Inhibiting VEGFRs has already proved a fruitful strategy for cancer therapy; a number of drugs that act in this way are on the market and more are in the pipeline
If a tumour is to survive, grow and thrive, it needs a supply of nutrients. This can be sourced via angiogenesis, with the tumour embedding itself into the patient’s vasculature. Various signalling proteins are involved in the angiogenesis process, including vascular endothelial growth factor, or VEGF. This is part of the normal formation process for new blood vessels, for example after injury and in the development of embryos, but it can also be expressed by some cancer cells, and when it is overexpressed the result is tumour growth.
Several isoforms of VEGF exist, and they work by binding to the different VEGFR tyrosine kinase receptors. Inhibiting VEGFRs has already proved a fruitful strategy for cancer therapy. A number of drugs that act in this way are on the market, and more are in the pipeline, including fruquintinib, which is being developed by Hutchison China MediTech.1 The novel oral small molecule selectively inhibits VEGFR 1, 2 and 3, having shown potent inhibitory effects on multiple human tumour xenografts.
In a Phase I first in human study, 16 heavily pretreated patients were given 1–6mg doses of the drug once a day, in five cohorts.2 Nine had colorectal cancer (one of whom had a bi-primary with breast cancer), and there were three lung, two further breast and two gastric cancers among the group. The most common adverse events were hypertension, proteinuria, hand–foot syndrome, diarrhoea and hoarseness.
Among the eight evaluable patients, a confirmed partial response for more than four months was achieved in one colorectal and one gastric cancer patient, and five more had stable disease, three of them for 3–8 months. It was well tolerated in doses up to 4mg.
A Phase Ib study has also been reported.3 A total of 40 patients with advanced colorectal cancer who had failed at least two prior systemic therapies were randomised to receive 4mg fruquintinib once daily continuously, or 5mg once daily for three weeks followed by a one-week break. The median treatment duration was 90 days for the once-daily regimen, and 119 for the 3/1 week regimen. The latter had fewer grade 3/4 adverse events than the daily group, particularly hand–foot syndrome.
Of the 17 patients evaluable for response in the once-daily group, there were two partial responses and two minor responses, and one partial response and three minor responses in the 3/1 group. The 3/1 regimen was selected as the recommended regimen.
A randomised, double blind, placebo controlled multi-centre Phase II trial in metastatic colorectal cancer has also been carried out.4 In all, 71 patients who had failed at least two prior therapies were randomised to receive 5mg oral doses in the 3/1 schedule or placebo in 28 day cycles until disease progression or non-tolerable toxicity occurred. Medium fruquintinib exposure was 84 days, compared with 21 days in the placebo arm. Those given the drug had a median progression-free survival of 4.7 months, compared with one month with placebo.
A Phase III trial is now underway in China in patients with metastatic colorectal cancer.
1. Q. Sun et al. Cancer Biol. Ther. 2014, 15, 1635
2. J. Li et al. J. Clin. Oncol. 2012, 30 (suppl.), Abst. 3038
3. J. Li et al. J. Clin. Oncol. 2014, 32 (suppl.), Abst. 3548
4. J. Li et al. Eur. Cancer Conf. 2015 (25–29 September, Vienna), Abst. 2111