PURPOSE:Data on treatment approaches in geriatric melanoma patients are scant. Efficacy of oncologic treatments across age groups, with special focus on immunotherapy, and the impact of comorbidities were analyzed. METHODS:A retrospective multicenter cohort study of the ADOREG registry included patients with cutaneous melanoma, who received oncological drugs at German skin cancer centers between 2013 and 2023. Outcomes were objective response rate (ORR), progression-free survival (PFS), melanoma-specific survival (MSS), toxicities and reasons for treatment discontinuation. Age groups were prespecified as < 75 vs ≥ 75 years (geriatric), comorbidities were summarized by Charlson-Comorbidity-Index (CCI). Comparisons across groups were conducted with X2-test, survival outcomes were compared via log-rank tests. RESULTS:Of 14,356 melanoma patients, 8213 met the inclusion criteria, 6063 and 2150 were < 75 and ≥ 75 years old, respectively. Among the 3646 patients with metastatic disease, older patients received fewer treatment lines and were less likely to undergo surgery, radiotherapy and systemic therapy. However, efficacy of any first-line treatment did not differ between both age groups (p = 0.306). Immunotherapy selection at any line was similar in both groups (p = 0.109), but geriatrics were treated mainly with first-line anti-PD1 monotherapy, whereas combination ICIs was preferred in younger patients. Efficacy was not impaired (PFS and MSS: p > 0.05), while toxicity rates were lower. This pattern persisted across CCI categories. CONCLUSION:Age influenced treatment selection in melanoma patients. However, in geriatric patients, efficacy was not impaired, and a balanced toxicity profile was noticed, particularly for immunotherapy. Future studies considering biological age and impairment by comorbidities seems important to assess individualized treatment approaches.

BACKGROUND:The anti-PD1 antibody (PD1i) cemiplimab is approved as second-line treatment for locally advanced or metastatic basal cell carcinoma (BCC), resulting in an ORR of 20-30 %. This study aimed to investigate the efficacy of cemiplimab as first-line or second-line treatment of BCC in a German real-world patient cohort. METHODS:Patients with histologically confirmed locally advanced or metastatic BCC who were treated with cemiplimab were retrospectively identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Therapy outcome was compared between patients receiving first-line cemiplimab and patients treated with cemiplimab in second-line. RESULTS:37 patients from 17 skin cancer centers were identified who received cemiplimab. The median follow-up after start of any first-line treatment was 37.1 months, and 17.9 months after initiation of any cemiplimab treatment. Patients who received first-line cemiplimab (n = 8) had an ORR of 62.5 %, compared to an ORR of 31.0 % for patients who received second-line cemiplimab (n = 29); Median PFS was 19.8 months for first-line cemiplimab and 5.3 months for second-line cemiplimab. Reinduction with HHIs after progression on second-line cemiplimab resulted in an ORR of 20.0 % and a median PFS of 3.8 months. CONCLUSION:We demonstrate a comparable outcome for cemiplimab as second-line treatment of BCC in our real-world patient cohort as reported in previous registration studies. Additionally, we found a trend for a more favorable outcome in first-line therapy, suggesting a rationale to further investigate cemiplimab as first-line treatment of advanced BCC.

Tebentafusp has emerged as the first systemic therapy to significantly prolong survival in treatment-naïve HLA-A*02:01 + patients with unresectable or metastatic uveal melanoma (mUM). Notably, a survival benefit has been observed even in the absence of radiographic response. This study aims to investigate the feasibility and prognostic value of artificial intelligence (AI)-assisted quantification and metabolic response assessment of [18F]FDG long axial field-of-view (LAFOV) PET/CT in mUM patients undergoing tebentafusp therapy. Fifteen patients with mUM treated with tebentafusp underwent [18F]FDG LAFOV PET/CT at baseline and 3 months post-treatment. Total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) were quantified using a deep learning-based segmentation tool On the RECOMIA platform. Metabolic response was assessed according to AI-assisted PERCIST 1.0 criteria. Associations between PET-derived parameters and overall survival (OS) were evaluated using Kaplan–Meier survival analysis. The median follow up (95

In a recent study published in Cancer Cell,Braun et al.introduced extracorporeal photopheresis(ECP)as a novel immunomodulatory approach to mitigate immune-related adverse events(irAEs)associated with immune checkpoint inhibitors(ICIs)without compromising anti-tumor immunity.1 ECP suppressed Th1/Trm cell activation and neutrophil infiltration while enhancing an anti-inflammatory macrophage phenotype through adiponectin,facil-itating the resolution of steroid-refractory irAEs.

Das Uveamelanom, auch Aderhautmelanom genannt, ist eine seltene Form von schwarzem Hautkrebs, die aus Pigmentzellen im Auge, hauptsächlich der Aderhaut, entsteht. Es kann auch die Iris oder den Ziliarkörper betreffen und führt häufig zu Fernmetastasen, besonders in der Leber. Im Gegensatz zu anderen Melanomen spricht das Uveamelanom schlecht auf Therapien mit Checkpointinhibitoren an und hat daher eine schlechtere Prognose. Eine neue Immuntherapie namens Tebentafusp bietet jedoch eine vielversprechende Behandlungsoption für Patienten mit dem Typ des humanen Leukozytenantigens (HLA-Typ) A*02:01. Tebentafusp ist ein bispezifisches Protein, das spezifisch ein Peptid des Melanozyten-Differenzierungsantigens gp100 erkennt und T‑Zellen aktiviert. Dies führt zu einer polyklonalen Aktivierung von T‑Zellen in der Tumorumgebung und zur Tumorabwehr. Eine Phase-III-Studie zeigte, dass Tebentafusp das Gesamtüberleben von Patienten mit metastasiertem Uveamelanom signifikant verbessert im Vergleich zu anderen Therapien. Nach 3 Jahren waren 27

BACKGROUND:Melanoma is the main cause of skin cancer-related death. Treatment with immune checkpoint inhibitors (CPI) has improved the prognosis in recent years. However, subtypes of melanoma differ in their response. Acral lentiginous melanoma (ALM) has a worse prognosis compared to cutaneous melanoma other than ALM (CM) and is therefore of particular relevance. AIMS:To evaluate the efficacy of CPI in first-line treatment of patients with advanced ALM compared CM. METHODS:Retrospective analysis of patients with metastatic ALM (n = 45) or CM (n = 328) who received first-line CPI therapy from the multicenter prospective skin cancer registry ADOREG. Study endpoints were best overall response (BOR), progression-free survival (PFS) and overall survival (OS). RESULTS:ALM patients had significantly higher rates of ulcerated tumors, loco regional metastases and fewer BRAF-mutated tumors compared to CM patients. Combined CPI was administered in 48.9 % ALM patients and 39.3 % of CM patients, while the remaining patients received PD-1 monotherapy. OS trended to be shorter in patients with ALM (18.1 vs. 43.8 months, p = 0.10) with no significant differences in PFS (7.0 vs. 11.5 months, p = 0.21). In patients with CM, median OS with combined CPI was not reached, whereas the median OS after PD-1 monotherapy was 37.8 months (p = 0.22). Conversely, in patients with ALM, OS with combined CPI was 17.8 months, compared to 26 months with PD-1 monotherapy (p = 0.15). There were no significant differences in BOR between patients with ALM or CM. CONCLUSION:Analysis of this real-world cohort of patients with metastatic melanoma showed a trend towards poorer survival outcomes upon first-line treatment with CPI in ALM compared to cutaneous melanoma of other subtypes.

BACKGROUND:Metastatic uveal melanoma (mUM) is a rare malignancy and is different from metastatic cutaneous melanoma (mCM) in tumor characteristics and efficacy to immunotherapies. Tumor-specific biomarkers are required for mUM patients to monitor early disease progression on immunotherapies. METHODS:We investigated clinical characteristics such as liver tumor burden and routine blood tumor markers, including lactate dehydrogenase (LDH) and transaminases in patients with mUM and with liver metastasized cutaneous melanoma (LmCM), treated with immune checkpoint inhibitors (ICIs) between May 2013-February 2024. In addition, we analyzed soluble cMET (scMET) in serum samples from these patients along with a cohort of mCM patients without liver metastases (nLmCM) using ELISA. Circulating tumor DNA (ctDNA) in the plasma was analyzed using digital droplet PCR (ddPCR) in mUM patients receiving immunotherapies. scMET, ctDNA, and LDH combination was used to simultaneously monitor disease progression in ICI and tebentafusp-receiving mUM patients. RESULTS:Sixty-nine patients with mUM and seventy-six patients with LmCM were treated with either anti-PD1 monotherapy (n = 69, 48%) or ipi + nivo combination therapy (n = 76, 52%). Irrespective of the type of melanoma and type of immunotherapy, patients with liver metastasis size greater than 8cm experienced rapid disease progression. ICI-treated mUM patients with increased LDH, aspartate aminotransferase (AST), alanine transaminase (ALT), scMET, ctDNA, and rapidly growing tumors were significantly associated with treatment resistance and shorter progression-free and overall survival (p < 0.05). scMET (AUC: 0.82) outperforms LDH (AUC: 0.77) and S100 (0.68) in predicting one-year overall survival in these patients. A validation set with LmCM and nLmCM patient samples showed that increased scMET is likely a mUM-specific feature and does not predict ICI outcomes in LmCM or nLmCM patients (p > 0.05). Moreover, monitoring ctDNA and scMET in mUM patients under ICIs or tebentafusp treatment revealed the potential for early detection of disease progression. CONCLUSION:Soluble cMET might serve as a tumor-specific biomarker to predict clinical outcomes in mUM patients. A combinational assessment of scMET and ctDNA in mUM patients' blood offers a highly sensitive potential approach to monitor early disease progression under immunotherapies with ICI or tebentafusp.

PURPOSE:Adjuvant treatment with immune checkpoint inhibition (PD-1) and targeted therapy (TT) with BRAF + MEK inhibitors significantly improved recurrence-free survival (RFS) of patients with stage III melanoma. We investigated efficacy of adjuvant therapy with PD-1 or TT under real-world conditions. MATERIALS AND METHODS:A total of 589 patients with stage III melanoma who started adjuvant PD-1 or TT between June 2018 and September 2019 from 11 major German Dermatologic Cooperative Oncology Group skin cancer centers were followed for 4 years. End points were RFS, overall survival (OS), and melanoma-specific survival. Survival analyses and adjusted hazard ratios (HRs) were estimated with Kaplan-Meier and Cox proportional hazards model, inverse probability treatment weighting, and propensity score matching. RESULTS:RFS at 48 months was 42.9% (95% CI, 38.5 to 47.8) for all PD-1 patients and 52.6% (95% CI, 43.6 to 63.3) for TT patients. Among patients with BRAF mutation, rate of recurrence was higher for PD-1 compared with TT (HR, 1.57 [95% CI, 1.09 to 2.26]). OS at 4 years was 80.8% (95% CI, 73.6 to 88.7) for PD-1-treated patients with BRAF mutation and 87.3% (95% CI, 81.0 to 94.0) for TT patients. Patients starting adjuvant PD-1 after resection of macroscopic lymph node metastases had a higher risk of rapid recurrence (1-year RFS all PD-1 58%) compared with 87% in TT patients. Rate of recurrence after premature discontinuation (≤6 v >6 months treatment) was higher in TT patients (HR, 1.47 [95% CI, 0.67 to 3.23]), but not in PD-1 patients (HR, 1.07 [95% CI, 0.73 to 1.55]). CONCLUSION:PD-1-treated patients with BRAF mutation had a markedly higher rate of relapse compared with TT patients. Rapid recurrences occurred particularly in PD-1-treated patients with previous macroscopic lymph node metastasis. Treatment duration shorter than 6 months did not negatively affect RFS in PD-1, but in TT patients.

PURPOSE:LOGIC 2 (NCT02159066), a multicenter, open-label, two-part, phase II study, assessed encorafenib plus binimetinib combined with a third targeted agent after tumor progression on encorafenib plus binimetinib in patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma. PATIENTS AND METHODS:Adults with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma who were BRAF inhibitor/MEK inhibitor (BRAFi/MEKi) treatment-naïve or pretreated received encorafenib plus binimetinib (part I/run-in). Based on the genomic testing at disease progression following encorafenib plus binimetinib, patients were assigned to one of four treatment arms to receive encorafenib plus binimetinib with an appropriate molecularly targeted agent (ribociclib, infigratinib, capmatinib, or buparlisib; part II). The primary endpoint was best overall response; safety, biomarkers, pharmacokinetics, and other efficacy endpoints were also assessed. RESULTS:In part I/run-in, 75 BRAFi/MEKi-naïve patients and 83 BRAFi/MEKi-pretreated patients were treated; in part II, 58 patients were treated (ribociclib, n = 38; infigratinib, n = 1; capmatinib, n = 13; buparlisib, n = 6). The overall confirmed response rate was 73.3% [95% confidence interval (CI), 61.9-82.9] in BRAFi/MEKi-naïve patients, 25.3% (95% CI, 16.4-36.0) in pretreated patients, 2.6% (95% CI, 0.1-13.8) in the ribociclib arm, and 0% in the other three arms. Adverse events were manageable and consistent with the known safety profile of each drug. CONCLUSIONS:LOGIC 2 supports the use of encorafenib plus binimetinib for treatment-naïve and previously treated, locally advanced, unresectable or metastatic BRAFV600-mutant melanoma. However, adding a third targeted agent following disease progression did not show meaningful efficacy; further research is needed to identify other therapeutic targets to circumvent resistance.

Immunotherapy with ipilimumab (ipi) and nivolumab (nivo) has shown impressive response rates in patients with melanoma brain metastases (MBM) with a clinical outcome comparable to patients without MBM. However, within clinical trials most patients had only single brain metastases and data in patients with multiple lesions is lacking. We retrospectively analyzed clinical outcome including response rates, progression-free and overall survival in patients with at least 5 MBM who received ipi-nivo +/- radiotherapy (RT). Collection of data is ongoing; in an interim analysis 74 patients were included: Patients had a median age of 58 (range 26-83), 50 (68%) male, 56 (76%) patients with multiple (> 10) MBM at therapy start. 29 (39%) had symptomatic MBM controlled with a median of 12mg dexamethasone (range 4-24mg). At start of ipi-nivo 29 (39%) patients received WBRT and 17 (23%) SRS. In patients without RT 11/28 (39%) responded to ipi-nivo, 2 of them received 4 and 12mg dexamethasone. In patients with combined RT 4/17 (24%, SRS of up to 10 MBM) and 6/29 (21%, WBRT) responded. 6 or 12 weeks after the initiation of ipi-nivo another 4 patients received SRS and 8 patients WBRT as salvage RT. Overall survival did not significantly differ in patients with 5-9 or multiple MBM or dependent on the addition of RT, no matter if SRS or WBRT was applied.To conclude, ipi-nivo demonstrated efficacy independent from added RT in patients with multiple MBM.

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.

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.

Tebentafusp is a gp100xCD3 bispecific ImmTAC designed to redirect polyclonal T cells against cells presenting the melanocyte lineage specific antigen gp100 on HLA-A*02:01. Skin-related adverse events, predominantly rash, are frequent and occur within a few hours after initial infusions, yet the mechanisms are unknown. Here we analysed clinical data from the randomised phase 3 trial (NCT03070392) of tebentafusp (n=252) versus investigator’s choice (n=126). Translational analyses were performed on paired on-treatment skin samples from 19 patients collected in the phase 1 trial (NCT01211262). Our analyses showed that rash is a clinical manifestation of tebentafusp-induced recruitment of T cells to cutaneous melanocytes. Development of rash depended on baseline expression levels of gp100 and other melanin pathway genes in the skin. On treatment, melanocyte number was reduced and expression of melanocytic genes decreased, while gene expression related to immunity and cytokine signalling increased. When adjusted for baseline prognostic features, patients with rash within the first week of tebentafusp treatment had the same overall survival compared to patients without a rash in the phase 3 randomized trial IMCgp100-202 (HR 0.84; 95% CI 0.53-1.32). In summary, skin rash is an off-tumour, on-target effect of tebentafusp against gp100+ melanocytes, in line with the mechanism of action.

Background/Objectives: Cutaneous side effects are the most common immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) and affect 70-90% of patients. Besides diverse types of exanthema, rare skin toxicity includes bullous dermatoses in 0.3% of cases. Systemic steroids are the first-line treatment for immune-related bullous pemphigoid (irBP); however, some cases are corticosteroid-resistant. IrBP is one of the irAEs most frequently chronic and associated with long-term steroid use. However, steroids may interfere with tumor response. Therefore, alternative treatment strategies for irBP are desperately needed. Dupilumab, a monoclonal antibody blocking the receptor binding of interleukin-4 (IL-4) and interleukin-13 (IL-13), has been successfully used to treat spontaneous forms of bullous pemphigoid (BP). In this study, we analyzed the gene expression profiles of BP and irBP. Patients and Methods: A retrospective multicenter study evaluated the gene expression profiles of irBP and BP in comparison to healthy controls. Gene expression analyses of skin biopsies were performed using NanoString technology from patients with BP (n = 17), irBP (n = 19), and healthy skin (n = 24) after the patients had consented to participate in this study, and differentially expressed genes (DEGs) were determined using Rosalind software. Results: Compared to healthy skin, BP showed 167 DEGs, and irBP revealed 99 DEGs. Some of the DEGs from irBP and BP vs. healthy skin overlapped. Specifically, IL-4- and IL-13-associated genes were upregulated in both irBP and BP compared to healthy skin. Interestingly, expression profiles of BP vs. irBP also showed 13 DEGs. Conclusions: These findings suggest a possibility for therapeutic efficacy of IL-4 and IL-13 inhibitors in the treatment of irBP.

PURPOSE:We investigated SAR441000 (mixture of four mRNAs encoding IL-12, single-chain IFN-α-2b, GM-CSF, and IL-15 sushi domain) alone or in combination with cemiplimab in patients with advanced solid tumors. PATIENTS AND METHODS:SAR441000 was intratumorally administered weekly in a 4-week cycle in monotherapy and in a 3-week cycle at a predefined dose level with 350 mg cemiplimab (intravenously) every 3 weeks in combination therapy. The primary objective was to determine MTD or maximum administered dose, overall safety, tolerability, and objective response rate of SAR441000. RESULTS:We enrolled 77 patients previously treated with anticancer therapies [escalation monotherapy: N = 21; escalation combination: N = 15; and expansion combination (PD-1-refractory melanoma): N = 41]. The maximum administered dose at dose level 8 was 4,000 µg. The most common grade ≥3 treatment-related adverse events was fatigue in the escalation phase (monotherapy: 28.6% and combination therapy: 66.7%) and injection-site pain (31.7%) in the expansion phase. In combination therapy, one patient in the escalation phase and two patients in the expansion phase achieved partial responses. At 4,000 μg (highest dose) across all cohorts, the maximum fold change in plasma cytokine concentration was the highest and lowest for IFN-α-2 (74.9-fold) and IL-15 (1.96-fold), respectively. Increased blood IFN-γ and inducible protein-10 levels were observed for most patients. CONCLUSIONS:Intratumoral administration of SAR441000 in combination with cemiplimab was generally well tolerated with antitumor activity in the locoregional disease setting. Anecdotal evidence of pharmacodynamic immunomodulatory effect and distant noninjected lesion antitumor response was observed, without significant effects in patients with advanced solid tumors previously treated with anti-PD-1 therapies.

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. ### Competing Interest Statement GMB has sponsored research agreements through her institution with Olink Proteomics, Teiko Bio, InterVenn Biosciences, and Palleon Pharmaceuticals. She served on advisory boards for Iovance, Merck, Moderna, Nektar Therapeutics, Novartis, and Ankyra Therapeutics. She consults for Merck, InterVenn Biosciences, Iovance, and Ankyra Therapeutics. She holds equity in Ankyra Therapeutics. DS has sponsored research agreement through his institution with Amgen, BMS, MSD, and Pfizer; consulting fees/honoraria from Philogen, lnFlarX, Neracare, Merck Sharp & Dohme, Novartis, Bristol Myers Squibb, Pfizer, Pierre Fabre, Replimune, SunPharma, Daiichi Sanyo, Astra Zeneca, IQVIA, LabCorp, UltimoVacs, Seagen, Immunocore, Immatics, BioNTech, PamGene, BioAlta, Regeneron, Agenus, Erasca, Formycon, NoviGenix, CureVac, and Sanofi Travel: Pierre Fabre; participation on data safety monitoring from Immunocore, AstraZeneca, BioAlta, Daiichi Sancyo, InFlarX, and Replimune; and leadership role for EORTC-MG steering board, DeCOG steering board, NVKH chair, and CCC chair. DL has received speaking honorariums and travel fees from Genentech and consulting fees from Oncovalent Therapeutics, not pertinent to or affected by the content of this publication. PKS is a co-founder and member of the BOD of Glencoe Software, member of the SAB for RareCyte, Reverb Therapeutics and Montai Health, and consultant for Merck; he holds equity in Glencoe and RareCyte. The other authors declare no potential conflicts of interest. BMBF Advanced Clinician Scientist Programme UMEA, 01EO2104 Melanoma Research Alliance, Young Investigator Award, David Liu Melanoma Research Alliance, https://ror.org/025ck6r46, Young Investigator Award, Florian Rambow American Italian Cancer Foundation, Postdoctoral Research Fellowship, Giuseppe Tarantino

Importance:Immune checkpoint inhibitors (ICIs) are efficacious in many cancer types but can produce immune-related adverse events (irAEs). As such, patients with preexisting autoimmune disorders are often excluded from clinical trials, although subsequent studies have shown that many of these patients have acceptable ICI tolerance. The safety and efficacy of ICIs among patients with preexisting neurologic autoimmune disorders (NAIDs) is not well characterized. Objective:To evaluate the safety and clinical outcomes associated with ICI therapy among patients with NAIDs. Design, Setting, and Participants:This multicenter retrospective cohort study included patients with cancer who were treated with ICIs between October 2013 and May 2023 and had preexisting multiple sclerosis (MS), myasthenia gravis (MG), Guillain-Barré syndrome (GBS), and other NAIDs as well as a control cohort of patients with Parkinson disease (PD). Exposure:ICI therapy. Main Outcomes and Measures:Demographic and clinical characteristics (neurologic disability, active or recent immunosuppression), ICI outcomes (response, progression-free survival [PFS], and overall survival [OS]), and safety outcomes (NAID exacerbation, irAEs) were collected. Results:A total of 135 patients were included; the median (range) age was 72 (40-88) years, 84 (62%) were men, and 51 (38%) were women. A total of 45 patients had MS; 18, MG; 10, GBS; 5, another NAID; and 57, PD. Exacerbations occurred most frequently in MG (12 of 18 patients [67%]), often resulting in hospitalization (6 [50%]) or death (2 [17%]), with much lower rates in the MS cohort (8 of 45 patients [18%]). Ten patients with a history of GBS tolerated ICI without exacerbations, although 1 developed a fatal case of Lambert Eaton myasthenic syndrome following ICI treatment. No differences in response rate, PFS, or OS were observed between NAID groups. Conclusions and Relevance:In this cohort study of ICI use in NAIDs, patients with MG had frequent and more severe exacerbations, while those with MS had few exacerbations. No obvious differences in survival between groups were observed. ICI may be an option for many patients with appropriate oncologic indications and preexisting NAIDs.

Uveal melanoma (UM) is the most common intraocular cancer in adults, with metastatic disease (mUM) occurring in approximately half of the patients. Tebentafusp, an immune-mobilizing monoclonal T cell receptor against cancer (ImmTAC), is a therapeutic shown to improve overall survival (OS) in HLA-A*02:01+ adult patients with mUM. Here we investigate the impact of tumor-associated macrophages (TAM) on ImmTAC activity. In vitro, M2 macrophages inhibit ImmTAC-mediated tumor-killing in a dose-dependent and contact-dependent manner. Accordingly, high baseline intratumoral TAM-to-T cell ratios correlate with shorter OS (HR = 2.09, 95% CI, 1.31–3.33, p = 0.002) in tebentafusp-treated mUM patients from a phase 2 trial. By contrast, IL-2 conditioning of T cells overcomes M2 macrophage-mediated suppression in vitro, while ImmTAC treatment leads to M2-to-M1 macrophage reprogramming both in vitro and in tebentafusp-treated mUM patients. Overall, we show that tebentafusp reshapes the tumor microenvironment to enhance anti-tumor T cell activity, whilst combining tebentafusp with IL-2 may enhance benefit in patients with high levels of TAM. ‘T cell engagers promote antitumor immunity, but how macrophage modulates this activity in tumor is still unclear. Here the authors show, using biopsies from patients with uveal melanoma and single cell analyses, that a T cell engager, tebentafusp, reprograms tumor-associated macrophages and ameliorates, in synergy with IL-2, immunosuppression to cancer.

OBJECTIVE:This study investigated the course of general well-being and health-related quality of life (HRQoL) in working-age melanoma patients during the first year following diagnosis. It also examines the use of psycho-oncological counseling and rehabilitation, and their impact on QoL. METHODS:Patients aged 18-65 years with stage 0 to IIIC melanoma were eligible for this single-center, prospective cohort study. Following informed consent, clinical data and data on general well-being (WHO-5), HRQoL (FACT-M) and need for psycho-oncological care (Hornheider Screening Instrument) were collected at baseline and every three months over one year. RESULTS:We included 221 melanoma patients (median age 51, range 19-65, 62% female). At baseline, 79% had melanoma stage IB or lower. After one year, 9% had progressed. 38% of patients showed a WHO-5 score below 52% following diagnosis, regardless of tumor stage. Women with stage 0 to IIA melanoma had significantly lower HRQoL in the first six months than men (p = 0.010), and a higher need for psychological support (p < 0.001). There was considerable variability in QoL trajectories both within individuals (median variation 11%) and across patients. In general, 52% needed psycho-oncological care at baseline, but neither counseling (24%) nor rehabilitation (18%) resulted in significant improvements in QoL over the year. CONCLUSIONS:Melanoma diagnosis leads to a marked QoL reduction, particularly in lower stage women, with most patients improving over time. However, substantial intra-individual variation emphasizes the need for regular QoL assessments. Further research is needed to assess the long-term effectiveness of psycho-oncological support and rehabilitation. TRIAL REGISTRATION:German Clinical Trials Register No. DRKS00010005, 08. March 2016.

BACKGROUND:In cutaneous squamous cell carcinoma (cSCC), programmed cell death protein 1 (PD-1) and epidermal growth factor receptor (EGFR) inhibitors are effective in a considerable proportion of patients. However, there is an unmet medical need for patients with perianogenital cSCC or cSCC refractory to PD-1 therapy. OBJECTIVES:To evaluate the combination avelumab (programmed death ligand 1 inhibitor) and cetuximab (EGFR inhibitor) in people with advanced cSCC treated for up to 1 year. METHODS:This multicentre phase II trial enrolled patients with advanced cSCC (prior systemic therapy allowed) to receive avelumab (10 mg  kg-1 Q2W) plus cetuximab (500 mg m-2 Q2W) for up to 1 year. The primary endpoint was objective response. Predefined subgroups were line of therapy and localization of the primary tumour (perianogenital/other locations). RESULTS:Of 52 enrolled patients, 49 received at least 1 treatment dose. Of these patients, 20 achieved an objective response [41%, 95% confidence interval (CI) 27-56; 9 partial responses/11 complete responses (CRs)]. While treatment-naïve patients (n = 35) achieved a higher objective response rate (46%, 95% CI 29-63) than those who were pretreated (29%, 95% CI 8-58), 4 of 14 pretreated patients experienced an objective response, 2 with prior PD-1 inhibition. Five of 14 patients with perianogenital cSCC achieved an objective response (36%, 95% CI 13-65), including 4 CRs. At a median follow-up of 35 months, median progression-free and overall survival were 8.4 and 23.1 months, respectively. Grade 1 and 2 treatment-related adverse events (TRAEs) were common, while grade ≥ 3 events occurred in only 10 patients (20%) and 7 experienced serious TRAEs (14%); 2 discontinued treatment due to drug-related toxicity. Notably, quality of life improved, especially in patients with perianogenital primaries. CONCLUSIONS:Avelumab in combination with cetuximab demonstrates encouraging clinical activity in advanced cSCC, including patients with challenging subgroups such as perianogenital primaries or those with disease that has progressed on anti-PD-1 monotherapy. This is especially true when patients are carefully selected for their ability to undergo treatment for at least 12 weeks.