In the JournalsPerspective

Prognostic features predict durable response to dabrafenib, trametinib

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.”

Georgina V. Long, MD, PhD
Georgina V. Long

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.

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.”

Georgina V. Long, MD, PhD
Georgina V. Long

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.

    Perspective
    Sanjiv S. Agarwala, MD

    Sanjiv S. Agarwala

    A burning question confronting clinicians who treat patients with metastatic melanoma who harbor the BRAF mutation is whether to first pick immunotherapy or therapy targeting the MAP kinase pathway with a combination of BRAF and MEK inhibitors.
    This decision has become even more important — and complicated — after the recent regulatory approval of combination checkpoint blockade immunotherapy with anti–CTLA-4 and anti–PD-1. In a recently published randomized trial, this checkpoint blockade showed impressive activity with the combination of nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb) over either agent alone in both BRAF-mutated and wild-type patients.
    So what’s a clinician to do?
    Historically, choices have been made based on clinical presentation. Patients with aggressive disease — including those with multiple visceral metastases, high tumor load and those who are symptomatic — have been treated with BRAF/MEK inhibitor therapy due to their ability to produce a rapid response. Patients with less aggressive disease and those with “more time” in the assessment of the clinician were often offered immunotherapy first. The reasons for this have been largely based upon the early data suggesting that, with targeted therapy, responses occur quickly but may not be that durable, the reverse being true for immunotherapy.
    The manuscript by Long and colleagues provides the longest follow-up for the data with the combination of dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, Novartis), the first BRAF/MEK combination to be approved for melanoma. These data provide reassurance that durable benefit can indeed be obtained with this combination with an impressive median OS of more than 2 years and a 20% PFS rate at 3 years, indicating the potential for long-term benefit for some patients. Not surprisingly, clinical benefit was most pronounced in patients with fewer metastases and lower lactate dehydrogenase levels.
    Survival data from the combination of nivolumab and ipilimumab are not yet available to make comparisons and these are awaited with interest.  
    It is good news for our patients that we have effective options and choices in what used to be a universally fatal disease.  It is hoped that the ongoing intergroup trial EA6134 — which randomly assigns patients with BRAF-mutated metastatic melanoma to either dabrafenib/trametinib or nivolumab/ipilimumab with crossover at progression — may help clarify the correct choice in this clinical scenario.
    In the meantime, clinical judgement and patient preference will continue to play a major role in decision-making.

    Reference:
    Larkin J, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1504030.

    • Sanjiv S. Agarwala, MD
    • HemOnc Today Editorial Board member
      St. Luke’s University Hospital
      Temple University

    Disclosures: Agarwala reports no relevant financial disclosures.