Outcome In Melanoma Research Articles

Symptomatic brain metastases in melanoma.

Although clinical outcomes in metastatic melanoma have improved in recent years, the morbidity and mortality of symptomatic brain metastases remain challenging. Response rates and survival outcomes of patients with symptomatic melanoma brain metastases (MBM) are significantly inferior to patients with asymptomatic disease. This review focusses upon the specific challenges associated with the management of symptomatic MBM, discussing current treatment paradigms, obstacles to improving clinical outcomes and directions for future research.

The influence of rurality on melanoma diagnosis in Indiana: A retrospective cohort study.

Research from across the United States has shown that rurality is associated with worse melanoma outcomes. In Indiana, nearly a quarter of all residents live in rural counties and an estimated 2180 cases of melanoma will be diagnosed in 2023. This study examines how geographical location affects the stage of melanoma diagnosis in Indiana, aiming to identify and address rural health disparities to ultimately ensure equitable care. Demographics and disease characteristics of patients diagnosed with melanoma at Indiana University Health from January 2017 to September 2022 were compared using Students t-tests, Wilcoxon tests, chi-squared or Fisher's exact tests. Patients from rural areas presented with more pathological stage T3 melanomas (15.0% vs. 3.5%, p < 0.001) in contrast to their urban counterparts. Additionally, rural patients presented with fewer clinical stage I melanomas (80.8% vs. 89.3%) and more clinical stage II melanomas (19.2% vs. 8.1%), compared to urban patients, with no stage III (p = 0.028). Concerningly, a significantly higher percentage of the rural group (40.7%) had a personal history of BCC compared to the urban group (22.6%) (p = 0.005) and fewer rural patients (78.0%) compared to urban patients (89.4%) received surgical treatment (p = 0.016). Patients from rural counties in Indiana have higher pathological and clinical stage melanoma at diagnosis compared to patients from urban counties. Additionally fewer rural patients receive surgical treatment and may be at higher risk of developing subsequent melanomas.

Association between Medicaid Expansion and Cutaneous Melanoma Diagnosis and Outcomes: Does Where You Live Make a Difference?

Early detection and standardized treatment are crucial for enhancing outcomes for patients with cutaneous melanoma, the commonly diagnosed skin cancer. However, access to quality health care services remains a critical barrier for many patients, particularly the uninsured. Whereas Medicaid expansion (ME) has had a positive impact on some cancers, its specific influence on cutaneous melanoma remains understudied. The National Cancer Database identified 87,512 patients 40-64 years of age with a diagnosis of non-metastatic cutaneous melanoma between 2004 and 2017. In this study, patient demographics, disease characteristics, and treatment variables were analyzed, and ME status was determined based on state policies. Standard univariate statistics were used to compare patients with a diagnosis of non-metastatic cutaneous melanoma between ME and non-ME states. The Kaplan-Meier method and log-rank tests were used to evaluate overall survival (OS) between ME and non-ME states. Multivariable Cox regression models were used to examine associations with OS. Overall, 28.6 % (n = 25,031) of the overall cohort was in ME states. The patients in ME states were more likely to be insured, live in neighborhoods with higher median income quartiles, receive treatment at academic/research cancer centers, have lower stages of disease, and receive surgery than the patients in non-ME states. Kaplan-Meier analysis found enhanced 5-year OS for the patients in ME states across all stages. Cox regression showed improved survival in ME states for stage II (hazard ratio [HR], 0.84) and stage III (HR, 0.75) melanoma. This study underscores the positive association between ME and improved diagnosis, treatment, and outcomes for patients with non-metastatic cutaneous melanoma. These findings advocate for continued efforts to enhance health care accessibility for vulnerable populations.

Efficiency and tolerance of second-line triple BRAF inhibitor/MEK inhibitor/anti-PD1 combined therapy in BRAF mutated melanoma patients with central nervous system metastases occurring during first-line combined targeted therapy: a real-life survey.

Although current systemic therapies significantly improved the outcome of advanced melanoma, the prognosis of patient with central nervous system (CNS) metastases remains poor especially when clinically symptomatic. We aimed to investigate the efficiency of CNS targets and tolerance of second-line combined anti-PD1/dual-targeted anti-BRAF/anti-MEK therapy implemented in patients with CNS progression after initially efficient first-line combined targeted therapy in patients with BRAF-mutated melanoma in a real-life setting. A monocentric retrospective analysis including all such patients treated from January 2017 to January 2022 was conducted in our tertiary referral center. The response of CNS lesions to second-line triple therapy was assessed through monthly clinical and at least quarterly morphological (according to RECIST criteria) evaluation. Tolerance data were also collected. Seventeen patients were included with a mean follow-up of 2.59 (±2.43) months. Only 1 patient displayed a significant clinical and morphological response. No statistically significant difference was observed between patients receiving or not additional local therapy (mainly radiotherapy) as to response achievement. Immunotherapy was permanently discontinued in 1 patient owing to grade 4 toxicity. Mean PFS and OS after CNS progression were 2.59 and 4.12 months, respectively. In this real-life survey, the subsequent addition of anti-PD1 to combined targeted therapy in melanoma patients with upfront CNS metastases did not result in significant response of CNS targets in most BRAF mutated melanoma patients with secondary CNS progression after initially successful first-line combined targeted therapy.

A national database analysis of the evolution of outcomes of surgery for anal melanoma.

This study assessed trends in treatment and outcomes of anal melanomas over a 17-year period. NCDB was searched for patients with anal melanoma (2004-2020). Receiver-operating characteristic curve analysis was used to determine cutoff year marking increased overall survival (OS) of anal melanoma. Characteristics, treatments, and outcomes in consecutive time periods were compared. A total of 815 patients (mean age: 67.2 years; 59.4% female) were included: 354 in Period 1 (2004-2012) and 461 in Period 2 (2013-2020). Period 2 included fewer abdominoperineal resections (18% vs. 28%, p = 0.002), more local tumor excisions (61.1% vs. 55%, p = 0.002), more often immunotherapy (odds ratio [OR]: 3.41, 95% confidence interval [CI]: 2.22-5.22, p < 0.001) and less often chemotherapy (OR: 0.516, 95% CI: 0.352-0.755, p < 0.001) administered and longer median OS (25.2 vs. 19.8 months, p = 0.006). Independent predictors of worse OS were older age (hazard ratio [HR]: 1.02, p = 0.012), higher Charlson score (HR: 2.32, p = 0.02), and greater number of positive lymph nodes (HR: 1.15, p < 0.001); conversely private insurance (HR: 0.385, p = 0.008) was predictive of increased OS. Anal melanoma patients diagnosed between 2013 and 2020 underwent fewer abdominoperineal resections and more local excisions than patients diagnosed between 2004 and 2013. Increased immunotherapy and longer median OS were noted in period two. Age and private insurance were significant predictors of OS, remaining constant across time periods.

Abstract 6411: The gut microbiome is associated with recurrence free survival in patients with resected Stage III or Stage IV melanoma treated with immune checkpoint inhibitors

Abstract The gut microbiome (GMB) plays a crucial role in immune checkpoint blockade (ICB) therapy outcomes for metastatic melanoma patients, yet there remains a lack of consensus regarding the specific microbiota associated with clinical outcomes, particularly across different geographic regions. Furthermore, investigations into the relationship between GMB and melanoma outcomes in the adjuvant setting are notably absent. This highlights the pressing need for a comprehensive, large-scale study spanning diverse geographic locations within a well-controlled clinical trial environment. In this study, we conducted shotgun sequencing on pre-treatment stool samples collected from 674 melanoma patients participating in an international, randomized, double-blind, phase III adjuvant trial evaluating clinical outcomes following adjuvant nivolumab plus ipilimumab versus nivolumab. Our recruitment encompassed three continents and five geographically distinct regions. Given the significant influence of geographic region on GMB composition, we employed three analytical approaches: (a) region-specific analyses, (b) combined meta-analyses across regions, and (c) sub-set paired analyses involving subjects closely matched for overall GMB. Additionally, we assessed GMB stability by examining samples collected serially prior to therapy and at weeks 7 and 29 of ICB treatment. Through region-specific and meta-analyses, we identified ten pre-treatment gut bacterial markers, including Eubacterium, Ruminococcus, Clostridium, and Firmicutes, which exhibited associations with melanoma recurrence in the adjuvant setting. The predictive capacity of these microbial markers was directly proportion to GMB similarity (Spearman correlation = 0.86, p&amp;lt;0.001 for AUC vs. beta-diversity). Notably, for closely matched patients in terms of their GMB composition, the prediction of recurrence using the recurrence-associated markers, in conjunction with clinical characteristics, yielded an AUC of 0.917 (95% CI: 0.825-1.00). Furthermore, GMB remained largely stable across serial samples collected before and after treatment (PERMANOVA R2 = 0.867, p-val&amp;lt;0.001, at baseline, week 7, and week 29). This study underscores the remarkable stability of GMB during adjuvant ICB therapy for melanoma and identifies specific bacterial biomarkers that hold promise for predicting melanoma recurrence within the adjuvant treatment setting. The gut microbiome emerges as a potential source of microbial biomarkers for individualized prediction of melanoma recurrence in clinical practice. Citation Format: Mykhaylo Usyk, Richard B. Hayes, Rob Knight, Antonio Gonzalez, Huilin Li, Iman Osman, Jeffrey S. Weber, Jiyoung Ahn. The gut microbiome is associated with recurrence free survival in patients with resected Stage III or Stage IV melanoma treated with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6411.

Abstract 4845: Evaluating racial disparities in immune checkpoint inhibitor survival and autoimmunity

Abstract Introduction: In recent years, immune checkpoint inhibitors (ICI) have revolutionized the landscape of treatment across a variety of cancers. Potential concerns regarding racial disparities in ICI access and therapeutic efficacy have been well documented. Recent studies have indicated improved ICI access and response outcomes in White patients compared to minority groups with head and neck cancer (HNC) and melanoma patients. In contrast, patients diagnosed with lung cancer have been mixed, with some research suggesting black patients may fare better with ICI therapy. Existing literature is largely limited to retrospective studies with small population sizes, and lacks comparisons of racial disparities across malignancies. We aim to describe and compare racial inequities in ICI outcomes in HNC, melanoma, and lung cancer. Methods: The TriNetX US Collaborative Network database was queried for patients &amp;gt;18 years-old with a diagnosis of head and neck cancer, melanoma or lung cancer that were treated with ICIs. Malignancy cohorts were defined by race: non-Hispanic White (NHW) and Black. Race cohorts were 1:1 propensity score matched (PSM) for comorbidities, oncologic stage, and chemoradiation treatment. Demographic differences in cohorts were evaluated prior to matching. Following PSM, overall survival and rates of autoimmunity were assessed at 5 years. Results: 19,443 NHW and 2,827 Black patients treated with ICI were identified. At a baseline, the Black patient cohorts had significantly higher rates of comorbidies (p&amp;lt;0.02). Across all malignancies, the geographic distribution of NHW patients was more equally distributed compared to Black patients (majority south). With PSM, black HNC patients had significantly lower survival rates compared to NHW [HR: 1.4 (1.2, 1.6), p=0.0002]. In melanoma, the same trend was present, though not significant [HR: 1.3 (0.95, 1.7), p=0.1]. In contrast, in lung cancer, Black patients had significantly higher survival rates compared to NHW patients [HR 0.78 (0.70, 0.86), p&amp;lt;0.0001]. In HN and lung cancer, NHW patients had significantly higher rates of autoimmune conditions after ICI therapy compared to Black [OR: 2.0 (1.4,2.8), 1.2 (1.0, 1.4), respectively]. Conclusion: This study represents the most extensive analysis of racial disparities on ICI outcomes across malignancies. This study found that black patients treated with ICIs had decreased survival rates at 5 years compared to NHW patients in HNC and melanoma, but increased survival rate in lung cancer. This disparity persisted following PSM, matching cohorts for comorbidities, oncologic stage and adjuvant therapy. Black patients also had significantly lower rates of autoimmunity in HN and lung cancer. Noted differences in survival may be a reflection of geographic practice differences, access to care and/or socioeconomic status. Further investigation is required to elucidate the underlying etiologies of these trends. Citation Format: Kathryn L. Nunes, Pablo Llerena, Praneet Kaki, Shreya Mandloi, Annie Moroco, Eric Mastrolonardo, David M. Cognetti, Adam J. Luginbuhl, Joseph M. Curry. Evaluating racial disparities in immune checkpoint inhibitor survival and autoimmunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4845.

Abstract 3823: Clinical outcomes of uveal melanoma patients in the emergency department

Abstract Purpose: Uveal melanoma is a rare ocular malignancy that has not been well characterized at a large scale. Specifically, uveal melanoma diagnosis and outcomes in the emergency department (ED) has not been characterized. Methods: The Nationwide Emergency Department Sample was queried from the last quarter of 2015 to 2019 to identify patients with a primary diagnosis of uveal melanoma. Multivariable logistic regression, with patient- and hospital-level characteristics as covariates, was used to identify factors associated with increased risk of inpatient admission. Results: From the last quarter of 2015 to 2019, there were 1,274 ED encounters with a primary diagnosis of uveal melanoma. Most patients were less than 11 years old (43.4%), male (51.1%), or a Medicaid beneficiary (37.8%), and most belonged to a family in the lowest income quartile (32.0%). The median age of these patients was 35 years (IQR: 2-64). Most patients presented to hospitals in the South (53.9%), with a Trauma Level I designation (51.4%), and most to a metropolitan teaching hospital (89.1%). The most common ED outcomes were same-day discharge (61.6%) and admission to the inpatient setting (31.2%). Patients presenting to Trauma Level I hospitals were most likely to be admitted (odds ratio [OR]=2.21; p=0.031). The factors that were most significantly associated with decreased odds of inpatient admission were: patients who were not charged for services (often due to charity) (OR=0.13; p=0.040), Medicaid beneficiaries (OR=0.27; p=0.031), and private insurance beneficiaries (OR=0.34; p=0.047). Among the admitted patients, patients can be discharged to home with self-care (76.2%) or with home-health care (14.9%) or can be transferred to an intermediate-care facility (8.1%). The mean hospital length of stay was 5.7±0.6 days. In-hospital mortality rate for admitted patients was very low (0.8%). Conclusion: Uveal melanoma patient outcomes are closely related to insurance status, indicating socioeconomic factors as a modulator of patient outcomes. Citation Format: Alice A. Beneke, Kamil Taneja, Lauren Ladehoff, Kevin Root, Eric Toloza. Clinical outcomes of uveal melanoma patients in the emergency department [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3823.

Surgical margins and outcomes for eyelid melanoma: a systematic review and meta-analysis.

No randomized trials exist to inform the peripheral surgical margins or depth of wide excision for eyelid melanoma. We performed a meta-analysis examining surgical margins and Breslow depth for eyelid melanomas. A systematic review was performed in August 2022 using PubMed, Cochrane, and Medline databases (1/1/1990 to 8/1/2022). Inclusion criteria included studies reporting surgical treatment of primary cutaneous melanomas of the eyelid with reported surgical margins. Ten articles were included. The studies were examined by surgical margin size (group 1: ≤ 0.5cm; group 2 > 0.5cm and ≤ 1.5cm) and Breslow depth (group 1: ≤ 1mm; group 2: > 1mm). The odds ratio (OR) for local recurrence was 2.55 [95% CI 0.36-18.12], p = 0.18; regional metastasis was 0.70 [95% CI 0.00-23671.71], p = 0.48; and distant metastasis was 2.47 [95% CI 0.00-1687.43], p = 0.66. When examining by Breslow depth, the OR for local recurrence was 0.53 [95% CI 0.14-1.94], p = 0.34; regional metastasis was 0.14 [0.00-176.12], p = 0.54; and the OR for distant metastasis was 0.24 [95% CI 0.01-8.73], p = 0.46. There was a trend toward higher likelihood of recurrence and metastasis in the ≤ 0.5cm group. Similarly, there is a trend toward higher likelihood of recurrence and metastasis with Breslow depth > 1mm. A surgical margin of at least 0.5cm and achievement of negative margins via permanent sections or MMS are likely needed to prevent adverse outcomes. En face sectioning may be a superior method of histological processing for eyelid melanoma.

Improved survival outcomes for melanoma of unknown primary in the era of novel therapies: A population-based retrospective analysis

Improved survival outcomes for melanoma of unknown primary in the era of novel therapies: A population-based retrospective analysis

A commentary on "Does the time interval between sentinel lymph node biopsy and completion lymph node dissection affect outcome in malignant melanoma? A retrospective cohort study" - correspondence.

A commentary on "Does the time interval between sentinel lymph node biopsy and completion lymph node dissection affect outcome in malignant melanoma? A retrospective cohort study" - correspondence.

Persistent poverty and incidence-based melanoma mortality in Texas.

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). 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. 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). 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.

Anti-PD-1 Therapy in Advanced Pediatric Malignancies in Nationwide Study: Good Outcome in Skin Melanoma and Hodgkin Lymphoma.

The role of immune checkpoint inhibitors (ICIs; anti-PD1) in the treatment of childhood cancers is still evolving. The aim of this nationwide retrospective study was to assess the safety and effectiveness of ICIs used in a group of 42 patients, with a median age of 13.6 years, with various types of advanced malignancies treated in pediatric oncology centers in Poland between 2015 and 2023. The indications for treatment with anti-PD1 were as follows: Hodgkin lymphoma (11); malignant skin melanoma (9); neuroblastoma (8); and other malignancies (14). At the end of follow-up, complete remission (CR) was observed in 37.7% (15/42) of children and disease stabilization in 9.5% (4/42), with a mean survival 3.6 (95% CI = 2.6-4.6) years. The best survival (OS = 1.0) was observed in the group of patients with Hodgkin lymphoma. For malignant melanoma of the skin, neuroblastoma, and other rare malignancies, the estimated 3-year OS values were, respectively, 0.78, 0.33, and 0.25 (p = 0.002). The best progression-free survival value (0.78) was observed in the group with malignant melanoma. Significantly better effects of immunotherapy were confirmed in patients ≥ 14 years of age and good overall performance ECOG status. Severe adverse events were observed in 30.9% (13/42) patients.

Multi-omics analysis for ferroptosis-related genes as prognostic factors in cutaneous melanoma.

Melanoma is highly malignant and heterogeneous. It is essential to develop a specific prognostic model for improving the patients' survival and treatment strategies. Recent studies have shown that ferroptosis results from the overproduction of lipid peroxidation and is an iron-dependent form of programmed cell death. Despite this, ferroptosis-related genes (FRGs) and their clinical significances remain unknown in malignant melanoma. This study aims to assess the role of FRGs in melanoma, with the goal of developing a novel prognostic model that provides new insights into personalized treatment and improvement of therapeutic outcomes for melanoma. We systematically characterized the genetic alterations and mRNA expression of 73 FRGs in The Cancer Genome Atlas (TCGA)-skin cutaneous melanoma (SKCM) dataset in this study. The results were validated with real-time RT-PCR and Western blotting. Subsequently, a multi-gene feature model was constructed using the TCGA-SKCM cohort. Melanoma patients were classified into a high-risk group and a low-risk group based on the feature model. As a final step, correlations between ferroptosis-related signatures and immune features, immunotherapy efficacy, or drug response were analyzed. By analyzing melanoma samples from TCGA-SKCM dataset, FRGs exhibited a high frequency of genetic mutations and copy number variations (CNVs), significantly impacting gene expression. Additionally, compared with normal skin tissue, 30 genes with significantly differential expression were identified in melanoma tissues. A prognostic model related to FRGs, constructed using the LASSO Cox regression method, identified 13 FRGs associated with overall survival prognosis in patients and was validated with external datasets. Finally, functional enrichment and immune response analysis further indicated significant differences in immune cell infiltration, mutation burden, and hypoxia status between the high-risk group and the low-risk group, and the model was effective in predicting responses to immunotherapy and drug sensitivity. This study develops a strong ferroptosis-related prognostic signature model which could put forward new insights into target therapy and immunotherapy for patients with melanoma.

Pathologic characteristics and clinical outcomes of primary dermal melanoma

Pathologic characteristics and clinical outcomes of primary dermal melanoma

The therapeutically actionable long non-coding RNA ‘T-RECS’ is essential to cancer cells’ survival in NRAS/MAPK-driven melanoma

Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA (AC004540.4) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS. Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.

Smoking and Melanoma Outcomes—Another Reason to Quit

Smoking and Melanoma Outcomes—Another Reason to Quit

Tumor characteristics of dissociated response to immune checkpoint inhibition in advanced melanoma

IntroductionImmune checkpoint inhibition (ICI) has improved patients’ outcomes in advanced melanoma, often resulting in durable response. However, not all patients have durable responses and the patients with dissociated response are a valuable subgroup to identify mechanisms of ICI resistance.MethodsStage IV melanoma patients treated with ICI and dissociated response were retrospectively screened for available samples containing sufficient tumor at least at two time-points. Included were one patient with metachronous regressive and progressive lesions at the same site, two patients with regressive and novel lesion at different sites, and three patients with regressive and progressive lesions at different sites. In addition, four patients with acquired resistant tumor samples without a matched second sample were included.ResultsIn the majority of patients, the progressive tumor lesion contained higher CD8+ T cell counts/mm2 and interferon-gamma (IFNγ) signature level, but similar tumor PD-L1 expression. The tumor mutational burden levels were in 2 out 3 lesions higher compared to the corresponding regressive tumors lesion.In the acquired tumor lesions, high CD8+/mm2 and relatively high IFNγ signature levels were observed. In one patient in both the B2M and PTEN gene a stop gaining mutation and in another patient a pathogenic POLE mutation were found.ConclusionIntrapatient comparison of progressive versus regressive lesions indicates no defect in tumor T cell infiltration, and in general no tumor immune exclusion were observed.

Identifying Novel Targets for Enhancing Anti-PD1 Immunotherapy in Melanoma

Checkpoint inhibitors targeting PD-1/PD-L1 have become prominent treatments for advanced melanoma. However, these inhibitors are effective in less than half of patients, highlighting the need for new pathways and strategies to improve response rates. Analysis of RNA sequencing data from melanoma patients receiving anti-PD1/PD-L1 therapy revealed an enrichment of FGFR signaling in nonresponders, which was associated with a poorer prognosis. Additionally, it was found that FGFR signaling is negatively correlated with B cell signaling in melanoma tumors. Conversely, B cell receptor signaling is enriched in responders' tumors and associated with a better prognosis. This suggests that inhibiting FGFR or increasing the activation of B cells may be novel therapeutic targets for melanoma patients and aid in checkpoint inhibitor therapy. Further validation is necessary to assess the impacts on anti-PD1/PD-L1 therapy response. Overall, characterizing distinguishable pathways between responders and nonresponders may lead to more personalized immunotherapy selections and improved clinical outcomes for advanced melanoma.

Tofacitinib is Effective in Treating Refractory Immune Checkpoint Inhibitor Hepatitis

Immune checkpoint inhibitors (ICI) have improved metastatic melanoma outcomes; however, toxicities, such as hepatitis, can be dose-limiting or even fatal.1 Systemic glucocorticoids and antimetabolite immunosuppressive medications remain the mainstay of treatment for ICI-hepatitis, but options for patients refractory to these therapies are limited.2 Herein we present 3 cases of glucocorticoid-refractory ICI-hepatitis treated with tofacitinib, an inhibitor of Janus kinase (JAK) 1 and 3. These patients represent consecutive patients referred to the Massachusetts General Hospital Severe Immunotherapy Complications service who were determined by our experts to have treatment failure with systemic glucocorticoid and antimetabolite combination therapy between August 2022 and September 2023.3 These were the only 3 patients managed by the Severe Immunotherapy Complications service who were treated with tofacitinib for ICI-hepatitis during that time.