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Simple Summary: Up to 50% of patients diagnosed with advanced melanoma develop brain metastases during the course of their disease. The prognosis of melanoma patients is heavily affected by the presence of brain metastases. Unfortunately, there is a lack of data on prognostic factors for these patients. Many of these patients are treated with immune checkpoint inhibitors. Therefore, the aim of our study was to identify prognostic factors in melanoma patients with brain metastases treated with immune checkpoint inhibitors. In a population of 1278 advanced melanoma patients, we found that serum lactate dehydrogenase levels were the strongest clinical parameter associated with survival. This information is useful for both doctors and patients to provide more insight into patients' prognoses. 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 FROM AUTHOR]

Simple Summary: Cutaneous melanoma is highly prone to metastasize to the brain, with a historically poor overall survival of only 4–5 months. Over the past decade, novel drugs such as targeted therapies and immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced melanoma. However, most prospective studies have excluded patients with melanoma brain metastasis (MBM) or included only patients with stable (steroid-free) or asymptomatic MBM. To assess the impact of novel treatments in patients with MBM in a real-world setting, we studied a cohort of consecutive patients over a period of sixteen years (2005 to 2021) in a large, tertiary referral center for melanoma (Erasmus MC, Rotterdam, the Netherlands). We found a significant improvement in overall survival in the modern (post-2015) era, associated with stereotactic radiotherapy and especially ICIs. These findings support that ICIs, if clinically feasible, should be considered first in clinical practice after a diagnosis of MBM. Background: Melanoma brain metastasis (MBM) is associated with poor outcome, but targeted therapies (TTs) and immune checkpoint inhibitors (ICIs) have revolutionized treatment over the past decade. We assessed the impact of these treatments in a real-world setting. Methods: A single-center cohort study was performed at a large, tertiary referral center for melanoma (Erasmus MC, Rotterdam, the Netherlands). Overall survival (OS) was assessed before and after 2015, after which TTs and ICIs were increasingly prescribed. Results: There were 430 patients with MBM included; 152 pre-2015 and 278 post-2015. Median OS improved from 4.4 to 6.9 months (HR 0.67, p < 0.001) after 2015. TTs and ICIs prior to MBM diagnosis were associated with poorer median OS as compared to no prior systemic treatment (TTs: 2.0 vs. 10.9 and ICIs: 4.2 vs. 7.9 months, p < 0.001). ICIs directly after MBM diagnosis were associated with improved median OS as compared to no direct ICIs (21.5 vs. 4.2 months, p < 0.001). Stereotactic radiotherapy (SRT; HR 0.49, p = 0.013) and ICIs (HR 0.32, p < 0.001) were independently associated with improved OS. Conclusion: After 2015, OS significantly improved for patients with MBM, especially with SRT and ICIs. Demonstrating a large survival benefit, ICIs should be considered first after MBM diagnosis, if clinically feasible. [ABSTRACT FROM AUTHOR]

Simple Summary: BRAF/MEK therapy and anti-PD-1 therapy have shown better recurrence-free survival of stage III melanoma in patients with BRAF V600 mutations in clinical trials. However, little is known about how these therapies compare to each other in everyday practice. The aim of our study was to describe the toxicity and survival of patients treated with BRAF/MEK therapy and anti-PD-1 therapy in daily practice. We demonstrated that grade ≥ 3 toxicity occurred in 11.5% of patients and was the most common cause of early treatment discontinuation (71.1%). We also show that at 12 months, patients treated with BRAF/MEK therapy have less progression than those treated with anti-PD-1 therapy. However, this is no longer the case at 18 months. Adjuvant BRAF/MEK- and anti-PD-1 inhibition have significantly improved recurrence-free survival (RFS) compared to placebo in resected stage III BRAF-mutant melanoma. However, data beyond the clinical trial setting are limited. This study describes the toxicity and survival of patients treated with adjuvant BRAF/MEK inhibitors and compares outcomes to adjuvant anti-PD-1. For this study, stage III BRAF V600 mutant cutaneous melanoma patients treated with adjuvant BRAF/MEK-inhibition or anti-PD-1 were identified from the Dutch Melanoma Treatment Registry. BRAF/MEK- and anti-PD-1-treated patients were matched based on propensity scores, and RFS at 12 and 18 months were estimated. Between 1 July 2018 and 31 December 2021, 717 patients were identified. Of these, 114 patients with complete records were treated with BRAF/MEK therapy and 532 with anti-PD-1. Comorbidities (p = 0.04) and geographical region (p < 0.01) were associated with treatment choice. In 45.6% of BRAF/MEK-treated patients, treatment was prematurely discontinued. Grade ≥ 3 toxicity occurred in 11.5% of patients and was the most common cause of early discontinuation (71.1%). At 12 and 18 months, RFS in BRAF/MEK-treated patients was 85% and 70%, compared to 68% and 68% in matched anti-PD-1-treated patients (p = 0.03). In conclusion, comorbidities and geographical region determine the choice of adjuvant treatment in patients with resected stage III BRAF-mutant melanoma. With the currently limited follow-up, BRAF/MEK-treated patients have better RFS at 12 months than matched anti-PD-1-treated patients, but this difference is no longer observed at 18 months. Therefore, longer follow-up data are necessary to estimate long-term effectiveness. [ABSTRACT FROM AUTHOR]

Simple Summary: More than 40% of patients initially diagnosed with 'low risk' (stage I–II) melanoma eventually develop melanoma recurrence or die as a result of melanoma. While the current standard of care at diagnosis for these patients is watchful waiting, they may benefit from adjuvant systemic treatment. The primary aim of this retrospective study was to assess the performance of a clinicopathologic and gene expression (CP-GEP) model, a model originally developed to predict sentinel node metastasis, to identify patients with stage I–II melanoma at risk of disease relapse. This study included Swedish and Dutch patients (18 years of age or older) with a melanoma of the skin without sentinel node metastasis. Using the non-invasive CP-GEP model, the patients could be divided into two groups: high (413 patients) or low risk (122 patients) of recurrence. While these results are promising, optimization of the CP-GEP model is recommended before implementing the model in clinical practice. Background: The current standard of care for patients without sentinel node (SN) metastasis (i.e., stage I–II melanoma) is watchful waiting, while >40% of patients with stage IB–IIC will eventually present with disease recurrence or die as a result of melanoma. With the prospect of adjuvant therapeutic options for patients with a negative SN, we assessed the performance of a clinicopathologic and gene expression (CP-GEP) model, a model originally developed to predict SN metastasis, to identify patients with stage I–II melanoma at risk of disease relapse. Methods: This study included patients with cutaneous melanoma ≥18 years of age with a negative SN between October 2006 and December 2017 at the Sahlgrenska University Hospital (Sweden) and Erasmus MC Cancer Institute (The Netherlands). According to the CP-GEP model, which can be applied to the primary melanoma tissue, the patients were stratified into high or low risk of recurrence. The primary aim was to assess the 5-year recurrence-free survival (RFS) of low- and high-risk CP-GEP. A secondary aim was to compare the CP-GEP model with the EORTC nomogram, a model based on clinicopathological variables only. Results: In total, 535 patients (stage I–II) were included. CP-GEP stratification among these patients resulted in a 5-year RFS of 92.9% (95% confidence interval (CI): 86.4–96.4) in CP-GEP low-risk patients (n = 122) versus 80.7% (95%CI: 76.3–84.3) in CP-GEP high-risk patients (n = 413; hazard ratio 2.93 (95%CI: 1.41–6.09), p < 0.004). According to the EORTC nomogram, 25% of the patients were classified as having a 'low risk' of recurrence (96.8% 5-year RFS (95%CI 91.6–98.8), n = 130), 49% as 'intermediate risk' (88.4% 5-year RFS (95%CI 83.6–91.8), n = 261), and 26% as 'high risk' (61.1% 5-year RFS (95%CI 51.9–69.1), n = 137). Conclusion: In these two independent European cohorts, the CP-GEP model was able to stratify patients with stage I–II melanoma into two groups differentiated by RFS. [ABSTRACT FROM AUTHOR]

Background: Nivolumab is administered in a weight-based or fixed-flat dosing regimen. For patients with non-small cell lung cancer (NSCLC), a potential exposure-response relationship has recently been reported and may argue against the current dosing strategies. The primary objectives were to determine nivolumab pharmacokinetics (PK) and to assess the relationship between drug clearance and clinical outcome in NSCLC, melanoma, and renal cell cancer (RCC). Methods: In this prospective observational cohort study, individual estimates of nivolumab clearance and the impact of baseline covariates were determined using a population-PK model. Clearance was related to best overall response (RECISTv1.1), and stratified by tumor type. Results: Two-hundred-twenty-one patients with metastatic cancer receiving nivolumab-monotherapy were included of whom 1,715 plasma samples were analyzed. Three baseline parameters had a significant effect on drug clearance and were internally validated in the population-PK model: gender, BSA, and serum albumin. Women had 22% lower clearance compared to men, while the threshold of BSA and albumin that led to > 20% increase of clearance was > 2.2m² and < 37.5 g/L, respectively. For NSCLC, drug clearance was 42% higher in patients with progressive disease (mean: 0.24; 95% CI: 0.22-0.27 L/day) compared to patients with partial/complete response (mean: 0.17; 95% CI: 0.15-0.19 L/day). A similar trend was observed in RCC, however, no clearance-response relationship was observed in melanoma. Conclusions: Based on the first real-world population-PK model of nivolumab, covariate analysis revealed a significant effect of gender, BSA, and albumin on nivolumab clearance. A clearance-response relationship was observed in NSCLC, with a non-significant trend in RCC, but not in melanoma. Individual pharmacology of nivolumab in NSCLC appears important and should be prospectively studied. [ABSTRACT FROM AUTHOR]

Purpose: Docetaxel is an important chemotherapeutic agent used for the treatment of several cancer types. As radiolabelled anticancer agents provide a potential means for personalized treatment planning, docetaxel was labelled with the positron emitter C. Non-invasive measurements of [C]docetaxel uptake in organs and tumours may provide additional information on pharmacokinetics and pharmacodynamics of the drug docetaxel. The purpose of the present study was to determine the biodistribution and radiation absorbed dose of [C]docetaxel in humans. Methods: Biodistribution of [C]docetaxel was measured in seven patients (five men and two women) with solid tumours using PET/CT. Venous blood samples were collected to measure activity in blood and plasma. Regions of interest (ROI) for various source organs were defined on PET (high [C]docetaxel uptake) or CT (low [C]docetaxel uptake). ROI data were used to generate time-activity curves and to calculate percentage injected dose and residence times. Radiation absorbed doses were calculated according to the MIRD method using OLINDA/EXM 1.0 software. Results: Gall bladder and liver demonstrated high [C]docetaxel uptake, whilst uptake in brain and normal lung was low. The percentage injected dose at 1 h in the liver was 47 ± 9%. [C]docetaxel was rapidly cleared from plasma and no radiolabelled metabolites were detected. [C]docetaxel uptake in tumours was moderate and highly variable between tumours. Conclusion: The effective dose of [C]docetaxel was 4.7 µSv/MBq. As uptake in normal lung is low, [C]docetaxel may be a promising tracer for tumours in the thoracic region. [ABSTRACT FROM AUTHOR]

Simple Summary: Melanoma is a malignant form of skin cancer. The overall survival of patients with advanced stages of disease were initially low. Fortunately, in recent years systemic treatment with immunotherapy has prolonged survival. We set out to answer the question whether men and women with advanced melanoma differ in prognostic factors, tumor-response to immunotherapy, and treatment-related adverse events. All patients in the Netherlands were registered between July 2013 and July 2018. We showed that although clinical and tumor characteristics differ, the safety profile of immunotherapy is comparable. Furthermore, overall, a 10% survival advantage for women was seen. Following immunotherapy there was no survival difference. Recent meta-analyses show conflicting data on sex-dependent benefit following systemic treatment for advanced melanoma patients. We examined the nationwide Dutch Melanoma Treatment Registry (July 2013–July 2018), assessing sex-dependent differences in advanced melanoma patients (stage IIIC/IV) with respect to clinical characteristics, mutational profiles, treatments initiated, grade 3–4 adverse events (AEs), treatment responses, and mortality. We included 3985 patients, 2363 men (59%) and showed that although men and women with advanced melanoma differ in clinical and tumor characteristics, the safety profile of immune checkpoint inhibition (ICI) is comparable. The data suggest a 10% survival advantage for women, mainly seen in patients ≥60 years of age and patients with BRAF V600 mutant melanoma. Following ICI there was no survival difference. [ABSTRACT FROM AUTHOR]

Simple Summary: Trials suggest no differences in immunotherapy treatment between older and younger patients, but mainly young patients with a good performance status were included in these trials. The aim of this study was to describe the treatment patterns and outcomes of "real-world" older patients with metastatic melanoma. We included 2216 patients aged ≥65 years from the Dutch Melanoma Treatment Registry and described outcomes of immunotherapy. The study showed that responses and severe side effects did not differ from previously reported younger populations and randomized trials, even in the oldest patients and in patients with other diseases. However, patients aged ≥75 discontinued treatment due to toxicity more often, resulting in fewer treatment cycles. We therefore conclude that immunotherapy seems to have similar effects in older patients compared to younger patients, but the impact of less severe toxicity on quality of life should be further studied as older patients are more likely to discontinue treatment. Background: Previous trials suggest no differences in immunotherapy treatment between older and younger patients, but mainly young patients with a good performance status were included. The aim of this study was to describe the treatment patterns and outcomes of "real-world" older patients with metastatic melanoma and to identify predictors of outcome. Methods: We included patients aged ≥65 years with metastatic melanoma from the Dutch Melanoma Treatment Registry. We described the reasons for hospital admissions and treatment discontinuation. Additionally, we assessed predictors of toxicity and response using logistic regression models and survival using Cox regression models. Results: We included 2216 patients. Grade ≥3 toxicity was not associated with age, comorbidities or WHO status. Patients aged ≥75 discontinued treatment due to toxicity more often, resulting in fewer treatment cycles. Response rates were similar to previous trials (40.3% and 43.6% in patients aged 65–75 and ≥75, respectively, for anti-PD1 treatment) and did not decrease with age or comorbidity. Melanoma-specific survival was not affected by age or comorbidity. Conclusion: Response rates and toxicity outcomes of checkpoint inhibitors did not change with increasing age or comorbidity. However, the impact of grade I-II toxicity on quality of life deserves further study as older patients discontinue treatment more frequently. [ABSTRACT FROM AUTHOR]

Simple Summary: Although the introduction of programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) has significantly improved the overall survival (OS) in patients with metastatic melanoma, a substantial number of patients do not benefit from ICIs. Therefore, the predictive value of single nucleotide polymorphisms (SNPs) in genes related to the PD-1 axis was investigated in patients with metastatic melanoma and anti-PD-1 monotherapy. Germline variation in the gene encoding for PD-1, PDCD1 804C > T (rs2227981), was associated with poorer OS with a 3-year OS rate of 51.8%, as compared to 71% in wild type patients. In addition, PDCD1 804C > T carriers had significantly lower mRNA expression in several tissues and a decreased fraction of PD-1+ CD4+ T cells, indicating that PDCD1 804C > T may affect clinical benefit from ICIs by decreasing transcriptional initiation and PD-1 expression in T cells. These findings show that germline genetics may significantly impact immune responses after ICIs. A substantial number of melanoma patients do not benefit from therapy with anti-PD-1. Therefore, we investigated the predictive value of single nucleotide polymorphisms (SNPs) in genes related to the PD-1 axis in patients with metastatic melanoma. From 119 consecutive melanoma patients who were treated with pembrolizumab or nivolumab monotherapy, blood samples were genotyped for 11 SNPs in nine genes. Associations between SNPs and OS were tested using Cox regression analysis and internally validated by bootstrapping. For SNPs with a statistical significance, an expression quantitative trait loci (eQTL) analysis was performed. In a subset of patients, immunophenotyping was performed. Patients with a SNP in PDCD1 (804C > T; rs2227981) had a significantly poorer OS with a 3-year OS rate of 51.8%, as compared to 71% in wild type patients (hazard ratio [HR] 2.37; 95% CI: 1.11–5.04; p = 0.026). eQTL analysis showed that this SNP was associated with decreased gene expression. In addition, PDCD1 804C > T carriers had a reduced fraction of peripheral PD-1+CD4+ T cells. No other associations between SNPs and OS were found. PDCD1 804C > T is associated with poorer OS after anti-PD-1 monotherapy in patients with metastatic melanoma. This SNP may affect clinical benefit from ICIs by decreasing transcription initiation and expression of PD-1 in T cells. [ABSTRACT FROM AUTHOR]

Opportunities for surgical treatment in metastatic melanoma patients have re-emerged due to the development of novel systemic therapeutics over the past decade. The aim of this study is to present data on outcomes of surgery in patients with unresectable stage IIIC and IV melanoma, who have previously been treated with immunotherapy or targeted therapy. Data was extracted from the Dutch Melanoma Treatment Registry (DMTR) on 154 patients obtaining disease control to systemic therapy and undergoing subsequent surgery. Disease control was defined as a complete response (CR), which was seen in 3.2% of patients; a partial response (PR), seen in 46.1% of patients; or stable disease (SD), seen in 44.2% of patients. At a median follow-up of 10.0 months (interquartile range 4–22) after surgery, the median overall survival (OS) had not been reached in our cohort and median progression-free survival (PFS) was 9.0 months (95% CI 6.3–11.7). A CR or PR at first follow-up after surgery was associated with both a better OS and PFS compared to stable or progressive disease (p < 0.001). We conclude that selected patients can benefit from surgery after achieving disease control with systemic therapy. [ABSTRACT FROM AUTHOR]