Angiogenesis is critical to colorectal cancer (CRC) growth and metastasis. Phase I/II studies have demonstrated the efficacy of nintedanib, a triple angiokinase inhibitor, in patients with metastatic CRC. This global, randomized, phase III study investigated the efficacy and safety of nintedanib in patients with refractory CRC after failure of standard therapies.
Eligible patients (Eastern Cooperative Oncology Group performance status 0–1, with histologically/cytologically confirmed metastatic/locally advanced CRC adenocarcinoma unamenable to surgery and/or radiotherapy) were randomized 1:1 to receive nintedanib (200 mg twice daily) or placebo (twice daily), until disease progression or undue toxicity. Patients were stratified by previous regorafenib, time from onset of metastatic disease to randomization, and region. Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) by central review. Secondary endpoints included objective tumor response and disease control by central review.
From October 2014 – January 2016, 768 patients were randomized; 765 were treated (nintedanib n=384; placebo n=381). Median follow-up was 13.4 months (interquartile range, 11.1–15.7). OS was not improved (median OS 6.4 months with nintedanib versus 6.0 months with placebo; hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.86 to 1.19; P = 0.8659). There was a significant but modest increase in PFS with nintedanib versus placebo (median PFS 1.5 versus 1.4 months, respectively; HR, 0.58; 95% CI, 0.49 to 0.69; P<0.0001). There were no complete or partial responses. Adverse events (AEs) occurred in 97% of 384 nintedanib-treated patients and 93% of 381 placebo-treated patients. The most frequent grade ≥3 AEs were liver-related AEs (nintedanib 16%; placebo 8%) and fatigue (nintedanib 9%; placebo 6%).
The study failed to meet both co-primary endpoints. Nintedanib did not improve OS and was associated with a significant but modest increase in PFS versus placebo. Nintedanib was well tolerated.This trial is registered at ClinicalTrials.gov: NCT02149108.