Factors Affecting Dabrafenib/Trametinib Outcomes in Melanoma Identified
In the largest-to-date analysis of treatment-naïve metastatic melanoma patients with BRAF V600 mutations treated with dabrafenib and trametinib, researchers have found that baseline LDH levels and number of disease sites were the most significant factors affecting survival.
Georgina Long, BSc, PhD, MBBS
In the largest-to-date analysis of treatment-naïve metastatic melanoma patients with BRAF V600 mutations treated with dabrafenib (Tafinlar) and trametinib (Mekinist), researchers have found that baseline LDH levels and number of disease sites were the most significant factors affecting survival.
In a pooled analysis of 3 randomized clinical trials with over 600 patients, the researchers concluded that those patients with LDH levels less than the upper limits of normal (ULN), and melanoma affecting less than 3 sites, had a 1-year overall survival (OS) of 90%, and a 3-year OS of 70%. These patients also showed a superior progression-free survival (PFS) of 61% at 1 year and 33% at 3 years.
“Patients who experienced a complete response also did very well,” said lead researcher Georgina Long, MD, PhD, medical oncologist at the Melanoma Institute Australia. Ninety-five percent of patients with compete responses were alive at 1 year, and 88% were alive at 3 years after treatment. Long presented data from the analysis at the 2015 Society for Melanoma Research Congress.
In the study, researchers looked at outcomes from 2 phase III clinical trials—the COMBI-V study, which compared treatment with dabrafenib plus trametinib versus vemurafenib (Zelboraf) alone, and the COMBI-D trial, which compared dabrafenib plus trametinib treatment with dabrafenib alone. A phase I/II trial with 54 patients that compared dabrafenib with trametinib treatment was also included in the analysis.
The researchers’ aims were to characterize the clinical features associated with progression and their influence on survival post-progression, Long said. After a median follow-up of 20 months, 35% of patients (n = 221) in the studies remained alive and progression-free, and 290 patients had died.
The researchers analyzed baseline factors known to be associated with prognosis in melanoma. These risk factors included age, BMI, target lesion diameter, LDH level, sex, ECOG performance status, number of disease sites, and whether or not the patient had visceral disease.
“After multivariate analysis, there were only 4 factors that affected overall survival and progression-free survival: LDH, ECOG performance status, the number of organ sites affected by melanoma, and sex,” Long said. The strongest risk factor, however, for survival and progression-free survival was LDH level.
“Patients with a normal LDH had a 71% risk reduction for progression and a 77% risk reduction for death,” Long said.
When the researchers analyzed PFS among patients with normal LDH versus those who had LDH ≥ULN, they found that those who had greater LDH levels (n = 219) had a 3-year PFS of just 13%. Those with the highest LDH levels (>2 X ULN, n=70) fared the worst with a 3-year PFS of 2%.
Even when the researchers considered the impact of disease sites combined with LDH levels, they found that abnormal LDH was more likely to adversely affect outcomes. Among patients with normal LDH and melanoma that affected >3 sites, the 3-year PFS was 17%, Long said.
After multivariate analysis, LDH levels were also a stronger factor in OS than number of disease sites or ECOG status. Patients with a normal LDH (n = 398) had a 3-year OS of 57%, while those with an LDH ≥ULN had a 3-year OS of 7%.
Those with the worst LDH levels (≥2 X ULN, n=70) fared the worst in terms of survival with a 2- and 3-year OS of 7%. Patients with an LDH of 1 to ≤2 X ULN (n = 149) had a 2-year OS of 33% and a 3-year OS of 9%.
The scientists then looked at the factors that affected survival after progression, and found that only the pattern of disease progression affected survival, Long said.
Patients who progressed in their baseline lesions survived for only 10.1 months after progression. Those who developed new non-CNS lesions survived for 9.5 months, and patients who developed new CNS lesions survived 3.8 months after progression. Patients who had baseline lesions and also developed new lesions survived for 4 months after progression, Long said.
“These results show us that it’s not just the kinetics of progression that matter. Survival is not just about speed, it’s also about the pattern of progression that occurs,” Long said.
Long noted that no baseline patient characteristics predicted survival outcomes after progression. “Survival after progression was only affected by what the patients were like at the time of progression,” she said.
“The data on patients with the poorest survival are important, because they will enable us to explore translationally in tumor tissues what targets might affect improve outcomes. It will help us find future target pathways,” Long said.
She noted that the researchers will also be building a model to analyze the influence of LDH levels among patients who had complete responses—and had the longest survival. “We’ll be looking at whether complete responses or LDH levels are more influential in predicting outcomes,” she said.
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