Martin-Luther-Universität Halle-Wittenberg, Germany.
T.J. Ettrich: Research grants: Baxalta/Shire; Consulting fees or other remuneration: Merck-Serono, Sanofi, Sirtex, Medical, Novartis, Bayer, Bristol-Myers Squibb, Pfizer. A.W. Berger: Consulting fees: Sanofi. R.D. Hofheinz: Consulting or advisory role: Boehringer Ingelheim. T. Seufferlein: Research Funding: Celgene, Sanofi Consulting or Advisory role: Celgene, Lilly Pharma, Boehringer Ingelheim, Merck Serono, Amgen. All other authors have declared no conflicts of interest.