Baseline Factors Linked With Outcome in BRAF-Mutant Melanoma

Baseline levels of lactate dehydrogenase (LDH) are significantly associated with progression-free survival (PFS) outcomes in patients with BRAF V600–mutated metastatic melanoma treated with BRAF and/or MEK inhibitors, according to a new study. Other baseline factors associated with outcome included ECOG performance status, disease burden, and gene signature.

“Extended follow-up of studies evaluating BRAF-inhibitor monotherapy or combined BRAF and MEK inhibition show a plateau in survival curves beyond about 3 years, suggestive of a subgroup of patients with prolonged survival,” wrote study authors led by Axel Hauschild, MD, of University Hospital Schleswig-Holstein in Kiel, Germany. “Development of prognostic models may provide insight into clinical trial results and inform clinical decision making in the management of patients with metastatic melanoma.”

The new retrospective study used recursive partitioning analysis (RPA) to model associations between baseline variables and survival outcomes in 1,365 patients in the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies. Most of the cohort (75.6%) was older than 65 years; 310 patients were treated with cobimetinib plus vemurafenib, 717 received vemurafenib alone, and 338 received dacarbazine. The results of the study were published in JAMA Oncology.

In the full cohort, baseline LDH level was the strongest determinant of PFS. Other factors significantly prognostic of PFS included ECOG performance status, presence or absence of liver metastases, and baseline sum of longest diameters of target lesions (SLDs).

A group with elevated LDH levels less than or equal to twice the upper limit of normal, an ECOG performance status score of 0, and SLD less than or equal to 44 mm had the longest median PFS at 11.1 months. Elevated LDH level greater than twice the upper limit of normal defined the group with shortest PFS, at 3.5 months.

The 3-year PFS rate was 51.8% if they received cobimetinib plus vemurafenib, which was higher than the vemurafenib group (26.0%) and the dacarbazine group (0.0%).

Similar results were seen for overall survival (OS), again with baseline LDH level emerging as the strongest prognostic factor. Median OS was longest in patients with normal LDH levels and an SLD of no more than 45 mm (22.7 months), and it was shortest in patients with LDH levels greater than twice the upper limit of normal (6.0 months).

In a subset of patients for whom gene expression analysis was available, those categorized as having an immune gene signature had improved PFS and OS compared with those with a cell cycle signature. “As baseline immune status has also been shown to predict improved clinical outcomes among melanoma patients treated with anti–PD-1, this result raises the possibility that immune assessments should be integrated into the clinical assessment of all stage IV melanoma patients, and potentially utilized in the design of clinical trials of targeted therapies in addition to immune therapies,” said Michael A. Davies, MD, PhD, of the University of Texas MD Anderson Cancer Center, a melanoma expert who was not involved with this study.

Davies said the results regarding elevated LDH levels are largely consistent with previous research, and “reinforce the critical need to improve our understanding and treatments for metastatic melanoma patients with elevated serum LDH levels.”