Continuous dosing of BRAF and MEK inhibitors improves PFS in melanoma subset
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Continuous dosing of dabrafenib and trametinib conferred superior PFS compared with intermittent dosing of the targeted agents among patients with BRAF V600E- and V600K-mutant melanoma, according to results of a randomized phase 2 study presented at the virtual American Association for Cancer Research Annual Meeting.
BRAF and MEK inhibitors induce objective responses in the majority of patients with the most common melanoma mutations, BRAF V600E and BRAF V600K. Acquired resistance to these treatments, however, limits response durations.
Preclinical data suggest intermittent dosing of these drugs could stave off acquired resistance by deselecting tumor cells that grow the most under these treatments.
“This trial was designed based on laboratory observations showing that continued exposure to BRAF inhibitors could lead to the development of resistance cells that require continued drug exposure for optimal growth,” Alain Algazi, MD, associate professor in the department of medicine at University of California, San Francisco, said during the presentation. “In essence, expanded BRAF protein levels compensated for the presence of the drug.”
Algazi and colleagues treated 242 patients, enrolled during a 5-year period from 68 clinical sites, with the BRAF inhibitor dabrafenib (Tafinlar, Novartis) and the MEK inhibitor trametinib (Mekinist, Novartis) continuously for 8 weeks. After that, the researchers randomly assigned 206 patients who did not experience disease progression to continuous treatment (n = 105) or intermittent dosing (n = 101) of both drugs on a 3-weeks-off, 5-weeks-on schedule.
Seventy percent of patients had not been treated previously with immune checkpoint inhibitors.
Study protocol prohibited unscheduled treatment interruptions of both drugs for more than 14 days.
Researchers assessed responses every 8 weeks, coinciding with periods on treatment in the intermittent dosing group. They also assessed adverse events monthly. The design assumed exponential PFS with a median of 9.4 months using continuous dosing, 206 patients and 156 PFS events, according to the abstract.
The study had 90% power with a two-sided alpha = 0.2 to detect a change to a median with an a priori hypothesis that intermittent dosing would improve the median PFS to 14.1 months using a Cox model stratified by the randomization stratification factors, the abstract stated.
Results showed longer median PFS with continuous dosing than with intermittent dosing (9 months vs. 5.5 months).
Researchers observed no difference in median OS between the two groups (29.2 months for both) at median follow-up of 2 years.
Treatment discontinuation due to disease progression occurred among 77% of patients in the continuous dosing group and 84% of patients in the intermittent dosing group. – by John DeRosier
Reference:
Algazi A, et al. Abstract CT02-01. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
Perspective
Back to TopCharles L. Sawyers, MD
The question asked here is whether kinase inhibitors are better if given intermittently vs. continuously.
Why would we even consider intermittent therapy? I’d remind you that it already is the standard dosing in many therapies because of the toxicity, not because of the desire for a better outcome.
In targeted therapies, sparing the normal tissues from toxicities provides the luxury of giving these drugs through a 24/7 target coverage mechanism. Because that is so compelling logically, why would we even consider intermittent dosing?
There are two main reasons. One is the concept that continuous selective pressure will allow a resistant subclone to evolve. In many cases, those resistant subclones are less fit than the parental subclone. Therefore, if you give drug holidays, you could get a longer response duration.
Another concept is the idea of giving higher overall doses in a pulse in order to achieve greater efficacy.
The rationale of this abstract was that continuous BRAF or BRAF-plus-MEK inhibition selects for subclones with mutations that lead to higher ERK output. With that higher ERK output, if you acutely withdraw the inhibitor, you can see a rebound in ERK activity that leads to toxicity.
The trial was designed to test that hypothesis, and it failed.
Why did it fail? One possible explanation is the right patients may not have been enrolled. The hypothesis is that increased BRAF levels set up this potential for ERK toxicity upon drug withdrawal. It is also clear from looking at patient samples that 80% of acquired resistance is associated with restored ERK signaling. But, if you look into the details of that 80%, only a third are due to BRAF amplification. Another third are due to splice variants, and another third are due to RAS pathway mutations.
So, it is possible that by enrolling all comers, a beneficial signal that might have been just restricted to the BRAF-amplified patients could have been missed?
It is very hard to imagine enrolling such a trial, because we don’t know the mechanism of acquired resistance before the patients develop resistance. So, you’d have to do a much larger trial with enough patients in each of these three categories, and then do a subset analysis after the fact.
The second point here is that it’s possible that the withdrawal schedule in this trial did not test the preclinical hypothesis adequately. The toxicity we were hoping to see with ERK rebound requires a very rapid drug withdrawal. Trametinib has a very long half-life, such that there would be a slow decay curve and maybe ERK was not seen.
It may have been better to test the hypothesis with a shorter half-life MEK inhibitor.
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