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10 pages, 1033 KiB

Open AccessArticle

Comparison of Efficacy in Patients with Metastatic Melanoma Treated with Ipilimumab and Nivolumab Who Did or Did Not Discontinue Treatment Due to Immune-Related Adverse Events: A Real-World Data Study

by Morten Fink, Anders Schwartz Vittrup, Lars Bastholt, Inge Marie Svane, Marco Donia, Adam A. Luczak, Christina H. Ruhlmann, Louise Mahncke Guldbrandt, Ulrich Heide Koehler, Mette Lerche Winther, Eva Ellebaek, Charlotte Aaquist Haslund and Henrik Schmidt

Cancers 2021, 13(21), 5550; https://doi.org/10.3390/cancers13215550 - 5 Nov 2021

Cited by 4 | Viewed by 2386

Abstract

Immune-related adverse events (irAEs) are very prevalent when treating patients with ipilimumab and nivolumab in combination, and 30–40% of patients discontinue the treatment for this reason. It is of high clinical relevance to investigate the consequences of discontinuing the treatment early since combination [...] Read more.

Immune-related adverse events (irAEs) are very prevalent when treating patients with ipilimumab and nivolumab in combination, and 30–40% of patients discontinue the treatment for this reason. It is of high clinical relevance to investigate the consequences of discontinuing the treatment early since combination therapy with ipilimumab and nivolumab is the first line of treatment for many patients with metastatic melanoma. In this follow-up study, with real-world data from the nationwide DAMMED database, we investigated whether there was a difference in progression-free survival (PFS) and overall survival (OS) for patients who discontinued or did not discontinue treatment within the first four doses of treatment due to irAEs. In total, 448 patients were treated with ipilimumab and nivolumab. Of these, 133 patients discontinued due to irAEs in the induction phase. Using the Cox proportional hazards model, there was no significant difference in PFS when comparing the group that discontinued with the group that did not discontinue. The group that discontinued had a significantly longer OS than the group that received the full length of treatment. Therefore, we conclude that there is no significant negative impact on efficacy for patients who discontinue due to irAEs in the induction phase of combination immunotherapy for metastatic melanoma. Full article

(This article belongs to the Special Issue Role of Immune Checkpoint Inhibitors in the Treatment of Patients with Melanoma)

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15 pages, 872 KiB

Open AccessArticle

No Impact of NRAS Mutation on Features of Primary and Metastatic Melanoma or on Outcomes of Checkpoint Inhibitor Immunotherapy: An Italian Melanoma Intergroup (IMI) Study

by Michele Guida, Nicola Bartolomeo, Pietro Quaglino, Gabriele Madonna, Jacopo Pigozzo, Anna M. Di Giacomo, Alessandro M. Minisini, Marco Tucci, Francesco Spagnolo, Marcella Occelli, Laura Ridolfi, Paola Queirolo, Ivana De Risi, Davide Quaresmini, Elisabetta Gambale, Vanna Chiaron Sileni, Paolo A. Ascierto, Lucia Stigliano, Sabino Strippoli and on behalf of the Italian Melanoma Intergroup (IMI) Study

Cancers 2021, 13(3), 475; https://doi.org/10.3390/cancers13030475 - 26 Jan 2021

Cited by 21 | Viewed by 3613

Abstract

Aims: It is debated whether the NRAS-mutant melanoma is more aggressive than NRAS wildtype. It is equally controversial whether NRAS-mutant metastatic melanoma (MM) is more responsive to checkpoint inhibitor immunotherapy (CII). 331 patients treated with CII as first-line were retrospectively recruited: 162 NRAS-mutant/BRAF [...] Read more.

Aims: It is debated whether the NRAS-mutant melanoma is more aggressive than NRAS wildtype. It is equally controversial whether NRAS-mutant metastatic melanoma (MM) is more responsive to checkpoint inhibitor immunotherapy (CII). 331 patients treated with CII as first-line were retrospectively recruited: 162 NRAS-mutant/BRAF wild-type (mut/wt) and 169 wt/wt. We compared the two cohorts regarding the characteristics of primary and metastatic disease, disease-free interval (DFI) and outcome to CII. No substantial differences were observed between the two groups at melanoma onset, except for a more frequent ulceration in the wt/wt group (p = 0.03). Also, the DFI was very similar in the two cohorts. In advanced disease, we only found lung and brain progression more frequent in the wt/wt group. Regarding the outcomes to CII, no significant differences were reported in overall response rate (ORR), disease control rate (DCR), progression free survival (PFS) or overall survival (OS) (42% versus 37%, 60% versus 59%, 12 (95% CI, 7–18) versus 9 months (95% CI, 6–16) and 32 (95% CI, 23–49) versus 27 months (95% CI, 16–35), respectively). Irrespectively of mutational status, a longer OS was significantly associated with normal LDH, <3 metastatic sites, lower white blood cell and platelet count, lower neutrophil-to-lymphocyte (N/L) ratio. Our data do not show increased aggressiveness and higher responsiveness to CII in NRAS-mutant MM. Full article

(This article belongs to the Special Issue Role of Immune Checkpoint Inhibitors in the Treatment of Patients with Melanoma)

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18 pages, 1566 KiB

Open AccessArticle

A Comprehensive Analysis of Baseline Clinical Characteristics and Biomarkers Associated with Outcome in Advanced Melanoma Patients Treated with Pembrolizumab

by Gil Awada, Yanina Jansen, Julia Katharina Schwarze, Jens Tijtgat, Lennert Hellinckx, Odrade Gondry, Sim Vermeulen, Sarah Warren, Kelly Schats, Pieter-Jan van Dam, Mark Kockx, Marleen Keyaerts, Hendrik Everaert, Teofila Seremet, Anne Rogiers and Bart Neyns

Cancers 2021, 13(2), 168; https://doi.org/10.3390/cancers13020168 - 6 Jan 2021

Cited by 26 | Viewed by 3076

Abstract

Background: Pembrolizumab improves the survival of patients with advanced melanoma. A comprehensive analysis of baseline variables that predict the benefit of pembrolizumab monotherapy has not been conducted. Methods: Survival data of patients with advanced melanoma who were treated with pembrolizumab in a single [...] Read more.

Background: Pembrolizumab improves the survival of patients with advanced melanoma. A comprehensive analysis of baseline variables that predict the benefit of pembrolizumab monotherapy has not been conducted. Methods: Survival data of patients with advanced melanoma who were treated with pembrolizumab in a single university hospital were collected. A multivariate Cox regression analysis was performed to correlate baseline clinical, laboratory, and radiologic characteristics and NanoString IO360 gene expression profiling (GEP) with survival. Results: 183 patients were included (stage IV 85.2%, WHO performance status ≥1 31.1%; pembrolizumab first-line 25.7%), of whom 112 underwent baseline ¹⁸F-FDG-PET/CT imaging, 58 had circulating tumor DNA (ctDNA) assessments, and GEP was available in 27 patients. Active brain metastases, a higher number of metastatic sites, lower albumin and absolute lymphocyte count (ALC), higher C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio, higher total metabolic tumor volume (TMTV), and higher ctDNA levels were associated with worse survival. Elevated lactate dehydrogenase (LDH) ≥ 2ULN (upper limit of normal), CRP ≥ 10ULN, or ALC < 750/mm³ delineate a subpopulation where treatment with pembrolizumab is futile. A TMTV ≥ 80 mL encompassed 17/21 patients with LDH ≥ 2ULN, CRP ≥ 10ULN, or ALC < 750/mm³. No significant associations were observed between baseline GEP scores and survival. Conclusion: Multiple baseline variables correlate with survival on pembrolizumab. TMTV is a more comprehensive baseline biomarker than CRP, LDH, or ALC in predicting the futility of pembrolizumab. Full article

(This article belongs to the Special Issue Role of Immune Checkpoint Inhibitors in the Treatment of Patients with Melanoma)

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15 pages, 1377 KiB

Open AccessArticle

Granzyme B Degraded Type IV Collagen Products in Serum Identify Melanoma Patients Responding to Immune Checkpoint Blockade

by Christina Jensen, Dovile Sinkeviciute, Daniel Hargbøl Madsen, Patrik Önnerfjord, Morten Hansen, Henrik Schmidt, Morten Asser Karsdal, Inge Marie Svane and Nicholas Willumsen

Cancers 2020, 12(10), 2786; https://doi.org/10.3390/cancers12102786 - 28 Sep 2020

Cited by 32 | Viewed by 2994

Abstract

A T-cell permissive tumor microenvironment, characterized by the presence of activated T cells and low fibrotic activity is crucial for response to immune checkpoint inhibitors (ICIs). Granzyme B has been shown to promote T-cell migration through the basement membrane by the degradation of [...] Read more.

A T-cell permissive tumor microenvironment, characterized by the presence of activated T cells and low fibrotic activity is crucial for response to immune checkpoint inhibitors (ICIs). Granzyme B has been shown to promote T-cell migration through the basement membrane by the degradation of type IV collagen. In this study, we evaluated the biomarker potential of measuring granzyme B-mediated degradation of type IV collagen (C4G) in combination with a fibroblast activation biomarker (PRO-C3) non-invasively for identifying metastatic melanoma patients responding to the ICI ipilimumab. A monoclonal antibody was generated against C4G and used to develop a competitive electro-chemiluminescence immunoassay. C4G and PRO-C3 were measured in pretreatment serum from metastatic melanoma patients (n = 54). The C4G assay was found specific for a granzyme B-generated neo-epitope on type IV collagen. The objective response rate (ORR) was 2.6-fold higher (18% vs. 7%) in patients with high C4G levels (>25th percentile) vs. low levels (≤25th percentile). Likewise, high C4G levels at baseline were associated with longer overall survival (OS) (log-rank, p = 0.040, and hazard ratio (HR) = 0.48, 95%CI: 0.24–0.98, p = 0.045). Combining high C4G with low PRO-C3 correlated with improved OS with a median OS of 796 days vs. 273 days (p = 0.0003) and an HR of 0.30 (95%CI: 0.15–0.60, p = 0.0006). In conclusion, these results suggest that high granzyme B degraded type IV collagen (C4G) combined with low PRO-C3 quantified non-invasively has the potential to identify the responders to ICI therapy. Full article

(This article belongs to the Special Issue Role of Immune Checkpoint Inhibitors in the Treatment of Patients with Melanoma)

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11 pages, 1290 KiB

Open AccessArticle

Improved Progression-Free Long-Term Survival of a Nation-Wide Patient Population with Metastatic Melanoma

by Anne Vest Soerensen, Eva Ellebaek, Lars Bastholt, Henrik Schmidt, Marco Donia and Inge Marie Svane

Cancers 2020, 12(9), 2591; https://doi.org/10.3390/cancers12092591 - 11 Sep 2020

Cited by 8 | Viewed by 2070

Abstract

Approval of immune checkpoint-inhibitors (ICIs) and BRAF-inhibitors has revolutionized the treatment of metastatic melanoma. Although these drugs have improved overall survival (OS) in clinical trials, real-world evidence for improved long-term survival is still scarce. Clinical data were extracted from the Danish Metastatic Melanoma [...] Read more.

Approval of immune checkpoint-inhibitors (ICIs) and BRAF-inhibitors has revolutionized the treatment of metastatic melanoma. Although these drugs have improved overall survival (OS) in clinical trials, real-world evidence for improved long-term survival is still scarce. Clinical data were extracted from the Danish Metastatic Melanoma database. This nation-wide cohort contains data on all patients who received systemic treatment for metastatic melanoma between 2008 and 2016. Ipilimumab, the first approved ICI, was implemented as standard-of-care in Denmark in 2012. Hence, patients were divided in a pre-ICI (2008–2011) and an ICI (2012–2016) era. Patients were defined as long-term survivors if they were alive 3 years after initiation of systemic therapy. Data from 1754 patients were retrieved. Patients treated in the ICI era had an improved median OS (11.3 months, 95% confidence interval (CI) 10.3–12.3) compared with those in the pre-ICI era (median OS 8.3 months, 95% CI 7.4–9.5, p < 0.0001). A higher proportion of long-term survivors was observed in the ICI era (survivors >3 years increased from 13% to 26% and survivors >5 years increased from 9% to 21%; both p < 0.0001). For long-term survivors, known prognostic factors were equally distributed between the two periods, except that long-term survivors in the pre-ICI era were younger. For long-term survivors, 70% were without progression in the ICI era compared with 43% in the pre-ICI era (p < 0.0001). For all patients, the proportion without progression increased from 5% to 18% between the pre-ICI and the ICI era (p < 0.0001), respectively. Implementation of ICI has led to a significant increase in progression-free, long-term survival for real-life patients with metastatic melanoma. Full article

(This article belongs to the Special Issue Role of Immune Checkpoint Inhibitors in the Treatment of Patients with Melanoma)

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15 pages, 1509 KiB

Open AccessArticle

Pre-Treatment Mutational and Transcriptomic Landscape of Responding Metastatic Melanoma Patients to Anti-PD1 Immunotherapy

by Carol M. Amato, Jennifer D. Hintzsche, Keith Wells, Allison Applegate, Nicholas T. Gorden, Victoria M. Vorwald, Richard P. Tobin, Kelsey Nassar, Yiqun G. Shellman, Jihye Kim, Theresa M. Medina, Matthew Rioth, Karl D. Lewis, Martin D. McCarter, Rene Gonzalez, Aik-Choon Tan and William A. Robinson

Cancers 2020, 12(7), 1943; https://doi.org/10.3390/cancers12071943 - 17 Jul 2020

Cited by 22 | Viewed by 4358

Abstract

Immunotherapy, such as anti-PD1, has improved the survival of patients with metastatic melanoma. However, predicting which patients will respond to immunotherapy remains a significant knowledge gap. In this study we analyzed pre-immunotherapy treated tumors from 52 patients with metastatic melanoma and monitored their [...] Read more.

Immunotherapy, such as anti-PD1, has improved the survival of patients with metastatic melanoma. However, predicting which patients will respond to immunotherapy remains a significant knowledge gap. In this study we analyzed pre-immunotherapy treated tumors from 52 patients with metastatic melanoma and monitored their response based on RECIST 1.1 criteria. The responders group contained 21 patients that had a complete or partial response, while the 31 non-responders had stable or progressive disease. Whole exome sequencing (WES) was used to identify biomarkers of anti-PD1 response from somatic mutations between the two groups. Variants in codons G34 and G41 in NFKBIE, a negative regulator of NFkB, were found exclusively in the responders. Mutations in NKBIE-related genes were also enriched in the responder group compared to the non-responders. Patients that harbored NFKBIE-related gene mutations also had a higher mutational burden, decreased tumor volume with treatment, and increased progression-free survival. RNA sequencing on a subset of tumor samples identified that CD83 was highly expressed in our responder group. Additionally, Gene Set Enrichment Analysis showed that the TNFalpha signaling via NFkB pathway was one of the top pathways with differential expression in responders vs. non-responders. In vitro NFkB activity assays indicated that the G34E variant caused loss-of-function of NFKBIE, and resulted in activation of NFkB signaling. Flow cytometry assays indicated that G34E variant was associated with upregulation of CD83 in human melanoma cell lines. These results suggest that NFkB activation and signaling in tumor cells contributes to a favorable anti-PD1 treatment response, and clinical screening to include aberrations in NFkB-related genes should be considered. Full article

(This article belongs to the Special Issue Role of Immune Checkpoint Inhibitors in the Treatment of Patients with Melanoma)

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15 pages, 2740 KiB

Open AccessArticle

Inflammatory Cytokines and ctDNA Are Biomarkers for Progression in Advanced-Stage Melanoma Patients Receiving Checkpoint Inhibitors

by Jesper Geert Pedersen, Anne Tranberg Madsen, Kristine Raaby Gammelgaard, Ninna Aggerholm-Pedersen, Boe Sandahl Sørensen, Trine Heide Øllegaard and Martin Roelsgaard Jakobsen

Cancers 2020, 12(6), 1414; https://doi.org/10.3390/cancers12061414 - 30 May 2020

Cited by 17 | Viewed by 3772

Abstract

Purpose: Checkpoint inhibitors have significantly improved treatment of metastatic melanoma. However, 40–60% of patients do not respond to therapy, emphasizing the need for better predictive biomarkers for treatment response to immune checkpoint inhibitors. Prorammed death-ligand 1(PD-L1) expression in tumor cells is currently used [...] Read more.

Purpose: Checkpoint inhibitors have significantly improved treatment of metastatic melanoma. However, 40–60% of patients do not respond to therapy, emphasizing the need for better predictive biomarkers for treatment response to immune checkpoint inhibitors. Prorammed death-ligand 1(PD-L1) expression in tumor cells is currently used as a predictive biomarker; however, it lacks specificity. Therefore, it is of utmost importance to identify other novel biomarkers that can predict treatment outcome. Experimental design: We studied a small cohort of 16 patients with advanced-stage melanoma treated with first-line checkpoint inhibitors. Plasma samples were collected prior to treatment initiation and continuously during the first year of treatment. Circulating tumor DNA (ctDNA) level and the expression of ten inflammatory cytokines were analyzed. Results: We found that the ctDNA-level in a blood sample collected after 6–8 weeks of therapy is predictive for response to checkpoint inhibitors. Patients with undetectable ctDNA had significantly longer progression-free survival (PFS) compared with patients with detectable ctDNA (median 26.3 vs. 2.1 months, p = 0.006). In parallel, we identified that high levels of the cytokines monocyte chemoattractant protein 1 (MCP1) and tumor necrosis factor α(TNFα) in baseline blood samples were significantly associated with longer PFS compared to low level of these cytokines (median not reached vs. 8.2 months p = 0.0008). Conclusions: These findings suggest that the levels of ctDNA, MCP1, and TNFα in baseline and early follow-up samples can predict disease progression in metastatic melanoma patients treated with checkpoint inhibitors. Potentially, these minimally invasive biomarkers may identify responders from non-responders. Full article

(This article belongs to the Special Issue Role of Immune Checkpoint Inhibitors in the Treatment of Patients with Melanoma)

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