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
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)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: March 15, 2021
Accepted:
January 28,
2021
Received in revised form:
January 24,
2021
Received:
November 27,
2020
Identification
Copyright
© 2021 Elsevier Ltd. All rights reserved.
