Algazi Attests to Benefit of Continuous Dosing of BRAF/MEK Inhibitors in Melanoma

Alain Algazi, MD, an associate professor in the Department of Medicine at University of California San Francisco

Alain Algazi, MD

Continuous dosing with the BRAF and MEK inhibitors dabrafenib (Tafinlar) and trametinib (Mekinist) resulted in superior progression-free survival (PFS) compared with intermittent dosing in patients with BRAF V600-mutated melanoma, according to Alain Algazi, MD, who added that these findings sharply contrasted with what had been observed in animal models.

Preclinical research in animal models suggested that intermittent dosing could potentially delay acquired resistance by selecting tumor cells that grow in the presence of these agents. When intermittent dosing was initiated in animal models, the animals were found to remain sensitive to the treatment for a significantly longer period of time than they did when treated with continuous dosing, according to Algazi.

In the phase 2 SWOG S1320 trial, investigators set out to determine whether intermittent versus continuous dosing of dabrafenib and trametinib would improve PFS in patients with advanced BRAF V600-mutant melanoma. All patients enrolled on the trial 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-weeks-off, 5-weeks-on schedule.

Results presented at the 2020 AACR Virtual Annual Meeting I showed that the median PFS was 9.0 months from randomization with continuous dosing compared with 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.

"We saw that continuous dosing provided longer disease control than intermittent dosing [did in this patient population," said Algazi. "This really differed from what we saw in animals. We rely on animal models to help us make decisions about what treatments to take into patients, so it is important to understand what might have made the findings different."

In an interview with OncLive, Algazi, 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, discussed the SWOG S1320 trial further, the future of intermittent dosing in melanoma, and future clinical trials in the field focusing on novel combinations to maximize the benefit of current therapies.

OncLive: Could you speak to the challenge of acquired resistance with regard to BRAF and MEK inhibitors in BRAF V600-mutant melanoma?

Algazi: When these drugs first came out, they were considered to be wonder drugs. With these agents, you could induce rapid remissions in about 70% of patients very quickly, usually within weeks or months. You would see the tumors melting away and patients would get better. However, the remissions [achieved with these agents are] transient; they typically last less than 1 year. As such, when the patients progress on these drugs, some of them will benefit from immunotherapy, but many do not have any viable options to turn to after that. These patients are really looking for answers to help keep their cancer under control.

What are some of the preclinical data to suggest that intermittent dosage of these agents may delay acquired resistance?

Preclinical data showed that some melanoma tumors that become resistant to BRAF inhibitors actually become dependent on the drugs in order to grow. It turns out that the BRAF is like a broken growth switch. Normally, it's a switch that can be turned on and off to tell the cells when to grow and when not to grow. When BRAF is mutated, the switch is on. When the switch is on, it sends that growth signal all the time and causes the tumor cells to grow out of control. With resistant cells, the cells cannot be turned off with the drugs; they just make more of that broken protein switch. You can turn off some of the switch, but there is enough switch left over that continues to send the BRAF signal, so the tumor cells grow anyway. Those resistant cells that are addicted to the drug do not grow very well when there is no drug.

For example, if you had a sensitive cell, the more drug you put into culture with it, the worse it would grow. With the resistant cells, they grow poorly when there is no drug, but they grow poorly when there is tons of drug. In intermediate concentrations, they grow optimally so basically, they are addicted to the drug for optimal growth. What happened in an animal model is when we pulsed the dosing of the BRAF inhibitor, the tumors in the animals somewhat fluctuated in size, but they remained sensitive for a long period of time, much longer than we would get with continuous dosing.

Could you discuss the phase 2 SWOG S1320 trial?

The basic goal of this study was to see whether the intermittent dosing approach that worked well in animals and prolonged drug sensitivity would work in people. This was a large, phase 2 clinical trial that was run by SWOG in cooperation with ECOG. In the trial, patients were randomized to receive wither continuous dosing of dabrafenib and trametinib or an intermittent schedule of dosing. All patients were treated continuously for 8 weeks to shrink the tumor. Half the patients continued on continuous dosing and the other half received intermittent therapy. We wanted to see whether the intermittent therapy would yield a longer PFS or a longer period of cancer control.

One thing I want to add is that this was a big cooperative group study and it was conducted with patients from almost 5 dozen enrollment sites; it was not just done in a few academic centers, but also at smaller practices. As such, it more closely approximates what can be done in a community setting with normal doctors taking care of their patients as opposed to specialists.

Could you speak to the findings presented on the AACR virtual platform?

Basically, we found that continuous dosing provided longer disease control than intermittent dosing; this was really a sharp contrast to what was seen in animals and it makes you start to think about why this would be different.

One issue is that animals metabolize drugs differently than we do. Sometimes they will eliminate a drug from their system more quickly than a person would. One of the thoughts had been that in order to get the resistant cells to die off, you would need to remove the drug very quickly. It may be that the drug lingered longer in people, and as such, we did not see such a robust effect of drug withdrawal that we saw in animals.

Another possibility is that people [have] many different resistance mechanisms that could [differ from those seen in animals] and that might be important. Trying to understand what you can learn from an animal model and what you need to know in order to test in people is important. Then, by putting those pieces together to understand the differences between people and animals, [we might get the] insight [we need to] make better therapies.

Do you think intermittent dosing will still be explored in the future? Are any other ways to delay acquired resistance with these inhibitors being explored?

Intermittent dosing is being investigated quite broadly. One of the reasons why this study is important is because maybe 70 different trials are examining intermittent dosing in different tumor types—at least 5 of these are being done in melanoma. Those results will come out in the near future and it may be that we see there are some differences based on schedule or which agents are used, so those data will be pretty interesting.

Other trials are evaluating different ways to deploy these agents and trying to maximize their benefits. For example, [one approach is evaluating the combination of] targeted therapy agents with immunotherapy; several trials have explored that approach. The trial right before we presented, which was delivered by Grant A. McArthur, MBBS, PhD, of Peter MacCallum Cancer Centre, showed that there was a survival benefit to giving immunotherapy and these BRAF/ MEK inhibitors at the same time in patients.

There is a lot of interesting work dedicated to determining how to leverage the effective drugs we have and trying to keep patients well for as long as possible. The intermittent dosing hypothesis is not dead, but we have to do more work to figure out how to best deploy it. There is an open question regarding whether an animal type of protocol can really be used effectively in people.

Are there any other unanswered questions left by this research?

A bunch of open questions exist. One of which that comes to mind is that the survival was no different in the 2 arms [of the study]. In fact, if you took the OS from the time the drug stopped working until just moving forward, the survival after disease progression was longer in the intermittent dosing arm. The intermittent dosing controlled the cancer for less time but after it was stopped, patients lived just as long as they would have had they been on the continuous dosing arm. That’s interesting to note.

We believe that these drugs actually have an effect on the immune system and understanding how to maximize that effect may be extremely important. We need to better understand this so that we can [figure out how to] leverage [that knowledge]. One thing about immunotherapy is that those responses can be very durable, so anything we can do to increase the number of patients who experience a long-lasting immune response to cancer is essential.

What is your take-home message to your colleagues regarding these findings?

My take-home message to my colleagues is that the devil is in the details. Major differences between models in mice and cancer in people exist; this is based on several factors. For example, the diversity of cancer and diversity of mechanisms of resistance in people may not be replicable in a mouse model. We need to take into account those differences. Mouse models can be extremely valuable in preclinical research. Certainly, the idea of using 2 drugs instead of 1 for this cancer came about because of preclinical work. However, again, we have to pay attention to some of the nuances and differences between mice and people if we want to get the most we can out of this work.

Beyond this research, are you working on any other research in this space that you wanted to highlight? Are there any interesting efforts being made that you want to hear more about?

One thing I wanted to highlight in particular is that there have been several studies in which we are examining triplet therapies or multiple agents to prevent resistance in BRAF-mutant cancers. This can be extremely tricky. It’s like if you have a leaking dam, and you try to put a finger in the dam, and then there's another leak and another finger is needed, and then you stick your toe in the third leak; the cancer finds a way around. Trying to prevent resistance or address resistance by blocking more signals may be very difficult. One of the appeals of the intermittent dosing hypothesis was that we may be changing when resistance develops and altering the selected pressure on these tumors. That kind of idea, where we're not just trying to plug 15 different holes or finding 15 ways in which the cancer can still grow, is still worth thinking about as we design studies moving forward.

[I'm also involved] in a number of studies examining immunotherapy. Specifically, I am interested in the idea that we can directly administer medicine into the tumor to help therapies work [more effectively]. Can we use injections to get a whole-body response to PD-1 antibodies, such as pembrolizumab (Keytruda) and nivolumab (Opdivo), when those drugs alone do not do the job? I am also doing work with biomarkers to try to identify which therapy would be best for which patients. I'm doing that research in collaboration with my colleague Matthew H. Spitzer, PhD, at UCSF.

What would you say were the most exciting studies presented at the meeting this year?

One of the things people ask about with regard to studies is whether the research is practice changing. What is practice changing? The combination of targeted therapy and immunotherapy may be practice-changing if [this approach results in] people living longer; as such, that may be worth doing in our patients. More studies are showing that people are living longer when you give that combination at the same time rather than waiting for one to stop working; that could change what we do.

Algazi A, Othus M, Daud A, et al. SWOG S1320: Improved progression-free survival with continuous compared to intermittent dosing with dabrafenib and trametinib in patients with BRAF mutated melanoma. Presented at: the 2020 AACR Virtual Annual Meeting I; April 27-28, 2020. Abstract CT013. bit.ly/3bXnMX5