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Original Research| Volume 148, P61-75, May 2021

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Outcome of melanoma patients with elevated LDH treated with first-line targeted therapy or PD-1-based immune checkpoint inhibition

Published:March 15, 2021DOI:https://doi.org/10.1016/j.ejca.2021.01.034

      Highlights

      • This multicentre cohort study investigated 403 melanoma patients with elevated LDH.
      • End-points were progression-free and overall survival (OS) in first-line therapy.
      • Targeted therapy (TT) achieved the highest response rates in BRAF-mutant patients.
      • OS appears longer for combined anti-PD-1 and anti-CTLA-4 than for TT.
      • OS appears longer for combined anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone.

      Abstract

      Background

      Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking.

      Methods

      This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting.

      Results

      Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4–1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2–2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3–1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8–2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6–1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5–1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding.

      Conclusions

      Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone.

      Graphical abstract

      Keywords

      Abbreviations:

      AJCC (American Joint Committee on Cancer), BOR (Best overall response), BRAF (B-Raf proto-oncogene), CI (Confidence interval), CR (Complete response), CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4), DAG (Directed acyclic graph), DCR (Disease control rate), ECOG (Eastern Cooperative Oncology Group), HR (Hazard ratio), ICI (immune checkpoint inhibition), IPTW (Inverse probability of treatment weighting), LDH (Lactate dehydrogenase), MEK (Mitogen-activated protein kinase), OS (Overall survival), ORR (Overall response rate), PFS (Progression-free survival), PD-1 (Programmed cell death 1), PR (Partial response), PD (Progressive disease), RR (Relative risk), SD (Stable disease), TT (Targeted therapy), ULN (Upper level normal), wt (Wildtype)
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