5 days. These efficacy data are very similar to those obtained with regorafenib in the aforementioned phase III study of 760 patients with metastatic CRC who had failed all standard selleck chem therapies. In the phase III trial, 4 month progression free survival was 20% in the regorafenib plus BSC arm and 4% in the placebo plus BSC arm. The data are also comparable to those seen in an earlier phase I dose escalation, monotherapy study of regorafenib in 53 patients with treatment refractory ad vanced solid tumours, where a disease control rate of 66% was reported. Among 38 patients with heavily pretreated advanced CRC, who were enrolled in an expansion cohort to this regorafenib phase I trial, the disease control rate was 74% and median PFS was 107 days.

Although fur ther studies are clearly needed, the similarity of the TTP/PFS data and patient populations between the re gorafenib trials and the present subanalysis implies that nintedanib may be potentially active in the salvage setting. The activity of nintedanib in CRC is further supported by recent data demonstrating similar efficacy and im proved tolerability of nintedanib plus modified FOLFOX6 versus bevacizumab plus mFOLFOX6 in a randomised phase II study of 126 patients with previously untreated metastatic CRC. In the phase II trial, 9 month PFS was shown to be 63% in the nintedanib plus mFOLFOX6 arm versus 69% in the bevacizumab plus mFOLFOX6 arm, while median PFS was 10. 6 months in both arms. The objective response rate was 61% and 54%, respectively.

In terms of safety, ninteda nib plus mFOLFOX6 was associated with lower incidences of serious AEs and serious gastrointestinal AEs than bevacizumab plus mFOLFOX6, indicating improved tolerability of the nintedanib containing regimen. Reassuringly, the safety profile of nintedanib observed in the present study was entirely consistent with that seen in other monotherapy studies conducted in patients with a range of solid tumours, including CRC. Nintedanib doses of up to 500 mg/day were generally well tolerated with no reports of new or unexpected tox icities. The most common drug related toxicities were mild or moderate gastrointestinal AEs and mild or moderate, reversible hepatic enzyme elevations. Most gastrointestinal AEs occurred during the first treatment cycle and responded well to medical intervention.

Furthermore, all hepatic enzyme in creases responded quickly to treatment interruption/discontinuation or dose reduction. Unlike other angiogenesis inhibitors, such as regorafenib, pazopa nib, sorafenib or sunitinib, nintedanib was not associated with skin toxicity, and reports of hyper tension were uncommon. these findings suggest a favourable comparative safety profile for nintedanib. In terms of limitations, this Brefeldin_A subanalysis is clearly con strained by the non randomised design of the phase I study and limited sample size.