Abstract
The prognosis of patients with advanced melanoma has improved dramatically. However, the clinical outcomes of patients with highly elevated serum lactate dehydrogenase (LDH) remain very poor. The aim of this study was to explore whether patients with normalized LDH after targeted therapy could benefit from subsequent treatment with immune checkpoint inhibitors (ICI). Data from all patients with BRAF-mutant metastatic melanoma with a highly elevated serum LDH at baseline (≥2× upper limit of normal) receiving first-line targeted therapy between 2012 and 2019 in the Netherlands were collected. Patients were stratified according to response status to targeted therapy and change in LDH at start of subsequent treatment with ICI. Differences in overall survival (OS) between the subgroups were compared using log-rank tests. After a median follow-up of 35.1 months, median OS of the total study population (n = 360) was 4.9 months (95% CI 4.4–5.4). Of all patients receiving subsequent treatment with ICI (n = 113), survival from start of subsequent treatment was significantly longer in patients who had normalized LDH and were still responding to targeted therapy compared to those with LDH that remained elevated (median OS 24.7 vs. 1.1 months). Our study suggests that introducing ICI upon response to targeted therapy with normalization of LDH could be an effective strategy in obtaining long-term survival in advanced melanoma patients with initial highly elevated serum LDH.
Highlights
Multiple effective systemic treatment options have emerged for patients with advancedBRAF-mutant melanoma over the last decade
The main objective of the study was to investigate whether the response to targeted therapy and level of serum lactate dehydrogenase (LDH) at start of subsequent treatment with immune checkpoint inhibitors (ICI) affects survival
LDH of ≥2x upper limit of normal (ULN) treated with first-line BRAF(/MEK) inhibitors, median overall survival (OS) was significantly longer in patients with normalized LDH and still responding to initial targeted therapy who started second-line treatment with ICI, compared to those with elevated LDH at start of treatment with ICI
Summary
Multiple effective systemic treatment options have emerged for patients with advancedBRAF-mutant melanoma over the last decade. The CTLA-4 antibody ipilimumab [2], combination therapy with a BRAF and MEK inhibitor [3] and treatment with anti-PD-1 antibodies as monotherapy [4,5] or combined with a CTLA-4 antibody [6]. Combination therapy with a BRAF and MEK inhibitor has resulted in a median overall survival of over two years [7], while treatment with anti-PD-1 concurrently showed significant improvements, with 2-year survival rates of 55–58% [8]. Elevated serum lactate dehydrogenase (LDH) level is a well-known marker for poor outcome, and a strong negative predictor for response to immune checkpoint inhibitors (ICI) and targeted therapy [7,8]. The majority of BRAF mutant patients with elevated serum
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