Frank Meiss

Severe immune-related adverse events (irAE) in cancer patients receiving immune checkpoint inhibitors (ICI) require treatment interruption and immunosuppression. Based on prior preclinical data, in this prospective, single arm, non-randomized phase-Ib/II clinical trial we test the activity of Extracorporeal Photopheresis (ECP) against steroid-refractory irAEs in 30 patients (EudraCT-No.:2021-002073-26). The primary endpoint is the evaluation of the safety of ECP treatment for patients with ICI-induced irAEs. The study meets its pre-specified primary endpoint of less than 50% of patients developing ECP-related severe adverse events (SAE). No ECP-related SAE is observed and ECP-related AEs are reported in 20% (6/30) of patients. Overall response rate for all irAEs is 96.3% (CI 81.0–99.91). Colitis-, hepatitis- and dermatitis-specific response rates are 100% (13/13), 86.7% (13/15) and 100% (3/3), respectively. Secondary endpoints include the assessment of response rate of irAE and overall survival. ECP therapy is associated with reduced granzyme-A/B/K, T-bet, interferon-γ and TNF in peripheral T cells and pro-inflammatory gene-expression in the intestinal tract. The 12-month overall survival rate is 84.3% (CI 63.4%-93.8%). Response correlates with a decrease in inflammatory gene expression in the intestinal tract. These results suggest that ECP is a safe treatment option for SR-irAEs and warrant further investigation in subsequent randomized clinical trials.

Immune checkpoint inhibitors (ICIs) and BRAF/MEK kinase inhibitors have substantially improved survival in advanced melanoma; however, therapeutic resistance and severe toxicities underscore the ongoing need for alternative strategies. Here, we evaluate the clinical utility of multi-omic profiling, biomarker-stratified recommendations, and survival outcomes within a prospective cohort of 98 patients with advanced cutaneous or uveal melanoma evaluated by the Molecular Tumor Board Freiburg (MTB-FR) between 2021 and 2024. Completed profiling revealed at least one potential actionable target beyond classical BRAF V600 mutations in 83.8% of cases. Alterations in NRAS , atypical BRAF variants, CDK4/6 pathway amplifications, and DNA-damage response (DDR) gene mutations most frequently guided board recommendations. Biomarker-stratified therapies were recommended for 68.4% of patients, and personalized immunotherapy combinations for 72.4%. The treatment implementation rate was 33.8% (n = 27), achieving an overall disease control rate (DCR) of 42.9% and an overall response rate (ORR) of 10.7%. These findings demonstrate that comprehensive molecular profiling in a real-world setting uncovers actionable alterations, providing viable subsequent treatment avenues that may optimize outcomes for heavily pretreated melanoma patients beyond established standards of care. Ultimately, prospective, randomized, biomarker-driven trials remain essential to validate whether these individualized diagnostic strategies translate into a reproducible survival benefit.

Summary: Robust long‐term survival data have transformed the prognosis of metastatic melanoma. For combination therapy with immune checkpoint inhibitors (ICIs), 10‐year melanoma‐specific survival rates now exceed 50 %, and durable disease control is achievable in a substantial proportion of patients, including those with brain metastases. With increasing long‐term survival, chronic and late‐onset treatment‐related toxicities are becoming increasingly relevant. In particular, chronic immune‐related adverse events (irAEs) may persist after discontinuation of ICI therapy or emerge with delayed onset. These toxicities can significantly impair long‐term quality of life and often require ongoing management; endocrine toxicities, for example, may necessitate lifelong hormone replacement therapy. In addition to physical sequelae, survivors frequently experience psychosocial and financial burdens, difficulties returning to work, and concerns related to fertility and family planning. These multidimensional challenges highlight the growing importance of survivorship care in patients treated with ICIs. Systematic assessment of physical and psychosocial burden as well as health‐related quality of life, especially through patient‐reported outcomes, can support clinical decision‐making and individualized follow‐up strategies. Integrating these assessments into structured, multidisciplinary survivorship care models is essential to address the complex long‐term needs of melanoma survivors and to optimize outcomes beyond disease control.

Zusammenfassung: Für das metastasierte Melanom liegen inzwischen robuste Daten zum Langzeitüberleben vor; so beträgt unter kombinierter Therapie mit Immuncheckpointinhibitoren (ICI) im metastasierten Stadium die melanomspezifische 10‐Jahres‐Überlebensrate über 50 %. Auch für Patienten mit Hirnmetastasen ist dauerhafte Krankheitskontrolle inzwischen bei einem substantiellen Anteil der Patienten erreichbar. Mit zunehmendem Langzeitüberleben, insbesondere nach zuvor erfolgter Therapie mit ICI, rücken chronische und spät auftretende therapieassoziierte Toxizitäten vermehrt in den Fokus, insbesondere chronische irAEs, die auch nach Beendigung einer Therapie mit ICI persistieren oder auch erst beginnen können. Langzeittoxizitäten können die Lebensqualität nachhaltig beeinträchtigen und erfordern zum Beispiel bei endokrinologischen Toxizitäten mitunter eine lebenslange Substitution. Neben den unmittelbar physischen Aspekten, sind häufig psychosoziale und finanzielle Belastungen, Schwierigkeiten beim beruflichen Wiedereinstieg, sowie Aspekte der Familienplanung und Fertilität zentrale Survivorship‐Themen. Die systematische Erfassung sämtlicher psychosozialer und physischer Belasungen, sowie der Lebensqualität, insbesondere als patientenberichtetes Outcome unterstützt Therapieentscheidungen und Nachsorgeplanung und sollte Teil des multidisziplinären Survivorship‐Care ‐Konzeptes sein.

Zusammenfassung: Hintergrund: Adjuvante Immuncheckpoint‐Inhibitoren (ICI) und zielgerichtete Therapien ( targeted therapy , TT) haben das Therapiemanagement für Patienten mit Melanom grundlegend verändert. Die aktuelle deutsche S3‐Leitlinie unterscheidet jedoch nicht zwischen Patienten mit und ohne adjuvante Therapie in ihren Empfehlungen zu Bildgebungsintervallen und der Nachsorge nach Beendigung der adjuvanten Therapie. Dies führt zu uneinheitlichen Vorgehensweisen zwischen den Hautkrebszentren. Diese Studie gibt einen Überblick über die Vorgehensweise der Hautkrebszentren der Arbeitsgemeinschaft dermatologische Onkologie (ADO). Methodik: Am 22. November 2023 wurde eine Umfrage an 80 Hautkrebszentren in Deutschland, Österreich und der Schweiz versandt. Alle bis zum 10. März 2024 eingegangenen Antworten wurden deskriptiv analysiert. Ergebnisse: Die Rücklaufquote betrug 64% (n = 51). Vierzig Zentren (78%) wichen von der Leitlinie ab. In Stadium IIB führen 34 Zentren (67%) vor und nach adjuvanter Therapie CT‐Bildgebungen durch. Nach Abschluss der adjuvanten Therapie halten sich 36 Zentren (71%) an die Leitlinie. Über 90% bieten eine ICI an, wenn unter TT eine Progression auftritt – wie auch umgekehrt. Im Stadium IV würden 32 Zentren (63%) nach einem Rezidiv unter ICI eine TT anbieten. Schlussfolgerungen: Die Vorgehensweisen variieren und stimmen oft nicht mit der Leitlinie überein. Ein konsensbasierter Ansatz würde Patienten und Ärzten zugutekommen.

Summary: Background: Adjuvant immune checkpoint inhibitors (ICI) and targeted therapy (TT) have revolutionized treatment management for patients with melanoma. However, the current German S3 guideline does not differentiate between patients with and without adjuvant therapy in its recommendations for imaging intervals and follow‐up monitoring, leading to variability in clinical practice. This study provides an overview of surveillance practices among skin cancer centers in the German Dermatologic Cooperative Oncology Group (DeCOG). Methods: A survey was sent to 80 skin cancer centers in Germany, Austria and Switzerland on November 22, 2023. Responses received by March 10, 2024 were analyzed descriptively. Results: Fifty‐one responses (64%) were received. Forty centers (78%) reported deviations from the guideline. In stage IIB, 34 centers (67%) conduct imaging including CT scans prior to and after adjuvant therapy. Post‐adjuvant therapy, 36 centers (71%) conduct imaging according to the guideline. Over 90% of the centers offer adjuvant ICI therapy if progression occurs on adjuvant TT and vice versa. In stage IV, after relapse while on adjuvant ICI, 32 centers (63%) would offer adjuvant TT. Conclusions: Surveillance practices differed among participating centers and often do not align with the current guideline. A consensus based consistent approach would benefit both patients and physicians.

Melanoma patients with in-transit metastasis (ITM), a stage of disease where melanoma has metastasized to sites in between the primary lesion and draining lymph node, vary significantly in their clinical outcomes, but the biology driving differential outcomes in ITM is poorly understood. To elucidate the mechanisms of differential outcomes, we utilized multimodal molecular profiling (WES, RNA-seq, highly multiplexed immunofluorescence, spatial transcriptomics) in 1) evolutionary analysis of longitudinal tumor samples and 2) identifying prognostic tumor intrinsic and microenvironmental features in a unique cohort of patients with unresectable ITM. Among other findings, we observed a persistent dedifferentiated AXL⁺/NGFR⁺ clonal lineage pre-existing and following immune checkpoint blockade in in-transit and distant metastases. Concordantly, we found that low pigmentation and high T cell exhaustion signatures were independently associated with distant progression. Our findings highlight tumor cell state and immune dysfunction as key predictors and potential biomarkers of metastatic risk in ITM. STATEMENT OF SIGNIFICANCE: What drives distant progression in melanoma is unclear. Analyzing tumor and immune features in a rare in-transit melanoma patient cohort, we identify biological signals highlighting how immune and tumor states observable in pre-distant metastasis melanomas shape long-term outcomes, and nominate potential prognostic biomarkers.