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

Knispel, Sarah ; Gassenmaier, Maximilian ; Menzies, Alexander M. ; Loquai, Carmen ; Johnson, Douglas B. ; Franklin, Cindy

; Gutzmer, Ralf ; Hassel, Jessica C. ; Weishaupt, Carsten ; Eigentler, Thomas ; Schilling, Bastian ; Schummer, Patrick

; Sirokay, Judith

; Kiecker, Felix ; Owen, Carina N. ; Fleischer, Maria I. ; Cann, Christopher ; Kähler, Katharina C. ; Mohr, Peter ; Bluhm, Leonie ; Niebel, Dennis

; Thoms, Kai-Martin ; Goldinger, Simone M. ; Reinhardt, Lydia ; Meier, Friedegund ; Berking, Carola ; Reinhard, Raphael ; Susok, Laura ; Ascierto, Paolo A. ; Drexler, Konstantin ; Pföhler, Claudia ; Tietze, Julia ; Heinzerling, Lucie ; Livingstone, Elisabeth ; Ugurel, Selma ; Long, Georgina V.

; Stang, Andreas ; Schadendorf, Dirk ; Zimmer, Lisa

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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. (C) 2021 Elsevier Ltd. All rights reserved.

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