Continuous dosing of BRAF and MEK inhibitors improves PFS in melanoma subset
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
Algazi A, et al. Abstract CT02-01. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).