Survival In Advanced Melanoma Patients Research Articles

P21-8 Ultra-sensitive tumor-informed ctDNA assay predicts survival in advanced melanoma patients treated with ICI treatment

P21-8 Ultra-sensitive tumor-informed ctDNA assay predicts survival in advanced melanoma patients treated with ICI treatment

Primary Tumor Characteristics as Biomarkers of Immunotherapy Response in Advanced Melanoma: A Retrospective Cohort Study.

Identifying patients likely to benefit from immune checkpoint inhibitor (ICI) treatment remains a crucial goal for melanoma. The objective of this study is to assess the association between primary tumor features and immunotherapy response and survival in advanced melanoma patients. In this single-center retrospective cohort study, disease characteristics, response to immunotherapy, PFS, and OS were assessed among melanoma patients (excluding mucosal and uveal primaries) treated with ICI. Among 447 patients, 300 (67.1%) received anti-PD-1 monotherapy and 147 (32.9%) received ipilimumab/nivolumab. A total of 338 (75.6%) had cutaneous melanoma, 29 (6.5%) had acral melanoma, and 80 (17.9%) had melanoma of unknown primary. Ulceration and stage at initial presentation were associated with inferior outcomes on univariate analysis. However, on multivariate analysis, this result was not observed, but cutaneous melanoma and each of its subtypes (superficial spreading, nodular, other, unknown) were positively associated with response, longer PFS, and longer OS. Metastatic stage (M1c, M1d) at presentation (OR = 1.8, p < 0.05) and BRAFV600E mutation status (OR = 1.6, p < 0.001) were associated with shorter PFS. This study is limited by its retrospective and single-center design. Cutaneous melanoma and its subtypes were significantly associated with response, PFS, and OS compared with acral or unknown primary melanoma.

High Serum Levels of CCL20 Are Associated with Recurrence and Unfavorable Overall Survival in Advanced Melanoma Patients Receiving Immunotherapy.

Immune checkpoint inhibition has revolutionized melanoma therapy, but many patients show primary or secondary resistance. Biomarkers are, therefore, urgently required to predict response prior to the initiation of therapy and to monitor disease progression. In this prospective study, we analyzed the serum C-C motif chemokine ligand 20 (CCL20) concentration using an enzyme-linked immunosorbent assay. Blood was obtained at baseline before the initiation of immunotherapy with anti-PD-1 monotherapy or Nivolumab and Ipilimumab in advanced melanoma patients (stages III and IV) enrolled at the University Medical Center Hamburg-Eppendorf. The CCL20 levels were correlated with clinico-pathological parameters and disease-related outcomes. An increased C-C motif chemokine ligand 20 (CCL20) concentration (≥0.34 pg/mL) at baseline was associated with a significantly impaired progression-free survival (PFS) in the high-CCL20 group (3 months (95% CI: 2-6 months) vs. 11 months (95% CI: 6-26 months)) (p = 0.0033) and could be identified as an independent negative prognostic factor for PFS in univariate (Hazard Ratio (HR): 1.98, 95% CI 1.25-3.12, p = 0.004) and multivariate (HR: 1.99, 95% CI 1.21-3.29, p = 0.007) Cox regression analysis, which was associated with a higher risk than S100 (HR: 1.74). Moreover, high CCL20 levels were associated with impaired overall survival (median OS not reached for low-CCL20 group, p = 0.042) with an HR of 1.85 (95% CI 1.02-3.37, p = 0.043) in univariate analysis similar to the established prognostic marker S100 (HR: 1.99, 95% CI: 1.02-3.88, p = 0.043). CCL20 may represent a novel blood-based biomarker for the prediction of resistance to immunotherapy that can be used in combination with established strong clinical predictors (e.g., ECOG performance score) and laboratory markers (e.g., S100) in advanced melanoma patients. Future prospective randomized trials are needed to establish CCL20 as a liquid biopsy-based biomarker in advanced melanoma.

Improving survival in advanced melanoma patients: a trend analysis from 2013 to 2021

The prognosis of advanced melanoma patients has significantly improved over the years. We aimed to evaluate the survival per year of diagnosis. All systemically treated patients diagnosed with advanced melanoma from 2013 to 2021 were included from the Dutch Melanoma Treatment Registry. Baseline characteristics and overall survival (OS) were compared between the different years of diagnosis. A multivariable Cox proportional hazards model was used to estimate the association between year of diagnosis and OS. For this cohort study, we included 6260 systemically treated advanced melanoma patients. At baseline, there was an increase over the years in age, the percentage of patients with an ECOG PS≥2, with brain metastases, and a synchronous diagnosis of primary and unresectable melanoma. Median OS increased from 11.2 months (95% CI 10.0-12.4) for patients diagnosed in 2013 to 32.0 months (95% CI 26.6-36.7) for patients diagnosed in 2019. Median OS was remarkably lower for patients diagnosed in 2020 (26.6 months; 95% CI 23.9-35.1) and 2021 (24.0 months; 95% CI 20.4-NR). Patients diagnosed in 2020 and 2021 had a higher hazard of death compared to patients diagnosed in 2019, although this was not significant. The multivariable Cox regression showed a lower hazard of death for the years of diagnosis after 2013. In contrast, patients diagnosed in 2020 and 2021 had a higher hazard of death compared to patients diagnosed in2019. After a continuous survival improvement for advanced melanoma patients between 2013 and 2019, outcomes of patients diagnosed in 2020 and 2021 seem poorer. This trend of decreased survival remained after correcting for known prognostic factors and previous neoadjuvant or adjuvant treatment, suggesting that it is explained by unmeasured factors, which-considering the timing-could be COVID-19-related. For the Dutch Melanoma Treatment Registry (DMTR), the Dutch Institute for Clinical Auditing foundation received a start-up grant from governmental organization The Netherlands Organization for Health Research and Development (ZonMW, project number 836002002). The DMTR is structurally funded by Bristol-Myers Squibb, Merck Sharpe & Dohme, Novartis, and Roche Pharma. Roche Pharma stopped funding in 2019, and Pierre Fabre started funding the DMTR in 2019. For this work, no funding was granted.

Serum Cell Division Cycle 42 before and after Programmed Death-1 Inhibitor Therapy in Advanced Melanoma Patients: Correlation with Tumor Features, Clinical Response, and Survival.

Cell division cycle 42 (CDC42) mediates immune escape in cancers. This study aimed to investigate linkages of CDC42 with tumor features, treatment response, and survival in advanced melanoma patients receiving programmed death-1 (PD-1) inhibitors. Pre-treatment and post-treatment (after 2 cycles) serum CDC42 of 35 advanced melanoma patients receiving PD-1 inhibitor was assessed by enzyme-linked immunosorbent assay. Patients with tumor-node-metastasis (TNM) stage IV (vs. III) (P = 0.050) and abnormal (vs. normal) lactate dehydrogenase (LDH) (P = 0.022) had higher pre-treatment CDC42. After 2-cycle therapy, CDC42 was declined (P < 0.001). Objective response and disease control rates were 34.3% and 62.9%, respectively. Additionally, pre-treatment and post-treatment CDC42 was reduced in patients with objective response and disease control than those without (all P < 0.050). Concerning survival, pre-treatment with CDC42 > 700 pg/mL was associated with shorter progression-free survival (PFS) (P = 0.013), but not overall survival (OS) (P = 0.060). Specifically, the 12-month PFS rate was 26.7% and 66.2%, and the 12-month OS rate was 61.1% and 82.5% in patients with pre-treatment with CDC42 > 700 pg/mL and ≤ 700 pg/mL, respectively. Post-treatment with CDC42 > 700 pg/mL was correlated with shortened PFS (P = 0.010) and OS (P = 0.006). The 12-month PFS rate was 12.5% and 62.0%, and the 12-month OS rate was 42.3% and 88.0% in patients with post-treatment with CDC42 > 700 pg/mL and ≤ 700 pg/mL, accordingly. Furthermore, post-treatment with CDC42 > 700 pg/mL was independently related to PFS [hazard ratio (HR): 2.704, P = 0.029 and OS (HR: 7.749, P = 0.005)]. Elevated CDC42 correlates with advanced TNM, abnormal LDH, worse clinical response, and dismal survival in advanced melanoma patients receiving PD-1 inhibitors.

Peripheral B-cell levels predict efficacy and overall survival in advanced melanoma patients under PD-1 immunotherapy.

Aims: Programmed death-1 (PD-1) blockade is a vital therapy for solid tumors, but not all patients benefit. Identifying which patients will benefit from immunotherapy is a key focus in oncology research. Patients & Methods:This studyanalyzed the correlation between the number of peripheral lymphocytes and the efficacy and prognosis of immunotherapy in advanced malignant melanoma. Results: Patients with a partial response had significantly lower peripheral B cell levels, and patients with a lower number of B lymphocytes had a longer survival time. Conclusion: These results suggest that peripheral B cells are correlated with the efficacy of PD-1 antibody and prognosis and are thus potential biomarkers for the efficacy and prognosis of PD-1 antibody immunotherapy in malignant melanoma.

Survival outcomes of metastasectomy and primary site resection in melanoma patients with isolated brain metastasis: A SEER analysis.

e21541 Background: Approximately 40–50% of Stage IV melanoma patients eventually develop brain metastases which is associated with poor prognosis. Breakthroughs in targeted and immunotherapies have improved long-term survival in advanced melanoma patients. In this new era, there is a paucity of evidence for the role of metastatectomy for melanoma patients with brain metastasis. Here, we investigate the survival benefit of metastasectomy and primary site resection in melanoma patients with isolated brain metastasis. Methods: A total of 636 patients with melanoma with isolated brain metastasis at diagnosis were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2019. Patients younger than 18 years, cases with missing information including age, gender, race, unknown stage, unknown primary site resection status, unknown metastasis site, or known metastasis to the lung, liver, or bones were excluded. Cox regression analysis estimated the prognostic value of metastasectomy and primary site resection, presented by hazard ratios (HR), among melanoma patients. Survival ratios were controlled for age, race, gender, and type of melanoma. All analyses were performed on STATA v17. Results: About 49.37% of melanoma patients with isolated brain metastasis underwent metastasectomy. Of the included sample, 25% (n = 159) underwent primary site resection. Cox regression demonstrated that metastasectomy was associated with improved survival outcomes in melanoma patients with isolated brain metastasis (HR 0.51, CI 0.42 – 0.63, p &lt; 0.001). Pooled primary site resection procedures were associated with improved survival (HR 0.64, CI 0.49 – 0.83, p = 0.001) compared to not having a primary site resection. When stratified per procedure type, “wide excision or re-excision of lesions with margins &gt; 1 cm and microscopically negative margins” was associated with improved survival (HR 0.27, CI 0.133 – 0.56, p &lt; 0.001) compared to not having surgical resection, all other primary site resection procedures had no significant improvement in survival with p &gt; 0.05. Conclusions: Metastasectomy and primary site resection significantly improved survival in melanoma patients with isolated brain metastasis. Wide excision with &gt; 1cm negative margins presents itself as the most effective surgical treatment modality in terms of improving survival for these patients. Thus, it should be attempted whenever feasible.

A Survival Tree of Advanced Melanoma Patients with Brain Metastases Treated with Immune Checkpoint Inhibitors.

The efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced melanoma that develop brain metastases (BM) remains unpredictable. In this study, we aimed to identify prognostic factors in patients with melanoma BM who are treated with ICIs. Data from advanced melanoma patients with BM treated with ICIs in any line between 2013 and 2020 were obtained from the Dutch Melanoma Treatment Registry. Patients were included from the time of the treatment of BM with ICIs. Survival tree analysis was performed with clinicopathological parameters as potential classifiers and overall survival (OS) as the response variable. In total, 1278 patients were included. Most patients were treated with ipilimumab-nivolumab combination therapy (45%). The survival tree analysis resulted in 31 subgroups. The median OS ranged from 2.7 months to 35.7 months. The strongest clinical parameter associated with survival in advanced melanoma patients with BM was the serum lactate dehydrogenase (LDH) level. Patients with elevated LDH levels and symptomatic BM had the worst prognosis. The clinicopathological classifiers identified in this study can contribute to optimizing clinical studies and can aid doctors in giving an indication of the patients' survival based on their baseline and disease characteristics.

Abstract 2298: Ultra-sensitive tumor-informed ctDNA assay predicts survival in advanced melanoma patients treated with immune checkpoint inhibition

Abstract Introduction: Immune checkpoint inhibition (ICI) elicits clinical benefit in a subset of cancer patients and monitoring of ctDNA in peripheral blood might improve our ability to predict responses or resistance earlier than imaging. Here, we analyzed melanoma patients receiving ICI over several years using a novel tumor-informed ctDNA platform, and correlated the findings to clinical outcome. Methods: Plasma from 23 advanced melanoma patients was collected at ICI treatment cycles for up to 1,200 days and retrospectively profiled using NeXT Personal™ in this research study. NeXT Personal is a tumor-informed liquid biopsy assay that leverages whole-genome sequencing of tumor/normal samples to generate a personalized liquid biopsy panel for each patient consisting of up to 1,800 selected variants to enable ultra-sensitive molecular residual disease (MRD) detection down to 1-3 parts per million (PPM). Each bespoke panel also covers a fixed set of &amp;gt;2,100 known clinical and resistance loci for detecting variants emerging under therapeutic pressure. We compared NeXT Personal results with imaging and RECIST assessments for each patient. Results: Results showed ultra-high sensitivity for ctDNA with a wide dynamic range of detections from approximately 100,000 PPM down to 2.3 PPM. The median limit of detection was 1.97 PPM. Excluding patients with recent second-line therapy, 94% (17/18) of baseline samples were ctDNA positive (ctDNA+), including all patients who progressed. 37% (22/59) of on-treatment ctDNA+ detections were &amp;lt;100 PPM. 100% of ctDNA+ detections had correlated imaging findings via RECIST confirming presence of tumor, including the lowest PPM detections. Similarly, 100% of complete responses (CR) assessed via RECIST were ctDNA negative for all corresponding plasma timepoints. ctDNA clearance preceded imaging derived CR by an average of 81 days (clearance = 131 days, CR = 212 days). Patients that attained ctDNA clearance at one or more plasma timepoints had significantly longer overall survival (OS) (log-rank test; p = 0.007). Patients with increasing ctDNA levels over the first 25 (or 50) days compared to baseline had significantly reduced OS (p &amp;lt; 0.05). Analysis of the fixed clinical portion of each bespoke panel showed dynamic variant allele frequency changes in 21 variants including therapeutic targets such as BRAF V600E. Conclusions: Advanced melanoma patients exhibit a wide range of ctDNA concentrations at the beginning and during the course of treatment. Ultra-sensitive ctDNA detection down to 2.3 PPM was achieved using the NeXT Personal platform. Most importantly, our pilot study indicates that ctDNA measurements correlated with clinical outcome. The de novo detection of emerging clinically actionable and resistance variants using NeXT Personal can potentially be used to inform treatment once validated in future studies. Citation Format: Laura Keller, Isabel Heidrich, Julian Kött, Charles W. Abbott, Sean Boyle, Jason Pugh, Richard O. Chen, Glen Geidel, Simon Ronald, Stephan W. Schneider, Christoffer Gebhardt, Klaus Pantel. Ultra-sensitive tumor-informed ctDNA assay predicts survival in advanced melanoma patients treated with immune checkpoint inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2298.

Abstract 1253: Dietary tryptophan catabolite released by intratumoralLactobacillus reuterifacilitates aPD-L1 therapy

Abstract The use of probiotics by cancer patients is increasing, including amongst those undergoing immune checkpoint inhibitor (ICI) therapy. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 T cells within the tumor microenvironment that potently enhances spontaneous antitumor immunity and facilitates ICI therapy in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (L.reuteri) translocates to, colonizes, and persists within melanoma, where via its released dietary tryptophan catabolite I3A, it locally promotes interferon-γ-producing CD8 T cells, thereby facilitating ICI therapy efficacy. Moreover, L.reuteri secreted I3A was both necessary and sufficient for antitumor immunity, and loss of AhR signaling within CD8 T cells abrogated L.reuteri’s ability to restrain melanoma growth. Further, a tryptophan-enriched diet potentiated both L.reuteri- and ICI-induced antitumor immunity. Finally, we provide evidence for a potential role of I3A in promoting ICI therapy efficacy and survival in advanced melanoma patients. Citation Format: Mackenzie Bender, Alex McPherson, Catherine Phelps, Diwakar Davar, Dario A. Vignali, Hassane Zarour, Marlies Meisel. Dietary tryptophan catabolite released by intratumoralLactobacillus reuterifacilitates aPD-L1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1253.

Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment

The use of probiotics by cancer patients is increasing, including among those undergoing immune checkpoint inhibitor (ICI) treatment. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 Tcells within the tumor microenvironment that potently enhances antitumor immunity and facilitates ICI in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (Lr) translocates to, colonizes, and persists within melanoma, where via its released dietary tryptophan catabolite I3A, it locally promotes interferon-γ-producing CD8 Tcells, thereby bolstering ICI. Moreover, Lr-secreted I3A was both necessary and sufficient to drive antitumor immunity, and loss of AhR signaling within CD8 Tcells abrogated Lr's antitumor effects. Further, a tryptophan-enriched diet potentiated both Lr- and ICI-induced antitumor immunity, dependent on CD8 Tcell AhR signaling. Finally, we provide evidence for a potential role of I3A in promoting ICI efficacy and survival in advanced melanoma patients.

PD-L1 Tumor Expression as a Predictive Biomarker of Immune Checkpoint Inhibitors' Response and Survival in Advanced Melanoma Patients in Brazil.

Immune checkpoint blockade (ICB) agents are prominent immunotherapies for the treatment of advanced melanoma. However, they fail to promote any durable clinical benefit in a large cohort of patients. This study assessed clinical and molecular predictors of ICB response and survival in advanced melanoma. A retrospective analysis was performed on 210 patients treated with PD-1 or CTLA-4 inhibitors at Barretos Cancer Hospital, Brazil. PD-L1 expression was assessed by immunohistochemistry using formalin-fixed paraffin-embedded tumor tissues collected prior to ICB therapy. Patients were divided into responders (complete and partial response and stable disease for more than 6 months) and non-responders (stable disease for less than 6 months and progressive disease). Among them, about 82% underwent anti-PD-1 immunotherapy, and 60.5% progressed after the ICB treatment. Patients that received ICB as first-line therapy showed higher response rates than previously treated patients. Higher response rates were further associated with superficial spreading melanomas and positive PD-L1 expression (>1%). Likewise, PD-L1 positive expression and BRAF V600 mutations were associated with a higher overall survival after ICB therapy. Since ICBs are expensive therapies, evaluation of PD-L1 tumor expression in melanoma patients should be routinely assessed to select patients that are most likely to respond.

Real-World Therapy with Pembrolizumab: Outcomes and Surrogate Endpoints for Predicting Survival in Advanced Melanoma Patients in Germany

Simple SummaryKnowledge on the real-world outcomes of patients with advanced melanoma and the value of different endpoints for evaluating survival benefits is limited. We investigated the outcomes and different surrogate endpoints for overall survival (OS) in 664 pembrolizumab-treated patients with advanced melanoma in Germany. Our findings support the effectiveness of pembrolizumab in real-world clinical practice. The real-world time to next treatment was most strongly correlated with OS, suggesting it as a valuable surrogate endpoint to assess treatment effectiveness. Real-world studies assessing time to next treatment could support clinical and payer decision making.Knowledge on the real-world characteristics and outcomes of pembrolizumab-treated advanced melanoma patients in Germany and on the value of different real-world endpoints as surrogates for overall survival (OS) is limited. A sample of 664 pembrolizumab-treated patients with advanced melanoma from the German registry ADOReg was used. We examined OS, real-world progression-free survival (rwPFS), real-world time to next treatment (rwTtNT), and real-world time on treatment (rwToT). Spearman’s rank and iterative multiple imputation (IMI)-based correlation coefficients were computed between the OS and the rwPFS, rwTtNT, and rwToT and reported for the first line of therapy and the overall sample. The median OS was 30.5 (95%CI 25.0–35.4) months, the rwPFS was 3.9 months (95%CI 3.5–4.9), the rwTtNT was 10.7 months (95%CI 9.0–12.9), and the rwToT was 6.2 months (95%CI 5.1–6.8). The rwTtNT showed the highest correlation with the OS based on the IMI (rIMI = 0.83), Spearman rank correlations (rs = 0.74), followed by the rwToT (rIMI = 0.74 and rs = 0.65) and rwPFS (rIMI = 0.69 and rs = 0.56). The estimates for the outcomes and correlations were similar for the overall sample and those in first-line therapy. The median OS was higher compared to recent real-world studies, supporting the effectiveness of pembrolizumab in regular clinical practice. The rwTtNT may be a valuable OS surrogate, considering the highest correlation was observed with the OS among the investigated real-world endpoints.

Time to next treatment or death as a candidate surrogate endpoint for overall survival in advanced melanoma patients treated with immune checkpoint inhibitors: an insight from the phase III CheckMate 067 trial

BackgroundTime to next treatment or death (TNT-D) may be a patient-relevant endpoint in patients treated with immune checkpoint inhibitors. This study investigated TNT-D as a surrogate endpoint (SE) for overall survival (OS) in previously untreated advanced melanoma patients.MethodsPatient-level data from the 60-month results of the CheckMate 067 randomised, controlled trial were used. Analyses were carried out for nivolumab monotherapy or nivolumab with ipilimumab versus ipilimumab monotherapy. The SE 1-step validation method based on a joint frailty-copula model was used where the country of enrolment was applied to define clusters. Kendall’s τ and the coefficient of determination (R2trial) were estimated for respective measurements of association at the individual and cluster levels. The surrogate threshold effect, the maximum threshold hazard ratio for TNT-D that would translate into OS benefit, was estimated. A leave-one-out cross-validation analysis was carried out to evaluate model robustness.ResultsFifteen clusters of data were generated from 945 patients. For both nivolumab-containing arms, the association between TNT-D and OS was deemed acceptable at the individual level (Kendall’s τ > 0.60) and strong at the cluster level, with R2trial fairly close to 1, with narrow confidence intervals. The estimated surrogate threshold effects were 0.61 for nivolumab versus ipilimumab and 0.49 for nivolimub + ipilimumab versus ipilimumab. Cross-validation results showed minimum variation of the correlation measures and satisfactory predictive accuracy for the model.ConclusionResults suggest that TNT-D may be a valuable SE in previously untreated advanced melanoma patients treated with immune checkpoint inhibitors. Surrogacy analyses considering multiple randomised controlled trials are warranted for confirming these findings.

Oxidative Stress-Related Mechanisms in Melanoma and in the Acquired Resistance to Targeted Therapies.

Melanoma is a highly aggressive cancer with the poorest prognosis, representing the deadliest form of skin cancer. Activating mutations in BRAF are the most frequent genetic alterations, present in approximately 50% of all melanoma cases. The use of specific inhibitors towards mutant BRAF variants and MEK, a downstream signaling target of BRAF in the MAPK pathway, has significantly improved progression-free and overall survival in advanced melanoma patients carrying BRAF mutations. Nevertheless, despite these improvements, resistance still develops within the first year of therapy in around 50% of patients, which is a significant problem in managing BRAF-mutated advanced melanoma. Understanding these mechanisms is one of the mainstreams of the research on BRAFi/MEKi acquired resistance. Both genetic and epigenetic mechanisms have been described. Moreover, in recent years, oxidative stress has emerged as another major force involved in all the phases of melanoma development, from initiation to progression until the onsets of the metastatic phenotype and chemoresistance, and has thus become a target for therapy. In the present review, we discuss the current knowledge on oxidative stress and its signaling in melanoma, as well as the oxidative stress-related mechanisms in the acquired resistance to targeted therapies.

Hospital Variation in Cancer Treatments and Survival OutComes of Advanced Melanoma Patients: Nationwide Quality Assurance in The Netherlands.

Simple SummaryThe survival of advanced melanoma patients has improved significantly over the last decade due to the introduction of new systemic therapies. It is unknown whether survival outcomes of advanced melanoma patients differ between melanoma centers in the Netherlands. This research aimed to assess center variation in treatments and 2-year survival probabilities of advanced melanoma patients diagnosed between 2013 and 2017 in the Netherlands. Significant center variation in 2-year survival probabilities of patients diagnosed in 2014–2015 was observed after correcting for case-mix and treatment with new systemic therapies. The different use of new systemic therapies partially explained the observed variation. From 2016 onwards, no significant difference in 2-year survival was observed between centers. This study shows the added value of quality monitoring with a national registry that enables the study of variation between centers.Background: To assure a high quality of care for patients treated in Dutch melanoma centers, hospital variation in treatment patterns and outcomes is evaluated in the Dutch Melanoma Treatment Registry. The aim of this study was to assess center variation in treatments and 2-year survival probabilities of patients diagnosed between 2013 and 2017 in the Netherlands. Methods: We selected patients diagnosed between 2013 and 2017 with unresectable IIIC or stage IV melanoma, registered in the Dutch Melanoma Treatment Registry. Centers’ performance on 2-year survival was evaluated using Empirical Bayes estimates calculated in a random effects model. Treatment patterns of the centers with the lowest and highest estimates for 2-year survival were compared. Results: For patients diagnosed between 2014 and 2015, significant center variation in 2-year survival probabilities was observed even after correcting for case-mix and treatment with new systemic therapies. The different use of new systemic therapies partially explained the observed variation. From 2016 onwards, no significant difference in 2-year survival was observed between centers. Conclusion: Our data suggest that between 2014 and 2015, after correcting for patient case-mix, significant variation in 2-year survival probabilities between Dutch melanoma centers existed. The use of new systemic therapies could partially explain this variation. In 2013 and between 2016 and 2017, no significant variation between centers existed.

Survival of advanced melanoma patients treated with immunotherapy and targeted therapy: A real-world study.

We aimed to examine the survival outcomes plus patient and treatment characteristics of advanced melanoma patients treated with first-line immunotherapy (IT), targeted therapy (TT), and chemotherapy (CTH) and compare findings with information from pivotal trials for each therapy. We retrospectively reviewed the use of systematic IT, TT and CTH therapies in melanoma patients in four Queensland public hospitals. We estimated median duration of overall survival (OS) and survival rates (6months, 1, and 2 years) using Kaplan-Meier methods. We compared our findings to those of clinical trials. Five hundred three patients who met the inclusion criteria were divided into three groups based on the first-line treatment: IT 232; TT 157; and CTH 114. OS was 18 months with IT (95% CI 13, 22); 12 months with TT (95% CI 8, 15); and 5months with CTH (95% CI 5, 6). The demographic characteristics, treatment protocols, and durations for IT and TT were generally consistent with trials but fewer patients in our study had subsequent therapy than in the trials. The OS in our study was slightly lower than the OS reported in trials. The OS of novel cancer therapy in the real world was lower than seen in trials but is expected given these are patients who have a poorer prognosis. A future study could investigate the impact of prognostic factors on survival in the longer term. This study provides evidence that we can use routinely collected real-world data to evaluate the effectiveness of checkpoint and kinase inhibitors in patients with advanced melanoma.

Expression of Potential Targets for Cell-Based Therapies on Melanoma Cells.

Tumor antigen-specific redirection of cytotoxic T cells (CTLs) or natural killer (NK) cells including chimeric antigen receptor (CAR-) and T cell receptor (TCR-) cell therapy is currently being evaluated in different tumor entities including melanoma. Expression of melanoma-specific antigen recognized by the respective CAR or TCR directly or presented by HLA molecules is an indispensable prerequisite for this innovative therapy. In this study, we investigated in 168 FFPE tumor specimens of patients with stage I-IV melanoma the protein expression of HER2, TRP2, ABCB5, gp100, p53, and GD2 by immunohistochemistry (IHC). These results were correlated with clinical parameters. Membrane expression of HER2 and GD2 was also investigated in ten melanoma cell lines by flow cytometry for which corresponding tumors were analyzed by IHC. Our results demonstrated that gp100 was the most frequently overexpressed protein (61%), followed by TRP2 (50%), GD2 (38%), p53 (37%), ABCB5 (17%), and HER2 (3%). TRP2 expression was higher in primary tumors compared to metastases (p = 0.005). Accordingly, TRP2 and ABCB5 expression was significantly associated with lower tumor thickness of the primary (p = 0.013 and p = 0.025). There was no association between protein expression levels and survival in advanced melanoma patients. Flow cytometric analysis revealed abundant surface expression of GD2 and HER2 in all melanoma cell lines. The discordant HER2 expression in situ and in vitro suggests a tissue culture associated induction. In summary, our data support the use of gp100 and GD2 as a potential target for developing engineered TCR- or CAR-cell therapies, respectively, against melanoma.

PCN105 Comparison of Healthcare Costs in France of Combination Nivolumab and Ipilimumab Treatment Versus Nivolumab Monotherapy and Ipilimumab Monotherapy in Advanced Melanoma

CheckMate 067 randomized clinical trial data has shown that a combination of immunology drugs, nivolumab (NIVO) and ipilimumab (IPI), results in longer progression-free and overall survival in advanced melanoma patients, compared with either monotherapy. We assessed the implications of these clinical benefits on costs associated with these treatments. The objective of this study was to evaluate and compare direct healthcare costs in France over 60 months for patients initiating treatment with NIVO+IPI against those initiating (i) NIVO monotherapy and (ii) IPI monotherapy from a societal costs perspective. Individual patient-level data for European patients in the CheckMate 067 trial were used to derive the resources utilized by patients. All melanoma-specific resources, both drug and non-drug, were considered in this evaluation. Unit costs for these resources were obtained from external sources. The mean cost per surviving patient in the respective regimen cohort each month was computed and aggregated. Total melanoma-specific healthcare costs incurred by the NIVO+IPI treated cohort (€230k) were 16% lower compared to the NIVO cohort (€272k) and 10% lower compared to IPI cohort (€255k). The cost advantage by the NIVO+IPI cohort is observed from month 22 (vs. NIVO cohort) and month 38 (vs. IPI cohort) and widens each month thereafter. The costs associated with subsequent melanoma therapies were greatest for the IPI cohort (€179k, 70% of total costs) and lowest for the NIVO+IPI regimen cohort (€64k, 28%). Despite the acquisition cost of two index drugs, costs incurred by the NIVO+IPI cohort over 60 months are lower than costs incurred by patients initiating treatment with either IPI or NIVO alone. The higher upfront costs of the NIVO+IPI regimen are offset by lower post-progression costs, as patients receiving NIVO+IPI enjoy a longer duration of response, delayed progression and consequently, reduced usage of subsequent melanoma therapies.

Abstract PO-020: Targeting metabolism to improve response to immune-checkpoint inhibition in melanoma

Abstract Immune checkpoint inhibitors improve long term survival of advanced melanoma patients, however, 40-50% of patients do not benefit. Reprogrammed tumor metabolism may hinder immune cell function. We aimed to reverse metabolic reprogramming in melanoma cells by inhibiting pyruvate dehydrogenase (PDK), thereby reducing lactate secretion, while preserving or enhancing immune cell activity. In addition, we strived to elucidate metabolic vulnerabilities arising during PDK inhibitor treatment by co-treating cells with other metabolically targeted inhibitors. We treated a panel of melanoma cell lines with genetic backgrounds similar to those most frequently found in the clinic with PDK inhibitor dichloroacetate (DCA) to determine effects on viability, expression of metabolic proteins and oxygen consumption/lactate secretion. IC50 values for DCA were 14.9 ± 1.0 for A375, 13.3 ± 0.6 for MeWo, 20.0 ± 1.4 for SK-MEL-28 and 27.3 ± 1.7 mM for SK-MEL-2 cells. PDK inhibition decreased expression of the phosphorylated (inactive) form of PDH (pPDH) in melanoma cells. DCA treatment led to an up to threefold increase in the oxygen consumption rate:extracellular acidification rate (OCR:ECAR) ratio in melanoma cells. Growth inhibition of DCA synergized with other metabolic inhibitors CB-839 (glutaminase inhibitor) and metformin. The combination index (CI) was less than 0.5, indicating strong synergy, for DCA with CB-839 or DCA with metformin in several models. DCA at concentrations affecting OCR:ECAR ratio of melanoma cells (7 mM) had only minimal effects on proliferation of activated T cells and peripheral blood mononuclear cells (PBMCs). Interestingly, the interferon-γ level as a marker of cytotoxicity was increased by DCA in culture media of both T cells and PBMCs. We conclude that PDK inhibition through DCA reverses metabolic programming in melanoma cells. Also, DCA toxicity was enhanced by other metabolic inhibitors, showing that DCA treatment leads to dependency on other metabolic pathways. DCA treatment was non-toxic to immune cells and even enhanced cytotoxicity. Therefore, DCA may be a valuable tool in improving response to immunotherapy in melanoma patients. Citation Format: Jiske F. Tiersma, Bernard Evers, Barbara M. Bakker, Steven de Jong, Mathilde Jalving. Targeting metabolism to improve response to immune-checkpoint inhibition in melanoma [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-020.