Circulating tumor DNA-based assessment of molecular residual disease in non-metastatic melanoma.

In patients with resected non-metastatic melanoma, the liquid biopsy for the assessment of molecular residual disease (MRD) by circulating tumour DNA (ctDNA) represents a promising tool to stratify the risk and to monitor tumour evolution. However, its validation requires the demonstration of analytical validity, clinical validity and utility. Indeed, the development of sensitive and specific assays can optimize prognostication and eventually help clinicians to modulate adjuvant treatments, in order to improve clinical outcomes. Data about ctDNA-guided prognosis stratification is emerging, but clinical trials assessing ctDNA-guided therapeutic decisions are still ongoing. This review aims to depict the role of ctDNA-based MRD assessment in patients with non-metastatic melanoma and to provide a roadmap to face challenges for its introduction into clinical practice.

Prospective Assessment of Fluorine-18-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography (FDG-PET/CT) for Early Identification of Checkpoint-Inhibitor-Induced Pseudoprogression.

The activity of immune checkpoint inhibitors (ICIs) in patients with metastatic melanoma is often monitored using fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scans. However, distinguishing disease progression (PD) from pseudoprogression (PsPD), where increased FDG uptake might reflect immune cell activity rather than tumor growth, remains a challenge. This prospective study compared the efficacy of dual-time point (DTP) FDG-PET/CT with modified response criteria (PERCIMT) in differentiating PsPD from PD. From July 2017-January 2021, 41 patients suspected to have PsPD on an evaluation scan were prospectively included (29 evaluable). A subsequent DTP FDG-PET/CT scan was conducted within 14 days, followed by a confirmatory FDG-PET/CT scan. Additionally, PERCIMT were applied. DTP FDG-PET/CT identified 24% with PsPD and 76% with PD. Applying PERCIMT criteria, 69% showed PsPD, while 31% had PD. On follow-up, 10 patients (34%) demonstrated confirmed PsPD, while 19 (66%) exhibited PD. The sensitivity and specificity of DTP FDG-PET/CT were 20% and 74%, respectively, and for PERCIMT this was 80% and 37%, respectively. Our findings suggest limited efficacy of DTP FDG-PET/CT in distinguishing PsPD from PD in ICI-treated patients with metastatic melanoma. The use of PERCIMT could complement clinical assessment and be incorporated in multidisciplinary team conferences for enhanced decision-making.

Sustained improved survival of patients with metastatic melanoma after the introduction of anti-PD-1-based therapies.

BACKGROUND: The introduction of modern therapies improved the median survival of patients with metastatic melanoma (MM). Here, we determined the real-world impact of modern treatments on the long-term survival of MM. METHODS: In a population-based study, we extracted all cases of MM diagnosed in four non-consecutive years marked by major changes in available 1st line treatments (2012, 2014, 2016, and 2018) from the Danish MM Database. Patients were grouped into "trial-like" and "trial-excluded" based on common trial eligibility criteria. RESULTS: We observed a sustained improved survival of "trial-like" patients diagnosed in 2016 or in 2018, compared to 2012 or 2014, but no major differences in 2018 versus 2016. In contrast, while survival of "trial-excluded" patients in 2016 was better compared to 2014 and 2012, survival in 2018 was improved over all previous years. We then developed a prognostic model based on multivariable stratified Cox regression, to predict the survival of newly diagnosed MM patients. Internal validation showed excellent discrimination and calibration, with a time-area-under-the-curve above 0.79 at multiple time horizons, for up to four years after diagnosis. CONCLUSIONS: The introduction of modern treatments such as anti-PD-1 has led to a sustained, improved survival of real-world patients with MM, regardless of their eligibility for clinical trials. We provide an updateable prognostic model that can be used to improve patient information. Overall, these data highlight a positive population-based impact of modern treatments and can help health technology assessment agencies worldwide to evaluate the appropriateness of drug pricing based on known cost-benefit data.

Nasopharyngeal malignant melanoma masquerading in the gallbladder: the importance of histological assessment.

Metastatic melanoma of the gallbladder is a rare entity that is often diagnosed late, leading to a poor prognosis. The disease may present insidiously as acute cholecystitis or remain asymptomatic. Optimal management remains unclear but surgical resection is considered the mainstay of treatment for this condition. We report the case of a 47-year-old man who suffered a protracted course of generalised abdominal symptoms eventually culminating in a diagnosis of acute cholecystitis. Following an emergency laparoscopic cholecystectomy, the histology revealed a melanoma with an unknown primary. Subsequently this was traced to the nasopharynx. Because of the presence of concurrent liver metastasis, systemic immunotherapy with palliative intent was commenced following a multidisciplinary team discussion. This case highlights the importance of sending clinical specimens for histological analysis. We argue against selectively choosing which specimens to send for histology because radiological and/or intraoperative macroscopic inspection of resected tissue alone can result in a missed diagnosis.

Health care and socioeconomic costs for long-term survivors after implementation of checkpoint-inhibitors and targeted agents for metastatic melanoma.

BACKGROUND: Real-life data on health care costs and loss of productivity after implementing new agents for metastatic melanoma are important to supplement model-based economic data. MATERIALS AND METHODS: All patients registered in the Danish Metastatic Melanoma Database (DAMMED) and the National Patient Registry in 2007-2011 were compared to 2012-2016 after the implementation of checkpoint inhibitors and targeted therapy. Health care costs, social transfer income (STI), and loss of productivity were calculated with a 2-step one model generalised linear regression (GLM) model. Medicine costs were calculated separately. RESULTS: In 2007-2011, 70 (15%) out of 464 patients were long-term survivors compared to 347 (32%) out of 1089 patients in 2012-2016. Total health care costs per patient year were significantly lower in the first treatment year (€41.457 versus €60.547, relative change (RC) 0.72, 95% confidence interval (CI) 0.56-0.94, p = 0.015) and without significant difference the second year in 2012-2016 compared to 2007-2011. Medicine costs per patient year increased the first (€85.464 versus €26.339, RC 3.39, 95% CI 2.61-4.41, p < 0.001) and the second (€26.464 versus €11.150, RC 2.59, 95% CI 1.98-3.40, p < 0.001) year in 2012-2016 compared to 2007-2011. Productivity increased for long-term survivors in 2012-2016 in contrast to 2007-2011. CONCLUSION: Implementation of targeted therapy and checkpoint-inhibitors has increased medicine costs more than three-fold for long-term survivors. Total health care costs excluding medicine costs were significantly lower for long-term survivors the first and without change the second treatment year in 2012-2016 compared to 2007-2011. However, the number of treated patients increased which leads to an increase in overall total health care costs. Importantly, productivity increased for long-term survivors in 2012-2016.

Cost-effectiveness of encorafenib with binimetinib in unresectable or metastatic BRAF-mutant melanoma.

OBJECTIVE: The objective of this study was to determine the cost-effectiveness of encorafenib with binimetinib (EncoBini) as compared to other targeted double combination therapies, namely dabrafenib with trametinib (DabraTrame) and vemurafenib with cobimetinib (VemuCobi), for the treatment of BRAF V600-mutant unresectable or metastatic melanoma (MM) from the French payer perspective. METHODS: A partitioned survival model was developed considering a lifetime horizon. The model structure simulated the clinical pathway of patients with BRAF V600-mutant MM. Clinical effectiveness and safety inputs were sourced from the COLUMBUS trial, a network meta-analysis and published literature. Costs, resource use, and the quality of life inputs were obtained from the literature and appropriate French sources. RESULTS: Over a lifetime horizon, EncoBini was associated, on average, with reduced costs and increased quality adjusted life years (QALYs), dominating both targeted double combination therapies. For a willingness-to-pay threshold of €90,000 per QALY, the probability of EncoBini being cost-effective against either comparator remained above 80%. The most influential model parameters were the hazard ratios for the overall survival of EncoBini vs DabraTrame and VemuCobi, the pre- and post-progression utility values, as well as treatment dosages and the relative dose intensity of all interventions. CONCLUSION: EncoBini is associated with reduced costs and increased QALYs, dominating other targeted double combination therapies (DabraTrame, VemuCobi) for patients with BRAF V600-mutant MM in France. EncoBini is a highly cost-effective intervention in MM.

A modified melanoma-molGPA scoring model: assessment of survival after and efficacy of different radiotherapy modalities in patients with melanoma brain metastases.

PURPOSE: Patients with malignant melanoma brain metastases (MBMs) have poor prognoses. For MBMs, the Melanoma-molGPA is the most widely used predictive score, but its predictive value remains uncertain in patients fully treated with radiotherapy. We identified MBMs prognostic factors and modified the prognostic scoring model. METHODS: We retrospectively analyzed patients diagnosed with MBMs between December 2010 and November 2021 for prognostic factors influencing overall survival (OS) by univariate and multivariate analyses. Nomogram plots were based on Cox regression modeling. We evaluated overall survival (OS) using Kaplan-Meier survival curves and log-rank tests. RESULTS: The median OS (mOS) was 7.9 months. On multivariate analysis, BRAF mutation status (p < 0.001), number of brain metastases (BM) (p < 0.001), presence of liver metastases (p < 0.001), brain metastases with a midline shift (p = 0.003), Karnofsky Performance Score (p = 0.02), and lymphocyte-to-monocyte ratio (p < 0.0001) were independent OS predictors. These were incorporated into a modified risk-stratification model. Overall, whole-brain radiotherapy (WBRT) did not significantly affect mOS (mOS, 6.89 vs. 8.83 months; p = 0.07). After risk stratification using our model, WBRT resulted in no significant survival benefit in the low-risk group (mOS 10.07 vs. 13.1 months; p = 0.71) but significantly worse prognosis in the high-risk group (mOS, 2.37 vs. 6.92 months; p = 0.026). CONCLUSION: We propose a modified model that accurately distinguishes the prognosis of patients with MBMs and guides decision-making for radiotherapy. Based on this novel model, WBRT should be cautiously selected for high-risk patients.

Cost-effectiveness of second-line ipilimumab for metastatic melanoma: A real-world population-based cohort study of resource utilization.

BACKGROUND: The efficacy-effectiveness gap between randomized trial and real-world evidence regarding the clinical benefit of ipilimumab for metastatic melanoma (MM) has been well characterized by previous literature, consistent with initial concerns raised by health technology assessment agencies (HTAs). As these differences can significantly impact cost-effectiveness, it is critical to assess the real-world cost-effectiveness of second-line ipilimumab versus non-ipilimumab treatments for MM. METHODS: This was a population-based retrospective cohort study of patients who received second-line non-ipilimumab therapies between 2008 and 2012 versus ipilimumab treatment between 2012 and 2015 (after public reimbursement) for MM in Ontario. Using a 5-year time horizon, censor-adjusted and discounted (1.5%) costs (from the public payer's perspective in Canadian dollars) and effectiveness were used to calculate incremental cost-effectiveness ratios (ICERs) in life-years gained (LYGs) and quality-adjusted life years (QALYs), with bootstrapping to capture uncertainty. Varying the discount rate and reducing the price of ipilimumab were done as sensitivity analyses. RESULTS: In total, 329 MM were identified (Treated: 189; Controls: 140). Ipilimumab was associated with an incremental effectiveness of 0.59 LYG, incremental cost of $91,233, and ICER of $153,778/LYG. ICERs were not sensitive to discounting rate. Adjusting for quality of life using utility weights resulted in an ICER of $225,885/QALY, confirming the original HTA estimate prior to public reimbursement. Reducing the price of ipilimumab by 100% resulted in an ICER of $111,728/QALY. CONCLUSION: Despite its clinical benefit, ipilimumab as second-line monotherapy for MM patients is not cost-effective in the real world as projected by HTA under conventional willingness-to-pay thresholds.

Geographic disparities in access to immunotherapy clinical trials for metastatic melanoma.

Survival outcomes for metastatic melanoma have drastically improved with the advent of immunotherapy. Access to ongoing immunotherapy clinical trials has become increasingly important to patients with advanced disease. We sought to quantify geographic disparities in access to these trials by U.S. division, region, urban/rural status, and median income. We searched ClinicalTrials.gov for interventional immunotherapy trials for metastatic melanoma from 2015 to 2021 and identified U.S. zip codes for each participating trial site. ArcGIS was used to calculate the one-way driving time from each zip code to the nearest treatment center. Melanoma burden in each zip code outside a 60 min driving radius was calculated by multiplying population by the corresponding state's cancer-specific mortality rate. χ2 tests were used to test for significance between census regions, divisions, and urban vs. rural zip codes, while logistic regression was used to quantify risk of poor access with median income. Across 148 trials, 4844 treatment centers were located in 1102 unique zip codes. 9010 zip codes were located greater than one-hour driving time from the nearest clinical trial. Southern regions were most likely to have poor access of all regions (p < 0.001), and rural status also significantly correlated with poor access (p < 0.001). For every $10,000 increase in median income, the likelihood of a zip code being within 60 min from a trial increased by 1.315. While immunotherapy continue to improve survival outcomes for metastatic melanoma, geographic access to clinical trials investigating these therapies remains a challenge for a significant proportion of the U.S. population.

Modeling the Ex Post Real Option Value in Metastatic Melanoma Using Real-World Data.

OBJECTIVES: Real option value (ROV) is created when a drug enables a patient to live long enough to benefit from a future innovation. Few studies have quantified ROV in the real world. We aimed to estimate the ex post ROV for ipilimumab in metastatic melanoma using real-world data (RWD). METHODS: We developed a framework for calculating ROV using RWD, accounting for the health gain in the standard therapy arm and the uptake of future innovations. A Markov model was developed to estimate the quality-adjusted life-years (QALYs) gained with ipilimumab compared with chemotherapy for patients with or without subsequent cancer immunotherapy (CIT). A nationwide electronic health record-derived, deidentified database was used to estimate survival and uptake of CIT. RESULTS: The incremental QALYs gained for ipilimumab compared with chemotherapy without subsequent CIT were 1.74. With subsequent CIT, the incremental QALYs compared with chemotherapy increased by 0.92, 0.60, 0.33, 0.18, 0.10, and 0.02 when CIT became available 0, 3, 6, 9, 12, and 24 months after the initiation of first-line treatment, respectively. The results were most sensitive to the survival benefit of ipilimumab, the survival benefit of subsequent CIT, and the uptake of CIT. CONCLUSIONS: This is the first study to estimate ex post ROV using RWD. The ex post ROV was between 1% and 54% of conventional value for patients who received a diagnosis within 2 years before CIT availability. Further studies are needed to understand ROV in other disease areas, particularly those with longer survival times.

Cost-Effectiveness of the Dabrafenib Schedule in Combination With Trametinib Compared With Other Targeted Therapies, Immunotherapy, and Dacarbazine for the Treatment of Unresectable or Metastatic Melanoma With BRAFV600 Mutation in Colombia.

OBJECTIVES: Advanced melanoma accounts for 4% of malignant skin tumors, and approximately 80% of deaths are attributed to it. The most frequent mutation of the RAF gene is BRAFV600, which has been associated with a worse prognosis. The objective of the research was to evaluate the cost-effectiveness of the combined regimen of dabrafenib plus trametinib (D + T) compared with other targeted therapies, immunotherapy, and dacarbazine for the treatment of unresectable/metastatic melanoma with BRAFV600 mutation from the perspective of the Colombian health system. METHODS: A partitioned survival model with 3 states (progression-free survival, progression, and death) was used to evaluate the cost-effectiveness for a time horizon of 20 years. Owing to the perspective of the analysis, only direct medical costs were taken into account. The efficacy of the evaluated treatment and the comparators were measured in terms of overall survival and progression-free survival. All costs were expressed in Colombian pesos as of 2018, and outcomes and costs were discounted at 5% annually. Two analysis scenarios were considered, one in which only monitoring and follow-up costs were included in the progression phase and another in which costs of acquisition of possible treatment sequences were also included. RESULTS: In the first scenario (without postprogression medication costs), the combined D + T regimen was a dominant alternative to vemurafenib + cobimetinib but was not a cost-effective option compared with vemurafenib, nivolumab, ipilimumab, nivolumab + ipilimumab, pembrolizumab, and dacarbazine. In the second scenario (with drug costs in postprogression), D + T was dominant compared with vemurafenib + cobimetinib and cost-effective compared with nivolumab and pembrolizumab. Compared with other schemes, the incremental cost-effectiveness ratio was above the threshold of 3 gross domestic product per capita. Probabilistic sensitivity analyses showed that a willingness-to-pay threshold of Col$56 484 300 (US$19 108) per quality-adjusted life-year would not be reached at the current price of schema in Colombia. CONCLUSIONS: The combined scheme could be a cost-effective and even a cost-saving alternative to vemurafenib + cobimetinib, nivolumab, and pembrolizumab if the costs associated with the use of other medications are taken into account after progression to the first line of treatment. Compared with the other comparators, it produces a greater number of quality-adjusted life-years, but the incremental cost-effectiveness ratio is above that of the willingness to pay.

Fractal and Multifractal Analysis of PET-CT Images for Therapy Assessment of Metastatic Melanoma Patients under PD-1 Inhibitors: A Feasibility Study.

Longitudinal whole-body PET-CT scans with F-18-fluorodeoxyglucose (18F-FDG) in patients suffering from metastatic melanoma were analyzed and the tracer distribution in patients was compared with that of healthy controls. Nineteen patients with metastatic melanoma were scanned before, after two and after four cycles of treatment with PD-1 inhibitors (pembrolizumab, nivolumab) applied as monotherapy or as combination treatment with ipilimumab. For comparison eight healthy controls were analyzed. As quantitative measures for the comparison between controls and patients, the nonlinear fractal dimension (FD) and multifractal spectrum (MFS) were calculated from the digitized PET-CT scans. The FD and MFS measures, which capture the dispersion of the tracer in the body, decreased with disease progression, since the tracer particles tended to accumulate around metastatic sites in patients, while the measures increased when the patients' clinical condition ameliorate. The MFS measure gave better predictions and were consistent with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT) in 81% of the cases, while FD agreed in 77% of all cases. These results agree, qualitatively, with a previous study of our group when treatment with ipilimumab monotherapy was considered.

Assessment of early metabolic progression in melanoma patients under immunotherapy: an 18F-FDG PET/CT study.

BACKGROUND: The usage of immune checkpoint inhibitors (ICIs) is the standard practice for the treatment of metastatic melanoma. However, a significant amount of patients show no response to immunotherapy, while issues on its reliable response interpretation exist. Aim of this study was to investigate the phenomenon of early disease progression in 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in melanoma patients treated with ICIs. METHODS: Thirty-one patients under ICIs serially monitored with 18F-FDG PET/CT were enrolled. All patients exhibited progressive metabolic disease (PMD) after two ICIs' cycles according to the European Organization for Research and Treatment of Cancer (EORTC) criteria, and were characterized as unconfirmed PMD (uPMD). They were further followed with at least one PET/CT for either confirmation of PMD (cPMD) or demonstration of pseudoprogression remission. Patients were also evaluated with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT). Moreover, in an attempt to investigate immune activation, the spleen to liver ratios (SLRmean, SLRmax) of 18F-FDG uptake were measured. RESULTS: Median follow up was 69.7 months [64.6-NA]. According to EORTC, 26/31 patients with uPMD eventually showed cPMD (83.9%) and 5/31 patients showed pseudoprogression (16.1%). Patients with cPMD (n = 26) had a median OS of 10.9 months [8.5-NA], while those with pseudoprogression (n = 5) did not reach a median OS [40.9-NA]. Respectively, after application of PERCIMT, 2/5 patients of the pseudoprogression group were correctly classified as non-PMD, reducing the uPMD cohort to 29 patients; eventually, 26/29 patients demonstrated cPMD (89.7%) and 3/29 pseudoprogression (10.3%). One further patient with pseudoprogression exhibited transient, sarcoid-like, mediastinal/hilar lymphadenopathy, a known immune-related adverse event (irAE). Finally, patients eventually showing cPMD exhibited a significantly higher SLRmean than those showing pseudoprogression after two ICIs' cycles (p = 0.038). CONCLUSION: PET/CT, performed already after administration of two ICIs' cycles, can identify the majority of non-responders in melanoma immunotherapy. In order to tackle however, the non-negligible phenomenon of pseudoprogression, another follow-up PET/CT, the usage of novel response criteria and vigilance over emergence of radiological irAEs are recommended. Moreover, the investigation of spleen glucose metabolism may offer further prognostic information in melanoma patients under ICIs.

The Danish metastatic melanoma database (DAMMED): A nation-wide platform for quality assurance and research in real-world data on medical therapy in Danish melanoma patients.

BACKGROUND: Clinical trials enroll patients with specific diseases based on certain pre-defined eligibility criteria. Disease registries are crucial to evaluate the efficacy and safety of new expensive oncology medicines in broad non-trial patient populations. METHODS: We provide detailed information on the structure, including variables, and the scientific results from a nation-wide Danish database covering advanced melanoma, illustrating the importance of continuous real-world data registration. Disease status and treatment-related information on all patients with American Joint Committee on Cancer (AJCC) 8th edition stage III or IV melanoma candidates to medical treatment in Denmark are prospectively registered in the Danish Metastatic Melanoma Database (DAMMED). RESULTS: By January 1st, 2021, DAMMED includes 4156 patients and 7420 treatment regimens. Response rates and survival data from published randomized clinical trial data are compared with real-world efficacy data from DAMMED and presented. Overall, nine independent manuscripts highlighting similarities and discrepancies between real-world and clinical trial results are already reported to date. CONCLUSION: Nation-wide disease registries take into consideration the complexity of daily clinical practice. We show a concrete example of how disease registries can complement clinical trials' information, improving clinical practice, and support health-related technology assessment.

Assessment of Cell-Free microRNA by NGS Whole-Transcriptome Analysis in Cutaneous Melanoma Patients' Blood.

MicroRNAs (miRs) are small RNA molecules (18-22 nucleotides) that regulate the transcriptome at a post-transcriptional level by affecting the expression of specific genes. This regulatory mechanism is critical to maintain cell homeostasis and specific functions. Aberrant expression of miRs have been associated with pathobiological processes including cancer. There are few technologies available that are able to profile whole-genome miR expression using minimal amounts of blood samples and without the need for time-consuming extraction steps. Here, we describe the HTG EdgeSeq miR Whole-Transcriptome Assay (WTA) in serum and plasma samples. To identify specific cell-free miR (cfmiR) patterns we have first focused on the analysis of normal donor samples and have then compared these to patients with cutaneous melanoma. The identification of specific cfmiR for melanoma patients will allow for better patient surveillance during targeted and/or checkpoint inhibitor immunotherapy (CII) treatment.

Immune checkpoint inhibitor use, multimorbidity and healthcare expenditures among older adults with late-stage melanoma.

Background: The objective of this study is to assess the impact of immune checkpoint inhibitors (ICIs) and multimorbidity on healthcare expenditures among older patients with late-stage melanoma. Materials & methods: A retrospective longitudinal cohort study using Surveillance, Epidemiology and End Results linked with Medicare claims was conducted. Generalized linear mixed models were used to analyze adjusted relationships of ICI, multimorbidity and ICI-multimorbidity interaction on average healthcare expenditures. Results: Patients who received ICI and those who had multimorbidity had significantly higher average total healthcare expenditures compared with ICI nonusers and no multimorbidity. In the fully adjusted model using ICI-multimorbidity interaction, no excess cost was added by multimorbidity. Conclusion: Use of ICIs, regardless of multimorbidity, is associated with increased healthcare expenditures.

Trend and socioeconomic disparities in survival outcome of metastatic melanoma after approval of immune checkpoint inhibitors: a population-based study.

BACKGROUND: The approval of immune checkpoint inhibitors (ICI) for metastatic melanoma in 2011 has changed the treatment landscape of this disease. However, current trend of the population-based survival remains unclear. METHODS: 8078 patients with metastatic melanoma diagnosed in the pre-ICI (2005-2010) and post-ICI period (2011-2016) were enrolled from the Surveillance, Epidemiology, and End Results (SEER) program for survival comparison. Propensity score matching (PSM) was performed to reduce selection bias. Cox proportional hazards model was applied for identifying survival-related factors and constructing a prognostic nomogram. The accuracy of the nomogram was determined by concordance index (C-index), calibration curves, and validated by an internal cohort. RESULTS: Patients in the post-ICI period had a significantly longer median overall survival (OS) than those in the pre-ICI period, even after performing PSM between the two periods. We also found socioeconomic disparities in the survival improvement. Significant differences in OS between the two periods were only observed in cases with medical insurance and patients living in urban or low-poverty area, but not uninsured cases and patients from rural or high-poverty area. For patients in the post-ICI period, multivariate analysis demonstrated that socioeconomic and insurance status were independent prognostic factors, which can be combined with other clinical variates into a nomogram for OS prediction with promising C-index of 0.672 and 0.650 in the training- and testing cohort, respectively. CONCLUSION: An overall trend to favorable survival at the population level and socioeconomic disparities in the survival trend are observed in metastatic melanoma after the ICI approval. The proposed nomogram is available for prognostication in the current melanoma management.

Healthcare Costs of Metastatic Cutaneous Melanoma in the Era of Immunotherapeutic and Targeted Drugs.

Immunotherapeutic and targeted drugs improved survival of patients with metastatic melanoma. There is, however, a lack of evidence regarding their healthcare costs in clinical practice. The aim of our study was to provide insight into real-world healthcare costs of patients with metastatic cutaneous melanoma. Data were obtained from the Dutch Melanoma Treatment Registry for patients who were registered between July 2012 and December 2018. Mean total/monthly costs per patient were reported for all patients, patients who did not receive systemic therapy, and patients who received systemic therapy. Furthermore, mean episode/monthly costs per line of therapy and drug were reported for patients who received systemic therapy. Mean total/monthly costs were € 89,240/€ 6809: € 7988/€ 2483 for patients who did not receive systemic therapy (n = 784) and € 105,078/€ 7652 for patients who received systemic therapy (n = 4022). Mean episode/monthly costs were the highest for nivolumab plus ipilimumab (€ 79,675/€ 16,976), ipilimumab monotherapy (€ 79,110/€ 17,252), and dabrafenib plus trametinib (€ 77,053/€ 12,015). Dacarbazine yielded the lowest mean episode/monthly costs (€ 6564/€ 2027). Our study showed that immunotherapeutic and targeted drugs had a large impact on real-world healthcare costs. As new drugs continue entering the treatment landscape for (metastatic) melanoma, it remains crucial to monitor whether the benefits of these drugs outweigh their costs.

Quality-of-life assessment in French patients with metastatic melanoma in real life.

BACKGROUND: Significant progress was recently observed in the treatment of metastatic melanoma (MM). With >50% of patients now reaching a second line of treatment and a significant improvement in the survival rate, an assessment of quality of life (QoL) during the whole course of the disease becomes necessary. The objective of this study was to describe the QoL of patients with MM in France, from their diagnosis of advanced disease to their death, in real life. METHODS: QoL data were collected through MelBase, a prospective, French, multicentric cohort dedicated to the follow-up of adults with MM. QoL was assessed using the EuroQoL-5D questionnaire and the Functional Assessment of Cancer Treatment (FACT)-Melanoma questionnaire at the time of study inclusion, every 3 months, and at the time of each treatment change until death. To assess longitudinal changes from baseline to death, mixed-effect models for repeated-measures analyses were used to control for baseline covariates. RESULTS: QoL was assessed in 1435 patients who were included in the study between 2013 and 2018. The median follow-up was 9.4 months, and 47% of patients died during follow-up. During first-line treatment, the model-based, mean utility score was 0.830 (95% CI, 0.818-0.843), the mean FACT-General score was 77.22 (95% CI, 76.23-78.22), and the mean FACT-Melanoma score was 129.46 (95% CI, 128.02-130.90). At the time of a change in treatment line, there was a decrease of -0.027 (95% CI, -0.03, -0.02) in the utility score, -1.82 (95% CI, -1.88, -1.76) in the FACT-General score, and -2.98 (95% CI, -3.05, -2.91) in the FACT-Melanoma score compared with first-line treatment. CONCLUSIONS: In the MelBase cohort, the QoL among patients with MM seems to be fairly stable over the whole disease course, although a small but significant decrease at time therapy is changed is observed.

Undetectable circulating tumor DNA (ctDNA) levels correlate with favorable outcome in metastatic melanoma patients treated with anti-PD1 therapy.

BACKGROUND: Treatment with anti-PD1 monoclonal antibodies improves the survival of metastatic melanoma patients but only a subgroup of patients benefits from durable disease control. Predictive biomarkers for durable benefit could improve the clinical management of patients. METHODS: Plasma samples were collected from patients receiving anti-PD1 therapy for ctDNA quantitative assessment of BRAFV600 and NRASQ61/G12/G13 mutations. RESULTS: After a median follow-up of 84 weeks 457 samples from 85 patients were analyzed. Patients with undetectable ctDNA at baseline had a better PFS (Hazard ratio (HR) = 0.47, median 26 weeks versus 9 weeks, p = 0.01) and OS (HR = 0.37, median not reached versus 21.3 weeks, p = 0.005) than patients with detectable ctDNA. Additionally, the HR for death was lower after the ctDNA level became undetectable during follow-up (adjusted HR: 0.16 (95% CI 0.07-0.36), p-value < 0.001). ctDNA levels > 500 copies/ml at baseline or week 3 were associated with poor clinical outcome. Patients progressive exclusively in the central nervous system (CNS) had undetectable ctDNA at baseline and at subsequent assessments. In multivariate analysis adjusted for LDH, CRP, ECOG and number of metastatic sites, the ctDNA remained significant for PFS and OS. A positive correlation was observed between ctDNA levels and total metabolic tumor volume (TMTV), number of metastatic sites and total tumor burden. CONCLUSIONS: Assessment of ctDNA baseline and during therapy was predictive for tumor response and clinical outcome in metastatic melanoma patients and reflected the tumor burden. ctDNA evaluation provided reliable complementary information during anti-PD1 antibody therapy.