Early On-Treatment Assessment of T Cells, Cytokines, and Tumor DNA with Adaptively Dosed Nivolumab + Ipilimumab: Final Results from the Phase 2 ADAPT-IT Study.

PURPOSE: The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT;NCT03122522) investigated adaptive ipilimumab discontinuation in melanoma based on early radiographic assessment. Initial findings indicated similar effectiveness compared with conventional nivolumab-ipilimumab (nivo-ipi). Exploratory biomarker analyses and final clinical results are now reported. PATIENTS AND METHODS: Patients with unresectable melanoma received two doses of nivo-ipi. Radiographic assessment at Week 6 informed continuation of ipilimumab before nivolumab maintenance. The primary endpoint was overall response rate at Week 12. Plasma was assayed for circulating tumor DNA and 10 cytokines using a multiplex immunoassay. Flow cytometry of peripheral blood mononuclear cells was performed with an 11-color panel. RESULTS: Among the treated patients, expansion of proliferating T-cell populations was observed in responders and nonresponders. Baseline IL6 levels were low in patients achieving an objective radiographic response (median 1.30 vs. 2.86 pg/mL; P = 0.025). High baseline IL6 levels were associated with short progression-free survival [PFS; HR = 1.24, 95% confidence interval (CI), 1.01-1.52; P = 0.041]. At Week 6, patients with response had lower average tumor variant allele fractions than nonresponders (median 0.000 vs. 0.019; P = 0.014). Greater increases in average variant allele fractions from baseline to Week 6 correlated with short PFS (HR = 1.11, 95% CI, 1.01-1.21; P = 0.023). Week 12 overall response rate was 47% (95% CI, 35%-59%) with a median follow-up of 34 months among survivors. Median PFS was 21 months (95% CI, 10-not reached); 76% of responses (95% CI, 64%-91%) persisted at 36 months. CONCLUSIONS: Adaptively dosed nivo-ipi responses are durable and resemble historical data for conventional nivo-ipi. Baseline IL6 and circulating tumor DNA changes during treatment warrant further study as biomarkers of nivo-ipi response.

Persistent poverty and incidence-based melanoma mortality in Texas.

PURPOSE: Previous studies have shown that individuals living in areas with persistent poverty (PP) experience worse cancer outcomes compared to those living in areas with transient or no persistent poverty (nPP). The association between PP and melanoma outcomes remains unexplored. We hypothesized that melanoma patients living in PP counties (defined as counties with ≥ 20% of residents living at or below the federal poverty level for the past two decennial censuses) would exhibit higher rates of incidence-based melanoma mortality (IMM). METHODS: We used Texas Cancer Registry data to identify the patients diagnosed with invasive melanoma or melanoma in situ (stages 0 through 4) between 2000 and 2018 (n = 82,458). Each patient's PP status was determined by their county of residence at the time of diagnosis. RESULTS: After adjusting for demographic variables, logistic regression analyses revealed that melanoma patients in PP counties had statistically significant higher IMM compared to those in nPP counties (17.4% versus 11.3%) with an adjusted odds ratio of 1.35 (95% CI 1.25-1.47). CONCLUSION: These findings highlight the relationship between persistent poverty and incidence-based melanoma mortality rates, revealing that melanoma patients residing in counties with persistent poverty have higher melanoma-specific mortality compared to those residing in counties with transient or no poverty. This study further emphasizes the importance of considering area-specific socioeconomic characteristics when implementing place-based interventions to facilitate early melanoma diagnosis and improve melanoma treatment outcomes.

Disparities in the Receipt of Systemic Treatment in Metastatic Melanoma.

BACKGROUND: In 2011, immunotherapy and targeted therapy revolutionized melanoma treatment. However, inequities in their use may limit the benefits seen by certain patients. METHODS: We performed a retrospective review of patients in the National Cancer Database for patients with stage IV melanoma from 2 time periods: 2004-2010 and 2016-2020, distinguishing between those who received systemic therapy and those who did not. We investigated the rates and factors associated with treatment omission. We employed Kaplan-Meier analysis to explore the impact of treatment on overall survival. RESULTS: A total of 19,961 patients met the inclusion criteria: 7621 patients were diagnosed in 2004-2010 and 12,340 patients in 2016-2020, of whom 54.9% and 28.3% did not receive systemic treatment, respectively. The rate of "no treatment" has decreased to a plateau of ∼25% in 2020. Median overall survival was improved with treatment in both time periods (2004-2010: 8.8 vs. 5.6 mo [ P <0.05]; and 2016-2020: 25.9 vs. 4.3 mo [ P <0.05]). Nonmedical factors associated with the omission of treatment in both periods included low socioeconomic status, Medicaid or no health insurance, and treatment at low-volume centers. In the period from 2016 to 2020, patients treated at nonacademic programs were also less likely to receive treatment. CONCLUSIONS: Systemic therapies significantly improve survival for patients with metastatic melanoma, but significant disparities exist with their receipt. Local efforts are needed to ensure all patients benefit from these revolutionary treatments.

Assessment of Treatment Effects and Long-term Benefits in Immune Checkpoint Inhibitor Trials Using the Flexible Parametric Cure Model: A Systematic Review.

Importance: Compared with standard cytotoxic therapies, randomized immune checkpoint inhibitor (ICI) phase 3 trials reveal delayed benefits in terms of patient survival and/or long-term response. Such outcomes generally violate the assumption of proportional hazards, and the classical Cox proportional hazards regression model is therefore unsuitable for these types of analyses. Objective: To evaluate the ability of the flexible parametric cure model (FPCM) to estimate treatment effects and long-term responder fractions (LRFs) independently of prespecified time points. Evidence Review: This systematic review used reconstructed individual patient data from ICI advanced or metastatic melanoma and lung cancer phase 3 trials extracted from the literature. Trials published between January 1, 2010, and October 1, 2019, with long-term follow-up periods (maximum follow-up, ≥36 months in first line and ≥30 months otherwise) were selected to identify LRFs. Individual patient data for progression-free survival were reconstructed from the published randomized ICI phase 3 trial results. The FPCM was applied to estimate treatment effects on the overall population and on the following components of the population: LRF and progression-free survival in non-long-term responders. Results obtained were compared with treatment effects estimated using the Cox proportional hazards regression model. Findings: In this systematic review, among the 23 comparisons studied using the FPCM, a statistically significant association between the time-to-event component and experimental treatment was observed in the main analyses and confirmed in the sensitivity analyses of 18 comparisons. Results were discordant for 4 comparisons that were not significant by the Cox proportional hazards regression model. The LRFs varied from 1.5% to 12.7% for the control arms and from 4.6% to 38.8% for the experimental arms. Differences in LRFs varied from 2% to 29% and were significantly increased in the experimental compared with the control arms, except for 4 comparisons. Conclusions and Relevance: This systematic review of reconstructed individual patient data found that the FPCM was a complementary approach that provided a comprehensive and pertinent evaluation of benefit and risk by assessing whether ICI treatment was associated with an increased probability of patients being long-term responders or with an improved progression-free survival in patients who were not long-term responders.

Age-Based Disparities in Metastatic Melanoma Patients Treated in the Immune Checkpoint Inhibitors (ICI) Versus Non-ICI Era: A Population-Based Study.

Immune checkpoint inhibitors (ICIs) have revolutionized metastatic melanoma treatment, but our knowledge of ICI activity across age groups is insufficient. Patients in different age groups with advanced melanoma were selected based on the ICI approval time in this study. Patients with melanoma were identified in the Surveillance, Epidemiology, and End Result (SEER) database program 2004-2016. The results showed that 4,040 patients had advanced melanoma before the advent of ICI (referred to as the "non-ICI era"), whereas there were 6,188 cases after ICI approval (referred to as the "ICI era"). In all age groups, the cases were dominated by men. The differences between the first (20-59 years) and second (60-74 years) age groups in both eras were significant in terms of surgery performance and holding of insurance policies (p = 0.05). The first and second groups (20-59 and 60-70 years old, respectively) showed no difference in survival (median = 8 months) during the non-ICI era, but the difference was evident in the first, second, and third age groups in the ICI era, with the younger group (20-59 years) having significantly better survival (median = 18, 14, and 10 months, respectively, p = 0.0001). Multivariate analysis of the first group (the youngest) in the ICI era revealed that surgery was significantly associated with an increase in survival among patients compared with those who did not undergo surgery (p < 0.0001). Furthermore, having an insurance policy among all age groups in the ICI era was associated with favorable survival in the first (20-59 years) and second (60-74 years) age groups (p = 0.0001), while there were no survival differences in the older ICI group (>74 years). Although there were differences in survival between the ICI era and the non-ICI era, these results demonstrate that ICI positively affected the survival of younger patients with advanced melanoma (first age group) than it had beneficial effects on older patients. Moreover, having had cancer surgery and holding an insurance policy were positive predictors for patient survival. This study emphasizes that adequate clinical and preclinical studies are important to enhance ICI outcomes across age groups.

Estimated Cost-effectiveness of Atezolizumab Plus Cobimetinib and Vemurafenib for Treatment of BRAF V600 Variation Metastatic Melanoma.

Importance: In the IMspire150 trial, triplet treatment with atezolizumab and vemurafenib plus cobimetinib significantly improved progression-free survival (PFS) compared with vemurafenib plus cobimetinib alone for treatment of BRAF V600 variation metastatic melanoma. However, considering high cost of this combination, it is unclear if the incremental cost is worth the additional survival benefit. Objective: To evaluate the cost-effectiveness of atezolizumab and vemurafenib plus cobimetinib vs vemurafenib plus cobimetinib alone in patients with newly diagnosed unresectable BRAF V600 variation metastatic melanoma from the US health care perspective. Design, Setting, and Participants: This economic evaluation study used a 3-state partitioned survival model to assess the cost-effectiveness of the combination of atezolizumab with vemurafenib plus cobimetinib vs vemurafenib plus cobimetinib alone. The observed Kaplan-Meier curves for overall survival and PFS were digitized from the IMspire150 trial (January 2017-April 2018) and the long-term survivals (over a lifetime horizon) beyond the end of the trial were extrapolated using 7 different survival models. The cost and health preference data were collected from a literature review. This study was performed from March 2021 through June 2021. Main Outcomes and Measures: The outcomes of interest were expected life-years (LYs) gained and quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratio (ICER), expressed as cost per LYs and per QALYs saved. Results: Adding atezolizumab to vemurafenib and cobimetinib provided an additional 3.267 QALYs compared with the doublet regimen of vemurafenib plus cobimetinib, at an ICER of $271 669 per QALY, which is not considered cost-effective at the willingness-to-pay threshold of $150 000 per QALY. However, the scenario analyses found that atezolizumab combined with vemurafenib plus cobimetinib could be cost-effective at 20-year (ICER, $121 432 per QALY) and 30-year ($98 092 per QALY) time horizons when both strategies were stopped after 2 years of treatments, and over a lifetime horizon ($122 220 per QALY) when only immunotherapy with atezolizumab was stopped after 2 years of treatment. Conclusions and Relevance: These findings suggest that the atezolizumab and vemurafenib plus cobimetinib regimen provides significant survival benefits over vemurafenib plus cobimetinib alone, and a price reduction would be encouraged to maximize the value of its survival gain.

Quality management of cutaneous melanoma: impact on short-term outcomes and costs.

Promoting standardization and quality assurance (QA) may guarantee better outcomes for patients and ensure a better allocation of healthcare system resources. The present study tested the association between process quality indicators of the clinical pathway for melanoma and both patient short-term mortality and budget utilization. Specific indicators were selected to assess quality of processes in different phases of the pathway as well as the pathway as a whole. Cox regression models were run for each phase to test the association between adherence to the quality indicator and overall mortality. A Tobit regression analysis was used to identify any association between adherence to the quality indicators and total costs over the two years after melanoma was diagnosed. This retrospective cohort study concerned 1,222 incident cases of melanoma in the Veneto Region (north-east of Italy). Adherence to the clinical pathway as a whole was associated with a significant decrease in risk of death (HR= 0.40; 95% CI: 0,19 -0,77). Adherence to quality processes in the diagnostic phase (HR= 0.55 95% CI: 0.31- 0.95) and surgical phase (HR= 0.33 95% CI: 0.16- 0.61) significantly reduced the hazard risk. Tobit regression revealed a significant increase in overall costs for patients who adhered to the whole pathway in comparison with those who did not (ß= 2,393.24; p= 0.013). This study suggests that adherence to the quality of management of clinical pathways modifies short-term survival as well as mean cost of care for patients with cutaneous melanoma. Physicians should be encouraged to improve their compliance with clinical care pathways for their melanoma patients, and steadily growing associated costs emphasize the need for policy makers to invest exclusively in treatments of proven efficacy.

Cost-effectiveness of ipilimumab versus high-dose interferon as an adjuvant therapy in resected high-risk melanoma.

BACKGROUND: Adjuvant ipilimumab was found to improve the overall survival and reduce toxicity compared to high-dose interferon (HDI) in patients with resected, high-risk melanoma. However, the cost of ipilimumab is substantially higher than HDI. This study evaluates the cost-effectiveness of ipilimumab as an adjuvant treatment in melanoma from a healthcare perspective. METHODS: We designed a Markov model simulating resected, high-risk melanoma patients receiving either ipilimumab or HDI. Transition probabilities, including risks of survival, disease progression, and toxicity, were ascertained from clinical trial data. Costs and quality of life measurements (health utilities) were extracted from the literature. Incremental cost-effectiveness ratios (ICERs), defined as incremental costs divided by incremental quality-adjusted life-years (QALYs), assessed cost-effectiveness. ICERs <$100,000/QALY were deemed cost-effective. We measured model uncertainty with one-way and probabilistic sensitivity analyses. RESULTS: In our base case model, ipilimumab increased costs by $107,100 and increased effectiveness by 0.43 QALY, yielding an ICER of $392,600/QALY. Our model was moderately sensitive to the costs of ipilimumab, though the cost of ipilimumab would need to decrease by 44% for ipilimumab to become cost-effective compared to HDI. The model was not sensitive to survival, toxicity, or other costs. Probabilistic sensitivity analysis showed that HDI would remain the cost-effective treatment option 96.2% of the time at a willingness-to-pay threshold of $100,000/QALY. CONCLUSIONS: Adjuvant ipilimumab increases the survival and decreases the toxicity compared to HDI in resected, high-risk melanoma patients, though this would not be considered cost-effective due to the high price of ipilimumab.

Global, regional and national incidence, mortality and disability-adjusted life-years of skin cancers and trend analysis from 1990 to 2019: An analysis of the Global Burden of Disease Study 2019.

BACKGROUND: Information about global and local epidemiology and trends of skin cancers is limited, which increases the difficulty of cutaneous cancer control. METHODS: To estimate the global spatial patterns and temporal trends of skin cancer burden. Based on the GBD 2019, we collected and analyzed numbers and age-standardized rates (ASR) of skin cancer incidence, disability-adjusted life years (DALYs) and mortality (ASIR, ASDR, and ASMR) in 204 countries from 1990 through 2019 were estimated by age, sex, subtype (malignant skin melanoma [MSM], squamous-cell carcinoma [SCC], and basal-cell carcinoma [BCC]), Socio-demographic Index (SDI), region, and country. Temporal trends in ASR were also analyzed using estimated annual percentage change. RESULTS: Globally, in 2019, there were 4.0 million BCC, 2.4 million SCC, and 0.3 million MSM. There were approximately 62.8 thousand deaths and 1.7 million DALYs due to MSM, and 56.1 thousand deaths and 1.2 million DALYs were attributed to SCC, respectively. The men had higher ASR of skin cancer burden than women. The age-specific rates of global skin cancer burden were higher in the older adults, increasing trends observed from 55 years old. Geographically, the numbers and ASR of skin cancers varied greatly across countries, with the largest burden of ASIR in high SDI regions. However, an unexpected increase was observed in some regions from 1990 to 2019, such as East Asia, and Sub-Saharan Africa. Although there was a slight decrease of the ASMR and ASDR, the global ASIR of MSM dramatically increased, 1990-2019. Also, there was a remarkable increase in ASR of BCC and SCC burden. CONCLUSIONS: Skin cancer remains a major global public health threat. Reducing morbidity and mortality strategies such as primary and secondary prevention should be reconsidered, especially in the most prevalent and unexpected increased regions, especially for those areas with the greatest proportions of their population over age 55.

Adverse events during immunotherapy in Slovenian patients with metastatic melanoma reveal a positive correlation with better treatment outcomes.

BACKGROUND: Immunotherapy with CTLA-4 inhibitors and PD1 checkpoint inhibitors has initiated a breakthrough in the treatment and prognosis of patients with metastatic melanoma. The survival of these patients has increased from the expected survival time of less than 12 months to at least forty months. However, immunotherapy with either anti-CTLA-4 antibodies or PD1 inhibitors alone or in combination has a broad palette of significant immune-related adverse events. The aim of the study was to assess the correlation of immune-related adverse events with treatment outcomes defined as significant differences in the overall response rate (ORR) and progression-free survival (PFS) of patients, who developed immune-related adverse events during immunotherapy. PATIENTS AND METHODS: A retrospective analysis of patients with metastatic melanoma treated with immunotherapy in 2020 at the Oncology Institute of Ljubljana was performed. Only patients with radiological evaluation of the immunotherapy response were included. The patients were divided into two cohorts: a cohort of patients with immune-related adverse events (irAE group) and a cohort of patients with no immune-related adverse events (NirAE group). Significantly better overall response and progression-free survival in the irAE cohort defined the primary aim of our study. To investigate the differences in progression-free survival between the irAE cohort and NirAE cohort, we used survival analysis. In particular, a Cox proportional hazards model with covariates of time to progression and adverse events was used for survival analysis. The Kruskal-Wallis H-test was applied, and a p-value of p <= 0.05 was considered the cut-off point for a statistically significant difference between the groups. RESULTS: Among the 120 patients treated with immunotherapy, radiological response evaluation was performed for 99 patients: 38 patients in the irAE cohort and 61 patients in the NirAE cohort. The ORRs for the irAE and NirAE cohorts were 57% and 37%, respectively. The PFS was significantly better for the irAE cohort (301.6 days) than for the NirAE cohort (247.29 days). The results of the survival regression analysis showed a significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort. CONCLUSIONS: Patients with metastatic melanoma treated with immunotherapy who developed immune-related adverse events showed better treatment outcomes with longer times to disease progression and better overall response rates than patients treated with immunotherapy who did not develop immune-related adverse events, with a significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort.

Epidemiology of Melanoma.

Please add expansion for AL. Melanoma is the most common fatal type of skin cancer and is an important and growing public health problem in the United States, Australia, New Zealand, and Europe. The mortality rate in most of the world has been rising as well, albeit slower than that for incidence. Likely due to the availability of new treatments for stage 4 melanoma, mortality rates in the United States dropped 18% from 2013 to 2016. We further describe trends in melanoma incidence and mortality, review the literature on risk factors, and provide an up-to-date assessment of population-wide screening and some of the inherent concerns.

Automated digital TIL analysis (ADTA) adds prognostic value to standard assessment of depth and ulceration in primary melanoma.

Accurate prognostic biomarkers in early-stage melanoma are urgently needed to stratify patients for clinical trials of adjuvant therapy. We applied a previously developed open source deep learning algorithm to detect tumor-infiltrating lymphocytes (TILs) in hematoxylin and eosin (H&E) images of early-stage melanomas. We tested whether automated digital (TIL) analysis (ADTA) improved accuracy of prediction of disease specific survival (DSS) based on current pathology standards. ADTA was applied to a training cohort (n = 80) and a cutoff value was defined based on a Receiver Operating Curve. ADTA was then applied to a validation cohort (n = 145) and the previously determined cutoff value was used to stratify high and low risk patients, as demonstrated by Kaplan-Meier analysis (p ≤ 0.001). Multivariable Cox proportional hazards analysis was performed using ADTA, depth, and ulceration as co-variables and showed that ADTA contributed to DSS prediction (HR: 4.18, CI 1.51-11.58, p = 0.006). ADTA provides an effective and attainable assessment of TILs and should be further evaluated in larger studies for inclusion in staging algorithms.

The ongoing racial disparities in melanoma: An analysis of the Surveillance, Epidemiology, and End Results database (1975-2016).

BACKGROUND: Although most patients with cutaneous melanoma are non-Hispanic whites (NHWs), minorities consistently suffer worse melanoma-specific survival (MSS). Much of the literature comes from analyses of registries from the 1990s and 2000s. OBJECTIVE: We sought to evaluate whether and to what degree racial disparity in MSS persists since 2010. METHODS: We analyzed 381,035 patients from the Surveillance, Epidemiology, and End Results registry. Race categories included Hispanic, NHW, non-Hispanic black (NHB), non-Hispanic Asian or Pacific Islander (NHAPI), and non-Hispanic American Indian/Alaska Native (NHAIAN). We evaluated the association between MSS and race in 3 time periods: before the year 2000, 2000 to 2009, and 2010 or later. NHW was the reference group for all analyses. RESULTS: Racial disparity worsened from before the year 2000 to 2010 or later for Hispanic (P < .001), NHB (P = .024), and NHAPI (P < .001) patients. Across all minority groups, patients with localized disease suffered increasing disparity (P = .010 for Hispanic, P < .001 for NHB, P = .023 for NHAPI, and P = .042 for NHAIAN patients). Among those with regional and distant disease, Hispanic patients were the only minority to experience worsening disparity (P = .001 and P = .019, respectively). LIMITATIONS: Lack of immunotherapy and targeted treatment information. CONCLUSIONS: Racial disparity in MSS is worsening. Improving postdiagnosis management for minorities with localized disease is imperative to mitigate disparity and improve survival.

The impact of demographics, socioeconomics, and health care access on melanoma outcomes.

Disparities in melanoma care exist in the United States. Disparities in provider type, patient demographics, place of residence, insurance status, socioeconomic status, race/ethnicity, and age impact melanoma outcomes. Melanomas detected by dermatologists are thinner, at an earlier stage, and have better survival outcomes compared with detection by primary care providers or patients. Lower socioeconomic status, race/ethnicity, and place of residence are associated with decreased access to or use of dermatologists, or both, and more advanced melanomas at diagnosis. Additionally, uninsured and publicly insured individuals are more likely to present with late-stage melanomas, resulting in worse outcomes. This review provides a comprehensive overview of how structural and patient-level characteristics influence melanoma outcomes in order to inform clinical care and health care policy as it relates to addressing gaps in melanoma care.

Burden of malignant melanoma in Ukraine in 2002-2013: incidence, mortality and survival.

BACKGROUND: The malignant melanoma (MM) incidence rates were increasing and later stabilizing in many regions of the world, while in South-Eastern Europe incidence rates are uniformly increasing and mortality rates are higher. AIM: To describe burden of MM in Ukraine in terms of incidence, mortality and survival by sex, age and stage for the period 2002-2013 and compare with European countries. MATERIALS AND METHODS: Database of the National Cancer Registry of Ukraine was used to extract MM incidence cases; number of MM deaths was obtained from the official mortality statistics. Age-standardised and age-specific incidence and mortality rates were calculated by sex, age groups (15-39, 40-59 and 60+); estimated annual percent of change was used to describe trends. Proportions of new cases by stage of disease and calendar period (2002-2007 vs 2008-2013) were compared as well as net survival estimates. RESULTS: In Ukraine, MM was more common in females (age-standardised 5.3 per 100,000 in 2013; annual percent of change 3.5%) than in males (5.1 per 100,000; 4.1%); around 50% of them diagnosed in the age group 60+. The observed increase in proportion of new cases with early stage (I-II) was due to stage II cases. The slight increase in mortality rates in males or stability in females were not accompanied with increase of survival. Net MM survival was consistently lower comparing to European countries. CONCLUSION: More resources should be targeted to increase the capacity of healthcare in diagnostics and treatment of malignant melanoma, but also in promoting healthcare and education in Ukraine.