Preliminary Evidence Suggests Intermittent Dosing Can Overcome Resistance to Vemurafenib in Melanoma

The Journal of Targeted Therapies in Cancer, June 2013, Volume 1, Issue 7

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.

Debu Tripathy, MD, Co-Leader, Women's Cancer Program, Norris Comprehensive Cancer Center, University of Southern California, discusses two important trials in breast cancer looking at extended hormonal therapy.

It is understood now that 10 years of tamoxifen is superior to 5 years in premenopausal patients with high-risk, early-stage disease. However, Tripathy says, most patients are postmenopausal and see benefit when treated with aromatase inhibitors. The question remains as to whether these patients could see benefit when treated with 10 years of an aromatase inhibitor compared to 5 years.

Clinical Pearls

While these results may not be the most scientifically interesting, Tripathy says, they will surely affect many patients.

  • For patients who are premenopausal with high-risk, early-stage breast cancer, 10 years of tamoxifen has shown superiority to 5 years of tamoxifen
  • In postmenopausal women, aromatase inhibitors have demonstrated superiority and a better side effect profile
  • Two large studies look to answer the question as to whether extended use (10 years) of aromatase inhibitors will show benefit compared to 5 years

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Nivolumab produced sustained survival with a manageable long-term safety profile in advanced melanoma, NSCLC and renal cell carcinoma, supporting its ongoing clinical development in controlled phase III trials with survival endpoints.

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Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid and durable responses were observed. PD-L1 tumor status correlated with response to MPDL3280A.

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Rates of dose adjustment in patients treated with tivozanib versus sorafenib in the phase III TIVO-1 study.

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View all coverage from the 2013 ASCO Meeting

Darrin Stuart, PhD

Results of a preliminary study presented at AACR 2013 suggest 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 melanoma patients, and vemurafenib extends survival for these patients. However, most of these patients will relapse with lethal drugresistant disease, Stuart said.

A previous study by Stuart and colleagues found that xenografts of melanoma tumors expressing BRAF mutations 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 tumor drug dependency observed in experimental animal models was also present in humans. They studied 42 patients with vemurafenibresistant 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,” he said.

The next step was to implant xenografts of patient-derived 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 said. “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.”

Reference

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.