Egle Ramelyte

Introduction: Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers, with a subset progressing to locally advanced (laSCC) or metastatic (mSCC) stages. The introduction of anti-PD1 immunotherapy has transformed treatment, but real-world data remain limited, particularly in immunosuppressed patients. Methods: This single-centre, retrospective study included 189 patients with advanced cSCC treated between 2012 and 2022. Demographic, clinical, and treatment data were analyzed to assess clinical management and outcomes before and after the introduction of anti-PD1. Results: Among the 189 patients, 72.5% were male, with a median age of 79 years. Overall, 86 patients presented with laSCC and 103 with mSCC. In 100 patients, a preceding primary cSCC was documented, and its complete resection (R0) was associated with significantly better overall survival (OS) after diagnosis of advanced disease (p < 0.001). Immunosuppressed patients, including organ transplant recipients and those with chronic lymphocytic leukemia (CLL), had significantly reduced OS (p = 0.017 and p = 0.0059, respectively). First-line treatment prior to 2018 predominantly involved surgery and radiotherapy. Following the introduction of anti-PD1 therapy, its use increased rapidly in both first- and second-line settings. From 2018 onward, the number of advanced cSCC cases discussed at the multidisciplinary tumorboard increased approximately threefold. Median OS was significantly longer for mSCC patients treated in the post-2018 era (p = 0.025), while the survival disadvantage of CLL patients compared to non-CLL patients widened, suggesting limited benefit from advances in systemic therapy in this subgroup. Best overall response to first-line anti-PD1 correlated significantly with OS, with complete responders achieving a 1-year progression-free survival of 83.3%. Conclusions: The introduction of anti-PD1 has demonstrated improved survival outcomes in advanced cSCC, though significant challenges remain for immunosuppressed patients, particularly those with CLL and solid organ transplant recipients. Future research should focus on optimizing treatment for these high-risk groups, therapeutic sequencing, and the role of perioperative (neoadjuvant and adjuvant) immunotherapy strategies.

Metastatic uveal melanoma (mUM) is an aggressive cancer with limited treatment options; 85−90% of tumors harbor activating GNAQ and GNA11 mutations. Uveal melanoma cells also express PMEL (also known as PMEL17 or gp100), a melanocyte lineage antigen. DYP688, a novel biology-matched antibody−drug conjugate, binds surface PMEL and delivers the potent Gα _q /Gα ₁₁ (G _q/11 ) inhibitor SDZ475 as payload by internalization. This dose-escalating first-in-human phase 1 study of DYP688 in patients with metastatic uveal melanoma and other GNAQ / GNA 11 -mutant melanomas assessed safety as the primary endpoint and pharmacokinetics and preliminary antitumor activity as secondary endpoints. Sixty-six patients received varying DYP688 doses and schedules. Grade 3 treatment-related adverse events occurred in five patients (7.6%), including one dose-limiting toxicity of grade 3 hypotension. Objective responses were seen in 13 out of 66 patients (19.7%) and tumor reduction in 47 out of 66 patients (71.2%). Median progression-free survival was 7.2 (95% CI: 5.3–7.8) months. In summary, DYP688 was well tolerated and showed preliminary efficacy, supporting this novel therapeutic approach. ClinicalTrials.gov identifier: NCT05415072 .

Background: Anti‐PD‐1 response has been associated with higher PD‐1 ligand (PD‐L1) expression levels in different cancer types. Cemiplimab, an anti‐PD‐1 antibody, has been shown to induce a response rate of 31% and 22% in patients with locally advanced basal cell carcinoma (BCC) and metastatic BCC respectively, who have progressed or are intolerant to Hedgehog Inhibitors (HHi). The lower‐than‐expected efficacy of anti‐PD‐1 antibodies and limited and conflicting data on PD‐L1 expression in BCC have prompted us to characterize the prerequisites for immune response—PD‐L1, dendritic cells (DCs), and HLA expression with immunohistochemistry in different BCC morphological subtypes, namely superficial, nodular, sclerosing/infiltrative, and basosquamous. Methods: In this retrospective study, a total of 77 tumor samples from 4 BCC subtypes were analyzed by immunohistochemistry. Among the BCC subtypes, we assessed PD‐L1 and CD11c + DCs expression within tumor and stroma, and HLA Class I expression in the tumor compared to the epidermis. Non‐automated quantification of positive tumor cells and peri‐ and intratumoral immune cells was performed by a board‐certified pathologist. Results: In all BCC subtypes, tumor cells (SOX9 positive) were negative for PD‐L1. PD‐L1 was expressed on intra‐ and peritumoral immune cells, predominantly in basosquamous BCCs, where 80% of the samples showed PD‐L1 positivity in immune cells. DCs were predominantly found in the peritumoral area, mostly in basosquamous BCC, whereas superficial BCCs showed the least DCs. HLA class I expression was downregulated compared to epidermis in most specimens without significant differences among the subtypes. Conclusion: Our findings support previous reports on the immune‐privileged status of BCC. Contrary to the literature, we could not confirm PD‐L1 expression on BCC cells, but rather on the intra‐ and peritumoral immune cells. Given these results and the literature suggesting a tendency of higher immunoreactivity compared to other BCC subtypes, basosquamous BCC might be a better target for anti‐PD‐1 therapy as opposed to other subtypes.

Uveal melanoma is a rare but aggressive intraocular malignancy with limited therapeutic options and a high risk of metastatic relapse. Although its mutational landscape is well defined, how genetic factors, uveal location, and disease progression shape cell states and the tumor ecosystem remains poorly understood. We integrate single-cell RNA sequencing and spatial transcriptomics across a cohort spanning healthy uveal tissue, primary tumors, and metastases. We uncover a continuous shift in melanoma cell states during disease progression, from differentiated, pigmentation-associated programs toward stress- and epithelial-to-mesenchymal transition-associated states. This trajectory is modulated by uveal tract location, with iris tumors exhibiting a more differentiated phenotype and choroidal tumors enriched for stemness-associated features that localize to melanoma-rich regions correlating with genomic instability. In parallel, genetic background defines distinct melanoma cell states and tumor–immune interactions. Together, these findings define clinically relevant cellular states and provide a framework for understanding metastatic progression and therapeutic vulnerability.

Background: Programmed cell death protein (ligand) 1 (PD-(L)1) inhibitors are well established in the treatment of dermatological tumors. Mostly, they are well tolerated, but in about 9–21% of patients, grade 3/4 immune-related adverse events (irAEs) occur. As treatment options are limited, it is of interest to determine whether readministration of another or the same PD-(L)1 inhibitor is safe. Methods: This is a multicenter, retrospective study on patients with metastasized dermatological tumors who were retreated with either the same or a different PD-(L)1 inhibitor after the development of irAEs. The study was conducted at centers in Heidelberg, Zurich, and Frankfurt. Results: 22 patients were included between April 2020 and December 2022 with a median age of 71 years. A total of 13 (59%) patients were re-exposed with the same antibody and nine (41%) received a different PD-(L)1 inhibitor. Six (46%) of the patients who were re-exposed to the same antibody had an irAE, of which 67% were identical with the first. In patients receiving a different PD-(L)1 inhibitor, four (44%) developed an irAE, of which 75% were identical with the first. Conclusions: Both an intraclass switch of PD-(L)1 inhibitor treatment and re-exposure with the same antibody after an irAE can be considered as options with a fair chance of improving therapy tolerance.

Background and Objectives: Melanoma is the leading cause of skin cancer-related mortality due to its high propensity for early metastasis, although survival rates have improved with the advent of targeted and immune-based therapies. Accurate detection of targetable mutations and assessment of tumor mutational burden are essential for informed therapeutic decision-making. Mutation profiling is routinely performed using next-generation sequencing (NGS). The Oncomine Focus Assay (OFA) detects common alterations in 52 genes across various tumor entities, whereas MelArray is a melanoma-specific NGS panel covering mutations in 190 melanoma-relevant genes and providing a genome-wide copy number analysis. Moreover, tumor mutational burden is being assessed. Materials and Methods: In this retrospective study, we analyzed the phenotypic characteristics of 100 patients with cutaneous melanoma who underwent NGS testing using either OFA or MelArray. The aims were to compare the diagnostic yield of the two panels and to investigate potential associations between mutational profiles and clinicopathological features of melanoma. Results: Tumor location, ulceration, and Breslow thickness showed significant correlations with the melanoma subtypes. BRAF mutations were the most frequent driver alterations across all cutaneous melanoma subtypes; however, no significant correlation between specific driver mutations and phenotypic characteristics was identified. MelArray detected a notably high number of alterations in the TERT promoter and CDKN2A genes, which were not captured by OFA and are of potential therapeutic relevance. Conclusions: In conclusion, MelArray enables a more comprehensive molecular characterization of cutaneous melanoma compared with a small generic cancer panel and may support more personalized therapeutic decision-making.

Supplementary ctDNA measurement data

Purpose:Circulating tumor DNA (ctDNA) refers to small DNA fragments, shed from tumor cells into the bloodstream. Measuring ctDNA provides a noninvasive tool for real-time disease monitoring. Although ctDNA predicted overall survival (OS) in metastatic uveal melanoma (mUM) treated with tebentafusp, its broader prognostic value across treatment modalities remains unclear. In this study, we assess the prognostic relevance of longitudinal ctDNA detection and mutant allele fraction (MAF) in patients with mUM treated with different modalities.Experimental Design:To assess ctDNA monitoring as a tool in evaluating therapy response and clinical outcomes in patients with mUM, using an IVDR-certified digital PCR assay targeting GNAQQ209 and GNA11Q209 mutations.Results:We analyzed 655 samples from 75 patients with mUM. Absence of detectable ctDNA in baseline samples prior to first-line therapy was associated with improved OS (HR = 0.13; P = 0.02) and progression-free survival (PFS; HR = 0.31; P = 0.008). Similar associations were observed in patients treated with any line of therapy (OS: HR = 0.19, P = 0.002; PFS: HR = 0.27, P = 0.02). Detection of ctDNA within 3 months of therapy initiation was associated with worse outcomes, independent of baseline detection. Furthermore, patients with MAF > 5% any time point had a significantly poorer prognosis compared with patients with MAF < 5% (median OS 4 months vs. 21 months, P < 0.001; median PFS 2.5 months vs. 3.6 months, P = 0.004), emphasizing the added value of quantitative assessment.Conclusions:Both the presence and level of ctDNA at baseline, along with persistence of ctDNA within 3 months of starting of treatment, are strong negative prognostic markers in mUM. These findings support the clinical utility of ctDNA as a noninvasive tool for disease monitoring.