Treatment with vemurafenib, a drug in the BRAF inhibitor family, results in rapid tumor shrinkage in metastatic melanoma patients with the V600E BRAF mutation. The response lasts for months, but unfortunately, tumors ultimately become resistant to the treatment. Currently, vemurafenib is given as an oral dose on a daily basis. But a new study published in Nature (doi:10.1038/nature11814) suggests that a 4-weeks-on, 2-weeks-off dosing schedule may help to stave off resistance.
The study was performed in a mouse model of metastatic melanoma by Darrin Stuart, a senior investigator at the Novartis Institutes for Biomedical Research in California and Martin McMahon, a professor of cancer biology at the Helen Diller Family Comprehensive Cancer Center at the University of California in San Francisco. These investigators and colleagues used mice that had received xenografts (transplants of human tissue) of BRAF-mutated melanoma. The researchers created vemurafenib-resistant tumors in these mice by giving them a daily, continuous dose of vemurafenib.
Culturing of vemurafenib-resistant tumor cells taken from the mouse models led to an interesting observation. The resistant cells had difficulty growing unless the media was spiked with vemurafenib. “The fitness benefit given to resistant cells by elevated BRAF (V600E) in the presence of vemurafenib becomes a fitness deficit when the drug is removed,” state the authors in the paper.
McMahon and colleagues then compared a continuous vemurafenib treatment schedule with a 4-weeks-on, 2-weeks-off schedule in the BRAF-mutant mouse model. While the mice that were continuously dosed developed vemurafenib-resistant melanoma within 100 days of starting the treatment, mice given vemurafenib on an on-off schedule did not have drug-resistant melanoma as many as 200 days after their initial therapy.
These results suggest that constant exposure to vemurafenib leads to resistance and that an intermittent dosing schedule could delay—if not prevent—resistance. Whether the same results will be observed in patients needs to be tested. The perfect dosing schedule would balance between allowing tumors to regress and stalling resistance
More basic research in mouse models is needed, but the concept could be tested in a metastatic melanoma clinical trial soon. This study also has implications for other targeted therapies. Hopefully, testing various dosing schedules of targeted agents to find an optimal balance between response and rate of resistance will now be a high priority for not just melanoma researchers, but for all cancer researchers. For example, it is possible that continuous dosing contributes to the rate of resistance to other targeted agents, such as imatinib (Gleevec) prescribed for chronic myeloid leukemia. This could be relatively easily tested in experimental models and then in clinical trials.