Pembrolizumab Versus High-Dose Interferon-α2b as Adjuvant Therapy for Pediatric Melanoma: A Retrospective Study.

INTRODUCTION: Pembrolizumab is well-tolerated in pediatric patients with advanced tumors, consistent with results in adults. However, information on the safety and efficacy of adjuvant pembrolizumab in children and adolescents with melanoma is lacking. OBJECTIVES: To compare pembrolizumab versus high-dose interferon-α2b (HDI) as adjuvant therapy in pediatric patients with melanoma. METHODS: We performed a retrospective study of pediatric patients diagnosed with melanoma between January 2008 and April 2022. Relapse-free survival (RFS) and the 1-year RFS rate were compared between patients receiving adjuvant pembrolizumab or HDI. RESULTS: Seventy-five pediatric patients with melanoma were screened from a database of 6,013 patients. Twenty-four patients were finally enrolled, of whom 9 received pembrolizumab and 15 received HDI as adjuvant therapy. By August 31, 2022, the median follow-up times were 23.6 months and 98.7 months in the pembrolizumab and HDI groups, respectively. There was no significant difference in median RFS between two groups (not reached versus 38.7 months, P = 0.11). The median overall survival was not reached in either group. The 1-year RFS rates were 88.9% and 66.7% in the pembrolizumab and HDI groups, respectively. All adverse events in the pembrolizumab group were grade 1 or 2, but grade 3-5 adverse events occurred in two (13%) patients receiving HDI. CONCLUSIONS: RFS was similar in pediatric patients with melanoma receiving adjuvant pembrolizumab or HDI, but pembrolizumab was associated with a reduced risk of recurrence and a more favorable safety profile. However, due to the small sample size and differences in follow-up time, larger and prospective studies are still warranted to explore better adjuvant therapies for pediatric melanoma.

Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy.

BACKGROUND: Accumulating data suggest that mucosal melanoma, well known for its poor response to immune checkpoint blockade (ICB) and abysmal prognosis, is a heterogeneous subtype of melanoma with distinct genomic and clinical characteristics between different anatomic locations of the primary lesions. Primary malignant melanoma of the esophagus (PMME) is a rare, highly aggressive disease with a poorer prognosis compared with that of non-esophageal mucosal melanoma (NEMM). In this study, we retrospectively analyzed the efficacy of anti-programmed death (PD)-1 in patients with PMME and explored its molecular basis. METHODS: The response and survival of patients with PMME and NEMM under anti-PD-1 monotherapy were retrospectively analyzed. To explore the molecular mechanisms of the difference in therapeutic efficacy between PMME and NEMM, we performed genomic analysis, bulk RNA sequencing, and multiplex immunohistochemistry staining. RESULTS: We found that PMME (n=28) responded better to anti-PD-1 treatment than NEMM (n=64), with a significantly higher objective response rate (33.3% (95% CI 14.3% to 52.3%) vs 6.6% (95% CI 0.2% to 12.9%)) and disease control rate (74.1% (95% CI 56.4% to 91.7%) vs 37.7% (95% CI 25.2% to 50.2%)). Genomic sequencing analysis revealed that the genomic aberration landscape of PMME predominated in classical cancer driver genes, with approximately half of PMME cases harboring mutations in BRAF, N/KRAS, and NF1. In contrast, most NEMM cases were triple wild-type. Transcriptome analysis revealed that, compared with NEMM, PMME displayed more significant proliferation and inflammatory features with higher expression of genes related to antigen presentation and differentiation, and a less immunosuppressive signature with lower expression of inhibitory immune checkpoints and dedifferentiation-related genes. The multiplex immunohistochemical analysis also demonstrated higher CD8+ T-cell infiltration in PMME than in NEMM. CONCLUSIONS: PMME is an outlier of mucosal melanoma showing a malicious phenotype but a particularly high response rate to ICB because of its distinct molecular characteristics. Patient stratification based on anatomic origin can facilitate clinical decision-making in patients with mucosal melanoma following the verification of our results in future prospective studies.

Prognostic impact of Breslow thickness in acral melanoma: A retrospective analysis.

BACKGROUND: Evidence for the prognostic importance of tumor thickness in acral melanoma (AM) patients is limited. OBJECTIVE: The objective of the study was to determine the prognostic impact of Breslow thickness in AM. METHODS: This multicenter study enrolled patients diagnosed with localized AM between January 1, 2000 and December 31, 2017. Melanoma-specific survival (MSS) in different tumor thickness strata (T1-T4: ≤1, >1-2, >2-4, >4 mm, respectively) was estimated by the Kaplan-Meier method. Comparisons were performed by the log-rank test and multivariable Cox regression. RESULTS: A total of 853 patients with clinical N0 (cN0) AM were included in the analysis. The median follow-up time was 60.1 months. The median MSS in patients with T1-T4 disease was not reached, 111.0, 92.8, and 67.1 months, respectively. MSS differed significantly among cN0 patients with T1-T3 AM (log-rank P = .004, .012, <0.001 for T1 vs T2, T2 vs T3, and T1 vs T3, respectively); however, there was no significant difference between T3 and T4 AM (hazard ratio = 0.82, 95% CI, 0.62-1.09). Six-subgroup analyses confirmed that survival outcomes were similar between different subgroups with tumor thickness >2 mm. LIMITATIONS: The limitations were retrospective design and some missing variables. CONCLUSIONS: There was no association between tumor thickness and survival in AM patients with a Breslow thickness >2 mm.

Prognostic value of ulceration varies across Breslow thicknesses and clinical stages in acral melanoma: a retrospective study.

BACKGROUND: Ulceration is regarded as an adverse prognostic factor and is used together with tumour thickness to subcategorize patients with cutaneous melanoma. However, the prognostic impact of ulceration in acral melanoma (AM) is controversial. OBJECTIVES: To assess the prognostic impact of ulceration in AM and the variability across different Breslow thicknesses and clinical stages. METHODS: A multicentre retrospective study of patients diagnosed with AM between January 2000 and December 2017. Differences in melanoma-specific survival (MSS) between patients with and without ulceration were assessed using the multivariable Cox proportional hazards model and log-rank test. RESULTS: Among 1053 enrolled patients, 62.6% had ulceration. After a median follow-up of 61 months, patients with ulceration had a lower median MSS than those without: 66.1 months, 95% confidence interval (CI) 60.0-86.0 vs. not reached; hazard ratio 1.41, 95% CI 1.09-1.82; P = 0.012. Among patients with thin (≤ 1 mm) melanoma, the survival curves of patients with vs. without ulceration clearly separated over time (P < 0.001). No association between ulceration and MSS was observed for melanomas of thickness > 1 mm (subgroups of T2, T3 and T4; all P-values > 0.05) or patients with stage III disease (hazard ratio 1.09, 95% CI 0.71-1.68, P = 0.39). CONCLUSIONS: Ulceration is an independent negative prognostic factor for patients with AM, but the impact varies across Breslow thicknesses and clinical stages. Ulceration has a significant effect on prognosis for patients with thin (≤ 1 mm) melanoma, but there was no association between ulceration and survival in intermediate/thick AM or stage III AM. What is already known about this topic? Ulceration status is used together with Breslow tumour thickness to subcategorize patients into different stages according to the America Joint Committee on Cancer melanoma staging system. As one distinctive subtype of cutaneous melanoma, acral melanoma (AM) is characterized by poor survival outcomes due to delayed diagnosis and a high prevalence of negative prognostic and genetic features. The prognostic impact of ulceration in AM is still controversial. What does this study add? This was the first large-scale study to assess the prognostic and staging values of ulceration in patients with AM. Ulceration has a significant effect on prognosis for patients with thin (≤1 mm) melanoma, but no association between ulceration and survival was found in intermediate/thick or stage III AM. These findings should be considered when using ulceration-based staging systems.

Immunotherapy in Acral and Mucosal Melanoma: Current Status and Future Directions.

Acral and mucosal melanomas are extremely rare in Caucasians; however, they are the predominant melanoma subtypes in Asians and other non-Caucasian populations. Acral and mucosal melanomas share many clinicopathological features, including aggressive phenotypes, similar genetic landscapes, and grim prognoses. In spite of advances in melanoma management, patients with acral and mucosal melanomas show limited benefit from current therapies. The rarity of these subtypes of melanoma is a significant factor contributing to the poor understanding of these pathological subtypes and the lack of effective interventions. Furthermore, the mechanisms contributing to disparities between different types of melanoma remain largely unclear. Herein, we comprehensively review current knowledge on the clinicopathological characteristics and mutational landscapes of acral and mucosal melanomas, as well as providing an overview of current therapies for patients with these aggressive melanoma subtypes, focusing on available immunotherapeutic interventions. We also discuss pathological differences between different melanoma subtypes and summarize current knowledge on melanoma disparities between Asians and Caucasians. Finally, we discuss emerging immunotherapeutic strategies for the treatment of acral and mucosal melanomas, focusing on combination therapies with immune checkpoint inhibitors. Unraveling the unique features of acral and mucosal melanomas is key for their early diagnosis and for the development of effective therapies.

Risk Models for Advanced Melanoma Patients Under Anti-PD-1 Monotherapy-Ad hoc Analyses of Pooled Data From Two Clinical Trials.

Background: The best response and survival outcomes between advanced melanoma patients treated with the anti-PD-1 monotherapy vary greatly, rendering a risk model in need to optimally stratify patients based on their likelihood to benefit from the said treatment. Methods: We performed an ad hoc analysis of 89 advanced melanoma patients treated with the anti-PD-1 monotherapy from two prospective clinical trials at the Peking University Cancer Hospital from April 2016 to May 2018. Clinicodemographical characteristics, baseline and early-on-treatment (median 0.6 months after anti-PD-1 monotherapy initiation) routine laboratory variables, including complete blood count and general chemistry, and best response/survival data were extracted and analyzed in both univariate and multivariate logistic and Cox proportional hazard models. Results: After three rounds of screening, risk factors associated with a poorer PFS included a high pre-treatment neutrophil, derived neutrophil-lymphocyte ratio (dNLR), low pre-treatment hemoglobin, and low early-on-/pre-treatment fold change of eosinophil; those with a poorer OS included a high pre-treatment neutrophil, eosinophil, PLT, early-on/pre-treatment fold change of LDH and neutrophil; and those with a poorer best response included a high pre-treatment NLR and early-on-/pre-treatment LDH fold change. Risk models (scale: low, median-low, median high, and high risk) were established based on these risk factors as dichotomous variables and M stage (with vs. without distant metastasis) for PFS (HR 1.976, 95% CI, 1.507-2.592, P < 0.001), OS (HR 2.348, 95% CI, 1.688-3.266), and non-responder (OR 3.586, 95% CI, 1.668-7.713, P = 0.001), respectively. For patients with low, median-low, median-high, and high risks of developing disease progression (PD), six-month PFS rates were 64.3% (95% CI, 43.5-95.0%), 37.5% (95% CI, 22.4-62.9%), 9.1% (95% CI, 3.1-26.7%), and 0%, respectively. For patients with OS risks of low, median-low, median-high, and high, OS rates at 12 months were 82.5% (95% CI, 63.1-100%), 76.6% (95% CI, 58.4-100%), 42.1% (95% CI, 26.3-67.3%), and 23.9% (95% CI, 11.1-51.3%), respectively. For patients with risks of low, median-low, median-high, and high of being a non-responder, objective response rates were 50.0% (95% CI, 15.7-84.3%), 27.8% (95% CI, 9.7-53.5%), 10.3% (95% CI, 2.9-24.2%), and 0%, respectively. Conclusion: A risk scoring model based on the clinicodemographical characteristics and easily obtainable routinely tested laboratory biomarkers may facilitate the best response and survival outcome prediction and personalized therapeutic decision making for the anti-PD-1 monotherapy treated advanced melanoma patients in Asia.

Palbociclib in advanced acral melanoma with genetic aberrations in the cyclin-dependent kinase 4 pathway.

BACKGROUND: Genetic aberrations in the cyclin-dependent kinase (CDK)4 pathway occur in 82% of patients with acral melanoma (AM), which is the predominant subtype of melanoma in China. We aimed to evaluate the anti-tumour activity of palbociclib, a selective CDK4/6 inhibitor, in patients with advanced AM with CDK4 pathway gene aberrations. METHODS: In this phase II trial, patients with advanced AM with CDK4 or/and CCND1 gain or/and CDKN2A loss were treated with oral palbociclib (125 mg) on days 1-21 of a 28-day cycle. The primary end-point was overall response rate (ORR). Secondary end-points were progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Whole-exome sequencing and multiplex immunohistochemistry of the available formalin-fixed, paraffin-embedded samples of nine patients were analysed to explore the predictive biomarkers of palbociclib response. RESULTS: Fifteen patients were enrolled. Three (20.0%) patients achieved tumour shrinkage at 8 weeks, including one with confirmed partial response. At data cut-off date, treatment was ongoing for one patient. The median PFS was 2.2 mo (range: 1.5-13.3 mo; 95% confidence interval [CI]: 1.9-2.5), and the median OS was 9.5 mo (range: 2.6-14.1 mo, 95% CI: 5.7-13.4). Eight patients died due to disease progression. The most common TRAEs were leukopenia (87%; Grade III/IV, 27%), neutropenia (80%; grade III/IV, 27%), and fatigue (53%; grade III/IV, 7%). Significant JAK2 deletions and SH2B3 amplifications were observed in patients who did not achieve any clinical benefit (CB) with palbociclib treatment. MCM7 amplification or protein expression level was found to be associated with CB. CONCLUSIONS: Palbociclib monotherapy demonstrated preliminary efficacy and an acceptable safety profile in advanced AM patients with CDK4 pathway aberrations. Patients with amplification or high protein levels of MCM7 were more prone to benefit from palbociclib. The JAK-STAT pathway might play a role in the mechanism of action of palbociclib in AM. TRIAL REGISTRATION NUMBER: NCT03454919. THE DATE OF REGISTRATION: March 6, 2018.

Current state and progression of advanced melanoma treatment under precision medicine / 中国肿瘤生物治疗杂志

@#[Abstract] In the past, surgery and chemotherapy were the main treatment strategies for malignant melanoma, but companied with poor prognosis. With the development of high-throughput gene sequencing technology and the deepening understanding of tumor molecular mechanisms, it has been found that tumor heterogeneity and the diversity of tumor microenvironment affect tumor formation, drug resistance and treatment selection, leading to different responses and benefits of melanoma patients to the same treatment. The emerge and progression of targeted therapy and immunotherapy have significantly increased the survival rates of patients with metastatic melanoma, promoting the individualization and precision of melanoma treatment and making precise treatment a research hotspot as well as a trend. This review mainly summarizes the research progress of systemic individualized treatment of advanced melanoma based on precise subtyping and molecular level, and to get a more comprehensive view of the survival status of melanoma patients in the era of precision medicine, as well as the prospect and necessity of developing various targeted therapy, immunotherapy or combination therapy.

Expressions of melanoma lineage antigens and nuclear antigen Ki-67 and their correlations with prognosis in melanoma patients / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To explore the expression patterns of melanoma lineage antigens and nuclear antigen Ki-67 and their correlations with survival in melanoma patients. Methods: A retrospective analysis was conducted to analyze the pathological data of melanoma patients treated at the Department of Melanoma, Peking University Cancer Hospital from February 2008 to August 2020, mainly including the expression patterns of melanoma lineage antigens (S-100, HMB-45, Melan-A) and Ki-67, demographics, clinical features and survival. The correlation between expression patterns of melanoma lineage antigens, Ki-67 and melanoma-specific survival (MSS) was analyzed. Results: In total, 603 patients were included in this study. The median follow-up time was 47.4 months. The positive rates of S-100, HMB, and Melan-A were 92.8%, 92.1% and 90.0%, respectively. The percentages of patients with melanoma lineage antigen scores (S-100, HMB-45 and Melan-A was scored each, as 1 when positive and 0 when negative) of 0, 1, 2, and 3 were 0.5%, 5.0%, 15.6%, and 78.8%, respectively. The percentages of patients with Ki-67 scores of 0, 1, 2, and 3 were 43.0%, 36.3%, 16.3%, and 4.5%, respectively. Ki-67 was highly expressed in mucosal and progressive melanomas. In a multivariate analysis, Ki-67 expression was an independent prognostic factor for poorer MSS (HR=1.506, 95%CI: 1.248-1.818, P<0.001) as the incidence of MSS event increased by 50% per 25% increase in Ki-67 expression, whereas there was no statistical correlation between melanoma lineage antigen expression and MSS (HR=0.991, 95%CI: 0.759-1.293, P=0.94). Conclusion: High expressions melanoma lineage antigens are ubiquitous in melanoma tissues, and Ki-67 is an independent prognostic factor for MSS.

The Clinicopathological and Survival Profiles Comparison Across Primary Sites in Acral Melanoma.

BACKGROUND: The clinicopathological and survival profiles across primary sites in acral melanoma (AM) are still controversial and unclear. METHODS: This is a multi-center retrospective study. Clinicopathological data of AM patients diagnosed between 1 January 2000 and 31 December 2017 from 6 large tertiary hospitals in China were extracted. Chi square tests were used to compare basic characteristics between primary sites of sole, palm and nail bed. Melanoma-specific survival (MSS) differences based on primary sites were compared by log-rank tests and multivariate Cox regressions were used to identify prognostic factors for MSS. RESULTS: In total, 1157 AM patients were included. The sole group had a more advanced initial stage, deeper Breslow thickness, higher recurrence rate and distant metastases risk (all P < 0.05). The proportion of age < 65 years and ulceration were statistically lower in nail bed and palm groups, respectively. A total of 294 patients underwent sentinel lymph node biopsy and rates of positive SLN status had no statistical difference across primary sites. Among 701 patients with genetic profiles, the mutational frequency of BRAF, C-KIT, and PDGFRA were similar except for NRAS (higher in sole group, P = 0.0102). The median MSS of sole, nail bed and palm patients were 65.0 months, 112.0 months, and not reached, respectively (log-rank P = 0.0053). In multivariate analyses, primary site, initial stage, ulceration and recurrence were the prognostic factors for MSS in overall population, but the statistical significance varied over primary sites. CONCLUSIONS: Substantial clinicopathological and survival heterogeneities exist across different primary sites in the AM population. Sole melanoma has worse prognosis compared with palm and nail bed subtypes.