Baseline Prognostic Factors for Metastatic Melanoma With BRAF V600 Mutation

Baseline lactate dehydrogenase (LDH) level, performance status, disease burden, and gene signature are key factors for determining the survival outcomes of patients with BRAF V600 mutation–positive metastatic melanoma, according to the results of a study by Axel Hauschild, MD, Professor of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany, and colleagues (JAMA Onc. 2018 Aug 2. Epub ahead of print).

Before the introduction of BRAF and MEK inhibitors, prognostic survival outcomes for patients with metastatic melanoma were generally determined via disease stage, LDH levels, and baseline Eastern Cooperative Oncology Group (ECOG) performance status. Recent research has shown that prognostic subgroups exist among patients with BRAF V600 mutation–positive metastatic melanoma who are receiving treatment with dabrafenib plus trametinib.

To expand on this, Dr Hauschild and colleagues carried out a retrospective exploratory recursive partitioning analysis to identify patient subgroups that are defined by baseline prognostic factors and who have unique survival outcomes regardless of the treatment they received. They also sought to apply the prognostic subgroups identified to survival outcomes across cohorts receiving dacarbazine, vemurafenib, or cobimetinib plus vemurafenib, and to assess the relationship between of previously defined gene expression signatures and survival outcomes in the context of prognostic models of patients with metastatic melanoma and BRAF V600 mutation that have already been developed.

Using pooled data from the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies, Dr Hauschild and colleagues modeled links between prespecified covariates—ie, age, sex, race, geographic region, baseline ECOG performance status, baseline LDH level, disease stage at enrollment, liver metastases, and the baseline sum of the longest diameters of target lesions (SLDs)—and survival outcomes among patients with BRAF V600 mutation–positive metastatic melanoma. The analysis included 1365 patients, 1032 (75.6%) of whom were aged >65 years. A total of 310 patients received cobimetinib plus vemurafenib; 717, vemurafenib alone; and 338, dacarbazine. The median follow-up time was 14.1 months.

Among all patients in the analysis, baseline LDH level, ECOG performance status, presence or absence of liver metastases, and baseline SLDs were significant predictive factors of progression-free survival (PFS). The median PFS was longest in patients with lower LDH levels (≤2 × upper limit of normal [ULN]), an ECOG performance status 0, and shorter SLD (≤44 mm), spanning 11.1 months (95% confidence interval [CI], 7.0-18.4 months), and shortest in those with elevated LDH levels (>2 × ULN; median PFS, 3.5 months; 95% CI, 3.0-3.8 months). Dr Hauschild and colleagues observed similar PFS trends when these prognostic subgroups were applied to the cohorts receiving cobimetinib plus vemurafenib, vemurafenib alone, or dacarbazine.

In addition, Dr Hauschild and colleagues reported that baseline LDH levels, ECOG performance status, and SLDs were significant prognostic factors for overall survival (OS). The longest median OS (27.2 months; 95% CI, 22.1-32.1 months) was seen in patients with normal LDH levels and shorter SLDs (≤45 mm), and shortest median OS was observed in those with elevated LDH (6.0 months; 95% CI, 5.3-6.8 months). Among patients with normal LDH levels and shorter SLDs, 3-year OS rates were 53.3% (95% CI, 39.5%-67.1%) in the cobimetinib plus vemurafenib cohort, 35.6% (95% CI, 27.4%-43.8%) in the vemurafenib cohort, and 35.6% (95% CI, 24.8%-46.4%) in the dacarbazine cohort.

A recursive partitioning analysis of patients with available gene expression data identified gene signature as a significant prognostic factor for PFS in those with normal LDH levels. The 3-year PFS rates were 21.9%, (95% CI, 15.4%-28.4%) and 8.8% (95% CI, 3.6%-14.1%) in immune and cell cycle signatures, respectively. Of note, however, the recursive partitioning analysis for OS did not identify gene signatures as a significant factor.

“[F]indings from this analysis are robust and generally consistent with those of other analyses, indicating that baseline LDH, performance status, extent of disease, and gene expression signature are key determinants of survival outcomes in patients with BRAF V600–mutated metastatic melanoma treated with BRAF and/or MEK inhibitors,” Dr Hauschild and colleagues said.

“The results of this analysis provide a framework that may be used to compare outcomes across trials and regimens in patients with metastatic melanoma. Understanding treatment effects of different regimens across prognostic groups, as described by us and others, may aid clinicians in clinical decision making for individual patients,” they concluded.—Janelle Bradley