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

Sarah Knispel, Maximilian Gassenmaier, Alexander M. Menzies, Carmen Loquai, Douglas B. Johnson, Cindy Franklin, Ralf Gutzmer, Jessica C. Hassel, Carsten Weishaupt, Thomas Eigentler, Bastian Schilling, Patrick Schummer, Judith Sirokay, Felix Kiecker, Carina N. Owen, Maria I. Fleischer, Christopher Cann, Katharina C. Kähler, Peter Mohr, Leonie BluhmDennis Niebel, Kai Martin Thoms, Simone M. Goldinger, Lydia Reinhardt, Friedegund Meier, Carola Berking, Raphael Reinhard, Laura Susok, Paolo A. Ascierto, Konstantin Drexler, Claudia Pföhler, Julia Tietze, Lucie Heinzerling, Elisabeth Livingstone, Selma Ugurel, Georgina V. Long, Andreas Stang, Dirk Schadendorf, Lisa Zimmer

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)61-75
Number of pages15
JournalEuropean Journal of Cancer
Volume148
DOIs
Publication statusPublished - May 2021

Keywords

  • CTLA-4
  • Immune checkpoint inhibition
  • LDH
  • Melanoma
  • PD-1
  • Progression
  • Response
  • Survival
  • Targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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