Tímea Balatoni

Background/Objectives: Metastatic uveal melanoma (mUM) carries a poor prognosis and limited systemic treatment options. While immune checkpoint inhibitors have improved outcomes in cutaneous melanoma, their activity in mUM remains modest. Tebentafusp has recently emerged as the first therapy to improve overall survival in HLA-A*02:01–positive patients, but effective options for others remain scarce. This study compared the real-world effectiveness and safety of ipilimumab plus nivolumab versus anti-programmed cell death protein 1 (PD-1) monotherapy. Methods: We conducted a retrospective single-center analysis of patients with mUM treated at the National Institute of Oncology, Budapest. Patients received either dual checkpoint inhibition (ipilimumab plus nivolumab) or anti-PD-1 monotherapy (nivolumab or pembrolizumab). Evaluated outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and immune-related adverse events (irAEs). Survival was analyzed using Kaplan–Meier methods, log-rank tests, and Cox regression. Results: Fifty-five patients were included (33 ipilimumab–nivolumab, 22 anti-PD-1). ORR was 21% versus 5%, and DCR was 42% versus 32%, respectively. Median PFS was 5.8 vs. 3.7 months (p = 0.053; HR 0.61, 95% CI 0.34–1.09), and median OS was 12.3 vs. 10.6 months (p = 0.214; HR 0.66, 95% CI 0.36–1.22). Grade 3–4 irAEs occurred in 48% of patients receiving ipilimumab–nivolumab compared with 9% on monotherapy. No treatment-related deaths were observed. Conclusions: Anti-PD-1 monotherapy demonstrated limited clinical activity, providing little benefit beyond conventional chemotherapy. Dual checkpoint blockade with ipilimumab and nivolumab achieved higher response and disease control rates, albeit with increased toxicity, suggesting a potential benefit for selected patients. Tebentafusp has emerged as an effective option and a new standard of care for a molecularly defined subgroup of HLA-A*02:01–positive patients. However, for the majority of individuals with metastatic uveal melanoma, effective systemic therapies remain an unmet need.

PD-1 inhibitors are known to be effective in melanoma; however, a considerable proportion of patients fail to respond to therapy, necessitating the identification of predictive markers. We examined the predictive value of tumor cell HLA class I and II expression and immune cell infiltration in melanoma patients treated with PD-1 inhibitors. Pretreatment surgical samples from 40 stage IV melanoma patients were studied immunohistochemically for melanoma cell expression of HLA class I molecules (using four antibody clones with different specificities), HLA-II, and immune cell infiltration (using a panel of 10 markers). Among the responders, the ratio of patients showing melanoma cell HLA-II expression was higher compared to non-responders (p = 0.0158), and similar results were obtained in the case of two anti-HLA-I antibodies. A combined score of HLA-I/II expression also predicted treatment response (p = 0.0019). Intratumoral infiltration was stronger in the responders for most immune cell types. Progression-free survival showed an association with HLA-II expression, the combined HLA score, and the density of immune cells expressing CD134 and PD-1, while overall survival was significantly associated only with HLA class II expression. Our findings corroborate previous results indicating the importance of immune cell infiltration and tumor cell HLA-II expression in the efficacy of PD-1 inhibitor treatment in a “real world” patient cohort and suggest the potential predictive role of HLA class I expression.

Background: The introduction of immuno- and targeted therapeutic modalities meant a breakthrough step in the therapy of melanoma. As a checkpoint inhibitor, the more effective and less toxic anti-PD1 therapy followed an anti-CTLA4 approach. Methods: From our patient pool, 222 advanced melanoma cases were selected, where anti-PD1 (pembrolizumab, nivolumab) therapy was initiated between March 2015 and December 2020. During our retrospective analysis, the efficacy and safety of the therapy were assessed. Results: The median follow-up was 16 months (interval: 0–64 months), and 150 patients (67.6%) received therapy in the first line, while second and third line therapy was performed among 72 patients (32.4%) for the median of 7.0 months (0–60). In 50 cases, BRAF mutations were detected. Ninety-six patients showed objective response (11.3% CR, 32.0% PR). The median PFS was 10.0 months (0–60), and the median OS was 23.0 months (0–64). Autoimmune side effects were found in 79 patients (35.5%); grade 3 occurred in 6.3% of the cases, while 1 patient died due to fulminant pneumonitis (0.25%). Conclusion: Although the range of immunotherapeutic options is getting wider, in the management of melanoma patients, anti-PD1 monotherapy remains an important, effective, and safe method. However, significant correlation was found between the immune-related side effects and therapeutic efficacy.

COVID-19 pandemic affected the diagnosis and management of many diseases, including the most vulnerable group of patients with cancer. In this retrospective survey we evaluated the course of disease of patients treated for melanoma, who got infected with COVID-19 virus between March 2020 and April 2021. 382 patients had been treated for advanced melanoma in our center in this time period. 24 of them had been infected with coronavirus. Six of them suffered in stage III melanoma, the remaining 18 patients had stage IV disease. 14, 5 and 4 of the infected patients had been administered with checkpoint inhibitor, targeted therapy and chemotherapy, respectively. Seven (29%) patients died in COVID-19 infection, in a median of 12 days. None of our patients who had been vaccinated at least one time, had severe symptoms. As a conclusion, the mortality of COVID-19 infection was significantly higher among our melanoma patients compared to the age-standardized mortality rate in Hungary.