Intermittent Dosing May Overcome Resistance to Vemurafenib in Patients With Melanoma

Stuart photo by © 2013 AACR/Todd Buchanan

Darrin Stuart, PhD

The availability of vemurafenib was considered a major advance in the treatment of melanoma. However, while patients with BRAF mutations initially respond to the drug, resistance eventually develops. A preliminary study presented at the 2013 AACR Annual Meeting suggests that using an intermittent dosing strategy with vemurafenib, instead of continuous dosing, has the potential to overcome the development of resistance in patients with melanoma treated with the drug.

“When vemurafenib was introduced, it was exciting to witness the translation of the discovery of BRAF mutations in melanoma into an effective therapy. However, it was disappointing to see patients stop responding to such a promising therapy after 6 to 8 months of treatment,” said Darrin Stuart, PhD, senior research investigator at the Novartis Institutes for Biomedical Research in Emeryville, California.

BRAF mutations occur in more than 50% of patients with melanoma, and vemurafenib extends survival for these patients. However, most of these patients will relapse with lethal drug-resistant disease, Stuart emphasized.

A previous study by Stuart and colleagues found that xenografts of melanoma tumors expressing BRAF mutations that were implanted in experimental mouse models developed resistance to vemurafenib; moreover, the tumors exhibited dependence on vemurafenib to sustain their growth. When the drug was stopped, tumor growth was suspended and some tumors regressed in the mouse model.

Stuart and colleagues sought to determine whether the drug dependency of the tumors observed in experimental animal models was also present in humans. They studied 42 patients with vemurafenib-resistant tumors. CT scans were available for 19 of these patients who were taken off treatment; 14 of the 19 demonstrated a decrease in the rate of tumor growth once they were no longer taking vemurafenib.

“This is the first evidence that the drug-addicted state that we observed in mouse models may also occur in humans,” said Stuart.

The next step was to implant xenografts of patientderived BRAF-positive tumors in mice and treat them with vemurafenib, either on an intermittent schedule of 4 weeks on/4 weeks off, or on continuous treatment. None of the animals in the intermittent dosing group developed drug resistance.

Continuous dosing maintained the selective pressure required for the few surviving tumor cells to develop resistance, and alternating the selective pressure through intermittent dosing appeared to prevent the evolution and expansion of resistant cells,” Stuart said.

At a press conference, Stuart was asked whether the next step for Novartis will be to study intermittent dosing and compare it with continuous dosing in patients.

“Novartis is interested in testing multiple approaches that include trying different dosing regimens to using different combinations of drugs with vemurafenib,” he replied. “I am not at liberty to say what the company is planning, but I can say we are enthusiastic about the findings I reported at this meeting. Patients derive a clinical benefit from vemurafenib and then develop resistance. Some sort of drug holiday makes sense. I hope people will study this clinically.”

Thakur MD, Fisher R, Salangsang F, et al. Modeling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Presented at: the AACR Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract LB-144.