9567 Background: Resected stage IIB/C and microscopic stage IIIA/B/C/D melanoma presents a significant risk of recurrence risk of 37 to 62% at 5 years (yrs). While 1 year of adjuvant PD1 therapy reduces this risk by approximately half, the individual patient’s baseline risk without treatment and their specific benefit from adjuvant PD1 remain unknown. We aimed to generate two separate predictive models for recurrence – one for untreated and one for treated pts - to calculate the individualised benefit of adjuvant PD1. Methods: Pts with resected stage IIB/C or microscopic stage IIIA/B/C/D melanoma, either treated with adjuvant PD1 or untreated at 13 major melanoma centres, and with at least 2 years of follow-up from surgery were included. We analysed pts demographics, disease characteristics, blood parameters, pathological and imaging data at baseline, and clinical outcomes. Propensity scores were estimated using logistic regression with covariates associated with treatment in univariate screening (p<0.05). Separate penalised multivariable logistic regression models were built to predict recurrence for treated and untreated pts. A tool based on these models was created to calculate the individual patient benefit from adjuvant PD1. Results: A total of 3560 pts was included, divided into untreated (discovery n=2384 and validation n=597) and treated (discovery n=404 and validation n=175) cohorts. The model for untreated pts included age, gender, primary site, histological subtype, Breslow thickness, ulceration, mitosis, number and site of regional lymph nodes (LN), mutation status and LDH (AUC 0.70 in discovery, 0.69 in validation). The model for treated pts included age, gender, Breslow thickness, site of regional LN, and mutation status (AUC 0.69 in discovery, 0.61 in validation). ADAPT-M (ADjuvant Anti-PD-1 Tool for Melanoma) calculates the individualized benefit of adjuvant PD1. For example, patient A, a woman ≤45 years old with a primary head & neck melanoma (superficial spreading, thickness >1-2 mm, no ulceration, 1 mitosis/mm 2 ), 2 clinically occult LN metastases in the neck, NRAS mutant, and normal LDH, has a 12-month recurrence risk of 21.9% untreated vs 2.3% treated (benefit 19.6%), and a 24-month risk of 41.1% untreated vs 6.4% treated (benefit 34.7%). While, patient B, a man ≤45 years old with a primary melanoma in the lower limb (nodular, thickness >1-2 mm, no ulceration, 1 mitosis/mm 2 ), 2 clinically occult LN metastases in the groin, BRAF V600 mutant, and normal LDH, has a 12-month recurrence risk of 14.2% untreated vs 11.8% treated (benefit 2.5%), and a 24-month risk of 28.0% untreated vs 30.1% treated (no benefit). Conclusions: ADAPT-M, a clinical tool that estimate individualized recurrence risks with and without adjuvant anti-PD1 therapy, quantifies the absolute benefit of treatment for pts with high-risk resected melanoma, facilitating personalized adjuvant therapy decisions.

Background The combination of a rising incidence of early-onset cancer and the trend towards delayed parenthood has made the impact of treatments on fertility highly significant. While there is abundant evidence on oncofertility outcomes of anti-cancer treatment protocols used in people with breast cancer and haematological malignancies, data regarding gonadal toxicity and fertility preservation in young people with other cancers are lacking. We aimed to systematically review gonadal toxicity, fertility outcomes, and preservation strategies in people with gastrointestinal, sarcoma, lung, and melanoma cancers. Methods We conducted a systematic review following the PRISMA guidelines and searched PubMed, Embase, through June 1, 2025. Eligible studies included observational designs and case reports on gonadal function, fertility outcomes, or preservation strategies in adults with the selected cancers. Pregnancy-associated and pediatric studies were excluded. Two reviewers independently screened, extracted data, and assessed quality using the JBI tool. Formal assessment of publication bias as not undertaken, given the limited number of studies per outcome. Due to clinical and methodological heterogeneity, results were synthesised narratively. Heterogeneity was assessed using the I2 statistic. The primary outcomes were treatment-related fertility impairment, including persistent amenorrhea or ovarian failure, return or maintenance of menses, and azoospermia and recovery of spermatogenesis at follow-up. Secondary outcomes included hormonal changes and reproductive outcomes such as pregnancy and live birth. This review was registered with PROSPERO (CRD42024557875). Findings Of 3337 records screened, 102 studies were included, comprising 33 case-based publications (30 case reports and 3 case series) and 69 analytical studies, including 64 observational studies (6 prospective and 58 retrospective) and 5 other analytical designs. Evidence across studies was highly heterogeneous in design, treatment exposures, and outcome definitions. In melanoma, most survivors appear to retain fertility, though rare cases of immune checkpoint inhibitor-induced orchitis or azoospermia were observed. Sarcoma regimens with alkylating and platinum agents appear to carry the highest risk of persistent gonadal failure in both sexes, with partial sperm recovery possible in some cohorts. In gastrointestinal cancers, chemotherapy-induced gonadal dysfunction was often transient in younger patients, whereas pelvic radiotherapy resulted in near-universal ovarian failure and long-term male hypogonadism. In lung cancer, platinum-based regimens were associated with to premature menopause and endocrine disruption, yet fertility counselling and preservation were rarely provided. Exploratory meta-analyses suggested that pooled estimates were imprecise and limited by substantial heterogeneity. Interpretation Gonadal toxicity risk varies by cancer type and treatment, while there is a paucity of robust evidence for the impact on malignancies that are emerging in the young population. Future prospective evaluation of gonadal function in the setting of early-onset cancer, as well as adequate evaluation of strategies to preserve fertility and minimise gonadal toxicity, is warranted. Funding No external funding was received for this work. This study received internal institutional support.

Cutaneous squamous cell carcinoma (CSCC) is a highly prevalent malignancy with rising incidence, particularly among elderly and immunosuppressed individuals. Although most early-stage cases are cured with surgery, a relevant minority present with high-risk features or anatomically complex disease. Immune checkpoint inhibitors (ICIs) have transformed the management of advanced CSCC and are increasingly being evaluated in perioperative settings. This review critically examines current evidence for adjuvant and neoadjuvant immunotherapy in resectable CSCC. Neoadjuvant ICIs studies, including cemiplimab, pembrolizumab, and nivolumab±ipilimumab, have reported consistent and striking rates of major and complete pathologic responses, frequently exceeding 50% and accompanied by opportunities for surgical or radiotherapy de-escalation. In contrast, adjuvant anti-PD-1 trials have produced divergent results: KEYNOTE-630 was negative, while C-POST improved disease-free, but not overall survival. These discrepancies highlight persistent limitations in risk stratification, since commonly used staging systems (American Joint Committee on Cancer, Brigham and Women’s Hospital, Salamanca) insufficiently reflect disease biology and fail to incorporate immunosuppression, functional outcomes, or extent of planned surgery. Furthermore, the generalizability of current evidence is constrained by the exclusion of immunosuppressed populations and by rigid trial protocols that often mandate multimodal treatment, irrespective of biological sensitivity. Such ‘one-size-fits-all’ approaches miss critical opportunities for organ preservation and de-escalation. The future of early CSCC management lies in response-adapted strategies to tailor the extent of surgery, radiation, and systemic therapy. Next-generation studies must embrace biomarker-driven designs and broader inclusion criteria, approaching CSCC as a unique biological entity that demands a precision-medicine framework.

9535 Background: MUM carries a poor prognosis with few effective treatments, especially for HLA-A*02:01-negative pts. While a subset of MUM pts responds to immune checkpoint inhibitors, the comparative efficacy of IPI+PD1 versus PD1 monotherapy is unclear. This study compares objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety between these regimens in MUM. Methods: MUM pts treated with PD1 or IPI+PD1 at 15 major melanoma centres (from Australia, Europe, United States and Israel) were included. Demographics, patient and disease characteristics, and clinical outcomes were examined. Univariate and multivariate (MVA) analyses were performed to identify clinical predictors of response and survival. Results: Of 412 MUM pts treated, 150 (36%) had PD1 and 262 (64%) received PD1+IPI. Compared to the PD1 group, PD1+IPI-treated pts were younger (64 vs. 70 years; p<0.001), had higher rate of elevated LDH (44% vs. 31%; p=0.037), and more frequently had prior treatment with tebentafusp (6.5% vs. 1.3%; p=0.031). Median follow-up from commencement of PD1+/-IPI was 4.9 years (95% CI 4.7 – 6.1). ORR was higher in IPI+PD1 group (18%) vs. PD1 (9%) (p=0.008), particularly in males (p=0.009), patients with liver metastases (p=0.018) and with lung metastases (p=0.011), with elevated LDH (p=0.047) and with no prior treatment with tebentafusp (p=0.007). PFS and OS at 1 and 2 years were numerically higher with IPI+PD1 (1- and 2-year PFS: 23% and 15%; 1- and 2-year OS: 63% and 39%) vs. PD1 (1- and 2-year PFS: 17% and 11%; 1- and 2-year OS: 54% and 36%), but these differences were not statistically significant (p>0.05). On MVA, adjusting for predefined variables (age, gender, ECOG PS, LDH, presence/absence of liver/lung metastases, prior treatment with tebentafusp), IPI+PD1 was associated with higher ORR (OR 2.71, 1.30 – 6.05; p=0.01) but not with PFS or OS compared to PD1. Presence of liver metastases (ORR [OR 0.28; 95% CI 0.13 - 0.64], PFS [HR 1.61; 95% CI 1.11 - 2.34], OS [HR 2.02; 95% CI 1.32 - 3.10]), ECOG PS≥2 (PFS [HR 1.82; 95% CI 1.07 - 3.10], OS [HR 2.24; 95% CI 1.25-4.01]), elevated LDH (PFS [HR 1.66; 95% CI 1.30 - 2.11], OS [HR 2.39; 95% CI 1.84-3.10]) and prior tebentafusp treatment (OS [HR 2.36; 95% CI 1.21-4.59]) were also independent predictors of response and/or survival. A higher percentage of pts experienced grade ≥3 immune-related adverse events (irAEs) in the IPI+PD1 group compared to the PD1 group (34% vs 13%, p<0.0001). Most pts ceased treatment due to progression (234, 57%), and more pts stopped due to toxicity in the IPI+PD1 vs. PD1 group (25% vs. 9%, p<0.0001). Conclusions: In pts with MUM, IPI+PD1 demonstrated a higher ORR but did not improve survival compared with PD1 alone. IPI+PD1 was more toxic, leading to early treatment discontinuation in one-quarter of pts. These findings may help guide treatment selection in MUM.

Tumour mutation burden (TMB) is a promising biomarker in predicting immunotherapy response, yet its reproducibility across target panels needs to be established. This study assessed the reproducibility of TMB estimates in melanoma using TruSight Oncology 500 across two laboratories and compared these results with the FoundationOne CDx and QIAseq TMB IO panels. High concordances in TMB estimation, mutation calls, and BRAF and N/K/HRAS hotspot variants were observed between platforms. In a cohort of 198 pre-treatment biopsies from patients treated with immune checkpoint inhibitors, high TMB (≥10 mut/Mb) was associated with significantly improved response and progression-free survival (PFS), while somatic mutations in PTPRD and a germline variant in PIK3CA (I391M) were associated with favourable outcomes independent of TMB. Neoantigen profiling of 135 samples demonstrated that neoantigen load, particularly neoepitopes with strong-binding to class II MHC, had a superior predictive value over TMB for PFS. Mutations in NF1 and ROS1 that produce a neoantigen were also linked to improved outcomes. These results support the reproducibility of TMB estimation and highlight the added value of neoantigen profiling in predicting immunotherapy benefits in melanoma.

Despite improvements in overall survival (OS) with immune-checkpoint inhibitors (ICIs) and targeted therapies, many patients with advanced melanoma and non-melanoma skin cancer still experience disease progression (PD) and remain on systemic therapy during the End of Life (EoL) phase. Evidence on treatment patterns, healthcare utilization, and palliative care integration in the last weeks of life remains scarce. We conducted a retrospective cohort study including consecutive patients with advanced skin cancers treated in a single Italian comprehensive cancer center who died from advanced skin cancer between 2015 and 2021. Data from the last six months of life on systemic therapies, radiotherapy, hospital admissions, emergency department (ED) visits, specialist consults, palliative care, and place of death were analysed. Descriptive statistics and logistic regression were applied to identify predictors of healthcare use. A total of 93 patients were included (melanoma n = 84, cutaneous squamous cell carcinoma (CSCC) n = 7, Merkel cell carcinoma (MCC) n = 2). In the last six months of life, 88 (95

The relationship between melanoma and female hormonal factors has long been a subject of investigation. While pregnancy-associated melanoma (PAM) has been widely studied, current evidence does not consistently demonstrate an increased risk of developing melanoma during pregnancy or a worse prognosis in pregnant women with pre-existing disease. This narrative review expands the scope beyond PAM, focusing specifically on the potential impact of hormone replacement therapy (HRT) and fertility treatments on melanoma risk and progression. We performed a comprehensive review of the literature, analyzing studies that explored the association between exogenous hormonal exposure and melanoma development, recurrence, or progression. Available evidence is often conflicting and limited by methodological heterogeneity. Some studies suggest a possible increased risk of melanoma with prolonged use of certain hormonal agents, particularly oral contraceptives and fertility drugs, while others do not support a significant association. The influence of these treatments on prognosis remains unclear. Our goal is to provide clinicians with a critical synthesis of existing data and practical insights for managing younger female patients with melanoma or at risk of melanoma. This review underscores the importance of individualized risk assessment and shared decision-making when hormonal therapies are considered in this setting. Further prospective studies are needed to clarify these associations and inform evidence-based clinical guidelines.

Immune checkpoint inhibitors (ICIs) have dramatically reshaped the therapeutic landscape of oncology, offering long-term survival benefits across multiple tumor types. However, ICIs are associated with a broad range of immune-related adverse events (irAEs), most of which are now well characterized and manageable. A subset of irAEs, however, remains rare, unpredictable, and poorly understood, both in terms of clinical presentation and pathogenesis. Here, we describe the case of a patient with advanced melanoma treated with combined anti-CTLA-4 and anti-PD-1 therapy who developed severe left hip pain during treatment. Imaging findings were initially suggestive of osteonecrosis of the femoral head. However, histopathological analysis of the resected femoral head revealed a dense lymphoplasmacytic infiltrate with fibrosis and vascular congestion, without evidence of bone necrosis, consistent with an immune-mediated osteitis. To our knowledge, this represents the first documented case of direct immune-related inflammation selectively affecting bone tissue during ICI therapy. Recognition of such atypical skeletal irAEs may be critical for improving diagnosis and management strategies in the expanding field of immuno-oncology.

9578 Background: Anti-PD1 immunotherapy has shown improved clinical outcomes in patients (pts) with advanced cSCC, and recently, in the neoadjuvant setting for resectable disease. Pathological (path) response is predictive of recurrence in melanoma and recent NeoIT trials suggests the same in cSCC; however, an analysis of clinical outcomes in pts with resectable cSCC treated with intended anti-PD1-based NeoIT in larger datasets remains unknown. Methods: Pts with resectable cSCC treated with intended anti-PD1-based NeoIT from 17 cancer centres globally were included. Baseline patient and disease characteristics, treatment regimen, path response and recurrence-free survival (RFS) or progression-free survival (PFS) were collected and examined. Results: 134 pts with resectable cSCC were treated with intended anti-PD1-based NeoIT. Median age was 75 years old (range, 39-97), 72% (n=97) were male. One fifth (22%, n=29) were immunocompromised and 43% (n=58) had ECOG PS of ≥1. Of 125 (93%) pts with known primary cSCC, 82% (n=102) were from the head & neck. Most pts (79%, n=106) were stage III/IV. The majority had anti-PD1 monotherapy (91%, n=122) and 9% (n=12) had anti-PD1+/-investigational agent. Median follow-up from commencement of NeoIT was 10 months (95% CI, 9 - 12). Nearly half of the pts (49%, n=66) underwent surgery; 37 (56%) pts had major pathological response (MPR; ≤10% viable tumour cells at the surgical specimen; 31 [47%] had complete path response [0% of viable tumour cells] and 6 [9%] had near complete path response [1-10% of viable tumour cells]), 6 (9%) had partial path response (pPR; >10% and ≤50% of viable tumour cells), and 23 (35%) had path non-response (pNR; >50% of viable tumour cells). Of the 66 pts who underwent surgery, 11% (n=7) had recurrence (5 loco-regional and 2 distant recurrence), all non-MPR pts (1 pPR and 6 pNR). 12-months RFS was improved with MPR vs non-MPR (100% vs 79%, p=0.004). 52% (n=34) pts had adjuvant treatment (23 anti-PD1 alone, 7 anti-PD1+/-investigational agent, 2 platinum and 2 cetuximab). Within non-MPR pts, 12 had adjuvant treatment (3 recurred; 25%), while 17 did not have adjuvant treatment (4 recurred; 24%). Fifty-one percent (n=68) of pts did not have surgery; 9 (13%) due to progressive disease (PD) and 53 (78%) due to clinical response. Of the 53 pts with a clinical response, 5 (9%) subsequently progressed. Fourteen (10%) pts have died, 6 (4%) related to cSCC; 2 had surgery (non-MPR) and 4 did not have surgery (all due to PD). Conclusions: Anti-PD1-based NeoIT is an active regimen in resectable stage II-IV cSCC and is associated with high clinical response and MPR rates. No pts with MPR from NeoIT has recurred to date, however, 9% of pts who did not have surgery due to clinical response eventually progressed. These findings highlight the importance of further research to investigate the role of surgery in this subgroup of patients.

Previous studies showed an association between single nucleotide gene variants (SNVs) of PD-1 and cancer susceptibility. We analyzed PD1.5 C > T and PD1.7 T > C SNVs to investigate their association with the risk of developing metastatic melanoma (MM). Utilizing a cohort of 125 MM patients treated with anti-PD-1 agents and 84 healthy controls, we examined genotype/allele frequencies through a modified Poisson regression model, adjusted for age and sex. Our findings indicate that the PD1.5 T allele is associated with a reduced risk of MM, showing a significantly lower risk in both codominant (RR = 0.56, 95

Immunotherapy has drastically changed the treatment of advanced cutaneous squamous cell carcinoma. In three clinical trials, cemiplimab and pembrolizumab have been administered up to 24 months, although most objective responses have been observed within the first 3 months. To determine if a shorter exposure time to cemiplimab was associated with the long-term maintenance of clinical activity, we assessed the outcomes of patients with advanced cutaneous squamous cell carcinoma that had an early discontinuation of cemiplimab. This is a single centre retrospective study including patients with histologically confirmed locally advanced or metastatic CSCC treated with cemiplimab at our Institution from August 19th, 2019, to August 8th, 2022. The objective response was assessed radiologically according to the RECIST 1.1 criteria or clinically according to the WHO criteria. A total of 48 patients receiving at least one dose of cemiplimab were included. Median time of treatment with cemiplimab was 6.8 (0 – 31.6) months, with an overall response rate (ORR) of 68%. Median time to response was 2.8 (0.6 - 19.1) months. Therapy was permanently discontinued in 20 patients due to adverse events (n=3) or patients' or physician’s choice after achieving a stable disease, partial or complete response (n=17). At a median follow-up of 11.6 (1.4 – 45.0) months, the median PFS after treatment discontinuation was 15.8 months. No patient relapsed. Only one patient, after being treated for a haematological pathology, developed a new primary CSCC, while pre-existing lesions maintained complete clinical response. Our findings suggest that early discontinuation of cemiplimab in patients with advanced CSCC upon achieving a tumour response does not appear to negatively impact on the duration of response.

In recent years, advances in melanoma treatment have renewed patient hope. This comprehensive review emphasizes the evolving treatment landscape, particularly highlighting first-line strategies and the interplay between immune-checkpoint inhibitors (ICIs) and targeted therapies. Ipilimumab plus nivolumab has achieved the best median overall survival, exceeding 70 months. However, the introduction of new ICIs, like relatlimab, has added complexity to first-line therapy decisions. Our aim is to guide clinicians in making personalized treatment decisions. Various features, including brain metastases, PD-L1 expression, BRAF mutation, performance status, and prior adjuvant therapy, significantly impact the direction of advanced melanoma treatment. We also provide the latest insights into the treatment of rare melanoma subtypes, such as uveal melanoma, where tebentafusp has shown promising improvements in overall survival for metastatic uveal melanoma patients. This review provides invaluable insights for clinicians, enabling informed treatment choices and deepening our understanding of the multifaceted challenges associated with advanced melanoma management.

Background: Colon cancer imposes a significant burden on global healthcare systems, necessitating efforts to improve oncology care quality and patient outcomes. We studied the correlation between care quality and survival outcomes among colon cancer patients within the Ligurian Oncology Network (Italy).Methods: We developed an Overall Quality Score (OQS) to evaluate the impact of oncology care quality on survival outcomes within the Ligurian Oncology Network. OQS indicators were selected through expert consensus, covering screening, diagnosis, treatment, and follow-up. A sample of colon cancer patients diagnosed in 2012 was randomly selected from administrative healthcare data. Analyses were performed using two models: a binary model (High and Low OQS) and a stratified model (Low, Medium, and High OQS). Statistical analysis involved survival curves, log-rank tests, and Cox proportional hazards models using SAS 9.4.Results: Of 175 eligible colon cancer patients, 150 were included. Following a median follow-up of 7.6 years, a correlation between High-OQS (>= 65%) and prolonged disease-free survival was observed (unadjusted HR 0.57, 95%CI 0.33-0.99, log-rank p=0.041). The five-year disease-free survival rate for High-OQS patients was 70% (95%CI 57-80%), compared to 53% (95%CI 41-64%) for Low-OQS patients. Similarly, the five-year overall survival rate was 78% (95%CI 65-86%) for High-OQS patients, compared to 58% (95%CI 45-68%) for Low-OQS patients (unadjusted HR 0.56, 95%CI 0.31-1.00, log-rank p=0.048).Conclusions: Our findings highlight the potential impact of the patient journey on colon cancer survival outcomes. Optimising care pathways might improve patient outcomes in colon cancer management.

Background While cutaneous melanomas are well-documented, primary melanoma of the lung (PMML), particularly with endobronchial origin, remains rare and poorly characterized. This case report addresses gaps in understanding by presenting a comprehensive case of a 71-year-old male with primary endobronchial melanoma and conducting a systematic review of PMML cases. Case Presentation The patient, a former smoker, presented with dyspnea, cough, and hemoptysis. Imaging revealed left lung atelectasis and a suspicious nodule. Bronchoscopy identified an endobronchial mass, subsequently treated with argon plasma coagulation and resection. Biopsy confirmed melanoma. Extensive examinations ruled out a primary skin lesion. Despite initial treatment, recurrence led to pneumonectomy. Histopathology confirmed melanoma. The patient received treatment with pembrolizumab and ipilimumab, but with poor clinical benefit. Conclusions Primary endobronchial melanoma is a rare entity, comprising 0.01% of lung tumors. This case underscores diagnostic challenges and emphasizes histological criteria to distinguish primary from metastatic lesions. The pathogenesis remains unclear, with theories proposing foetal melanocyte migration or squamous metaplasia. Prognosis varies, necessitating radical surgical extirpation. A systematic review revealed diverse outcomes, supporting the need for further research. In conclusion, endobronchial melanoma involves an endoscopic and surgical management, but evolving therapies, such as immunotherapy, may reshape treatment paradigms. This case contributes to our understanding of PMML, guiding future research and clinical management. As therapeutic options evolve, continued research is crucial to refine our understanding and improve outcomes for this rare malignancy.

Basal cell carcinoma (BCC) is the most common form of cancer, with a high impact on the public health burden and social costs. Despite the overall prognosis for patients with BCC being excellent, if lesions are allowed to progress, or in a small subset of cases harboring an intrinsically aggressive biological behavior, it can result in local spread and significant morbidity, and conventional treatments (surgery and radiotherapy) may be challenging. When a BCC is not amenable to either surgery or radiotherapy with a reasonable curative intent, or when metastatic spread occurs, systemic treatments with Hedgehog inhibitors are available. These guidelines were developed, applying the GRADE approach, on behalf of the Italian Association of Medical Oncologists (AIOM) to assist clinicians in treating patients with BCC. They contain recommendations with regard to the diagnosis, treatment and follow-up, from primitive tumors to those locally advanced or metastatic, addressing the aspects of BCC management considered as priorities by a panel of experts selected by AIOM and other national scientific societies. The use of these guidelines in everyday clinical practice should improve patient care.

Background: Treatment options for advanced melanoma have increased with the US Food and Drug Administration approval of the anti-LAG3 plus anti-PD-1 relatlimab/ nivolumab combination. To date, ipilimumab/nivolumab is the benchmark of overall survival, despite a high toxicity profile. Furthermore, in BRAF-mutant patients, BRAF/MEK in-hibitors and the atezolizumab/vemurafenib/cobimetinib triplet are also available treatments, making the first-line therapy selection more complex. To address this issue, we conducted a systematic review and network meta-analysis of the available first-line treatment options in advanced melanoma. Methods: Randomised clinical trials of previously untreated, advanced melanoma were in-cluded if at least one intervention arm contained a BRAF/MEK or an immune-checkpoint inhibitor (ICI). The aim was to indirectly compare the ICIs combinations ipilimumab/nivo-lumab and relatlimab/nivolumab, and these combinations with all the other first-line treat-ment options for advanced melanoma (irrespective of BRAF status) in terms of activity and safety. The coprimary end-points were progression-free survival (PFS), overall response rate (ORR) and grade >= 3 treatment-related adverse events (>= G3 TRAEs) rate, defined according to Common Terminology Criteria for Adverse Events. Results: A total of 9070 metastatic melanoma patients treated in 18 randomised clinical trials were included in the network meta-analysis. No difference in PFS and ORR was observed between ipilimumab/nivolumab and relatlimab/nivolumab (HR = 0.99 [95% CI 0.75-1.31] and RR = 0.99 [95% CI 0.78-1.27], respectively). The PD-(L)1/BRAF/MEK inhibitors triplet combinations were superior to ipilimumab/nivolumab in terms of both PFS (HR = 0.56 [95% CI 0.37-0.84]) and ORR (RR = 3.07 [95% CI 1.61-5.85]). Ipilimumab/nivolumab showed the highest risk of developing >= G3 TRAEs. Relatlimab/nivolumab trended to a lower risk of >= G3 TRAEs (RR = 0.71 [95% CI 0.30-1.67]) versus ipilimumab/nivolumab. Conclusion: Relatlimab/nivolumab showed similar PFS and ORR compared to ipilimumab/ nivolumab, with a trend for a better safety profile. (c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND:Immune checkpoint inhibitors (ICIs) have revolutionized the management of multiple tumors, due to improved efficacy, quality of life, and safety. While most immune-related adverse events (irAEs) are mild and easily managed, in rare cases such events may be life-threatening, especially those affecting the neuromuscular and cardiac system. The management of neuromuscular/cardiac irAEs is not clear due to the lack of consistent data. Therefore, we carried out a pooled analysis of collected cases from selected Italian centers and individual data from published case reports and case series, in order to improve our understanding of these irAEs. PATIENTS AND METHODS:We collected retrospective data from patients treated in six Italian centers with ICIs (programmed cell death protein 1 or programmed death-ligand 1 and/or cytotoxic T-lymphocyte antigen 4 inhibitor) for any solid tumor who experienced neuromuscular and/or cardiovascular toxicity. Then, we carried out a search of case reports and series of neuromuscular/cardiac irAEs from ICIs with any solid tumor. RESULTS:This analysis includes cases from Italian institutions (n = 18) and the case reports identified in our systematic literature search (n = 120), for a total of 138 patients. Among these patients, 50 (36.2%) had complete resolution of their neuromuscular/cardiac irAEs, in 21 (15.2%) cases there was a clinical improvement with mild sequelae, and 53 (38.4%) patients died as a result of the irAEs. Factors significantly associated with worse outcomes were early irAE onset, within the first two cycles of ICI (Fisher P < 0.0001), clinical manifestation of both myositis and myocarditis when compared with patients who developed only myositis or myocarditis (chi-square P = 0.0045), and the development of arrhythmia (Fisher P = 0.0070). CONCLUSIONS:To the best of our knowledge, this is the largest collection of individual cases of immune-related myocarditis/myositis. Early irAE onset, concurrent development of myositis and myocarditis, as well as occurrence of arrhythmias are associated with worse outcomes and should encourage an aggressive immunomodulatory treatment.