Prognostic features predict durable response to dabrafenib, trametinib
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Favorable baseline prognostic features, such as fewer metastases and lower lactate dehydrogenase, appeared associated with durable responses and prolonged survival in patients with BRAF V600-mutated metastatic melanoma, according to findings from an international study.
Further, the combination resulted in a median OS of longer than 2 years in BRAF inhibitor-naive patients. Because dabrafenib (Tafinlar, Novartis) combined with trametinib (Mekinist, Novartis) has become the standard of care in this setting, these results validated findings from other phase 3 trials that compared the doublet to single-agent BRAF inhibitors.
“There are a subgroup of BRAF-mutation positive patients who benefit long-term from treatment with combined BRAF and MEK inhibition,” Georgina V. Long, MD, PhD, associate professor of melanoma biology and translational research at University of Sydney in Australia, told HemOnc Today. “These drugs work for a time in almost everyone, but now we show that not all patients develop resistance. In this study we have looked at some of the clinical predictors of the long-term responders and survivors.”
Due to the study’s extended duration of follow-up, researchers were able to report on OS and analyze the clinical correlates of those who experienced prolonged survival.
The original open-label study had four parts; however, this analysis focused on 78 BRAF inhibitor-naive patients enrolled in part B (n = 24) or part C (n = 54) who received dabrafenib (150 mg twice daily) and oral trametinib (2 mg once daily).
Among patients in part B of the study, 44% achieved 1-year PFS, 22% achieved 2-year PFS and 18% achieved 3-year PFS. Among patients in part C, PFS rates were 41% at 1 year, 25% at 2 years and 21% at 3 years.
The median OS was 27.4 months (95% CI, 12.9-not reached) in part B and 25 months (95% CI, 17.5-36.5) in part C.
In part B, OS rates were 72% at 1 year, 60% at 2 years and 47% at 3 years. For the part C patients, OS rates were 80% (95% CI, 66-88) at 1 year, 51% (95% CI, 37-64) at 2 years and 38% (95% CI, 25-51) at 3 years.
Prolonged survival appeared associated with metastases in fewer than three organ sites (HR = 0.34; 95% CI, 0.17-0.7) and lower baseline lactate dehydrogenase (HR = 0.21; 95% CI, 0.1-0.44).
Sixty-two percent (95% CI, 42.4-76.1) of patients with normal baseline lactate dehydrogenase achieved 3-year OS.
The rate of 3-year OS among patients who achieved a complete response to therapy was 63% (95% CI, 22.9-86.1).
The researchers added that the use of immunotherapies after cessation of the dabrafenib/trametinib combination may have affected the OS outcomes, as 28% of the patients received ipilimumab (Yervoy, Bristol-Myers Squibb) and 11% received a PD-1/PD-L1 inhibitor after progression in part C of the study.
“The next steps are to determine if there are tissue biomarkers that can predict who the long-term beneficiaries are,” Long said. – by Anthony SanFilippo
Reference:
Long GV, et al. J Clin Oncol. 2016;doi:10.1200/jco.2015.62.9345.
For more information:
Georgina V. Long, MD, PhD, can be reached at georgina.long@sydney.edu.au.
Disclosure: Long reports consultant/advisory roles with Amgen, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Merck, Novartis and Provectus Pharmaceuticals. Please see the full study for a list of all other researchers’ relevant financial disclosures.