S100B and LDH as early prognostic markers for response and overall survival in melanoma patients treated with anti-PD-1 or combined anti-PD-1 plus anti-CTLA-4 antibodies

Wagner, Nikolaus Benjamin; Forschner, Andrea; Leiter, Ulrike; Garbe, Claus; Eigentler, Thomas

doi:10.1038/s41416-018-0167-x

Cited by 89 publications

(83 citation statements)

References 42 publications

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“…Not only baseline LDH levels, but also the changes in LDH levels during the first weeks of checkpoint inhibition appear to relate with treatment outcomes. [56][57][58] A retrospective study in 238 melanoma patients showed that patients responding to pembrolizumab had a marked reduction in LDH levels after 6 weeks of treatment (median: −15.6%; ICR: −23.1% to −1.3%), whereas LDH levels increased in patients with progressive disease (median: + 6.2%, ICR: −12.8% to +44.5%) (p = .0088). Increases in LDH levels of 25% or more were strongly associated with a detrimental OS (HR 10.75; 95% CI 4.62-25.02).…”

Section: On-treatment Ldh Levelsmentioning

confidence: 99%

“…However, the differences were less pronounced, possibly due to a high incidence of immune-related adverse events in these patients, which can also elevate LDH levels. 57 At the Radboudumc, we assessed the changes in LDH levels in 58 bladder cancer patients treated with anti-PD-(L)1. Here, we also identified a decline in LDH levels in responding patients after two cycles (median: −10,9%, ICR: −21,4% to +1,1%), whereas LDH levels increased in non-responders (median: +5,1%, ICR: −2,9% to +18,0%) (p = 0,003) [unpublished data].…”

Section: On-treatment Ldh Levelsmentioning

confidence: 99%

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Lactate dehydrogenase: a marker of diminished antitumor immunity

et al. 2020

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Lactate dehydrogenase (LDH) levels are inversely related with response to checkpoint inhibitors. Elevated LDH levels are the product of enhanced glycolytic activity of the tumor and tumor necrosis due to hypoxia, the latter being associated with high tumor burden. In this review, we elucidate the effects of glycolysis and hypoxia on antitumor immunity and set forth ways to improve response to immunotherapy in cancer patients with elevated LDH levels. We discuss the current knowledge on combining immunotherapy with glycolysis inhibitors, anti-acidifying drugs, anti-angiogenic or cytoreductive therapy.

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Section: On-treatment Ldh Levelsmentioning

confidence: 99%

Section: On-treatment Ldh Levelsmentioning

confidence: 99%

Lactate dehydrogenase: a marker of diminished antitumor immunity

et al. 2020

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“…The percentage of patients that had elevated LDH is similar in both reports (32% in our cohort vs. 36% in the CheckMate 067 trial). In the CheckMate 067 trial, the S100B levels, which are a known prognostic factor [38,39], were not reported; in our study, 44% of the patients had elevated S100B. Together, these aspects define a collective of patients that probably had a worse prognosis compared to the patients included in the clinical trial.…”

Section: Discussionmentioning

confidence: 45%

Primary Resistance to PD-1-Based Immunotherapy—A Study in 319 Patients with Stage IV Melanoma

Amaral

Seeber

Mersi

et al. 2020

Cancers

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Background: Primary resistance to immunotherapy can be observed in approximately 40–65% of the stage IV melanoma patients treated with immune checkpoint inhibitors. A minority of the patients receive a second-line therapy, and the clinical benefit is small. Patients and methods: Stage IV melanoma patients treated with first-line PD-1-based immunotherapy between January 2015 and December 2018 were investigated. Primary resistance was defined as progressive disease (PD) at the time of the first tumor assessment after starting immunotherapy. Patients with complete response, partial response, and stable disease were classified as having disease control (DC). Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan–Meier estimator. Univariate and multivariate logistic regression analyses were performed to determine prognostic factors associated with OS. Results: Three hundred and nineteen patients were included, and 40% had primary resistance to immunotherapy. The median follow-up time was 22 months. Patients with primary resistance had 1-, 2-, and 3-year OS rates of 41%, 15%, and 10%, respectively, compared to 91%, 81%, and 65% for the patients who achieved DC. The following independently significant prognostic factors for OS were identified: protein S100B level and primary tumor localization. There was a statistically significant difference for OS (p < 0.0001) but not for PFS (p = 0.230) when analyzing risk groups formed with a combination of these two variables (low-, intermediate-, and high-risk subgroups). Conclusions: Melanoma patients with primary resistance to immunotherapy have a dismal prognosis. Response at the first tumor assessment after starting immunotherapy is a stronger prognostic factor for the further course of the disease than pretreatment risk factors.

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“…25 Furthermore, baseline LDH was significantly associated with an impaired overall survival in metastatic melanoma patients treated with combination anti-CTLA-4 and anti-PD-1. 1 , 26,27 These findings highlight the need for assessment of immune parameters along with clinical and histopathologic factors for the administration of personalized therapies for patients with metastatic melanoma.…”

Section: Discussionmentioning

confidence: 99%

Close proximity of immune and tumor cells underlies response to anti-PD-1 based therapies in metastatic melanoma patients

et al. 2019

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Immune checkpoint blockade has greatly improved the clinical outcomes of many patients with metastatic melanoma, however, almost half do not respond. Whether the interspatial distribution of immune and tumor cells predicts response to anti-PD-1-based therapies and patient outcomes in any cancer, including melanoma, is currently unknown. Here, we examined the spatial distribution of immune and tumor cells via multiplex immunofluorescence. Pre-treatment melanoma specimens from 27 patients (n = 18 responders; n = 9 nonresponders) treated with anti-PD-1 monotherapy and 34 patients (n = 22 responders; n = 12 non-responders) treated with combined ipilimumab and anti-PD-1 immunotherapy were studied. Responders displayed significantly higher densities of CD8 + tumor-infiltrating lymphocytes within a 20 µM distance from a melanoma cell compared to non-responders in both anti-PD-1 alone (p = .0024) and combination-treated patients (p = .0096), that were associated with improved progression-free survival for both therapies (anti-PD-1 p = .0158; combination therapy p = .0088). In multivariate analysis, the best model for 12-month progression-free survival for anti-PD-1 monotherapy included PD-L1 + cells within proximity to tumor cells and intratumoral CD8 + density (AUC = 0.80), and for combination therapy included CD8 + cells in proximity to tumor cells, intratumoral PD-L1 + density and LDH (AUC = 0.85). Assessment of the spatial distribution of immune cells in relation to tumor cells provides insight into their role in modulating immune response and highlights their potential role as predictors of response to anti-PD-1 based therapies.

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S100B and LDH as early prognostic markers for response and overall survival in melanoma patients treated with anti-PD-1 or combined anti-PD-1 plus anti-CTLA-4 antibodies

Abstract: S100B could serve as a strong baseline marker for OS in melanoma patients receiving anti-PD-1 therapy. Rising S100B levels during the first weeks of therapy could help guide treatment decisions.

Cited by 89 publications

References 42 publications

Lactate dehydrogenase: a marker of diminished antitumor immunity

Lactate dehydrogenase: a marker of diminished antitumor immunity

Primary Resistance to PD-1-Based Immunotherapy—A Study in 319 Patients with Stage IV Melanoma

Close proximity of immune and tumor cells underlies response to anti-PD-1 based therapies in metastatic melanoma patients

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