BACKGROUND:Adjuvant pembrolizumab prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with resected stage IIB/IIC melanoma in KEYNOTE-716. Results of a post hoc 4-year analysis are reported, including progression/recurrence-free survival 2 (PRFS2). METHODS:Patients were randomly assigned 1:1 to pembrolizumab 200 mg or placebo intravenously every 3 weeks (part 1). RFS was the primary end point; DMFS was secondary. Patients with recurrence following placebo or 17 cycles of pembrolizumab could cross over to or be rechallenged with pembrolizumab (part 2). RESULTS:Median follow-up (n = 976) was 52.8 months (range, 39.4-64.8). RFS (HR, 0.62 [95 % CI, 0.50-0.78]) and DMFS (HR, 0.59 [0.45-0.77]) favored pembrolizumab. At 48 months, RFS rates were 71.3 % for pembrolizumab and 58.3 % for placebo, and DMFS rates were 81.0 % and 70.1 %, respectively. The HR for PRFS2 was 0.75 (95 % CI, 0.56-1.01); 48-month PRFS2 rates were 82.5 % for pembrolizumab and 76.7 % for placebo. In the crossover population, median follow-up was 36.9 months; median RFS was not reached (NR; 95 % CI, 16.8-NR; 48-month RFS, 50.6 %) in patients with resectable disease (n = 41) and median progression-free survival was 22.0 months (4.5-NR) in patients with unresectable disease (n = 30). Among patients rechallenged, median follow-up was 21.9 months; none with resectable disease had recurrence (n = 6) and 1 with unresectable disease had best response of stable disease (n = 3). No new safety signals were observed. CONCLUSIONS:With > 4 years follow-up, pembrolizumab continued to prolong RFS and DMFS and had antitumor activity in patients who crossed over to pembrolizumab. TRIAL REGISTRATION:NCT03553836.

mRNA-4157 is a novel mRNA-based individualized neoantigen therapy (INT) designed to enhance endogenous antitumor T-cell responses by targeting unique patient-specific tumor mutations. In the phase 2 mRNA-4157-P201 (KEYNOTE-942) trial, patients with completely resected high-risk stage IIIB-IV melanoma receiving mRNA-4157 + pembrolizumab (pembro) showed prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus those receiving pembro alone (Weber JS, et al. Lancet 2024). Here, we characterized the dynamics of T cell and T cell receptor (TCR) repertoire in peripheral blood following mRNA-4157 plus pembro or pembro alone. Patients were randomized 2:1 to receive mRNA-4157 + pembro or pembro alone. Whole blood samples from longitudinal time points (baseline: pre-pembro & pre-INT; post-pembro & pre-INT; post-pembro & post-INT; and longer-term follow-up after completion of treatment; 116, 101, 108, and 79 patients respectively) were collected and TCR sequencing was performed. TCR beta chains were down sampled and normalized to the top 10k clones by rank sum unique molecular identifier. Shannon clonality was calculated on down sampled data. Differential clone abundance between screening and on-treatment samples was calculated by binomial test. Baseline TCR clonality was not associated with RFS of mRNA-4157 + pembro or pembro alone. However, longitudinal analysis of samples post-INT showed clonality was increased in 70% (55 out of 78) and 31% (12 out of 38) of the patients treated with mRNA-4157 + pembro and pembro alone, respectively. Analysis of clonotypes showed median number of novel expanded clonotypes after mRNA-4157 + pembro (n=78) and after pembro alone (n=38) was 38 and 22, respectively, suggesting that mRNA-4157 + pembro was associated with expansion of more novel clonotypes relative to pembro alone. Furthermore, among 78 patients in the mRNA-4157 + pembro arm, patients without recurrence (n=59) had median number of 40 novel expanded clonotypes while patients with recurrence (n=19) had median number of 16 novel expanded clonotypes. Additional analysis of neoantigen-specific T cells is ongoing and will be reported. Expansion of novel T cell clonotypes in peripheral blood was observed to a greater extent after mRNA-4157 + pembro compared to pembro alone, and the degree of novel expansion was associated with RFS. Min Lu, Ryan J. Sullivan, Jacky Chow, Janice M. Mehnert, Matteo S. Carlino, Adnan Khattak, George Ansstas, Matthew H. Taylor, Meredith McKean, Georgina V. Long, Mark B. Faries, Jason J. Luke, Anjali Rao, Laureen S. Ojalvo, Filippos Porichis, Igor Feldman, Lakshmi Srinivasan. Dynamics of T cell and T cell receptor following mRNA-4157 (V940) plus pembrolizumab or pembrolizumab alone in resected melanoma from the mRNA-4157-P201 (KEYNOTE-942) trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 855.

BACKGROUNDCheckpoint inhibitor-associated autoimmune diabetes mellitus (CIADM) is a rare but life-altering complication of immune checkpoint inhibitor (ICI) therapy. Biomarkers that predict type 1 diabetes (T1D) are unreliable for CIADM.AIMIn the present study, we sought to identify biomarkers for the prediction of CIADM.METHODSFrom our prospective biobank, we identified 14 patients with CIADM who had metastatic melanoma treated with anti-programed antibody death 1 (anti-PD-1) with or without anti-cytotoxic T lymphocyte-associated antibody protein 4 (anti-CTLA4). Controls were selected from the same biobank, matched 2:1. Pretreatment, on-ICI, and post-CIADM serum and PBMCs were analyzed. Serum was analyzed for T1D autoantibodies, C-peptide, glucose, and cytokines. PBMCs were profiled using flow cytometry. Pancreatic volume was measured using CT volumetry.RESULTSBefore treatment, patients with CIADM had smaller pancreatic volume (27% reduction, P = 0.044) and higher anti-glutamic acid decarboxylase autoantibody (anti-GAD) titers (median 2.9 vs. 0, P = 0.01). They had significantly higher baseline proportions of Th17 cells (P = 0.03), higher CD4+ central memory cells (P = 0.04), and lower naive CD4+ T cells (P = 0.01). With ICI treatment, greater declines in pancreatic volume were seen in patients with CIADM (P < 0.0001). Activated CD4+ T cell subsets increased significantly in CIADM and controls with immune-related adverse effects (IRAEs) but not in controls without IRAEs. Using only pretreatment results, we found that pancreatic volume, anti-GAD antibody titers, and the baseline immune flow profile were highly predictive of CIADM development, with an AUC of greater than 0.96.CONCLUSIONSPeople who develop CIADM are immunologically predisposed and have antecedent pancreatic and immunological changes that accurately predict disease with excellent sensitivity. These biomarkers could be used to guide ICI use, particularly when planning treatment for low-risk tumors.FUNDINGNational Health and Medical Research Council (NHMRC) Investigator grants 2033228, 2009476, and 2007839.

Immune checkpoint inhibitors (ICIs) have improved overall survival in patients with advanced-stage cancers. However, data on their efficacy and safety in solid organ transplant recipients (SOTRs) are limited. To examine cancer-specific and patient survival among SOTRs with advanced-stage cancer receiving ICIs and identify factors associated with patient and graft outcomes. Electronic databases and clinical registries, including MEDLINE, Embase, ClinicalTrials.gov, Australia New Zealand clinical trials registry, and the World Health Organization International Clinical Trials Registry Platform, were searched from inception to June 2024 without language restriction. Case reports and series, observational studies, and clinical trials that described the treatment of advanced-stage cancers using ICIs in SOTRs were included. Individual participant data were extracted and synthesized using a single-stage random-effect model. Time to cancer-related death was the primary outcome. The main secondary outcomes included time from ICI initiation to first rejection and cancer response according to Response Evaluation Criteria in Solid Tumors 1.1 criteria. Adjusted Cox proportional hazards regression models were conducted for time-to-event analyses. Of 140 studies, 128 studies involving 343 SOTRs treated with ICI were included. Most participants were male (76.9%), kidney transplant recipients (70.9%), with a median (IQR) age of 63 years (14-88 years), and treated with programmed cell death protein-1 inhibitors (72.9%). Within 3 years of ICI initiation, 52.8% (95% CI, 43.9%-61.6%) died of cancers. Acute rejection occurred in 36.2% (95% CI, 30.7%-41.7%) at 1 year, and 18.4% (95% CI, 13.7%-23.1%) experienced graft loss at 1 year. Objective response at 1 year was 31.6% (95% CI, 25.0%-37.7%), with a higher response observed in patients with cutaneous squamous cell carcinoma (cSCC) (61.0% [95% CI, 45.5%-76.4%]) than melanoma (48.5% [95% CI, 26.8%-70.3%]), and other solid organ cancers (26.9% [95% CI, 14.5%-39.3%]). Transplant recipients with melanoma (hazard ratio [HR], 2.29; 95% CI, 1.31-3.99) and solid organ cancers (HR, 2.84; 95% CI, 1.70-4.74) experienced higher rates of cancer-related deaths than those with cSCC. Recipients with melanoma have a higher risk of acute rejection (HR, 2.88; 95% CI, 1.69-4.90) than cSCC. Maintenance with steroids and mammalian target of rapamycin inhibitors (mTORIs) was associated with a lower risk of rejection compared with other immunosuppressive agents (HR, 0.30; 95% CI, 0.14-0.63). In this study, cancer outcomes in SOTRs receiving ICIs varied by cancer type, with a higher probability of achieving response among those with cSCC than other cancers. Concurrent use of mTORIs and steroids during ICI therapy may reduce the risk of acute allograft rejection.

Despite advances in systemic therapies, cutaneous melanoma remains a highly deadly disease. Patients with high-risk stage III melanoma have a significant likelihood of recurrence following surgery. Although adjuvant immunotherapy has been the standard of care, recent evidence demonstrates that neoadjuvant immunotherapy is more effective for higher-risk stage III patients, showing superior survival outcomes compared with adjuvant immunotherapy. This has led to an immediate paradigm shift in clinical practice toward neoadjuvant therapy for this cohort. The NeoTrio clinical trial assessed the efficacy of sequential or combination BRAF-targeted therapy with anti-programmed cell death-1 in the neoadjuvant setting. However, research on longitudinal histopathologic changes during this treatment period remains limited. Analysis of hematoxylin and eosin slides from 60 patients across 4 matched neoadjuvant timepoints revealed dynamic changes in a number of treatment response features. Females achieved significantly higher rates of major pathologic response (P = .002) and displayed higher levels of inflammatory fibrosis (P = .04) and hyalinized fibrosis (P = .01). The presence of tertiary lymphoid structures (P = .013) and plasma cells (P = .02) at resection was significantly associated with response. Combination scoring of histopathologic features (composite score and the immune-related pathologic response [irPR] score) was significantly associated with response early during the neoadjuvant period (composite score at week 2 on-treatment, P = .03; high irPR score at week 2 on-treatment, P = .01). A high irPR score at week 2 on-treatment was also found to be significantly associated with a lower chance of recurrence at this early neoadjuvant timepoint (P = .02). Other features associated with a lower likelihood of recurrence included increased hyalinized fibrosis (P = .015) and the presence of extensive lymphocyte density score (P = .01), tertiary lymphoid structures (P = .03), and plasma cells (P = .01). This study deepens our understanding of treatment response markers and their dynamic changes during neoadjuvant therapy. It underscores the significance of these features, particularly given their early emergence and strong associations with response and recurrence.

Background Metabolic conditions, such as obesity and type 2 diabetes mellitus (T2DM), cause changes in immune function that may influence immunotherapy effectiveness and immune-related adverse events (irAEs). Objectives To investigate the prognostic and predictive effects of BMI and T2DM and investigate the effect of BMI on toxicity using data from the EORTC 1325/KEYNOTE-054 randomised controlled trial. Methods Pembrolizumab (n=514) was administered every three weeks for 1 year and prolonged recurrence-free survival (RFS) compared to placebo (n=505) among patients with resected high-risk stage III melanoma. Here, we used multivariate Cox regression to investigate associations of BMI and T2DM with RFS, and Fine and Gray regression to investigate the association of BMI with the cumulative incidence of irAEs. Results BMI had an approximately U-shaped association with RFS (p=0.004) in both treatment arms combined. The RFS hazard ratios (HR)s for BMIs of 20, 30 and 35kg/m2 (compared to 25kg/m2) were 1.28 (95% CI 1.05-1.56), 0.96 (95% CI 0.88-1.06) and 1.14 (95% CI 0.98-1.34), respectively. There was no evidence that BMI was associated with pembrolizumab effectiveness (p=0.20) or the cumulative incidence of irAEs (p=0.74). T2DM was not associated with RFS (HR 1.01, 95% CI 0.73-1.40) in both arms combined and there was no evidence of an association between T2DM and pembrolizumab effectiveness (p=0.83). In summary, in patients with resected high-risk stage III melanoma, BMI was associated with RFS in patients overall and within each treatment group. Conclusions BMI appeared to confer a prognostic effect but was not predictive of pembrolizumab effectiveness regarding RFS. BMI was not related to irAEs among patients receiving pembrolizumab, while T2DM was not associated with RFS irrespective of treatment.

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.

9568 Background: Neoadjuvant immunotherapy (NeoIT) has significantly improved clinical outcomes for pts with macroscopic stage III resectable melanoma and is the current standard of care for these pts. Here, we analysed longitudinal peripheral immune profiles and their correlation with path response for 3 different PD1-based NeoIT regimens. Methods: Pts with macroscopic stage III resectable melanoma treated with neoadjuvant PD1-based regimens (PD1 alone, PD1+IPI and PD1+Lenvatinib) for 6 weeks, followed by surgery, were included. Cytometry by time-of-flight (CYTOF; 39-marker panel) was performed on peripheral blood mononuclear cells (PBMCs) at baseline and week 6 (wk 6; pre-surgery). Results: Of 64 pts included, 17 PD1 alone (7 [41%] had major pathological response [MPR; ≤ 10% of viable tumour cells at the surgical specimen]), 26 PD1+IPI (20 [77%] had MPR) and 21 PD1+Lenvatinib (12 [57%] had MPR). We analysed >200 peripheral immune cell types/phenotypes, and present the statistically significant treatment effects (from baseline to wk 6), overall and based on path response (MPR vs. non-MPR), in patients treated with PD1 alone, PD1+IPI and PD1+lenvatinib (see Table). Conclusions: IPI+PD1 and PD1+Lenvatinib induced stronger peripheral blood immune activation, compared with PD1 alone, irrespective of path response. There were differences in the MPR vs non-MPR pts, particularly for PD1 alone. A more in-depth analysis of the effects of these PD1-based regimens and their association with recurrence is underway to identify key immune cell types/phenotypes associated with response & resistance to NeoIT. Effect of neoadjuvant PD1 alone, PD1+IPI and PD1+lenvatinib in the peripheral immune profile of melanoma patients. Overall treatment effect MPR (vs. non-MPR) Non-MPR (vs. MPR) PD1 Increase in:- OX40+ / ICOS+ regulatory T cells (Tregs)- KI67+ ICOS+ CD4 T cells Increase in:- GZM+ CD4+ & CD8+ T cells- Double negative [CD27- IgD-] B cells Increase in:- Non-classic [CD14low+CD16++] HLA-DR+ monocytesDecrease in:- CD4 T effector memory cells- Th1 cells PD1+IPI Increase in:- Tregs- Activated [ICOS+ / LAG3+ / TIGIT+] CD4+ T cells- TIM3+ CD4+ & CD8+ T cells- Non-classic [CD14low+CD16++] monocytes- Cytotoxic [CD56dim CD16+] NK cellsDecrease in:- Stem-like [TCF7+] CD4+ & CD8+ T cells Increase in:- OX40+ / T-BET+ CD127- CD8+ T effector memory cells PD1+lenvatinib Similar changes seen with PD1+IPI, as well as an increase in:- Th1- Th17- CD8+ T effector memory cellsDecrease in:- Double negative [CD27- IgD-] B cells Increase in:- CD127- Tregs Increase in:- HLA-DR+ non-classic [CD14low+CD16++] monocytes

9528 Background: Adjuvant PD1 treatment improves clinical outcomes in high-risk resected melanoma. We have shown that adjuvant PD1 can lead to irAEs that become chronic in up to 46% of treated patients (pts). We performed longer follow-up (f/u) to further characterize chronic irAEs from adjuvant PD1 treatment and assessed risk factors to determine predictors for their development. Methods: We retrospectively analyzed pts treated with adjuvant PD1 for resected stage III-IV melanoma from 2015-2024 from 6 institutions. All pts had at least 12 months of f/u after PD1 initiation. We collected demographics, treatment details, and outcomes. We characterized type, grade, management, duration, and resolution of acute (onset during PD1) and chronic (persisting at least 3 months after PD1 cessation) irAEs. We performed Olink 96-protein inflammation assay in plasma from pts with and without chronic non-endocrine irAEs at 12 months after PD1 initiation. Results: We included 304 pts; 184 (61%) were male, and median age at PD1 initiation was 64 years. Among all pts, 221 (73%) developed acute irAEs, and 147 (48%) developed chronic irAEs; 59 pts had chronic endocrine irAEs, 99 had chronic non-endocrine irAEs, and 11 had both. At last f/u (median 61.4 months), 104 (34%) pts had ongoing irAEs. The most common chronic irAEs were hypothyroidism/thyroiditis (n=45, 15%), arthritis (n=25, 8%), dermatitis (n=17, 6%), hypophysitis/adrenal insufficiency (n=16, 5%), and xerostomia (n=10, 3%). Twenty (7%) pts experienced chronic toxicities outside of classical irAEs, most often fatigue (n=14, 5%), orthostasis (n=2, 1%), and headache (n=2, 1%). We then assessed risk factors for chronic irAEs compared with acute, resolving irAEs (excluding endocrine irAEs since nearly all become chronic). We found that peak steroid dose was similar in patients with and without chronic irAEs (median 50 mg for both groups, p=0.33). Time to irAE onset was similar in patients with and without chronic irAEs (median 91 vs. 114 days, p=0.78). Time to steroids from symptom onset trended longer for those with chronic irAEs (median 7 vs. 4 days, p=0.18) but was not statistically significant. In proteomic analysis, 24/96 cytokines had higher expression (0 with lower expression) in pts with chronic irAE (n=17) compared with controls (n=10), including IL-8 (p=0.02), IL-17 (p=0.049), TNF (p=0.02), VEGFA (p=0.005), and soluble PD-L1 (p=0.03). Conclusions: Among this large cohort of pts with melanoma treated with adjuvant PD1, chronic irAEs were common, persistent, and associated with elevated circulating cytokines, which could suggest possible therapeutics. No obvious predictors of chronic irAEs were identified outside of organ affected; analyses are ongoing. Given the long-term survival of pts treated with adjuvant PD1, monitoring and managing chronic irAEs is crucial.

Glioblastoma (GBM) is an aggressive primary adult brain tumor that rapidly recurs after standard-of-care treatments, including surgery, chemotherapy and radiotherapy. While immune checkpoint inhibitor therapies have transformed outcomes in many tumor types, particularly when used neoadjuvantly or as a first-line treatment, including in melanoma brain metastases, they have shown limited efficacy in patients with resected or recurrent GBM. The lack of efficacy has been attributed to the scarcity of tumor-infiltrating lymphocytes (TILs), an immunosuppressive tumor microenvironment and low tumor mutation burden typical of GBM tumors, plus exclusion of large molecules from the brain parenchyma. We hypothesized that upfront neoadjuvant combination immunotherapy, administered with disease in situ, could induce a stronger immune response than treatment given after resection or after recurrence. Here, we present a case of newly diagnosed IDH-wild-type, MGMT promoter unmethylated GBM, treated with a single dose of neoadjuvant triplet immunotherapy (anti-programmed cell death protein 1 plus anti-cytotoxic T-lymphocyte protein 4 plus anti-lymphocyte-activation gene 3) followed by maximal safe resection 12 days later. The anti-programmed cell death protein 1 drug was bound to TILs in the resected GBM and there was marked TIL infiltration and activation compared with the baseline biopsy. After 17 months, there is no definitive sign of recurrence. If used first line, before safe maximal resection, checkpoint inhibitors are capable of immune activation in GBM and may induce a response. A clinical trial of first-line neoadjuvant combination checkpoint inhibitor therapy in newly diagnosed GBM is planned (GIANT; trial registration no. NCT06816927 ).

Immune checkpoint inhibitors (ICI) can achieve durable responses in patients with advanced melanoma, and results from clinical trials suggest cure may be possible for a subset of patients. Despite clinical trial data, little is known about the risk, character, and clinical outcome of late recurrences after ICI. This study aimed to explore the disease outcomes and survival in a cohort of patients with long-term responses to ICI.We retrospectively identified patients treated with ICI for advanced melanoma with long-term disease control, defined as not requiring a subsequent line of systemic therapy within 3 years of ICI commencement. We analysed disease characteristics, treatment, toxicity, recurrence patterns, management, and outcomes.A total of 567 patients were identified with a median follow-up of 7.1 years: 504 (89%) without disease progression within 3 years (cohort 1) and 63 (11.1%) with disease progression within 3 years managed without a change in systemic therapy (cohort 2). Subsequent progression after 3 years occurred for 39 (7.7%) patients in cohort 1, compared to 14 (22%) in cohort 2. Predictors for late progression after 3 years were a non-complete radiological response (CR) best response and prior progression within 3 years. Thirty-two patients (5.6%) died during follow-up, 8 (1.4%) from melanoma, 6 (1.2%) from cohort 1 and 2 (3.2%) from cohort 2.In this population of patients with advanced melanoma with long-term disease control from ICI, the risk of subsequent disease progression and death was low. This suggests that a significant proportion of long-term ICI responders are likely cured and may inform the frequency and duration of follow-up.

BACKGROUND:Prognosis for AJCC stage III melanoma varies significantly. Adjuvant therapies, including pembrolizumab, nivolumab, and dabrafenib/trametinib, have markedly reduced recurrence risk, as shown in pivotal trials (Keynote-054, CheckMate-238, and Combi-AD). Despite these advancements, clinicians lack tools to dynamically assess recurrence risk across the patient journey. PATIENTS AND METHODS:Using pooled individual patient data (IPD) from Kaplan-Meier curves of these trials, we developed a tool to dynamically estimate relapse-free survival (RFS) and distant metastasis-free survival (DMFS) over time. Conditional survival analyses incorporated AJCC-8 substages, treatment regimens, and recurrence data. RESULTS:The analysis included 2206 patients (IIIA: 174, IIIB: 768, IIIC: 1169, IIID: 95). Of these, 861 received adjuvant anti-PD-1 therapy (pembrolizumab or nivolumab), 434 were treated with dabrafenib/trametinib, and 911 were in the observation group. Median follow-up ranged from 61 to 74 months. The dynamic calculator, hosted at the MIA website (Risk Prediction Tools: www.melanomarisk.org.au), allows input of time since treatment initiation, AJCC-8 stage, and therapy type, providing dynamic RFS and DMFS estimates up to 60 months. Case examples illustrate both baseline and conditional risks, facilitating tailored clinical discussions. CONCLUSIONS:This tool enhances accessibility to individualized, dynamic, time-specific risk estimates for patients with stage III melanoma. It serves as a practical resource for clinicians to support personalized follow-up plans, empowering informed decision-making. Updates will incorporate emerging data to maintain clinical relevance.

Immunotherapy has significantly improved survival in patients with metastatic melanoma, achieving objective response rates of 45–60

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.

Neoadjuvant therapy followed by surgery is the current standard for stage III melanoma, but 60% of patients achieve a major pathological response (MPR) with good long-term outcomes. This raises the potential for modifying treatment strategies to identify patients who may safely omit surgery. Biomarkers such as circulating tumor DNA (ctDNA) and imaging modalities have shown promise in assessing therapeutic response, yet each has limitations when used independently. This study evaluates the relationship between ctDNA clearance and changes in fluorodeoxyglucose(FDG)-positron emission tomography(PET) SUVmax from pre-treatment to pre-surgery, to predict pathological response and the feasibility of non-surgical management in appropriately selected patients. In the discovery cohort, plasma ctDNA levels and computed tomography (CT) RECIST data were retrospectively analyzed in stage III melanoma patients from the OpACIN-neo trial (N=9), where two doses of neoadjuvant combination immunotherapy was administered. For validation, FDG-PET SUVmax changes and ctDNA dynamics will be assessed in two trial cohorts: NeoTrio (N=45, pembrolizumab ± dabrafenib and trametinib) and NeoPele (N=20, pembrolizumab and Lenvatinib). PET responses will be categorized into complete metabolic response (CMR), near-CMR (SUVmax reduction >90%), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD). In the OpACIN-neo cohort, 7/9 (78%) patients achieved ctDNA clearance pre-surgery and RECIST partial response, with five achieving MPR and two non-MPR. Two patients with persistent ctDNA pre-surgery, which cleared post-surgery, had RECIST stable disease (one achieved MPR and one non-MPR). None of these nine patients experienced clinical recurrence. Preliminary data from the validation cohort shows that all eight patients (8/33; 24%) with CMR or near CMR achieved MPR, while 5/6 (83%) patients with PMD were pathological non-responders. CT RECIST was useful in evaluating disease burden in the discovery cohort; however, PET imaging is expected to provide greater specificity and stronger correlation with pathological outcomes. Furthermore, ctDNA clearance has demonstrated potential in identifying patients who may avoid surgery and remain recurrence-free, highlighting the complementary value of both modalities. Combining ctDNA dynamics with FDG-PET SUVmax changes can improve the prediction of pathological response to neoadjuvant therapy in stage III melanoma. This integrated approach could help identify patients who will achieve durable responses and can safely avoid surgery, supporting the development of more personalized treatment strategies. Wei Yen Chan, Li Zhou, Edward Hsiao, Jenny H. Lee, Ashleigh Stewart, Russell J. Diefenbach, George Au-Yeung, Maria Gonzalez, Andrew J. Spillane, Robyn P. Saw, Sydney Ch'Ng, Matteo Carlino, Richard A. Scolyer, Alexander M. Menzies, Georgina V. Long, Helen Rizos. Integrating ctDNA and FDG-PET dynamics to predict pathological response following neoadjuvant systemic therapy in stage III melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 731.

Previous results from the KEYNOTE-716 trial demonstrated significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) with adjuvant pembrolizumab versus placebo in patients with resected stage IIB or IIC melanoma. We present a post hoc analysis of efficacy according to primary tumor location. KEYNOTE-716 (NCT03553836) is a randomized, multicenter, double-blind, phase III study. Patients aged ≥ 12 years with newly diagnosed, resected stage IIB or IIC melanoma (sentinel node-negative) were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. This post hoc analysis evaluated RFS and DMFS by primary tumor location of the head/neck, trunk, or extremities. Overall, 976 patients were assigned to pembrolizumab (n = 487) or placebo (n = 489). Median follow-up was 39.4 months (range 26.0–51.4). The hazard ratios HRs (95

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.

Background: The gut microbiome plays a pivotal role in regulating immunity. Gastric acid suppressants (GAS) are known to alter the gut microbiome and might therefore modify response to immunotherapy in cancer patients. We estimated associations of GAS with recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in the EORTC 1325/KEYNOTE-054 trial. Methods: Patients with resected stage III melanoma were randomized to receive 200 mg of pembrolizumab or placebo. Pembrolizumab prolonged RFS and DMFS (reported elsewhere). We used Cox models to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for the association between GAS at baseline, and RFS and DMFS, overall and by treatment arm. Results: Out of 1019 randomized patients, 109 (10.7 %) used GAS at baseline. We did not find a prognostic importance for RFS (HR 1.06, 95 % CI 0.79-1.42) or DMFS (HR 1.05, 95 % CI 0.77-1.43), neither a predictive importance (HR for RFS in the pembrolizumab arm: 1.02 (95 % CI 0.66-1.56) and 1.09 (95 % CI 0.74-1.62) in the placebo arm (p = 0.81); corresponding HRs for DMFS: 1.17 (95 % CI 0.75-1.82) and 0.95 (95 % CI 0.62-1.48) (p = 0.52)). Conclusion: GAS showed no impact on RFS or DMFS in patients with stage III melanoma receiving adjuvant pembrolizumab or placebo.

Importance:Immune checkpoint inhibitors (ICIs) have improved overall survival in patients with advanced-stage cancers. However, data on their efficacy and safety in solid organ transplant recipients (SOTRs) are limited. Objective:To examine cancer-specific and patient survival among SOTRs with advanced-stage cancer receiving ICIs and identify factors associated with patient and graft outcomes. Data Sources:Electronic databases and clinical registries, including MEDLINE, Embase, ClinicalTrials.gov, Australia New Zealand clinical trials registry, and the World Health Organization International Clinical Trials Registry Platform, were searched from inception to June 2024 without language restriction. Study Selection:Case reports and series, observational studies, and clinical trials that described the treatment of advanced-stage cancers using ICIs in SOTRs were included. Data Extraction and Synthesis:Individual participant data were extracted and synthesized using a single-stage random-effect model. Main Outcomes and Measures:Time to cancer-related death was the primary outcome. The main secondary outcomes included time from ICI initiation to first rejection and cancer response according to Response Evaluation Criteria in Solid Tumors 1.1 criteria. Adjusted Cox proportional hazards regression models were conducted for time-to-event analyses. Results:Of 140 studies, 128 studies involving 343 SOTRs treated with ICI were included. Most participants were male (76.9%), kidney transplant recipients (70.9%), with a median (IQR) age of 63 years (14-88 years), and treated with programmed cell death protein-1 inhibitors (72.9%). Within 3 years of ICI initiation, 52.8% (95% CI, 43.9%-61.6%) died of cancers. Acute rejection occurred in 36.2% (95% CI, 30.7%-41.7%) at 1 year, and 18.4% (95% CI, 13.7%-23.1%) experienced graft loss at 1 year. Objective response at 1 year was 31.6% (95% CI, 25.0%-37.7%), with a higher response observed in patients with cutaneous squamous cell carcinoma (cSCC) (61.0% [95% CI, 45.5%-76.4%]) than melanoma (48.5% [95% CI, 26.8%-70.3%]), and other solid organ cancers (26.9% [95% CI, 14.5%-39.3%]). Transplant recipients with melanoma (hazard ratio [HR], 2.29; 95% CI, 1.31-3.99) and solid organ cancers (HR, 2.84; 95% CI, 1.70-4.74) experienced higher rates of cancer-related deaths than those with cSCC. Recipients with melanoma have a higher risk of acute rejection (HR, 2.88; 95% CI, 1.69-4.90) than cSCC. Maintenance with steroids and mammalian target of rapamycin inhibitors (mTORIs) was associated with a lower risk of rejection compared with other immunosuppressive agents (HR, 0.30; 95% CI, 0.14-0.63). Conclusions and Relevance:In this study, cancer outcomes in SOTRs receiving ICIs varied by cancer type, with a higher probability of achieving response among those with cSCC than other cancers. Concurrent use of mTORIs and steroids during ICI therapy may reduce the risk of acute allograft rejection.