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Distinct Features Associated With Benefit for BRAF/MEK Inhibition

Sigrid Eckardt
Published Online: May 23,2016
With the development of novel targeted and immunotherapeutic agents that are more efficacious than traditional chemotherapy, treatment paradigms in melanoma have undergone major changes. Current recommendations for first-line systemic therapy for patients with advanced or metastatic melanoma consider BRAF mutation status, tumor growth rate, and the presence or absence of cancer-related symptoms. 

Immunotherapies with agents that block CTLA-4 or PD-1/PD-L1 checkpoints have been associated with durable responses in a subset of patients, and are often considered for patients with low-volume, asymptomatic metastatic melanoma. Targeted therapies, on the other side, are preferred for patients with BRAF-mutant tumors who have symptomatic disease and benefit from the rapid response associated with these agents.1 

A main concern with targeted therapies is tumor resistance that ultimately develops in most patients within 6-12 months. However, as Jason J. Luke, MD, with the University of Chicago Medicine states, “A sizable fraction of patients do very, very well for a long time on targeted therapy.”

A long-term analysis has shown that approximately one fifth of patients with BRAF V600-mutant melanoma receiving combined dabrafenib/trametinib remained progression-free after 3 years, suggesting a plateau of the survival curve.

According to lead author Georgina Long, MD, with the Melanoma Institute Sydney, Australia, and co-authors,2 this defines, “a need to understand the characteristics of patients who derive the greatest benefit from each mode of therapy.” Specifically, “future selection of patients for combined BRAF and MEK inhibition, and the rational design of clinical trials for those who fail it, may be assisted by an analysis of the clinicopathological features of those experiencing long-term benefit and those who progress.”

In their study, Long and colleagues found that good prognostic features such as normal lactate dehydrogenase (LDH) levels, earlier-stage melanoma, and fewer metastatic sites were consistently associated with durable response and prolonged overall survival (OS) with BRAF/MEK inhibitor therapy.2 Patients who survived longest on treatment included those with a complete response (CR), according to RECIST, and patients with a normal baseline LDH (63% and 62%, respectively). Data were from 2 cohorts of BRAF-inhibitor naïve patients (n = 78) who had been treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily).2

Similarly, a study evaluating long-term outcomes of patients who received either BRAF or combined BRAF and MEK inhibitor regimens in phase I to III trials with single agent dabrafenib or vemurafenib, or combined dabrafenib/trametinib found that female sex and normal pretreatment LDH levels were the only factors associated with longer progression-free survival (PFS) and OS.

Lactate Dehydrogenase Serum Level

LDH below the upper limit of normal (ULN) was significantly associated with prolonged survival of patients receiving BRAF/MEK inhibitor combination therapy with dabrafenib/trametinib.2 Patients with a normal LDH at baseline had a median OS of 45.5 months (95% CI, 45.5 to not reached) compared with 16.6 months (95% CI, 11.1-22.6) for patients with an elevated LDH.2 Overall survival rates of patients with normal versus elevated LDH levels at baseline, respectively, were 88% versus 68% at 1 year, 75% versus 18% at 2 years, and 62% versus 5% at 3 years.2

Recent data from phase III COMBI-v trial have also linked baseline LDH serum levels to survival benefits with the dabrafenib/trametinib combination.4 According to lead author Caroline Robert, MD, of Institut Gustave Roussy in Paris, “The longest benefit was in patients with an LDH less than or equal to the upper limit of normal, who had a 2-year overall survival rate of 66% and a median progression-free survival of 17.5 months.” 

In this patient group, median OS was not yet reached with dabrafenib/trametinib and was 21.5 months with vemurafenib (HR, 0.56), translating to a 44% OS benefit with the combination. Patients with an LDH above the ULN had less benefit with a median OS of 10.6 months with the combination and 8.9 months with vemurafenib monotherapy (HR, 0.81).4

Similar observations are emerging from the phase III evaluation of cobimetinib/vemurafenib. OS benefits of the combination were observed in all patient subgroups.5 For patients with both LDH baseline levels, median OS was not reached with the combination and was 23.3 months with vemurafenib. Patients with elevated LDH levels had an OS of 14.8 months with the combination and 11.2 months with vemurafenib alone. According to lead author Victoria Atkinson, MD, of the Princess Alexandra Hospital in Queensland, Australia, “This is consistent with previous combination studies showing that patients with poor prognostic factors do worse.”5

Longer-term analyses of patients who had received both BRAF monotherapy and combined BRAF/MEK therapy have also reported a significant association of normal LDH levels with prolonged survival. Patients with normal LDH levels had a median OS of 23.5 months compared with 7.3 months in patients with elevated LDH levels.3

Across all studies, normal serum LDH levels correlated with continued long-term response without progression (per Cox proportional hazards regression analysis; P = .024,2 or per univariate and multivariate analyses).3 In COMBI-v, in patients with low LDH levels, median PFS was 17.5 and 9.2 months with the combination and monotherapy, respectively (HR, 0.55) and 5.5 versus 4.0 months in patients with elevated LDH levels (HR, 0.70).4

According to Alexander Menzies, MBBS, with the Melanoma Institute Sydney, Australia, and co-authors,3 this evidence “suggests that LDH is not simply prognostic. The biology of metastatic tumors that produce different levels of LDH may be distinct; for example, it has been shown that a high serum LDH level reflects an anaerobic oxidative metabolic state. As such, the best treatments for metastatic patients with normal and elevated LDH levels may be different.”

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Distinct Features Associated With Benefit for BRAF/MEK Inhibition
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