Continuous dosing superior to intermittent in BRAF-mutated melanoma

Approximately half of patients with metastatic melanoma have BRAF mutations, specifically BRAF V600E and BRAF V600K mutations, that enable tumor cells to grow out of control. Continuous dosing with a combination of BRAF and MEK inhibitors has shown better results than intermittent dosing in these cases, according to recent research, while combination regimens also show promise.

Any patient with metastatic melanoma, as well as those with stage III node-positive melanoma should receive BRAF testing on their tumor, according to Alain Algazi, MD, associate professor in the department of medicine at University of California, San Francisco.

“It’s one of the basic features we need to know about cancer before we initiate treatment,” he told Healio.

In the United States, many patients receive immunotherapy first if they have indolent disease or a BRAF and MEK inhibitor combination if they have a more aggressive disease.

Some studies have shown some success in using all three – immunotherapy, BRAF inhibitors and MEK inhibitors – in combination, according to Algazi.

“The issue there is the more drugs you give at one time, the more likely to have side effects,” he said. “That’s one potential constraint, especially for patients who are physically unwell for reasons other than cancer.”

Most patients are currently treated with both BRAF and MEK inhibitors continuously until disease progression slows, which has had a great deal of success, but for a limited time.

“The BRAF inhibitors and the BRAF/MEK inhibitor combinations would take the majority of patients and put them into a very deep remission within weeks,” Algazi said. “There still remains no treatment that is quite as fast for inducing remission in these patients. The main problem with the therapy is that if you just use these drugs they only work for a certain period of time.”

Almost any patient with the BRAF mutation can be treated with BRAF inhibitors, excluding those who have negative reactions or side effects, and it is often used in patients with aggressive disease.

The average patient, however, stays in remission for approximately 1 year after treatment, but the cancer ends up coming back.

“It adapts. Just like natural selection, it finds a way to survive,” Algazi said. “When you give these BRAF inhibitors you get a rapid reduction of tumor, but then the tumors find their way around. They adapt under the selective pressure of the drug.”

Researchers have found success in intermittent dosing in preclinical studies, leading to a clinical examination.

One such trial, led by Algazi, examined the response of patients who received a combination of BRAF and MEK inhibitors continuously compared with those who were treated with both drugs on a 3-week-off, 5-week-on schedule.

All patients received dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, Novartis) for 8 weeks to begin and were then randomized into the two groups.

“You’re varying the selective pressure. You’re not just allowing the population and tumor cells to grow and adapt because the drug is not always there. The idea is if you start intermittent dosing, you might select against resistant cells and in favor of sensitive cells so the tumors might be under control for longer,” Algazi said. “In animals, that works great.”

Previous mice studies showed the intermittent dosing to maintain sensitivity to the drug for longer periods.

The large human study found, however, that the hypothesis did not translate in human patients as it had in mice models.

“This approach to controlling acquired resistance didn’t really work,” Algazi said. “We used the most commonly used combination of BRAF and MEK inhibitors, we put this in the clinic at dozens of sites – both academic and community sites – and it was not something that could be translated to patients.”

Reasons why intermittent dosing did not work as well in humans could be numerous. For example, it’s known that the drug is metabolized differently in patients compared to animals.

Algazi suggested evaluating whether there are drugs that could be used during intermittent dosing treatment gaps that could accelerate tumor death or different intermittent dosing schedules, such as rapid cycling on and off treartment hat might be more effective based on more recent animal studies.

“If we’re going to try to use intermittent dosing, we’re going to have to study the parameters and we have to consider the differences in how drugs are metabolized between people and animals. We have to have a very specific reason to believe that the schedule we are using is going to be better,” he said. “A lot of things could be explored to make this work. But it would be appropriate to pilot this in a smaller number of patients if we’re going to do intermittent dosing in the future.”