Dr. Algazi on Benefit of Continuous Dabrafenib/Trametinib Dosing in BRAF+ Melanoma

Alain Algazi, MD, associate professor in the Department of Medicine, leader of the UCSF Head and Neck Medical Oncology program and melanoma specialist at UCSF Helen Diller Family Comprehensive Cancer Center, discusses the benefit of continuous dosing with dabrafenib (Tafinlar) and trametinib (Mekinist) in patients with BRAF mutation—positive advanced melanoma.

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In the randomized, phase 2 SWOG S1320 trial, investigators sought to determine whether intermittent versus continuous dosing of dabrafenib and trametinib would improve progression-free survival (PFS) in patients with advanced BRAF melanoma. All patients received continuous dabrafenib and trametinib for 8 weeks. Non-progressing patients were then randomized to receive either continuous treatment or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. A total of 242 patients were treated and 206 patients without disease progression after 8 weeks were randomized (n = 105 continuous; n = 101 intermittent). The median PFS was 9.0 months from randomization with continuous dosing versus 5.5 months from randomization with intermittent dosing (P =.064). The median overall survival in both groups was 29.2 months (P =.93) at a median follow up of 2 years.

Investigators found that the continuous dosing provided longer disease control than intermittent dosing, says Algazi. This was a sharp contrast to what had been observed in animals, which prompts the question of why these results differed between animals and humans. Investigators rely on animal models to determine what treatments should be evaluated in patients, says Algazi. As such, it is important to understand the reason behind these contrary findings.

One issue is that animals metabolize drugs differently than humans do and sometimes they will eliminate a drug from their system more quickly than a human would. Another thought is that in order to get the resistant cells to die off, the drug needs to be moved very quickly; it may be that the drug lingers longer in people and did not produce such a robust effect of drug withdrawal that had been seen in animals, postulates Algazi. Another possibility is that an animal model might not have as many resistant mechanisms as a human does, which could be an important factor. Trying to understand what is learned from an animal model and what to test in people is important. Once investigators can better understand the differences between people and animals, that will provide them with improtant insight to inform the development of better therapies, concludes Algazi.