Long-term survival after anti-PD-1 discontinuation in advanced cutaneous squamous cell carcinoma (cSCC): a proof of concept of benefit of concomitant cemiplimab and radiotherapy.

BACKGROUND: In a princeps study we conducted in patients with advanced cutaneous squamous cell carcinoma treated with concomitant anti-Programmed cell death protein 1 (PD-1) and radiotherapy, we demonstrated a clinico radiological response to cemiplimab that appeared to persist over time, 1 year after treatment discontinuation. METHOD: We conducted a single-center descriptive study at Caen Hospital from September 1, 2021 to September 2023, in 14 patients with advanced carcinoma treated with cemiplimab until September 1, 2021. The aim of this update is to examine clinical and radiological follow-up 2 years after discontinuation of cemiplimab. RESULTS: Of the 12 patients with a partial or complete response, we report 8 (66.7%) persistent responses 2 years after stopping cemiplimab, with only 2 patients progressing to distant disease, one lost to follow-up, and one death a priori unrelated to the disease. CONCLUSION: Our study confirms a long-term and persistent effect despite discontinuation of cemiplimab at least up to 2 years later.

Clinical outcomes of adjuvant nivolumab in resected stage III melanoma: comparison of CheckMate 238 trial and real-world data.

OBJECTIVES: Nivolumab is approved as adjuvant therapy for resected stage III/IV melanoma based on the phase 3 CheckMate 238 trial. This analysis compared outcomes from CheckMate 238 with those from the real-world Flatiron Health electronic health record-derived de-identified database in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab. MATERIALS: Outcomes included baseline characteristics, overall survival (OS) in the CheckMate 238 cohort (randomization until death or last known alive), and real-world overall survival (rwOS) in the Flatiron Health cohort (nivolumab initiation until death or data cutoff). rwOS was compared with OS using unadjusted and adjusted Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) was combined with the adjusted model to reduce baseline discrepancies. RESULTS: The CheckMate 238 and real-world cohorts included 369 and 452 patients, respectively (median age, 56.0 and 63.0 years; median follow-up, 61.4 vs. 25.5 months). rwOS was not different from OS in the unadjusted (hazard ratio [HR] 1.27; 95% CI 0.92-1.74), adjusted (HR 1.01; 95% CI 0.67-1.54), and adjusted IPTW (HR 1.07; 95% CI 0.70-1.63) analyses. In the adjusted analysis, 2-year OS and rwOS rates were 84%. Median OS and rwOS were not reached. After IPTW, OS and rwOS were not different (HR 1.07; 95% CI 0.70-1.64). CONCLUSIONS: In this comparative analysis, OS in the CheckMate 238 trial was similar to rwOS in the Flatiron Health database after adjustments in patients with resected stage III melanoma (per AJCC-8) treated with adjuvant nivolumab, validating the trial results.

Incidence Rates and Outcomes of Nodular and Superficial Spreading Melanoma along the Rural-Urban Continuum in Kentucky and Their Relationship to Provider Care Access.

OBJECTIVES: This study compared incidence rates, stage at presentation, and cause-specific mortality of nodular and superficial spreading melanoma along the rural-urban continuum in Kentucky. We compared resulting patterns in our data with sample demographic and other potential factors, including population by county and primary care provider rate. METHODS: Retrospective patient data were extracted from the Surveillance, Epidemiology, and End Results database from 2010 through 2017. These data were supplemented by environmental, demographic, and socioeconomic data derived from publicly accessible databases. Correlation and χ2 analyses were used to test for significant differences in outcome variables by US Department of Agriculture Rural-Urban Continuum Code (RUCC) categories and other potential predictor variables. RESULTS: Incidence rates by Kentucky county were not associated with RUCC or population; likewise, there was no relationship between stage at presentation and RUCC category. There was, however, a highly significant association between cause-specific mortality and RUCC; patients from rural areas were significantly more likely to die from melanoma than those in urban areas. This overall difference was due to differences in mortality for superficial spreading melanoma. CONCLUSIONS: Our results suggest that a disparity in patients' ability or tendency to access primary care and/or specialist providers postdiagnosis may be critical factors in determining the ultimate outcome of a melanoma diagnosis. Further studies should explore the availability of dermatologists and/or treatment options for melanoma in rural areas. Our data also provide additional support for inclusion of melanoma subtype in the American Joint Committee on Cancer guidelines.

Global burden and prediction study of cutaneous squamous cell carcinoma from 1990 to 2030: A systematic analysis and comparison with China.

Background: China has the highest number of new cancer cases and deaths globally. Due to particularly low scores in health care quality for cutaneous squamous cell carcinoma (cSCC), the country's cSCC burden requires greater awareness. Consequently, we aimed to evaluate and predict the trend of the cSCC burden globally and in China from 1990 to 2030. Methods: We retrieved data from the Global Burden of Disease 2019 study, which provided estimates of the incidence, mortality, prevalence, and disability-adjusted life years (DALYs) of cSCC from 1990 to 2019. We set up joint-point analyses and Bayesian age-period-cohort (BAPC) models to predict the disease burden of cSCC up to 2030. Results: In 2019, China reported age-standardised rates of cSCC prevalence, incidence, mortality, and DALYs of 2.54, 2.12, 0.88, and 16.76 per 100 000 population, respectively. The country's prevalence and incidence rates from 1990 to 2019 were lower than the global levels, but its mortality and DALY rates were higher. The age-standardised rates were higher for males, and the disease burden increased with each age group globally and in China. Moreover, the average annual percentage change showed all indicators were growing faster than the global levels. According to the BAPC model, there will be an upward trend in the prevalence and incidence globally and in China between 2020 and 2030, with a decrease in mortality and DALYs. Conclusions: We observed an upward trend in the cSCC burden over the past 30 years in China. Prevalence and incidence are expected to continue at a higher rate than the global average in the next decade, while mortality and DALYs are predicted to decrease. As the Chinese population ages, efforts toward managing and preventing cSCC should be targeted towards the elderly population.

PARP1 expression predicts PARP inhibitor sensitivity and correlates with metastatic potential and overall survival in melanoma.

Metastatic melanoma is still a difficult-to-treat cancer type owing to its frequent resistance mechanisms to targeted and immunotherapy. Therefore, we aimed to unravel novel therapeutic strategies for melanoma patients. Preclinical and clinical studies show that melanoma patients may benefit from a treatment with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). In this study, we focus on PARP1 as a potential biomarker to predict the response of melanoma cells to PARPi therapy. We found that melanoma cells with high basal PARP1 expression exhibit significantly increased cell death after PARPi treatment owing to higher PARP1 trapping compared with melanoma cells with low PARP1 expression. In addition, we could demonstrate that PARP1 expression levels are low in nonmalignant skin cells, and metastatic melanomas show considerably higher PARP1 levels compared with primary melanomas. Most strikingly, we found that high PARP1 levels correlate with worse overall survival of late stage metastasized melanoma patients. In conclusion, we show that PARP1 might act as a biomarker to predict the response to PARPi therapy, and that in particular the late stage metastasized melanoma patients are especially sensitive to PARPi therapy owing to elevated PARP1 expression. Our data suggest that the PARPi cytotoxicity primarily will affect the high PARP1 expressing melanoma cells, rather than the low PARP1 expressing nonmalignant skin cells resulting in only low side effects.

Experimentally validated oxidative stress -associated prognostic signatures describe the immune landscape and predict the drug response and prognosis of SKCM.

Background: Skin Cutaneous Melanoma (SKCM) incidence is continually increasing, with chemotherapy and immunotherapy being among the most common cancer treatment modalities. This study aims to identify novel biomarkers for chemotherapy and immunotherapy response in SKCM and explore their association with oxidative stress. Methods: Utilizing TCGA-SKCM RNA-seq data, we employed Weighted Gene Co-expression Network Analysis (WGCNA) and Protein-Protein Interaction (PPI) networks to identify six core genes. Gene co-expression analysis and immune-related analysis were conducted, and specific markers associated with oxidative stress were identified using Gene Set Variation Analysis (GSVA). Single-cell analysis revealed the expression patterns of Oxidative Stress-Associated Genes (OSAG) in the tumor microenvironment. TIDE analysis was employed to explore the association between immune therapy response and OSAG, while CIBERSORT was used to analyze the tumor immune microenvironment. The BEST database demonstrated the impact of the Oxidative Stress signaling pathway on chemotherapy drug resistance. Immunohistochemical staining and ROC curve evaluation were performed to assess the protein expression levels of core genes in SKCM and normal samples, with survival analysis utilized to determine their diagnostic value. Results: We identified six central genes associated with SKCM metastasis, among which the expression of DSC2 and DSC3 involved in the oxidative stress pathway was closely related to immune cell infiltration. DSC2 influenced drug resistance in SKMC patients. Furthermore, downregulation of DSC2 and DSC3 expression enhanced the response of SKCM patients to immunotherapy. Conclusion: This study identified two Oxidative Stress-Associated genes as novel biomarkers for SKCM. Additionally, targeting the oxidative stress pathway may serve as a new strategy in clinical practice to enhance SKCM chemotherapy and sensitivity.

The immune response-related genomic alterations in patients with malignant melanoma.

Immune checkpoint inhibitors (ICIs) significantly improve the survival outcomes of patients with advanced melanoma. However, response varies among from patient to patient and predictive biomarkers are urgently needed. We integrated mutational profiles from next-generation sequencing (NGS) data and clinicopathologic characteristics of melanoma patients to investigate whether tumor genomic profiling contribute to clinical benefit of ICIs treatment. The majority of genes identified with high mutation frequency have all been reported as well-known immunotherapy-related genes. Thirty-five patients (43.2%) had at least 1 BRAF/RAS/NF1 mutation. The other 46 (56.8%) melanomas without BRAF/RAS/NF1 mutation were classified as Triple-WT. We identified mutational signature 6 (known as associated with defective DNA mismatch repair) among cases in this cohort. Compared to patients with PD-L1 expression (TPS < 1%), patients with PD-L1 expression (TPS ≥ 1%) had significantly higher median progression-free survival (mPFS), but no significantly higher durable clinical benefit (DCB) rate. In contrast, FAT1, ATM, BRCA2, LRP1B, and PBRM1 mutations only occurred frequently in patients with DCB, irrespective of PD-L1 expression status. Our study explored molecular signatures of melanoma patients who respond to ICIs treatment and identified a series of mutated genes that might serve as predictive biomarker for ICIs responses in melanoma.

Identification of an anoikis-related gene signature and characterization of immune infiltration in skin cutaneous melanoma.

Anoikis is considered strongly associated with a biological procession of tumors. Herein, we utilized anoikis-related genes (ARGs) to predict the prognosis and immunotherapeutic efficacy for skin cutaneous melanoma (SKCM). RNA-seq data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. After dividing patients into novel subtypes based on the expression of prognostic ARGs, K-M survival was conducted to compare the survival status. Subsequently, differentially expressed ARGs were identified and the predictive model was established. The predictive effects were validated using the areas under the curve about the receiver operating characteristic. Moreover, tumor mutation burden, the enriched functional pathway, immune cells and functions, and the immunotherapeutic response were also analyzed and compared. The distribution of model genes at cell level was visualized by the single-cell seq with tumor immune single-cell hub database. Patients of The Cancer Genome Atlas-SKCM cohort were divided into 2 clusters, the cluster 1 performed a better prognosis. Cluster 2 was more enriched in metabolism-related pathways whereas cluster 1 was more associated with immune pathways. A predictive risk model was established with 6 ARGs, showing the areas under the curves of 1-year, 3-year, and 5-year ROC were 0.715, 0,720, and 0.731, respectively. Moreover, risk score was negatively associated with tumor mutation burden and immune-related pathways enrichment. In addition, patients with high-risk scores performed immunosuppressive status but the decreasing scores enhanced immune cell infiltration, immune function activation, and immunotherapeutic response. In this study, we established a novel signature in predicting prognosis and immunotherapy. It can be considered reliable to formulate the complex treatment for SKCM patients.

Establishment and validation of a nomogram model for predicting the specific mortality risk of melanoma in upper limbs based on the SEER database.

For patients with upper limb melanoma, the significance of specific death is more important than that of all-cause death, and traditional survival analysis may overestimate the mortality rate of patients. Therefore, the nomogram model for predicting the specific mortality risk of melanoma in the upper limbs was developed. A population with melanoma in the upper limbs, diagnosed from 2010 to 2015, were selected from the National Cancer Institute database of Surveillance, Epidemiology, and End Results (SEER). The independent predictive factors of specific death were confirmed by the competing risk model of one-factor analysis and multi-factor analysis, and the nomogram was constructed according to the independent predictive factors. 17,200 patients with upper limb melanoma were enrolled in the study (training cohort: n = 12,040; validation cohort: n = 5160). Multi-factor analysis of the competing risk model showed that age, marital status, gender, tumor stage, T stage, M stage, regional lymph node surgery information, radiotherapy, chemotherapy, mitotic cell count, ulcer and whether there were multiple primary cancers, were independent factors affecting the specific death of upper limb melanoma patients (P < 0.05). The nomogram has good predictive ability regarding the specific mortality risk of melanoma in the upper limbs, and could be of great help to formulate prognostic treatment strategies and follow-up strategies that are conducive to survival.

Prognostic Value of the Neutrophil-to-lymphocyte Ratio, Platelet-to- lymphocyte Ratio and Monocyte-to-lymphocyte Ratio in Melanoma Patients: A Cohort Study.

The prognostic value of the neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio in patients with melanoma has yielded controversial results in the literature. A retrospective single-centre cohort study was conducted from 1998 to 2020, including patients diagnosed with invasive melanoma. A total of 2,721 patients were included in the study. The median follow-up was 8.23 years (IQR 4.41-13.25). The median baseline neutrophil- lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio values increased significantly (p < 0.001) with the increasing American Joint Committee on Cancer stage. The optimal cut-off values for neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio were determined as 2.1, 184 and 0.2, respectively. In the multivariate analysis, high levels of neutrophil-lymphocyte ratio (≥ 2.1), platelet-lymphocyte ratio (≥ 184) and monocyte-lymphocyte ratio (≥ 0.2) were independently associated with significantly shorter melanoma-specific survival (neutrophil-lymphocyte ratio: HR 1.30, 95% CI 1.06-1.60, p = 0.013; platelet-lymphocyte ratio: HR 1.37, 95% CI 1.06-1.76, p = 0.014; monocyte- lymphocyte ratio: HR 1.29, 95% CI 1.05-1.58, p = 0.015) and overall survival (neutrophil-lymphocyte ratio: HR 1.39, 95% CI 1.19-1.64, p < 0.001; platelet- lymphocyte ratio: HR 1.44, 95% CI 1.19-1.74, p < 0.001; monocyte-lymphocyte ratio: HR 1.42, 95% CI 1.21-1.66, p < 0.001). High levels of neutrophil- lymphocyte ratio and monocyte-lymphocyte ratio were also associated with poor relapse-free survival, while platelet-lymphocyte ratio was not. In conclusion, baseline neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio were identified as independent predictors for the prognosis of melanoma.

Interferon-gamma signature as prognostic and predictive marker in macroscopic stage III melanoma.

BACKGROUND: A substantial proportion of patients with macroscopic stage III melanoma do not benefit sufficiently from adjuvant anti-PD-1 therapy, as they either recur despite therapy or would never have recurred. To better inform adjuvant treatment selection, we have performed translational analyses to identify prognostic and predictive biomarkers. PATIENTS AND METHODS: Two cohorts of patients with macroscopic stage III melanoma from an ongoing biobank study were included. Clinical data were compared between an observation cohort (cohort 1) and an adjuvant intention cohort (cohort 2). RNA sequencing for translational analyses was performed and treatment subgroups (cohort 1A and cohort 2A) were compared for possible biomarkers, using a cut-off based on the treatment-naïve patients. In addition, two validation cohorts (Melanoma Institute Australia (MIA) and University Medical Centre Utrecht (UMCU)) were obtained. RESULTS: After a median follow-up of 26 months of the 98 patients in our discovery set, median recurrence-free survival (RFS) was significantly longer for the adjuvant intention cohort (cohort 2, n=49) versus the observation cohort (cohort 1, n=49). Median overall survival was not reached for either cohort, nor significantly different. In observation cohort 1A (n=24), RFS was significantly longer for patients with high interferon-gamma (IFNγ) score (p=0.002); for adjuvant patients of cohort 2A (n=24), a similar trend was observed (p=0.086). Patients with high B cell score had a longer RFS in cohort 1A, but no difference was seen in cohort 2A. The B cell score based on RNA correlated with CD20+ cells in tumor area but was not independent from the IFNγ score. In the MIA validation cohort (n=44), longer RFS was observed for patients with high IFNγ score compared with low IFNγ score (p=0.046), no difference in RFS was observed according to the B cell score. In both the observation (n=11) and the adjuvant (n=11) UMCU validation cohorts, no difference in RFS was seen for IFNγ and B cell. CONCLUSIONS: IFNγ has shown to be a prognostic marker in both patients who were and were not treated with adjuvant therapy. B cell score was prognostic but did not improve accuracy over IFNγ. Our study confirmed RFS benefit of adjuvant anti-PD-1 for patients with macroscopic stage III melanoma.

Neoadjuvant-Intent Immunotherapy in Advanced, Resectable Cutaneous Squamous Cell Carcinoma.

Importance: In clinical trials, preoperative immune checkpoint inhibitors (ICIs) have shown clinical activity in advanced cutaneous squamous cell carcinoma (cSCC). However, these studies excluded patients with relevant comorbidities. Objective: To evaluate radiologic and pathologic response rates to neoadjuvant-intent programed cell death protein 1 (PD-1) ICIs in a clinical population. Design, Setting, and Participants: This cohort study of patients who were treated with neoadjuvant cemiplimab or pembrolizumab for advanced cSCC from January 2018 to January 2023 was conducted at 2 academic institutions in Boston, Massachusetts. Median follow-up was 9.5 months (range, 1.2-40.5). Exposures: Cemiplimab or pembrolizumab. Main Outcomes and Measures: Primary outcomes were radiologic and pathologic response rates. Secondary outcomes were 1-year recurrence-free survival, progression-free survival, disease-specific survival, and overall survival. Results: This cohort study included 27 patients (including 9 patients [33.3%] with a history of lymphoma). Most patients were male (18 of 27 [66.7%]), with a median age of 72 years (range, 53-87 years). Most primary tumors were located on the head/neck (21 of 27 [77.8%]). There were no unexpected delays in surgery. The median number of doses before surgery was 3.5 (range, 1.0-10.0). Five patients (18.5%) ultimately declined to undergo planned surgery due to clinical responses or stability, and 1 (3.7%) did not undergo surgery due to progressive disease. The overall pathologic response rate (pathological complete response [pCR] or major pathological response) was 47.4% (9 of 19), and the overall radiologic response rate (radiologic complete response or partial response) was 50.0% (8 of 16). The pCR rate (7 of 19 [36.8%]) was higher than the radiologic complete response rate (2 of 16 [12.5%]). The pCR rate among patients with cSCC and concomitant lymphoma was 25.0%. The 1-year recurrence-free survival rate was 90.9% (95% CI, 50.8%-98.7%), progression-free survival was 83.3% (95% CI, 27.3%-97.5%), disease-specific survival was 91.7% (95% CI, 53.9%-98.8%), and overall survival was 84.6% (95% CI, 51.2%-95.9%). Conclusions and Relevance: The results of this cohort study support the reproducibility of neoadjuvant-intent immunotherapy for cSCC in the clinical setting, including for patients with a history of lymphoma. Outside of clinical trials, it is not infrequent for patients to opt out of surgery for regressing tumors. The inclusion of higher-risk patients and preference for nonsurgical treatment are 2 factors that might explain the numerically lower pathologic response rate in this institutional experience.

Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Final Analysis of Distant Metastasis-Free Survival in the Phase III KEYNOTE-716 Study.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Pembrolizumab adjuvant therapy was shown to significantly improve recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with resected stage IIB or IIC melanoma in earlier analyses of the randomized, double-blind, phase III KEYNOTE-716 study (ClinicalTrials.gov identifier: NCT03553836). We report results of the protocol-specified final analysis of DMFS for KEYNOTE-716. Overall, 976 patients were randomly allocated to pembrolizumab (n = 487) or placebo (n = 489). As of January 4, 2023, median follow-up was 39.4 months (range, 26.0-51.4 months). The median DMFS was not reached in either treatment group, and the estimated 36-month DMFS was 84.4% for pembrolizumab and 74.7% for placebo (hazard ratio [HR], 0.59 [95% CI, 0.44 to 0.79]). The median RFS was not reached in either treatment group, and the estimated 36-month RFS was 76.2% for pembrolizumab and 63.4% for placebo (HR, 0.62 [95% CI, 0.49 to 0.79]). DMFS and RFS results were consistent across most prespecified subgroups, including stage IIB and stage IIC melanoma. The safety profile of pembrolizumab was manageable and consistent with previous reports. These results continue to support the use of pembrolizumab adjuvant therapy in patients with resected stage IIB or IIC melanoma.

Distinct presentation of melanoma in Black patients may inform strategies to improve outcomes.

INTRODUCTION: Melanoma guidelines stem largely from data on non-Hispanic White (NHW) patients. We aimed to identify features of melanoma within non-Hispanic Black (NHB) patients to inform strategies for earlier detection and treatment. METHODS: From 2004 to 2019 Surveillance, Epidemiology, and End Results (SEER) data, we identified nonmetastatic melanoma patients with known TN category and race. Kaplan-Meier cancer-specific survival (CSS) estimates and multivariable Cox proportional hazard modeling analyses were performed. RESULTS: Of 492 597 patients, 1499 (0.3%) were NHB, who were younger (21% vs. 17% age <50) and more commonly female (54% vs. 41%) than NHW, both p < 0.0005. For NHBs, lower extremity was the most common site (52% vs. 15% for NHWs, p < 0.0001), T category was higher (55% Tis-T1 vs. 82%; 27% T3-T4 vs. 8%, p < 0.0001) and stage at presentation was higher (19% Stage III, vs. 6%, p < 0.0001). Within the NHB cohort, males were older, and more often node-positive than females. Five-year Stage III CSS was 42% for NHB males versus 71% for females, adjusting for age and clinical nodal status (hazard ratio 2.48). CONCLUSIONS: NHB melanoma patients presented with distinct tumor characteristics. NHB males with Stage III disease had inferior CSS. Focus on this high-risk patient cohort to promote earlier detection and treatment may improve outcomes.

Long-term follow-up results from KEYNOTE-041: Phase 1b study of pembrolizumab in Japanese patients with advanced melanoma.

Pembrolizumab demonstrated an acceptable safety profile and promising antitumor activity in Japanese patients with advanced melanoma in the phase 1b KEYNOTE-041 (Study of Pembrolizumab [MK-3475] in Participants With Advanced Melanoma) trial. To evaluate the long-term efficacy and safety of pembrolizumab in Japanese patients with advanced melanoma in KEYNOTE-041. The current analysis reports results of additional follow-up of approximately 12 months since the initial analysis. Eligible patients had locally advanced (unresectable stage III) or metastatic (stage IV) melanoma not amenable to local therapy and had received two or fewer prior systemic therapies. Pembrolizumab 2 mg/kg was given every 3 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points included safety, tolerability, and overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 by independent central review. The data cutoff for this analysis was August 30, 2017. Forty-two patients were followed up for a median of 22.3 months (range, 2.63-30.82 months). The ORR was 24.3% (nine of 37 evaluable patients [95% confidence interval (CI), 11.8%-41.2%]). Two patients with partial response at the time of the initial analysis achieved complete response. The median overall survival (OS) was 25.1 months (95% CI, 13.1-not reached] and the 30-month OS rate was 46.3% (95% CI, 29.8%-61.3%). The median duration of response was not reached. Treatment-related adverse events (TRAEs) were reported in 78.6% of patients; the incidence of grade 3 to 5 TRAEs was 23.8%. No additional treatment-related deaths occurred since the initial analysis. Pembrolizumab provided durable antitumor activity and an acceptable safety profile in Japanese patients with advanced melanoma.

The Effectiveness of Adjuvant PD-1 Inhibitors in Patients With Surgically Resected Stage III/IV Acral Melanoma.

Our aim was to assess the efficacy of adjuvant programmed cell death protein-1 (PD-1) inhibitors and compare the other adjuvant treatments in patients with surgically resected stage III or IV acral melanoma. This study is a multicenter, retrospective analysis. We included 114 patients with stage III or IV acral malignant melanoma who underwent surgery within the past 10 years. We analyzed the effect of adjuvant programmed cell death protein-1 inhibitors on disease-free survival (DFS). The mean follow-up was 40 months, during which 69 (59.5%) patients experienced recurrence. Among the participants, 64 (56.1%) received systemic adjuvant therapy. Specifically, 48.4% received anti-PD-1 therapy, 29.7% received interferon, 14.1% received tezozolomide, and 7.8% received B-Raf proto-oncogene/mitogen-activated protein kinase inhibitors. Patients who received adjuvant therapy had a median DFS of 24 (10.9-37.2) months, whereas those who did not receive adjuvant therapy had a median DFS of 15 (9.8-20.2) months. Multivariate analysis for DFS revealed that the receipt of adjuvant therapy and lymph node metastasis stage were independent significant parameters ( P = 0.021, P = 0.018, respectively). No statistically significant difference was observed for DFS between programmed cell death protein-1 inhibitor treatment and other adjuvant treatments. Regarding overall survival (OS), patients who received adjuvant treatment had a median OS of 71 (30.4-111.7) months, whereas those who did not receive adjuvant treatment had a median OS of 38 (16.7-59.3; P = 0.023) months. In addition, there were no significant differences in OS observed between various adjuvant treatment agents ( P = 0.122). In our study, we have shown that adjuvant therapy had a positive effect on both DFS and OS in patients with stages III-IV acral melanoma who underwent curative intent surgery. Notably, we found no significant differences between anti-PD-1 therapy and other adjuvant therapies.

Proposal for the applicability of modified Breslow (measured from the basal membrane) as a predictor of survival and sentinel lymph node outcome in patients with cutaneous melanoma.

BACKGROUND: Cutaneous melanoma is a neoplasm with a high mortality rate and risk of metastases to distant organs. The Breslow micrometric measurement is considered the most important factor for evaluating prognosis and management, measured from the granular layer to the deepest portion of the neoplasm. Despite its widespread use, the Breslow thickness measurement has some inaccuracies, such as not considering variations in the thickness of the epidermis in different body locations or when there is ulceration. OBJECTIVE: To evaluate the applicability of a modified Breslow measurement, measured from the basal membrane instead of from the granular layer, in an attempt to predict sentinel lymph node examination outcome and survival of patients with melanoma. METHODS: A retrospective and cross-sectional analysis was carried out based on the evaluation of slides stained with hematoxylin & eosin from 275 cases of melanoma that underwent sentinel lymph node biopsy from 2008 to 2021 at a reference center in Brazil. RESULTS: Analysis of the Cox model to evaluate the impact of the Breslow measurement and the modified Breslow measurement on survival showed that both methods are statistically significant. Logistic regression revealed a significant association between both measurements and the presence of metastasis in sentinel lymph nodes. CONCLUSION: Measuring melanoma depth from the basal membrane (modified Breslow measurement) is capable of predicting survival time and sentinel lymph node outcome, as well as the conventional Breslow measurement.

Risk of progression of early-stage mycosis fungoides, 10-year experience.

BACKGROUND: Mycosis fungoides is the most frequent form of cutaneous T-cell lymphoma. It is characterized by a chronic, slow, and progressive course, and is associated with mortality rates that depend on several factors, such as clinical staging. A median survival time of up to 13 months is found in patients with advanced stages that require more aggressive treatments, with greater toxicity and higher costs. In Latin America, few prognostic studies of the disease are available. OBJECTIVE: To determine the rate of progression from early stages (IA, IB, IIA) to more advanced stages (> IIB) in patients older than 18 years with mycosis fungoides treated at two medical centers in Colombia between January 1, 2010, and December 31, 2019. METHODS: Retrospective cohort study with a longitudinal design. RESULTS: 112 patients diagnosed with early mycosis fungoides were included. 56.2% were male (n = 63), with a median age of 53 years (IQR 43‒67). The most frequent clinical variant was classic (67.9%; n = 76), followed by folliculotropic (16%; n = 18), and hypopigmented (10.7%; n = 12). The most common first-line treatment was NB-UVB phototherapy (27.7%; n = 31), followed by PUVA phototherapy (25.8%; n = 29%), and topical corticosteroids (25%; n = 28). The global rate of disease progression was 8% (n = 9), with an overall mortality of 12.5% (n = 14). STUDY LIMITATIONS: Its retrospective design and the lack of molecular studies for case characterization. CONCLUSIONS: Early mycosis fungoides is a disease with a good prognosis in most patients, with a progression rate of 8% (n = 9).

Avelumab in the Treatment of Advanced Merkel Cell Carcinoma: A Systematic Review.

BACKGROUND: Avelumab, a programmed death ligand-1 inhibitor, has shown success in providing durable responses for difficult-to-treat Merkel cell carcinomas (MCCs). OBJECTIVE: Evaluate the efficacy and safety of avelumab in the treatment of advanced MCC. METHODS: Studies reporting the use of avelumab as a monotherapy or in combination with other agents in the treatment of stage III or IV (advanced) MCC were included. The primary outcomes were overall response rate, overall survival (OS), and treatment-related adverse events. RESULTS: A total of 48 studies were included, involving 1,565 patients with advanced MCC. Most patients were male (1,051, 67.3%) with stage IV MCC (517, 97.0%). The overall response rate was 46.1% (partial response-25.4% and complete response-20.7%) after a mean follow-up period of 9.5 months. Kaplan-Meier survival curves for the pooled stage III and IV group demonstrated OS rates of 58% at 1 year, 47% at 2 years, and 28% at 5 years after completion of treatment with avelumab (median OS: 23.1 months). The most common treatment-related adverse events consisted of constitutional (44%), gastrointestinal (19%), and dermatologic (12%) symptoms. CONCLUSION: Avelumab monotherapy and combination therapy have shown success in the overall response rate and survival for patients with advanced MCC.