PFS and OS by detection of BRAF V600 alterations in ctDNA at (A and B) baseline and (C and D) on treatment. Only patients with BRAF V600 alteration detections at baseline are shown in C and D. Bini, binimetinib; D, detectable; Enco, encorafenib; ND, nondetectable; Vemu, vemurafenib.

Correlation matrix between clinical and ctDNA variables

Mutations in specific pathways of interest at baseline and at discontinuation

PURPOSE:Treatment with encorafenib ± binimetinib is associated with improved survival versus vemurafenib in patients with BRAF V600E/K-mutant advanced melanoma. We retrospectively analyzed genomic and transcriptomic data from the phase III COLUMBUS trial to identify molecular correlates of benefit with encorafenib ± binimetinib. EXPERIMENTAL DESIGN:In COLUMBUS, patients with BRAF V600E/K-mutant locally advanced, unresectable, or metastatic melanoma (n = 921) were randomized to receive encorafenib plus binimetinib, encorafenib, or vemurafenib. We used whole-exome sequencing (n = 666), whole-transcriptome sequencing (RNA sequencing; n = 514), and assessment of circulating tumor DNA (ctDNA) at baseline (n = 336) and on treatment (cycle 2 day 1, n = 184) to evaluate biomarker associations with progression-free and overall survival. RESULTS:Survival benefits with encorafenib plus binimetinib versus vemurafenib were greatest in patients with higher tumor mutational burden (TMB) and those with evidence of tumor immune infiltration (i.e., higher cytolytic score, PD-L1 expression, or IFNγ gene signature scores). Clustering of gene expression profiles identified three tumor subgroups, including an "immune" subgroup associated with improved survival. Detection of BRAF V600 alterations in baseline ctDNA was associated with shorter survival; clearance of BRAF V600 alterations at cycle 2 day 1 was associated with improved survival across arms. CONCLUSIONS:The greatest benefits of encorafenib plus binimetinib were observed in patients with evidence of high TMB and/or tumor-immune infiltration, suggesting potential immune contributions to efficacy, which were not observed with vemurafenib. BRAF V600 detectability in ctDNA seems to have utility as a marker of prognosis and response in this population.

Rosai-Dorfman disease (RDD) is a rare histiocytic disorder with unifocal to multisystemic involvement. Activating mutations in the MAPK/ERK pathway can occur in up to 50% of RDD cases. We report a case of cutaneous RDD (C-RDD) with facial and truncal lesions harboring an activating MAP2K1 (MEK1) mutation that showed a complete response to a combined treatment with MAPK inhibitors encorafenib and binimetinib. This case suggests that MAPK inhibitors may represent a therapeutic option for C-RDD in certain cases.

Pediatric cutaneous malignancies are rare but form distinct clinical and molecular biological subgroups from adult skin cancers. This review focuses on major diseases of childhood and adolescence-malignant melanoma, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and dermatofibrosarcoma protuberans (DFSP)-outlining their epidemiology, clinical features, molecular drivers, and treatment strategies. Pediatric malignant melanoma is primarily classified into adult-like tumors with BRAF/NRAS mutations, Spitz melanoma arising from kinase fusion genes, and congenital nevi with NRAS mutations. Spitz tumors form a clinically challenging diagnostic spectrum, but advances in molecular profiling have enabled subclassification and risk stratification. Pediatric BCC typically arises from syndromic or iatrogenic factors, whereas pediatric SCC is strongly associated with DNA-repair defects, immunosuppression, and chronic inflammation; both require long-term follow-up. Although rare, DFSP is the most frequent cutaneous sarcoma in pediatric patients and typically exhibits COL1A1-PDGFB fusions. Considering the pediatric-specific factors common to these malignancies, individualized treatment approaches are required. This review integrates the latest findings in molecular pathology and clinical guidelines to support accurate diagnosis, treatment, and follow-up in pediatric dermatology.

Abstract Brain metastases affect up to 30% of patients with metastatic cancer and are a major cause for morbidity and mortality. Treatment approaches include neurosurgery, various approaches to radiotherapy and systemic pharmacotherapy. Encouraging response rates have been observed in patients with melanoma and non-small cell lung cancer (NSCLC) with asymptomatic or oligo-symptomatic brain metastases treated with novel systemic therapies, including immune checkpoint inhibitors and targeted therapy, challenging the need for immediate radiosurgery. Eligible patients for STRIKE must have newly diagnosed and untreated asymptomatic or oligo-symptomatic brain metastases from melanoma or NSCLC, with an indication for systemic therapy. The treatment regimen consists of standard systemic treatment with (Arm A) or without (Arm B) stereotactic radiosurgery. Systemic therapy follows the current standard of care according to the primary tumor. Primary endpoint is CNS-specific progression-free survival (PFS), locally assessed according to RANO criteria. Secondary endpoints include CNS-specific PFS per tumour cohort, objective CNS response rate, duration of CNS response, pattern of CNS-specific progression, extra-CNS progression, incidence of radionecrosis and pseudoprogression, overall survival, neurocognitive function, quality of life and functional independence, and toxicity. We assume that the addition of radiosurgery to systemic treatment will increase median CNS-specific PFS by 62% from a median of 4 and 8 months for melanoma and NSCLC, respectively, corresponding to an overall hazard ratio of 0.62 for time to CNS failure. According to the log-rank test, at a 5% one-sided significance level, 143 events provide 88% power for a sample size of 180 patients. The USZ-STRIKE trial is an academic study sponsored by ETOP IBCSG Partners Foundation, with substantial funding from the USZ Foundation. The trial is being conducted in 15 centres in Switzerland, Italy, the Netherlands, Spain and the United Kingdom. Current accrual is 57 patients. he study is registered on ClinicalTrials.gov: NCT05522660.

PFS and OS for encorafenib plus binimetinib or encorafenib vs. vemurafenib by (A and B) TMB and (C and D) cytolytic score. E, Volcano plots of univariable gene expression associations with OS in each arm based on z-scored gene expression values. F, Gene-set enrichment analysis of gene expression associations against hallmark gene signatures; signatures with greatest average NES across arms shown. Bini, binimetinib; BM, biomarker; CYT, cytotoxic score; Enco, encorafenib; NES, normalized enrichment scores; Vemu, vemurafenib.

Cox regression forest plot for BRAF V600E allele frequency

INTRODUCTION:In view of rising incidence rates worldwide, the prevention of skin cancer is a central pillar of public health. While UV protection forms the basis of primary prevention, pharmacological strategies (chemoprevention) are becoming increasingly important. This paper provides a practice-oriented synthesis of current evidence, ranging from behavioural prevention and systemic approaches with nicotinamide and retinoids to experimental strategies such as immune checkpoint inhibitors and DNA repair enzymes.

Background and objectives: Pruritus is a frequent cutaneous immune-related adverse event (irAE) associated with immune checkpoint inhibitors (ICI), impacting patients' quality of life. This study investigates the incidence, severity and management of pruritus in melanoma patients treated with ICI. Patients and methods: Clinical data from 461 melanoma patients at the University Hospital of Zurich were analyzed in a retrospective, monocentric study. Patients received ICI either as combination therapy (ipilimumab and nivolumab) or monotherapy (nivolumab or pembrolizumab). Results: Immune-related pruritus (irPruritus) was associated with increased overall survival. It affected 23.0 % of patients (106/461), with a significantly higher frequency and earlier onset observed in combination therapy compared to monotherapy (p < 0.001). A significant, pronounced increase in eosinophil counts was noted from baseline to onset of irPruritus. Topical steroids proved effective in 90.9 % of cases. Additionally, irPruritus was significantly correlated with both irFatigue (p < 0.01) and irRash (p < 0.001). Conclusions: Pruritus is a common side effect of ICI therapy. Its correlation with irFatigue and irRash highlights the broader systemic impact impairing patients' quality of life. Further prospective studies are needed to elucidate the underlying mechanisms such as involvement of eosinophils and identify optimal treatment strategies while maintaining ICI effectiveness.

BACKGROUND:Resistance to anti-PD-1/PD-L1 therapy is a major unmet need. Growth Differentiation Factor 15 (GDF-15) has been identified as a key resistance factor for anti-PD-1/PD-L1 immunotherapy. Visugromab, a neutralizing anti-GDF-15 antibody, plus the anti-PD-1 antibody nivolumab (V+N) was evaluated in the first-in-human phase 1/2a GDFATHER-01 trial in heavily pretreated participants with locally advanced/metastatic non-squamous non-small-cell lung cancer (nsq NSCLC), urothelial carcinoma (UC), or hepatocellular carcinoma (HCC), stringently defined as anti-PD-1/PD-L1-relapsed/refractory, and showed encouraging objective responses. This analysis reports long-term follow-up of these three phase 2 expansion cohorts of the GDFATHER-01 trial. METHODS:Seventy-seven participants with nsq NSCLC (N=22), UC (N=27), and HCC (N=28) received visugromab (10 mg/kg) plus nivolumab (240 mg) every two weeks until disease progression or unacceptable toxicity. RESULTS:Objective response rates (RECIST v1.1) were 18.2% for nsq NSCLC (4/22; 95%CI 5.2-40.3), 18.5% for UC (5/27; 95%CI 6.3-38.1), and 14.3% for HCC (4/28; 95%CI 4.0-32.7). Median duration of response (DoR) was 32.2 months (95%CI 5.5-38.0), 28.8 months (95%CI 7.4-39.4), and 19.4 months (95%CI 5.8-39.7; with protracted recruitment), respectively, with 7/13 responses (53.8%) ongoing. Confirmed complete response or complete metabolic response (CR or CMR) among responders was 61.5% (8/13), with 7/8 ongoing. In addition, 46.2% (6/13) of responders achieved a deeper response on V+N per RECIST v1.1 than with the prior anti-PD-(L)1 therapy; median DoR on V+N was 28.8 months (95%CI 7.4-38.0) versus 12.0 months (95%CI 8.0-24.0) on initial anti-PD-1/PD-L1 treatment. V+N was generally well tolerated. CONCLUSIONS:In heavily pretreated, advanced/metastatic participants with nsq NSCLC, UC, or HCC who were anti-PD-1/PD-L1-relapsed/refractory, V+N achieved deep and durable objective responses. The observed DoR, depth of response, and CR+CMR rate among responders exceeded those reported for their initial anti-PD-1/PD-L1 therapy. These findings suggest that GDF-15 blockade with visugromab can overcome resistance and enhance the magnitude and durability of anti-PD-1/PD-L1 responses, and warrant further exploration in randomized trials. REGISTRY:ClinicalTrials.gov, TRN: NCT04725474, Registration date: 25 January 2021; EudraCT, TRN: 2020-002103-19, Registration date 16 Dec 2020.

ctDNA change from baseline separated by disease control and prior BRAFi treatment

Background: Cutaneous squamous cell carcinoma (cSCC) is among the most common human cancers, yet the cellular identity and molecular programs of its preinvasive precursor, actinic keratosis (AK), remains poorly defined. Methods: We applied CITE-seq to patient-matched AK, UV-exposed normal skin, and non-UV-exposed normal skin (n=5 patients, 12 biopsies) and performed spatial whole-transcriptome profiling in an independent cohort (n=4) to map pre-invasive keratinocyte states at single-cell resolution. Results: We identify AK-specific keratinocytes (ASK), a discrete population localized to the dysplastic basal epidermis and characterized by UV-associated mutational signatures (SBS7b), high mutational burden, and recurrent copy number alterations including 9p loss and 8q gain. ASK occupies a basal-like undifferentiated state sustained by a ΔNp63/PITX1 regulatory module that attenuates Notch/HES1-driven differentiation and activates glycolytic metabolism. Comparison with published cSCC data reveals that ASK share core tumor-propagating gene networks with tumor-specific keratinocytes (TSK), including IGFBP6, IGFBP2, and ITGA6, but lack invasion effectors MMP1, MMP10, and PTHLH. Functional experiments identify IGFBP6 as a pro-proliferative factor in AK-derived keratinocytes. The AK microenvironment shows expansion of inflammatory basal keratinocytes, barrier disruption, and early immunosuppressive T cell remodeling. Conclusions: These findings define the molecular identity of a pre-invasive malignant keratinocyte population governed by p63/PITX1 and distinguish early oncogenic programs shared with invasive cSCC from later-acquired invasion effectors, identifying candidate targets for prevention or treatment of squamous cell carcinoma.

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.

A false-negative diagnosis of cancer can lead to a delay in effective treatment and a poorer prognosis. Here, we use the example of cutaneous melanoma to examine how many years of life are lost after a false-negative diagnosis compared to a primarily correct diagnosis. From 1996 to 2015, 9,063 patients are prospectively registered in the German Central Malignant Melanoma Registry and followed up until December 2023. A false-negative diagnosis is found in 206 (2.3%) patients. The median time to correct diagnosis is 24.0 months. The 10-year recurrence-free survival probabilities are 32.9% for false-negative diagnoses and 76.2% for correct diagnoses (p < 0.001). The 10-year melanoma-specific survival probabilities are 62.1% versus 85.0% (p < 0.001). On average, each person with an initial false-negative diagnosis loses 8.2 years of life compared to people with a correct diagnosis. This high number of years of life lost raises the question of whether similar results also apply to other types of cancer.

Significant associations between clinical and ctDNA variables

PURPOSE:BRAF V600 mutations are tumor-agnostic oncogenic drivers whose targeted inhibition is challenged by therapeutic resistance. Mosperafenib is a novel paradox breaker and brain-penetrant BRAF inhibitor (BRAFi), tested in this study for safety, maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary clinical activity. PATIENTS AND METHODS:This phase Ia/b study was conducted in patients with advanced solid tumors harboring a BRAF V600 mutation (ISRCTN13713551). The modified continuous reassessment method guided dose escalation of mosperafenib, which was given orally up to 3,600 mg once daily in 28-day cycles. The primary objective was to estimate the MTD and/or recommended phase II dose(s). RESULTS:Eighty patients (60% BRAFi-exposed)-63 with colorectal cancer (CRC), 13 with melanoma, and 4 with other solid tumors-received ≥1 dose of mosperafenib as a single agent for a median of 3.7 months (range, 0.2-28.6). Two dose-limiting grade 3 toxicities of rash and rash maculopapular were reported. MTD was not reached. Grade 3 to 4 treatment-related adverse events (TRAEs) occurred in 13 patients (16.3%); no grade 5 TRAEs events were reported. Two patients (2.5%) discontinued study treatment due to TRAEs. There were no reports of palmar-plantar erythrodysesthesia or keratoacanthoma. Linear and time-independent PK was demonstrated across the tested dose range, achieving exposure levels with sustained PK-derived pERK inhibition ≥90%. An exposure-response relationship was observed. Overall response rate was 24.2%, including two complete responses and 14 partial responses. Median progression-free survival was 6.4 months in patients with CRC (200 mg once daily-1200 mg three times a day) and 3.5 months in patients with melanoma (200 mg once daily-800 mg twice a day). CONCLUSION:Mosperafenib demonstrated a favorable safety profile, sustained target inhibition, and early signs of clinically meaningful single-agent activity in BRAFi-naïve and BRAFi-exposed patients.

Background Randomised trials recently showed that sequencing of first-line (1L) immune checkpoint inhibitor (ICI) and second-line (2L) BRAF-MEK-inhibitor (BRAF/MEKi) combination therapy provides better clinical outcomes in BRAFV600-mutated, irresectable/metastatic melanoma than the inverse sequence. However, efficacy benchmark data for 2L BRAF/MEKi are limited as the combination was developed for 1L use, lacking estimates for the impact of prior ICI. Methods This retrospectively study analysed 2,343 patients from the EUMelaReg registry with BRAFV600-mutated melanoma who received BRAF/MEKi either as 2L after failing 1L ICI (n=654) or as 1L treatment (n=1,689). Patients with prior adjuvant ICI or BRAF/MEKi were excluded. Prognostic imbalances between the two groups were adjusted using 1:1 inverse propensity score matching. Key efficacy outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and time on treatment (TOT). Results Patients in the 2L cohort achieved outcomes from start of treatment at least equivalent to the matched 1L BRAF/MEKi cohort. Kaplan-Meier estimates demonstrated longer median PFS (8.4 vs 7.7 months; p=0.01) and longer median TOT (7.8 vs 6.2 months; p=0.002) for patients treated with 2L BRAF/MEKi compared to 1L. Median OS from start of 2L (17.2 months) or 1L (16.0 months) BRAF/MEKi was similar (p=0.73) despite inherent bias from differing index dates. ORR among both groups (56.4% vs 53.5%; p=0.32) was equal. Conclusion This study further supports the recommended sequencing of ICI as 1L and BRAF/MEKi as 2L therapy for patients with BRAFV600-mutated melanoma. It shows that prior failure of ICI does not compromise the efficacy of BRAF/MEKi treatment.