BACKGROUND:The increasing use of pembrolizumab in oncological treatments results in substantial healthcare costs. The recently approved subcutaneous (SC) pembrolizumab formulation remains expensive. The aim of this study was to evaluate alternative SC pembrolizumab dosing strategies that reduce costs while maintaining equivalent exposure and improving convenience. METHODS:A previously published population pharmacokinetic model was used to evaluate alternative dosing strategies achieving exposure equivalent to the intravenous (IV) 2 mg/kg Q3W dosing (reference) compliant with FDA guidelines and reducing costs. First, extended fixed dosing intervals irrespective of bodyweight were investigated. Second, body-weight-adjusted dosing intervals were evaluated. Finally, we explored to inject SC formulation (790 mg) intravenously. RESULTS:Identified alternative regimens included SC 790 mg Q7W for all patients; SC 790 mg Q8W (<55 kg), 790 mg Q7W (55-85 kg), and 790 mg Q6W (>85 kg); and IV administration of 790 mg Q9W using the SC formulation. The extended-interval SC regimen (790 mg Q7W) would reduce annual cost to €85,000 (-14%). A bodyweight-adjusted SC strategy would reduce yearly cost from €99,166 to €85,000 (-14%; 55-85 kg) and to €74,375 (-25%; <55 kg). Using the SC formulation intravenously can potentially save annual costs by €33,055 (-33%). In addition, extracting 5 doses of 150 mg Q3W out of one 790 mg SC dose could reduce the annual costs even to €39,666 (-60%). CONCLUSIONS:Dose interval extension of subcutaneous pembrolizumab maintains equivalent exposure and complies with regulatory requirements. Intravenous administration of the subcutaneous formulation is a promising highly cost-effective intervention but requires prospective safety investigation before implementation.

9513 Background: Elevated levels of serum lactate dehydrogenase (LDH) in patients (pts) with metastatic melanoma are associated with reduced response to immune checkpoint inhibitors (ICIs). In a phase 2 trial, we investigated whether upfront reduction of tumor burden and normalization of LDH through six weeks of BRAF/MEK inhibitor (BRAF/MEKi) induction, prior to the initiation of ICIs, could improve response rates compared to standard first-line dual ICI. Methods: In this two-arm, multicenter, phase 2 trial, treatment naïve pts with unresectable stage III or stage IV BRAFV600E/K mutation-positive melanoma and elevated baseline LDH levels (< 5x upper limit of normal) were randomized 1:1 (stratified by LDH) to one of two treatment arms. Arm A received 6 weeks of induction with vemurafenib 960 mg bid + cobimetinib 60 mg QD on a 21/7-day schedule, directly followed by four courses of ipilimumab 3 mg/kg q3wk (ipi3) plus nivolumab 1 mg/kg q3wk (nivo1). Arm B directly started with four courses of ipi3 + nivo1. Both arms received response-adapted nivolumab maintenance. The primary endpoint was to compare the best overall response rate (BORR) within 18 weeks from the start of treatment between two treatment arms, as assessed by RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the rate of grade 3/4 toxicity. Exploratory endpoints focused on circulating tumor DNA dynamics (ctDNA), blood transcriptome, and tumor immunoprofiling. ClinicalTrials.gov identifier: NCT02968303. Results: Between 2017-2021, 71 pts were randomly assigned, 36 to arm A and 35 to arm B. The study was prematurely terminated due to slow patient accrual (planned accrual: 200 pts). The median follow-up time was 27.9 months (IQR 16.8-57.8). In arm A, the BOR was partial response (PR) in 75% of the pts (36.1% had an ongoing response after treatment switch), stable disease (SD) in 22.2%, and progressive disease (PD) in 2.8%. In arm B, 54.3% had PR, 22.9% SD, and 20% PD (1 pt was not evaluable). BRAF/MEKi induction prior to ICI was associated with a significantly shorter median PFS as compared with upfront dual ICI (4.4 months vs 25.0 months, HR 0.52, 95% CI 0.30-0.91; p=0.02). Median OS was also shorter in arm A (13.5 months), whereas the median OS was not reached in arm B (HR 0.38, 95% CI 0.19-0.68; p=0.002). Treatment-related grade ≥3 adverse events occurred in 25 of 36 pts (69%) in arm A and 15 of 35 pts (43%) in arm B. When combining both arms, pts with undetected ctDNA at 6-12 weeks after ICI initiation had significantly longer PFS than those with detected ctDNA (HR 2.05, 95% CI 1.05-4.0; p=0.03). Conclusions: BRAF/MEKi induction prior to dual ICI did not improve response rates to ICI and was associated with worse PFS and OS in pts with BRAFV600E/K mutated melanoma and elevated LDH compared to upfront dual ICI. Clinical trial information: NCT02968303 .

BACKGROUND:Currently, no comprehensive overview exists of response and survival outcomes for first-line immune checkpoint inhibition, BRAF/BRAF + MEK inhibition (BRAF(/MEK)i), and talimogene laherparepvec (T-VEC) in melanoma patients with unresectable in-transit metastases (ITM). This study aims to provide a real-world overview of these outcomes. METHODS:Using data from the nationwide Dutch Melanoma Treatment Registry, all patients receiving systemic treatment from 2012 to July 2025 for unresectable ITM, with or without lymph node metastases (LNM) (stage III-IVM1a), were analysed for overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and melanoma-specific survival (MSS). A multivariable Cox model adjusted for age, sex, ECOG PS, LDH, and LNM. RESULTS:In total, 530 patients were identified: 213 received first-line anti-PD1, 182 T-VEC, 67 BRAF(/MEK)i, 37 ipilimumab (IPI), and 31 ipilimumab + nivolumab (IPI+NIVO). Patients receiving T-VEC had more favorable baseline characteristics, including less often stage IV disease, less often LNM, and lower LDH. ORR were comparable between treatments: anti-PD1 53.1%, T-VEC 52.2%, BRAF(/MEK)i 62.7%. Median PFS was significantly shorter for T-VEC (5.6months; 95%CI 4.2-8.1) than for anti-PD1 (8.1months; 95%CI 5.9-13.8) and BRAF(/MEK)i (9.2months; 95%CI 6.9-14.3). Median OS favored T-VEC (not reached (NR); 95%CI 61.5-NR) over anti-PD1 (37.2months; 95%CI 32.3-64.7) and BRAF(/MEK)i (24.7months; 95%CI 18.0-62.1), but this difference between T-VEC and anti-PD1 disappeared after adjusting for confounders and no differences were observed in MSS. In the ITM-only subgroup, T-VEC-treated patients demonstrated longer observed OS than anti-PD1 and BRAF(/MEK)i, while in patients with ITM and LNM, anti-PD1 showed longer PFS but similar OS compared with T-VEC. CONCLUSIONS:For ITM unresectable melanoma, first-line anti-PD1, T-VEC, and BRAF(/MEK)i can induce clinically meaningful and durable responses. The optimal treatment choice depends on patient and disease characteristics and preferences.

BACKGROUND:Evidence on the efficacy of percutaneous hepatic perfusion (PHP) in metastatic uveal melanoma (mUM) is largely derived from single-arm studies without comparators, complicating interpretation of treatment benefit, particularly for survival. This meta-analysis aimed to synthesize available evidence on the efficacy and safety of PHP in patients with mUM and compare outcomes with best alternative care (BAC). MATERIAL AND METHODS:PubMed, Embase, Cochrane, and Web of Science were searched from database inception to Feb 17, 2026. Studies evaluating PHP in patients with mUM and BAC cohorts derived from randomized trials of PHP or isolated hepatic perfusion were included. The endpoints were 1-year overall survival (OS), 2-year OS, median OS (mOS), 1-year progression-free survival (PFS), median PFS (mPFS), overall response rate (ORR), and safety. Random-effects meta-analyses were performed using restricted maximum likelihood estimation. RESULTS:Eleven studies were included (one reporting on both PHP and BAC), comprising 455 patients treated with PHP (nine studies) and 125 treated with BAC (three studies). The pooled 1-year OS was 65.5% (95% CI 52.8-75.5%) for PHP and 64.3% (95% CI 13.3-90.7%) for BAC. The pooled 2-year OS was 35.4% (95% CI 28.5-42.4%) and 28.1% (95% CI 9.6-50.2%), and mOS 17.3 months (95% CI 11.8-22.8) and 14.0 months (95% CI 4.3-23.6), respectively. PHP was associated with higher ORR (47.4% vs 6.0%), longer 1-year PFS (30.1% vs 6.4%) and mPFS (7.7 vs 2.6 months). Hematologic adverse events were the most frequently reported toxicities in PHP studies. CONCLUSION:PHP is associated with improved ORR and PFS compared with BAC in patients with mUM, although no clear survival benefit was observed.

9527 Background: Brenetafusp (brene) is an ImmTAC bispecific (PRAME × CD3) therapy that promotes T cell recruitment into tumors. Initial Phase (Ph) 1 data showed acceptable safety, robust T cell activation at target doses (TD) ≥ 20 mcg and promising clinical activity in multiple tumors including heavily pretreated cutaneous melanoma (CM) (Hamid 2022, 2024; NCT04262466]). We present updated monotherapy (mono) and PD1 immune checkpoint inhibitor (ICI) combination (combo) safety and efficacy results supporting brene dose selection in Mel (CM, mucosal [Mu] or acral [Ac]). Methods: HLA-A*02:01+ Mel patients (pts) who exhausted standard treatments were eligible. Primary objectives: safety and recommended dose; additional objectives included efficacy, biomarkers and ctDNA response. Brene mono was administered intravenously weekly (QW) with 1-2 step-up doses to TD; TD 40 and 160 mcg were evaluated in expansion. Combo was 160 mcg brene QW + 400 mg pembrolizumab (pembro) Q6W. Molecular response: ≥ 0.5 log [68%] ctDNA reduction by week 9 (Hamid 2024). T cell fitness defined as 3-gene (TESPA1, CD28 and GPR183) signature in blood (Sacco 2024). Tumor PD-L1 measured by immunohistochemistry, beta2 microglobulin (B2m) by immunofluorescence. Results: As of Oct 2025, 66 pts with Mel (median 2.5 prior lines, 100% prior PD1, 30% PD1 refractory [progression <6 mo post start of first anti-PD1], 68% St IV-c/IV-d) received brene mono (TD 40, n=16; TD 160, n=24; other TD 10-320 mcg, n=26). The 40-mcg cohort had more favorable baseline prognostic factors (ECOG PS, tumor burden, ctDNA, prior treatment) and T cell fitness. Ten pts (median 2.5 prior lines, 90% prior PD1, 50% prior BRAF/MEKi, 70% St IV-c/IV-d) received brene + pembro. Safety was similar at TD 40 and 160 mcg with Gr1/2 CRS (56% vs 42%) and rash (44% vs 42%) initially. Gr3/4 events occurred in 25% vs 54%: mainly transient lymphocyte decrease, consistent with mechanism. Of 10 pts with prior ICI Gr3/4 irAE, none had recurrence. Combo profile resembled each agent alone. No new safety signals observed. Disease control, RECISTv1.1 response and ctDNA molecular response rates were numerically higher at 160 vs 40 mcg (Table), with similar rates across subgroups typically less responsive to anti-PD1. Overall survival was associated with baseline T cell fitness and tumor B2m, but not with PD-L1 status. Conclusions: Brene shows promising monotherapy activity in late-line Mel, including difficult to treat populations, without causing ICI-like irAEs, and can be safely combined with pembro. Ph1 results support 160 mcg as the selected dose in the Ph3 PRISM-MEL trial evaluating brene with nivolumab versus standard nivolumab regimens (NCT06112314). Clinical trial information: NCT04262466 . N DCR% (PR + SD) ORR% 6mo OS% ctDNA-evaluableN ctDNA response% Brene mono 66 52 12 83 50 38 40 mcg 16 56 6 81 10 20 160 mcg 24 67 17 79 15 33 PD1 refractory 20 55 10 70 15 53 Ac / Mu 7 57 14 86 5 40 Sum target lesions >10 cm 25 44 12 80 19 32 Brene + pembro 10 70 20 80 5 40 PD1 refractory 6 67 33 67 2 50

The increasing use of the immune checkpoint inhibitor nivolumab places a significant financial burden on healthcare systems, contributes to environmental concerns, and strains hospital capacities. The nivolumab average exposure and exposure variation of a fixed subcutaneous (SC) dosing regimen (1200 mg every 4 weeks) is significantly higher compared with 3-mg/kg every 2 weeks intravenous dosing. We aimed to develop alternative dosing regimens for SC nivolumab to reduce drug expenses and lower the treatment burden for patients while ensuring effective exposure. Population pharmacokinetic simulation was conducted using a population pharmacokinetic model developed by the license holder to explore alternative SC regimens. In this process, patients were divided into three weight groups: less than 60 kg, 60–90 kg, and more than 90 kg. Furthermore, two experimental progressive alternative dosing regimens were developed, one based on a minimum effective concentration-driven approach. The second progressive alternative regimen was based on using the 1200-mg SC formulation as an intravenous infusion. We developed an alternative bodyweight-based regimen consisting of SC 1200 mg every 7 weeks (<60 kg), 1200 mg every 6 weeks (60–90 kg), and 1200 mg every 5 weeks (>90 kg). This new alternative dosing regimen would save an average of €24,345 (35

PURPOSE:Stage IIB/IIC melanoma has a high risk of recurrence after resection. Combined BRAF/MEK inhibitor therapy showed benefit in resected high-risk stage III and advanced melanoma. The objective of this study was to investigate its role in stage IIB/IIC. METHODS:Adult patients with resected stage IIB/IIC cutaneous melanoma which had a BRAF V600E/K mutation were randomized 1:1 to receive encorafenib (enco) 450 mg QD + binimetinib (bini) 45 mg BID orally for one year or placebo. The study planned to randomize 815 patients and was designed to demonstrate superiority regarding recurrence-free survival (RFS). Following a premature termination of accrual, the study was amended with safety as the primary endpoint and RFS as secondary endpoint. RESULTS:Between June 9, 2022, and October 9, 2023, 339 patients were screened for a BRAF mutation and 110 randomized. Data cutoff was 19 Nov. 2024, after the last patient discontinued study participation. Among randomized patients, 87 (79%) had a BRAF V600E mutation, and 39 (35%) AJCC8 stage IIC. Median follow-up was 12 and 7 months for enco/bini and placebo arms, respectively. Among 54 patients who initiated enco + bini, grade ≥ 3 treatment-related adverse events (AE) occurred in 13 (24%) patients, and 18 (33%) patients had an AE leading to permanent treatment discontinuation. RFS at 12 months was 86% (95% CI: 65-95%) in the enco + bini and 70% (95% CI: 46-85%) in the placebo arm, distant metastasis-free survival at 12 months was 92% (95% CI: 77-97%) for enco + bini and 82% (95% CI: 55-93%) for placebo. CONCLUSION:EORTC 2139 - Columbus-AD demonstrated a consistent and manageable safety profile and encouraging efficacy results for the combination of enco and bini in resected stage IIB/C BRAF V600E/K-mutated cutaneous melanomas.

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 Gαq/Gα11 (Gq/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/GNA11-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 .

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 G alpha q/G alpha 11 (Gq/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: .

INTRODUCTION:Readily available predictive biomarkers for immune checkpoint inhibitor (ICI) response in advanced melanoma are limited. This study evaluates the predictive value of AI-based histopathology analysis. METHODS:Patients with advanced cutaneous melanoma treated with first-line anti-PD1 ±anti-CTLA4 between 2016 and 2023 across 11 Dutch centers were retrospectively identified using prospectively collected registry data. Pre-treatment H&E-stained metastatic slides were collected from 30 pathology labs and analyzed using 14 foundation models combined with attention-based or clustering-constrained multiple-instance learning. Primary outcome was best overall response (ORR) (RECIST 1.1) assessed through leave-one-hospital-out cross-validation. Response probabilities were added to a clinical model built with AIC-based backward selection (including WHO performance status, liver metastases, LDH, ICI-type, AJCC stage, brain metastases). Feature embedding clusters were labelled by three pathologists blinded to outcomes to assess histology driving predictions. RESULTS:Of 1935 patients, 1177 had a pre-treatment metastatic specimen available, most commonly lymph node or skin/soft tissue; 35.3% was treated with anti-PD1 +anti-CTLA4 combination therapy. ORR was 56.7% (n = 667/1177). The best AI-based model achieved an AUROC of 0.63 (95% CI:0.60-0.66) with overestimated risk. Combining the AI-based analysis with clinical information increased AUROC to 0.66 (95% CI:0.63-0.69) with improved calibration. Model predictions were driven by immune infiltration and epithelioid morphology for response, and by spindle-cell morphology, and necrosis for non-response. CONCLUSION:AI-based analysis of diagnostic pre-treatment metastatic melanoma samples predicts ICI outcomes by using explainable histological features, such as immune infiltration, cell morphology, and necrosis. The predictive performance of the AI-based analysis improves further upon addition of clinical information.

BACKGROUND:The programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) is used as a biomarker to predict benefit from immune checkpoint blockade (ICB) in patients with non-small cell lung cancer (NSCLC). However, additional biomarkers are needed. The potential of kinase activity profiling of peripheral blood mononuclear cells (PBMCs) for predicting response to ICB was previously shown in a discovery study. The goal of this prospective study is to evaluate the predictive value of blood-based kinase profiling for ICB response in patients with NSCLC and to compare the performance and added value to TPS. METHODS:Advanced stage patients with NSCLC, treated with anti-programmed cell death protein 1 ICB (±chemotherapy) were included in this multicenter study (N=210 patients). PBMCs were collected prior to ICB treatment and profiled using a peptide microarray with multiple kinase substrates (PamChip). Classification analysis was performed to discriminate between patients with or without progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 <24 weeks after treatment start. A predictive model was first established based on TPS and kinase activity profiles. Subsequently, the performance of the model was tested in a second (validation) cohort. RESULTS:In the validation cohort, a significantly higher progression-free survival (PFS) rate was observed for patients with predicted benefit than for patients without predicted benefit according to the kinome-based prediction model (HR=0.56, p=0.01), which tended better compared with TPS alone (HR=0.66, p=0.07). When the kinome-based model was combined with TPS, the difference in PFS between patients with and without predicted benefit was further increased (HR=0.38, p<0.001). PFS rates were also higher for patients with predicted benefit in subgroups with decreased PD-L1 expression (TPS <1% (HR=0.46, p=0.027) and TPS 1-50% (HR=0.20, p=0.005)). CONCLUSIONS:This study shows the predictive value of kinase activity profiling of PBMCs for ICB response in advanced NSCLC, which was superior compared with TPS. In particular, for patients with NSCLC with TPS <50%, combining TPS with the blood-based kinase test may identify patients with limited benefit from ICB. TRIAL REGISTRATION NUMBER:NTR7015/NL6828.

BACKGROUND:Accurate quantification of iodine uptake is essential for performing pre-treatment dosimetry of 131I therapy after redifferentiation of radioiodine-refractory thyroid cancer. Standardized procedures for 124I PET/CT-based dosimetry are currently lacking. We aim to evaluate the relation between 18F and 124I imaging for two different PET/CT scanners, the effect of bias correction on recovery across scanners and investigate the impact of clinically-encountered background (BG)-to-lesion ratios on recovery correction. METHODS:Cylindrical and NEMA body phantoms were scanned following vendor-recommended 124I acquisition using clinically representative activity concentrations (5.6-5.7 kBq/mL in cylindrical phantom, 45.1-59.2 kBq/mL in NEMA spheres) and BG-to-sphere ratios (∼1:125 to 1:infinity) using two digital PET/CT scanners (Philips Vereos and GE Healthcare Omni). Additionally, BG-to-sphere ratio ∼1:10 was acquired to compare 124I to the EARL 18F standards 1 (EARL1). Calibration accuracy and recovery coefficients (RCmax, RCmean) were compared between scanners with and without bias correction. RESULTS:124I recovery was ∼20% higher for the Omni compared to the Vereos, showing calibration accuracies of 1.12-1.15 vs. 0.94, and RCmean reaching 0.86 vs. 0.69. After bias correction, RCmean was comparable between scanners (<1%) but below the lower limits of EARL1. A single fit for recovery correction (R2 = 0.97) was obtained for different BG-to-sphere ratios for both scanners as RCmean was comparable (p > 0.4). CONCLUSION:Vendor-recommended 124I acquisition and reconstruction leads to differences in quantification but can be compensated using a bias correction. Recovery correction is minimally affected by different BG-to-lesion ratios, suggesting that one RC curve is sufficient, simplifying 124I calibration procedures in studies requiring 124I quantification.

BACKGROUND:Percutaneous hepatic perfusion can lead to meaningful hepatic tumour control in metastatic uveal melanoma, but its benefit is confined to liver metastases and does not address extrahepatic disease. Immune checkpoint inhibitors ipilimumab and nivolumab show limited activity in uveal melanoma, although retrospective studies suggest improved outcomes when combined with liver-directed therapies. This study aimed to evaluate the efficacy and safety of combining percutaneous hepatic perfusion with ipilimumab and nivolumab. METHODS:In this investigator-initiated, single-centre, open-label, randomised, phase 2 trial, adults aged 18-80 years with unresectable liver-only or liver-dominant metastatic uveal melanoma, WHO performance status 0-1, and with no previous systemic therapy were randomly assigned (1:1) to receive percutaneous hepatic perfusion alone (perfusion group) or percutaneous hepatic perfusion combined with ipilimumab plus nivolumab (combination group). Two perfusions with melphalan (3 mg/kg; maximum 220 mg) were scheduled in weeks 1 and 7. The combination group also received intravenous ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) once every 3 weeks in weeks 0, 3, 6, and 9 without maintenance therapy. The primary endpoint, 1-year progression-free survival, was analysed in the intention-to-treat population; the safety analysis included all treated patients and was prospectively collected and graded using Common Terminology Criteria for Adverse Events version 5.0. The trial is registered with ClinicalTrials.gov (NCT04283890) and EudraCT (2018-004248-49) and is ongoing but no longer enrolling. FINDINGS:Between Dec 10, 2020, and Nov 15, 2024, 80 patients were screened, of whom 76 were eligible and assigned to the combination group (n=38) or perfusion group (n=38), including 49 (64%) men and 27 (36%) women. Median follow-up was 24·9 months (IQR 15·4-36·0). 1-year progression-free survival was 54·7% (95% CI 36·8-69·5) with combination therapy versus 15·8% (5·8-30·1) with perfusion alone (adjusted hazard ratio 0·34 [95% CI 0·19-0·60]; p=0·0002). Grade 3-4 treatment-related adverse events occurred in 31 (82%) of 38 patients with combination therapy compared to 15 (41%) of 37 patients with perfusion alone, due to both a higher incidence of severe perfusion-related events and immunotherapy-related adverse events. The most common grade 3-4 adverse events were thrombocytopenia (13 [34%] in the combination group vs five [14%] in the perfusion group), leukopenia (ten [26%] vs five [14%]), γ-glutamyl transferase increase (seven [18%] vs three [8%]), and anaemia (five [13%] vs one [3%]). One treatment-related death (due to triple M syndrome) occurred in the combination group. INTERPRETATION:Adding ipilimumab and nivolumab to percutaneous hepatic perfusion significantly improved progression-free survival, but with a higher rate of adverse events. The combination therapy offers a promising new treatment paradigm for patients with metastatic uveal melanoma. These results would ideally be validated in larger, multicentre randomised trials; however, conducting such studies is challenging due to the low incidence of uveal melanoma. FUNDING:Leiden University Medical Centre, Delcath Systems, and Bristol Myers Squibb.

Neoadjuvant ipilimumab plus nivolumab has become standard therapy for stage III melanoma based on the NADINA trial, although long-term data are lacking. In the phase 2 PRADO cohort of OpACIN-neo, 99 patients with stage III macroscopic melanoma received this regimen. Here we report first-time 5-year survival data: 71 NCT02977052 . Five-year survival data and biomarker analysis of the PRADO extension cohort of the phase 2 OpACIN-neo trial, in which patients with high-risk stage III melanoma received neoadjuvant ipilimumab and nivolumab and underwent pathologic response-directed surgery and adjuvant therapy, show 71

The use of mobile health (mHealth) technologies in oncology, such as wearable devices and smartphone applications, is gaining momentum due to their potential to improve quality of life, enhance treatment adherence, and positively impact survival outcomes for cancer patients. However, as a relatively new and evolving field, mHealth research faces a set of challenges in both study design and implementation. This article identifies key obstacles by drawing on preliminary experience from three mHealth studies in oncology: the eBladder study, the CHOPIN study, and the LAPSTAR study (ongoing studies at publication date). The topics covered are clustered into four categories: (1) planning and design (e.g., determining appropriate follow-up durations and inclusion criteria, defining digital support as an endpoint, developing response windows for digital questionnaires, establishing active measurement frequency); (2) technology set-up and study execution (e.g., aligning treatment and mHealth schedules, managing treatment heterogeneity and changes, establishing device configuration, scheduling data checks, determining end-of-study visits); (3) adherence (e.g., developing integrated platforms, balancing passive and active measurements, considering treatment goals as motivators, evaluating mHealth literacy); and (4) data reliability (capturing adverse events in real-time, ensuring device accuracy, and privacy considerations). This article also contains some practical recommendations in response to these challenges, meant to inspire researchers who are embarking on future mHealth studies in oncology.Clinical Trial Registrationhttps://onderzoekmetmensen.nl/en, identifiers NL81928.029.22 (eBladder trial), NL69508.058.19 (CHOPIN trial), and NL85622.041.24 (LAPSTAR trial).

More detailed information on: 1) Immune-fluorescent staining, 2) Mass spectrometry, 3) MLTC and TIL cultures.

Question: What is the predictive value of artificial intelligence–detected tumor-infiltrating lymphocytes (TILs) for clinical outcomes in patients with advanced melanoma receiving first–line immune checkpoint inhibition? Findings: In this multicenter cohort of 1202 patients, TILs in pretreatment metastases were quantified using a melanoma-specific publicly available AI model trained on an independent dataset. A 10% increase was associated with response (aOR 1.40 [95% CI 1.23—1.59]), progression-free survival (aHR 0.85 [95% CI 0.79—0.92]), and overall survival (aHR 0.83 [95% CI 0.76—0.91]). Associations were independent of clinical predictors. Conclusion: AI-detected TILs in pretreatment melanoma metastases independently correlate with response and survival. ### Competing Interest Statement 1. Dr. De Groot has advisory board relationships with BMS. 2. Dr. Hospers has consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi and Pierre Fabre and has received research grants from Bristol Myers Squibb and Seerave and all were paid to the institution. 3. Dr. Kapiteijn has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Merck, Pierre Fabre, Lilly and Bayer not related to current work and paid to institute, and received research grants not related to this paper from Bristol Myers Squibb, Delcath and Pierre-Fabre. 4. Dr. Piersma had advisory board relationships with BMS, Novartis and Pierre Fabre, honoraria were paid to institution. 5. Dr. Suijkerbuijk has advisory/consultancy relations with AbbVie, and Sairopa. She received research grants from Bristol-Myers Squibb, Genmab, Philips, Pierre Fabre, Philips and Tigatx, all paid to institution. She does data and safety monitoring for Sairopa. No other competing interests were reported. 6. Dr. Schrader received honoraria/research funding from Kyowa Kirin paid to the institution and not related to the study. 7. Dr. van den Eertwegh has consulting/advisory relationships with Bristol-Myers Squibb, MSD Oncology, Ipsen, Pierre Fabre, Janssen Cilag BV, honoraria were paid to institution. 8. Dr. Haanen has advisory/consultancy relations with AZ, BioNTech, CureVac, Eisai, Ipsen, Instil Bio, Iovance Bio, MSD, Novartis, Neogene Therapeutics, Roche, Sanofi, Sastra Cell Therapy, Third Rock Ventures, and T-Knife. He received research grants from Amgen, BioNTech, Bristol Myers Squibb, Novartis, Sastra Cell Therapy. He is editor-in-Chief of ESMO Immmuno-Oncology & Technology (IOTECH). 9. Dr. Blank received research grants from Philips, Bracco, Sensius, all paid to institution. CUB has advisory/consultancy relations with Bristol Myers Squibb, Roche, Merck and Third Rock Ventures. He received research grants from 4SC, Bristol Myers Squibb, Roche, Merck, NanoString Technologies, all paid to institution. He received an individual research grant from Third Rock Ventures. He is co-founder of Signature Oncology and Imagene BV, and has a pending patent (Patent number WO 2021/177822 A1) 10. Dr. de Groot has consultancy/advisory relationships with Bristol Myers Squibb, Pierre Fabre, Servier, MSD, and Novartis 11. Dr. Boers Sonderen has consultancy/advisory relationships with Pierre Fabre, MSD, and Novartis. 12. Dr. van Diest has consultancy/advisory relationships with Paige, Visiopharm, Sectra, Pantarei, and Samantree paid to the institution and research grants from Pfizer, none related to current work and paid to the institute ### Funding Statement This research was funded by The Netherlands Organization for Health Research and Development (ZonMW, project number 848101007), by an unrestricted grant of Stichting Hanarth Fonds, The Netherlands, and by Philips. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of University Medical Center Utrecht waived ethical approval for this work. See below: To whom it may concern, Referring to our letter of 04 February 2020 (reference number WAG/mb/20/004260) it is hereby confirmed that the Medical Research Involving Human Subjects Act (WMO) does not apply to the above mentioned study and that therefore an official approval of this study by the MREC Utrecht is not required under the WMO. Yours sincerely, on behalf of the Medical Research Ethics Committee, Department of Research Review I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Part of the developmental dataset used for model training is publicly available on Zenodo 1. The model architecture is available on Github2 and model specific weights are automatically downloaded upon usage. The whole slide images and associated patient outcome data used in this study cannot be shared due to confidentiality agreements and data sharing restrictions related to patient privacy. 1. Schuiveling M. (2025) Melanoma Histopathology Dataset with Tissue and Nuclei Annotations. Published online March 19, 2025. https://zenodo.org/records/15050523 2. Schuiveling M. (2025) HoVer-NeXt inference for TIL quantification in melanoma: Fork of HoVer-NeXt inference by Baumann et al. with additional pipelines and dataset support for melanoma research [Computer software]. Published online May 27, 2025. Available at: https://github.com/mschuiveling/hover-next-inference-tils-melanoma Forked from: Baumann E, Dislich B, Rumberger JL, Nagtegaal ID, Martinez MR, Zlobec I. HoVer-NeXt inference. [Original software]. Available at: https://github.com/digitalpathologybern/hover\_next\_inference

This pilot study investigates the relationship between endogenous cortisol and subjective distress and immunotherapy response in patients with advanced melanoma. Patients were asked to donate hair and complete questionnaires. This data was related to immunotherapy response, 3 and 6 months after start. Results from 21 patients were analyzed and showed that there was a significant relationship between depressive symptoms before start of immunotherapy and response 3 and 6 months after start of immunotherapy. Also, a higher baseline level of glucocorticoids was found to be significantly associated with a higher response rate 6 months after start of immunotherapy. The present pilot study warrants further investigation into the relationship between stress and the effectiveness of immunotherapy in patients with advanced melanoma.

HLA class I and II expression on melanoma cell lines derived from early and later metastatic lesions.

T cell recognition of melanoma cell lines derived from early and later metastatic lesions.