When vascular endothelial growth factor (VEGF) is over-expressed, it can lead to rapid tumour growth. Brivanib is a new agent from Bristol-Myers Squibb that is targeted to VEGF receptor 2, and is being developed as a potential treatment for cancer, notably liver cancer.1 It is dosed as its L-alaninate prodrug to improve oral bioavailability and increase drug plasma concentrations.
In one Phase I open label, dose escalation trial patients with advanced gastric or duodenal tumours who had failed previous therapy were given the drug orally on the first day, and then daily from day 8, with a starting dose of 320mg, in combination with cetuximab weekly from day 8.2 Doses were escalated to 800mg, when patients with advance colorectal cancer were added to the trial. There was no dose-limiting toxicity at this dose.
A Phase II open label study was carried out in 101 patients with unresectable, locally advanced metastatic hepatic cell carcinoma.3 A total of 55 patients had not received any systemic cancer drug treatment, and the remainder had progressed after treatment with at least one other antiangiogenic drug – 43 had failed on sorafenib, and three on thalidomide.
Six of the 47 evaluable naïve patients had a partial response, two of whom were unconfirmed, with an overall median time to progression of 2.8 months, and median overall survival of 10 months. One of the 37 evaluable previously treated patients had a partial response, and 16 stable disease. Time to progression and overall survival were similar to the naïve group. Serious side-effects included encephalopathy, and common adverse events were fatigue, hypertension and diarrhoea. Interestingly, two-thirds of the naïve patients were Asian, and they achieved a significantly better overall survival and better reduction in tumour volume.4
Several Phase III trials are now under way in advanced liver cancer, including a comparison with sorafenib, a comparison with placebo in patients who have failed sorafenib, and a comparison with placebo in conjunction with transarterial chemoembolisation.
References
1. Z.W. Cai et al. J. Med. Chem 2008, 51, 1976
2. C. Garrett et al. J. Clin. Oncol. 2008, 26 (May, suppl.), Abst 4111
3. J.-L. Raoul et al. ASCO Gen. Meet. (May 29 – Jun 2, Orlando) 2009, Abst. 4577
4. J.W. Park et al. Asian Pacific Ass. Study Liver (Apr 13–16, Hong Kong), 2009, Abst PE256
