Intermittent Vemurafenib May Overcome Resistance

Vemurafenib is a relatively new effective option for the treatment of melanoma, but most patients who respond will develop resistance. Studies by researchers at Novartis suggest that an intermittent dosing strategy may be able to overcome the resistance that occurs with standard continuous dosing.

“We were excited about the translational science that led to approval of the BRAF inhibitor vemurafenib, which extends survival in these patients. But most patients relapse with lethal drug-resistant disease,” explained Darrin Stuart, PhD, Novartis Institutes for Biomedical Research in Emeryville, California, who presented results of early animal and human studies at the American Association for Cancer Research Annual Meeting.

In a previous study, Stuart and colleagues implanted xenografts of BRAF-expressing tumors in mice and found that the tumors developed resistance to vemurafenib. But possibly more important was the observation that the tumors were dependent on the drug for their proliferation. When drug treatment was withdrawn, the tumors stopped growing and regressed.

The next step was to determine if the drug dependency of the tumors was exhibited in humans. The investigators collaborated with scientists at the Royal Marsden Hospital in London, United Kingdom, and evaluated 42 patients with vemurafenib-resistant tumors. Of these, 19 patients had computed tomography scans obtained after drug treatment was stopped. Fourteen of 19 scans showed regression in the rate of tumor growth.

Stuart and colleagues then performed another experiment on mice implanted with BRAF-expressing tumor xenografts and treated them with vemurafenib 4 weeks on and 4 weeks off (intermittent strategy) or continuous vemurafenib. None of the tumors in the animals treated intermittently developed resistance.

This suggests that a drug holiday and intermittent treatment could be beneficial in patients taking vemurafenib and might overcome resistance. Stuart was not at liberty to discuss Novartis’ plans for the future, but stated that intermittent dosing was a strategy that he hopes researchers will pursue.

Reference
Das Thakur M, Fisher R, Salangsang F, et al. Modeling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Presented at: American Association for Cancer Research 2013 Annual Meeting; April 8, 2013; Washington, DC. Abstract LB-144.