MONETTE study design, Baseline tumor sample and blood samples, DoR, best percentage change from baseline in target lesion size, OS in PD-L1 and CD8/Ki67 biomarker evaluable populations, micrographs of PD-L1 expression and CD8+/Ki67 cells, baseline area of CD8+ T cells, Ki67+ cells, and proliferating CD8+ Ki67 + T cells in the central tumor region, OS in the baseline circulating immune cell biomarker population, longitudinal pharmacodynamic effects on T cells, OS in GDF-15 biomarker population and baseline GDF-15 as a prognostic marker for OS in monotherapy and combination therapy.

DNA methylation provides a stable record of cellular identity, capturing epigenetic programs that distinguish specialized cell states despite a shared genome. Because malignant transformation and tumour progression are accompanied by extensive epigenetic remodeling, we hypothesized that the methylome of melanocytic lesions contains biologically and clinically relevant information for both diagnosis and disease progression. In a cohort of 1,001 tissue samples prospectively collected across eight German university hospitals profiled using Illumina Infinium MethylationEPIC arrays, we compared machine-learning models based on selected Cytosine phosphate Guanine (CpG) methylation sites with models incorporating biology-guided features, including epigenetic age acceleration, cell type composition and copy-number variation burden. In an external test set, the best diagnostic classifier was CpG-based and distinguished melanocytic nevi, noninvasive melanoma and invasive melanoma with a macro-averaged area under the receiver operating characteristic curve of 0.919 (95

PURPOSE:Data suggest that ceralasertib, a potent and selective oral inhibitor of the ataxia-telangiectasia and Rad3-related (ATR) DNA damage response kinase, may overcome resistance to prior immunotherapy. PATIENTS AND METHODS:In this phase II study, patients with unresectable or metastatic melanoma of cutaneous, acral, or mucosal subtype and confirmed progression during anti-PD-(L)1 therapy with or without anti-CTLA-4 were randomized 2:1 to ceralasertib 240 mg twice daily on days 1 to 7 and then durvalumab 1,500 mg intravenously on day 8, every 28 days or ceralasertib 240 mg twice daily on days 1 to 7, every 28 days. The primary endpoint was objective response rate (ORR). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Exploratory analyses of baseline (tumor and circulating) and on-treatment (circulating only) biomarkers were conducted. RESULTS:ORR was 9.3% [95% confidence interval (CI), 4.3-16.9] for ceralasertib plus durvalumab (below the prespecified minimum threshold) and 5.8% (95% CI, 1.2-15.9) for ceralasertib monotherapy; median PFS was 2.0 months (95% CI, 1.9-3.5) versus 1.9 months [95% CI, 1.9-3.1; hazard ratio (HR), 0.80; 95% CI, 0.54-1.18]; and median OS was 16.0 months [95% CI, 10.5-not calculated (NC)] versus 12.3 months (95% CI, 9.5-NC; HR, 0.81; 95% CI, 0.49-1.37). Both regimens were well tolerated. Exploratory analyses indicated a possible link between higher baseline pretreatment tumor CD8+ T-cell counts and improved OS across both arms and suggested that ceralasertib treatment may induce transient, cyclical changes in circulating CD14+ monocytes and GDF-15 plasma levels. CONCLUSIONS:Both ceralasertib plus durvalumab and ceralasertib monotherapy demonstrated low response rates in anti-PD-(L)1-resistant advanced melanoma.

Abstract Background: Metastatic uveal melanoma (mUM) has a very poor prognosis with a historical survival rate of <10% at 5 yrs. Tebentafusp, a first in class ImmTAC bispecific (gp100 x CD3), is approved for adult HLA-A*02:01+ patients with unresectable or mUM based on a phase 3 study demonstrating improved overall survival (OS) compared to investigator’s choice (IC) (HR 0.51; IMCgp100-202; NCT03070392). This benefit was maintained at the 3-yr follow-up (HR 0.68), with a 3-yr OS rate of 27% for tebentafusp and 18% for IC. Molecular response assessed by ctDNA reduction was a better indicator of OS benefit than traditional RECISTv1.1 measurements. Here we report updated analyses of OS after a minimum follow-up of 5 yrs. Methods: In this randomized, open-label, Phase 3 trial, first line HLA-A*02:01+ mUM patients were randomized 2:1 to receive tebentafusp or IC of single-agent pembrolizumab, ipilimumab or dacarbazine, stratified by lactate dehydrogenase. Primary endpoint was OS. ctDNA reduction was an exploratory endpoint. OS was estimated using Kaplan-Meier methods and treatment effects compared using Cox proportional hazards model. A Cox model, adjusted for baseline and time-varying covariates at progression, compared post-progression survival in tebentafusp patients with versus without treatment beyond radiographic progression (TBP). Results: 378 patients were randomized to tebentafusp (252) or IC (126; 82% pembrolizumab). With extended follow-up, the OS continued to favor tebentafusp, with a stratified hazard ratio of 0.67 (95% CI, 0.54-0.85). The 5-year OS rate for tebentafusp was 16% (95% CI, 11-21) vs 8% (95% CI, 4-14) for IC. The OS benefit was evident even in patients with known poor prognostic factors, including those with large tumors ≥ 10 cm. OS benefit was also seen in patients who did not have radiographic response including those with best response of progressive disease (PD) or those with a best change of tumor growth (>20%). Notably, in the tebentafusp arm, TBP was associated with better OS compared to no TBP, even after adjusting for covariates (HR 0.61; 95% CI, 0.44-0.83). In tebentafusp-treated patients, longer OS was associated with undetectable ctDNA at baseline or ctDNA reductions ≥50% by week 9. Among 21 ctDNA-evaluable patients who survived ≥ 5 years, 15 had undetectable baseline ctDNA and the remaining 6 had ctDNA clearance. Deep reductions in ctDNA were seen in patients regardless of baseline tumor burden and across all RECIST categories. Conclusions: Tebentafusp demonstrates durable, long-term OS benefit in first line HLA-A*02:01+ patients, which at 5 years is the longest OS follow-up in a randomized trial in mUM. OS benefit is evident in those with poor prognostic factors and remains independent of radiographic response, with ctDNA levels proving to be a better indicator of activity. This is the first report of long-term OS benefit in a solid tumor treated with an ImmTAC therapy. Citation Format: Paul Nathan, Sophie Piperno-Neumann, Jessica C. Hassel, Marcus O. Butler, Max Schlaak, Ryan J. Sullivan, Reinhard Dummer, John M. Kirkwood, Joseph J. Sacco, Alexander N. Shoushtari, Josep M. Piulats, April KS Salama, Marlana Orloff, Anthony M. Joshua, Sebastian Ochsenreither, Lauris Gastaud, Brendan Curti, Lev Demidov, Mohammed Milhem, Bartosz Chmielowski, Kari Kendra, Paolo Antonio Ascierto, Eric H. Bernicker, Richard D. Carvajal, Omid Hamid, Laura Collins, Sarah Lockwood, Jaymin M. Patel, Jean-Francois Baurain, Piotr Rutkowski. Five-year survival with tebentafusp in previously untreated metastatic uveal melanoma in a phase 3 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT029.

BACKGROUND AND OBJECTIVES:Complete lymph node dissection (CLND) is the standard of care in patients with regional nodal melanoma macrometastasis. However, evidence on surgical procedures in the era of adjuvant systemic therapies is lacking. PATIENTS AND METHODS:This retrospective multi-center study included stage IIIB-D melanoma patients with nodal macrometastasis undergoing CLND or selective lymph node extirpation (LNE) prior to adjuvant therapy. CLND and LNE were compared regarding recurrence-free survival (RFS), nodal metastasis-free survival (NFS) and overall survival (OS). RESULTS:320 melanoma patients were included (median age 62; 55.5% male). Patients received PD-1 monotherapy (77.8%), targeted therapy (21.3%) or both sequentially (0.9%), as well as adjuvant radiotherapy in 40.9%. RFS and OS did not differ significantly between patients receiving CLND or LNE, while NFS was significantly prolonged following CLND (HR 0.3917; p = 0.005). After adjustment for risk factors by multivariate Cox regression, a prolonged RFS for CLND vs. LNE was found (HR 0.676; p = 0.04), but no benefit for OS. The rate of complications was significantly higher in the CLND group. CONCLUSIONS:CLND showed no OS benefit compared to LNE, while local control was improved. CLND can be recommended in the context of adjuvant therapies, however, the increased rate of complications should be considered.

Study treatment discontinuation criteria and Flow Cytometry Immunophenotyping.

Time till treatment progression and overall survival stratified by TGFBR1 expression

BackgroundPrimary cutaneous B cell lymphomas (CBCL) are chronic diseases with frequent relapses. Time to next treatment (TTNT) is an endpoint reflecting clinical benefit of treatments including patient perspectives. The objectives were to evaluate clinical characteristics, survival, prognosis and TTNT in CBCL.Patients and methodsIn this monocentric study, clinical data were extracted between 1998 and 2022. TTNT were calculated. Univariate and multivariate analyses were conducted.ResultsAltogether, 46 patients with follicle center lymphoma (pcFCL), 41 with marginal zone lymphoproliferative disorder (pcMZLPD) and 11 with diffuse large B-cell lymphoma, leg type (DLBCL-LT) were identified. 26% of pcFCL patients relapsed frequently. The 5-year relapse-free survival was 71%, 87% and 23% in pcFCL, pcMZLPD and DLBCL-LT, respectively. In pcFCL and pcMZLPD, skin-directed treatments, such as excision or intralesional triamcinolone, performed best based on TTNT, while chemotherapy achieved a mean TTNT of 38 months in DLBCL-LT. In multivariate analysis of all patients, leg involvement was significantly associated with a decreased TTNT of the first treatment, while comorbidities were associated with an increased TTNT.ConclusionsDLBCL-LT had the worst survival. Skin-directed treatments tend to achieve higher TTNT in pcFCL and pcMZLPD, while systemic treatments had higher TTNT in DLBCL-LT.

TRAE occurring in patients with mUM treated with tebentafusp.

Summary of clinical data and results of AI analysis of whole-slide image.

BackgroundAlthough systemic therapies have improved considerably over the last decade, up to 50% of patients with metastatic melanoma still die due to disease progression. Oncological treatment at the end-of-life phase is challenging. The aim of this study was to investigate the frequency and type of systemic therapy received by melanoma patients in their end-of-life phase.MethodsPatients with metastatic melanoma who had died between January 1, 2018 and October 31, 2022 were identified from the prospective multicenter skin cancer registry ADOReg. Study endpoints were percentage of patients who had been treated with systemic therapy within the last three months of life, timepoint of initiation of the last-line therapy, overall survival, treatment benefit and the incidence of treatment-related adverse events.ResultsIn total, 1067 patients from 46 skin cancer centers were included. Most of the patients (63%) had received immune checkpoint inhibitors (ICI) as last-line therapy, 22% targeted therapies (TT) and 12% chemotherapy (CTX). Comparing last-line ICI and TT, patients with TT were significantly more likely to benefit from treatment and had significantly fewer and milder treatment-related AE than patients with ICI. Even though two thirds of patients had received ICI as a last-line therapy, the majority of these patients (61%) had stopped therapy within the last 30 days of life, whereas the majority of patients with TT (66%) still continued their treatment to the end of life. We found markedly fewer patients with initiation of ICI within 30 days before their death (19%) compared to a historic cohort including patients who died in 2016 or 2017 (39%).ConclusionTreatment approaches near the end of life have markedly changed in skin cancer centers in Germany over recent years, with ICI prescribed less frequently in the end-of-life phase. In contrast, TT are frequently administered, even within the last 30 days of life. It should also be considered that discontinuation of TT can result in rapid tumor progression. Due to the oral administration and a low rate of severe toxicity, TT appear to be a suitable treatment option, even in the end-of-life situation of melanoma patients.

Relative log expression plots of the original counts and after performing upper quantile normalization

PURPOSE:We conducted an integrated safety analysis from three clinical studies of tebentafusp, a first-in-class ImmTAC bispecific T-cell engager, which can redirect T cells to target glycoprotein 100-positive cells, in metastatic uveal melanoma. EXPERIMENTAL DESIGN:HLA-A*02:01-positive patients with unresectable or metastatic uveal melanoma enrolled in three clinical trials (IMCgp100-01, IMCgp100-102, and IMCgp100-202) who received ≥1 dose of tebentafusp were included. Safety data were pooled to evaluate the profile, onset, and management of treatment-related adverse events (TRAE). Adverse events of special interest included cytokine release syndrome (CRS), acute skin reactions (ASR), and liver function test elevations. Primary prophylaxis with medications was not permitted. RESULTS:Among 410 tebentafusp-treated patients, the most common TRAE were pyrexia (77%), pruritus (71%), and chills (53%). Most patients experienced CRS (88%), almost always mild (grade 1, 19%) to moderate (grade 2, 67%) in severity, with only 2% experiencing grade 3 (n = 6) or 4 (n = 1) CRS. Additionally, 92% had at least one ASR, primarily pruritus and rash, with 21% having a grade 3 event. Onset of CRS and ASR was within 1 to 2 days of infusion and generally reversible with standard interventions. Elevated liver function tests were generally mild and resolved without intervention. Most TRAE occurred following the first few infusions and diminished in frequency and severity with repeated dosing; no cumulative TRAE were detected. Discontinuations due to TRAE were rare (2%); there were no treatment-related deaths. CONCLUSIONS:TRAE were consistent with tebentafusp's mechanism of action, mostly occurred during dose escalation, and were predictable, reversible, and manageable with appropriate surveillance and intervention.

Primär kutane B‐Zell‐Lymphome (CBCL) sind chronische Erkrankungen mit häufigen Rezidiven. Die Zeit bis zur nächsten Therapie ( Time to next treatment , TTNT) ist ein Endpunkt, der den klinischen Nutzen von Therapieoptionen einschließlich der Patientenperspektive widerspiegelt. Ziele waren es, klinische Merkmale, Überleben, Prognose und TTNT bei CBCL zu analysieren. In dieser monozentrischen Studie wurden klinische Daten von Patienten zwischen 1998 und 2022 erhoben. Die TTNT wurde berechnet. Es wurden univariate und multivariate Analysen durchgeführt. Insgesamt wurden 46 Patienten mit Follikelzentrumslymphom (pcFCL), 41 mit marginalzonen‐lymphoproliferativer Störung (pcMZLPD) und elf mit diffus großzelligem B‐Zell‐Lymphom, Bein‐Typ (DLBCL‐LT) identifiziert. Bei 26% der Patienten mit pcFCL traten mehrere Rezidive auf. Das rezidivfreie 5‐Jahres‐Überleben betrug 71%, 87% beziehungsweise 23% bei pcFCL, pcMZLPD und DLBCL‐LT. Bei pcFCL und pcMZLPD schnitten hautgerichtete Behandlungen wie Exzision oder intraläsionales Triamcinolon am besten ab, während Chemotherapien bei DLBCL‐LT eine mittlere TTNT von 38 Monaten erreichten. In der multivariaten Analyse war eine Beinbeteiligung signifikant mit geringerer TTNT der ersten Behandlung bei allen Patienten assoziiert, während Komorbidität mit höherer TTNT einherging. DLBCL‐LT hatte die schlechteste Überlebensrate. Hautgerichtete Therapieoptionen erreichten tendenziell eine höhere TTNT bei pcFCL und pcMZLPD, während systemische Behandlungen eine höhere TTNT bei DLBCL‐LT aufwiesen.

INTRODUCTION:While BRAF-/MEK-inhibitor therapy is well established in V600E/K-mutated melanoma, the efficacy in advanced melanoma with rare BRAF mutations remains uncertain. This is an updated analysis of an international data collection including 49 new patients, accompanied by development of a publicly accessible global database. PATIENTS AND METHODS:A retrospective analysis was conducted at 20 international cancer centers, evaluating 143 patients with rare BRAF V600 (V600-nonE/K; 48 %) and non-V600 (52 %) mutations. Treatments included BRAF/MEK inhibitor combination therapy (BRAFi/MEKi) and the respective monotherapies. Clinical outcomes concerning overall response rate (ORR), progression-free (PFS), and overall survival (OS) were collected. RESULTS:Included patients had a median age of 65 years (range 20-93), 101 (71 %) were male. Most patients (n = 92, 64 %) received BRAFi/MEKi, 42 (29 %) BRAFi monotherapy, and 9 (6 %) MEKi monotherapy. The ORR was 35 % and higher in V600-nonE/K (45 %) than non-V600 melanomas (26 %, p = 0.025). Median duration of response was similar, with 8.2 months (range 2.9-53.1 +) for V600-nonE/K and 7.4 months (range 0.8-73.8 +) for non-V600. Combination therapy achieved best results in both groups, however, differences between V600-nonE/K and non-V600mutation were only found in ORR (51 % vs. 33 %, p = 0,11) and median PFS (6.5 vs. 3.2 months, p = 0.01). Patients with the longest PFS (> 50 months) had V600D/R, V600_K601D/E/N or K601E/N-, L597V/S/R/Q/P/K- mutations. OS was similar in both groups (16.1 vs. 11.7 months, p = 0.96). Of note, in non-V600 melanomas MEKi monotherapy revealed similar response rates as combination treatment (ORR 33 %, PFS 3 months); however, median OS was shorter (6.6 months, p = 0.02). CONCLUSIONS:This updated analysis reinforces the benefit of BRAFi/MEKi therapy in rare BRAF mutations. A database for ongoing data collection was developed and is available at https://www.klinikum.uni-heidelberg.de/en/hautklinik-zentrum/hauttumorzentrum/forschung/datenbank-seltene-braf-mutationen.

Cutoff values used to stratify patients

Landmark OS for corticosteroid use within the first 30 days of the first tebentafusp dose. Kaplan–Meier plot of inverse probability of treatment–weighted OS (ATE weights) by corticosteroid use within the first 30 days of the first tebentafusp dose, landmarked at day 30. HR (95% confidence interval), 1.09 (0.67–1.76). ATE, average treatment effects.

PURPOSE:Treatment with immune checkpoint inhibitors (ICI) in advanced melanoma can result in durable responses, yet an algorithm to decide which patients can safely discontinue ICI is still lacking. EXPERIMENTAL DESIGN:We used a multimodal approach combining clinical data, artificial intelligence-based analysis of hematoxylin and eosin-stained whole-slide images of melanoma before ICI start, and gene expression signatures to identify biomarkers for relapse after discontinuing ICI in the absence of treatment progression. RESULTS:Univariable Cox regression analysis identified the best overall response, mRNA expression of six genes, tumor cell density, and the lymphocyte-to-plasma cell ratio as factors predictive of relapse upon the cessation of the ICI. Multivariable Cox regression analysis showed that both TGFBR1 expression and the integral digital pathology parameter-based prognostic system were independently associated with relapse after ICI discontinuation. Training a multivariate adaptive regression spline model achieved the highest overall predictive accuracy of 84.6% for relapse after ICI discontinuation. CONCLUSIONS:The identified prognostic markers are fully explainable and easily implementable in routine practice, facilitating risk stratification upon the cessation of ICI therapy.