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

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

Randomized trials have shown that neoadjuvant immune checkpoint inhibitor (ICI) therapy improves outcomes compared with adjuvant therapy in patients with resectable stage III-IV melanoma. However, the generalizability of these findings to routine clinical practice is unclear. We conducted a nationwide, population-based cohort study including 279 consecutive patients with resectable stage III-IV cutaneous melanoma treated with neoadjuvant ICI in Sweden. Outcomes included pathological response, survival and adverse events. Among patients, 94% received PD-1 inhibitor monotherapy and 92% underwent surgery as planned. Major pathological response occurred in 43%, including 37% with complete response. After a median follow-up of 20 months, estimated 24-month EFS was 69%, DMFS 75%, and OS 87%. Pathological response was strongly associated with outcomes. Among 119 patients achieving major pathological response (MPR), withholding adjuvant therapy was associated with recurrence. Outcomes after neoadjuvant ICI were comparable to randomized trials. Withholding of adjuvant therapy after MPR warrants further study.

Abstract We have previously identified links between gut microbial community assemblages, defined by the ratio of Ruminococcaceae to Bacteroidaceae, and response to immune checkpoint inhibitor (ICI) immunotherapy, suggesting microbiome-immune interactions may prime patients for treatment outcomes. To investigate how these microbial states shape baseline immune tone and anti-tumor immunity we profiled peripheral immune and tumor-intrinsic features across these stratified patient groups. In 129 Australian and Dutch stage III melanoma patients treated on trial with neo-adjuvant anti-PD-1/anti-CTLA-4 immunotherapy (OpACIN-neo/PRADO), pre-treatment stool (microbiome; 16S rRNA gene sequencing) and PBMCs (immune profiles; mass cytometry) were analyzed. Tumor biopsies were subject to DNA/RNA sequencing, with tumor mutation burden (TMB) and IFN-γ score assessed. Clear differences in baseline peripheral immune profiles were observed upon stratifying patients by microbial community types. Ruminococcaceae (Ru)-dominated gut microbiomes were associated with higher ICI response rates, had greater frequencies of circulating memory B and T cell subsets (CD27+ B cells, CD8+ Tem (CD45RA-CCR7-)) and higher ICOS+ Tregs. Bacteroidaceae (Ba)-dominated patients had higher frequencies of total B cells and a more naïve immune profile. Further, the pre-treatment tumors of Ru-dominated patients were enriched with pathways involved with immune signalling and antigen presentation while Ba-dominated patient tumors were enriched with pathways associated with dysregulated metabolism and cell proliferation. The distribution of tumor TMB and IFN-γ groups between responders (R) and non-responders (NR) within each microbial community type was also significantly different; 81% of Ba-R had high TMB, compared to only 54% of Ru-R, and 72% of Ba-dominated patients belonged to the IFN-γ low group compared to 48% of Ru-dominated patients, with all Ba-NR being IFN-γ low. Gene ontology enrichment analysis further revealed distinct biological programs associated with response within each microbial community type. Ru-R were enriched for T, B and NK cell differentiation and cytotoxicity, while Ba-R showed enrichment for extracellular matrix remodelling. Together this demonstrates that different microbial community types are associated with altered baseline peripheral immune tone and tumor features. Furthermore, it suggests that ICI response within each microbial community type may be characterised by divergent predictive markers and mechanisms of response. This is highly relevant to optimally targeting the gut microbiome in the clinic and identifying patients who will benefit most from microbiome-modifying interventions. Citation Format: Rebecca C. Simpson, Ines Pires Da Silva, Jayden Beckwith, Irene L. M. Reijers, Judith M. Versluis, Camelia Quek, Alexander M. Menzies, Gonzalez Maria, James S. Wilmott, Christian U. Blank, Richard A. Scolyer, Erin R. Shanahan, Georgina V. Long. Divergent gut microbial communities are linked to differences in baseline immune profiles, tumor features and ICI outcomes in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2883.

The cross-sectional AILEEN study evaluated long-term cognitive function after immune checkpoint inhibition (ICI) for melanoma and compared outcomes between neoadjuvant combination therapy (ipilimumab/nivolumab) versus adjuvant monotherapy (nivolumab or pembrolizumab). Patients with stage III/IV melanoma were invited approximately two years after ICI initiation. Patients completed the online Amsterdam Cognition Scan and questionnaires on self-reported cognitive problems, fatigue, anxiety, and depression. Scores were evaluated at group- and individual-level against cancer-free norm groups and well-established cutoffs. Prevalences of cognitive impairment were compared to estimated false-positive rates accounting for the number and correlation of tests. Patients treated with ICI (N = 107) showed significantly worse verbal memory, processing speed, and executive functioning and reported clinically meaningful lower cognitive function at group-level compared to normative data. At individual-level, 34

9566 Background: Randomized trials have shown that neoadjuvant PD-1–based immunotherapy improves outcomes compared with adjuvant therapy alone in patients with resectable stage III–IV cutaneous melanoma. In trials, patients experiencing a major pathological response (MPR) rarely relapse, and in the NADINA trial, adjuvant therapy was omitted in this group. However, the need for continued adjuvant treatment after MPR has never been prospectively tested, and real-world evidence is limited. Methods: This population-based cohort study included all patients with macroscopic, resectable cutaneous melanoma treated with neoadjuvant immune checkpoint inhibitor(s) across all academic melanoma centers in Sweden between January 1, 2022 and December 30, 2025. Clinical and pathological data were extracted from medical records. MPR was defined as pathological complete response (pCR) or near-pCR. Recurrence-free survival (RFS) was estimated using the Kaplan–Meier method and differences assessed with log-rank test. Results: A total of 279 patients initiated neoadjuvant treatment; 254 (91%) underwent surgery as planned, and 251 had evaluable pathological assessment. Overall, 103 patients (37%) experienced pCR and 17 (6%) near-pCR, yielding 120 patients (43%) with MPR. At a median follow-up of 19 moths, the estimated 24-month RFS for patients with MPR was 92%. Among MPR patients, 52 (43%) received continued adjuvant immune checkpoint inhibitor therapy, while 68 (57%) received no adjuvant treatment. RFS differed significantly between groups, with estimated 24-month RFS of 96% in patients receiving adjuvant therapy versus 80% in those who did not ( P =0.048). In the non-adjuvant group, there were five recurrences (three had pCR and two had near pCR), two were local recurrences and three were distant metastatic events, compared with no recurrence events in the adjuvant group. One unrelated death occurred in the non-adjuvant group and two unrelated deaths in adjuvant group. Conclusions: In this nationwide real-world cohort, patients experiencing MPR after neoadjuvant immunotherapy had excellent outcomes overall. However, a small but clinically relevant risk of relapse was observed among patients who did not receive continued adjuvant therapy after MPR. These findings emphasize the need for individualized assessment when considering adjuvant treatment in patients with MPR. Longer follow-up is needed to determine whether additional events emerge and, importantly, whether relapses can be effectively salvaged with immune checkpoint inhibitor rechallenge.

9565 Background: Randomized trials have shown that neoadjuvant immune checkpoint inhibitor (ICI) improves outcomes compared with adjuvant therapy alone in patients with resectable stage III–IV cutaneous melanoma. Furthermore, pathological response was a strong predictor for relapse-free survival (RFS). The translationability to routine real-world patients is unknown. Methods: This population-based cohort study included all patients with macroscopic, resectable cutaneous melanoma treated with neoadjuvant immune checkpoint inhibitor(s) across all academic melanoma centers in Sweden between January 1, 2022 and December 30, 2025. Clinical and pathological data were extracted from medical records. Results: A total of 279 patients initiated neoadjuvant ICI and received a median of two treatment cycles, 94% received PD1-inhibitor monotherapy, 91% underwent surgery as planned and 251 had evaluable pathological assessment. Among all patients who started treatment, 37% had a complete pathological response (pCR), 6% near pCR, 15% a partial pathological response (pPR) and 32% no pathological response (pNR). At a median follow-up time of 20 months, the estimated 24-month event-free survival was 69% (95% CI, 62-76), distant metastasis-free survival (DMFS) 75% (95% CI, 69-82) and overall survival (OS) 87% (95% CI, 82-92). Among those who underwent surgery and had an evaluable pathological assessment, RFS, DMFS and OS stratified by pathological response are shown in the table. Conclusions: Early nationwide implementation of neoadjuvant ICI in patients with resectable cutaneous melanoma resulted in favourable outcomes that closely mirror those reported in randomized clinical trials. Pathological response N RFS at 24 months% (95% CI) DMFS at 24 months% (95% CI) OS at 24 months% (95% CI) pCR 103 92 (85-100) 93 (86-100) 94 (87-100) near pCR 17 76 (56-100) 83 (64-100) 90 (73-100) pPR 41 83 (71-97) 85 (74-98) 92 (81-100) pNR 90 48 (36-63) 63 (52-78) 81 (70-92)

The identification of reliable predictors for immunotherapy response remains a critical challenge in precision oncology. Here, we integrated patient clinical features with DNA and RNA sequencing data derived from 229 melanoma samples. We use 138 melanoma samples to develop and train machine learning models predicting patient treatment response. Feature selection included a univariate Mann-Whitney U-test screen (p <  = 0.05) prior to unique tailoring for each model using SHAP. We identify random forest as the optimal classifier, on an independent cohort of 53 melanoma patients. We test the usefulness of the model using additional test data comprising patients with stable disease (n = 15) and non-cutaneous melanoma (n = 23). Using SHAP, we identified features linked to treatment response including mutation features, immune cell-type abundance and LAG3 expression, highlighting the contributions of both tumour intrinsic and extrinsic factors. Further leveraging SHAP we infer potential numerical thresholds for certain features separating good versus poor immunotherapy response. This explainability driven methodology has potential implications for the clinical translation of biomarker discovery and guiding treatment options to enable precision oncology.

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

Neoadjuvant immune checkpoint blockade is becoming the standard of care for stage III melanoma, and biomarkers to refine these regimens are urgently needed. Intratumoral tumor-infiltrating lymphocytes (iTIL) are essential for response, but their clinical scoring is hampered by high inter-observer variability, particularly in lymph node biopsies. Here, we present a pathologist-in-the-loop deep learning workflow, to quantify iTIL in hematoxylin and eosin-stained biopsies from melanoma lymph node metastases. Our model was trained on 127,278 pathologist-annotated cells, and externally validated on 159 whole-slide images from three pioneering phase I/II trials testing neoadjuvant ipilimumab and nivolumab in stage III melanoma, with exceptionally long-term follow up (>5 years). AI-assisted iTIL% correlated strongly with pathologist-based iTIL% (Spearman ρ = 0.76, P < 0.0001) and was predictive of major pathological response (P = 0.0008). A high AI-assisted iTIL% was associated with longer event-free survival (HR = 0.40, P = 0.010), especially when combined with a high tumor mutational burden (TMB; HR = 0.18, P = 0.0056); in the double high subgroup (n = 33), only one melanoma-related event occurred in 5 years of follow up. This work provides a roadmap towards standardised, AI-assisted iTIL scoring in melanoma lymph node metastases. Prospective studies are indicated to confirm that iTIL metrics, particularly with the TMB, could inform standard of care protocols and future trials.

Accumulating evidence from randomized phase 3 trials in multiple tumor types supports the application of neoadjuvant or perioperative immunotherapy to significantly enhance clinical benefit in patients with resectable solid tumors. While systemic immunotherapy in this setting can be very effective, immune-related toxicity and resistance remain important challenges. Local administration of immune checkpoint blockade and/or other immune modulatory agents at lower doses offers a promising alternative strategy. Access to the proximal tumor microenvironment and tumor-draining lymph nodes (TDLNs) minimizes systemic exposure and potentially mitigates toxicity without compromising efficacy. Local neoadjuvant immunotherapy may enable more potent immune priming and activation within preserved TDLN, potentially reducing both local and distant recurrence rates and improving clinical outcomes. The availability of post-treatment resection specimens allows for the subsequent in-depth analysis of induced immune responses and co-evolving resistance mechanisms. Notwithstanding these potential advantages, challenges remain, such as lack of consensus on preferred delivery techniques, optimal (combinatorial) agents, dosing, and timing of administration. Carefully designed clinical trials, randomized against systemic administration, are needed to address these issues, establish durable clinical benefit, and guide broader implementation of locally administered neoadjuvant immunotherapy.

BACKGROUND:Pathological complete response (pCR) and circulating tumor DNA (ctDNA) clearance are increasingly used as intermediate endpoints in neoadjuvant and perioperative immunotherapy (IO) trials. However, whether complete pathological and molecular responders share comparable residual risk across tumor types remains uncertain. METHODS:We performed a post-hoc pan-tumor analysis using reconstructed individual patient data from published Kaplan-Meier curves of phase II/III trials. All included trials contained a neoadjuvant immunotherapy component; trials that additionally incorporated postoperative adjuvant immunotherapy were classified as perioperative. We evaluated associations of pCR and ctDNA clearance, defined as conversion from baseline ctDNA positivity to undetectable ctDNA after neoadjuvant therapy, with event-free survival (EFS) and tested whether these biomarkers modified the association between treatment timing (neoadjuvant-only versus perioperative) and EFS. FINDINGS:We reconstructed survival data for 1,867 patients achieving pCR and 352 patients achieving ctDNA clearance across 8 tumor types. Among patients with pCR, 3-year EFS varied substantially by tumor type (from 78.6% to 100%). In tumor types where such a comparison was possible, postoperative adjuvant IO did not improve EFS among patients achieving pCR. In contrast, ctDNA clearance showed heterogeneous prognostic dynamics. In within-tumor analyses restricted to trials reporting both endpoints, pCR was associated with superior EFS. CONCLUSION:pCR remains the most reproducible prognostic indicator across tumor types following neoadjuvant or perioperative IO. In cross-trial comparisons, no EFS benefit from postoperative adjuvant IO was observed among patients with pCR. ctDNA clearance showed substantial variability across tumors, likely reflecting both biological heterogeneity in tumor shedding and inter-trial assay differences.

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

TPS9612 Background: Neoadjuvant immunotherapy, administered upfront of surgery in patients with resectable stage III melanoma, has shown superior efficacy in recent trials compared to post-surgical adjuvant treatment, due to enhanced anti-tumor immunity when the tumor microenvironment is intact. A pre-operative regimen of 2 cycles of ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy (as per NADINA trial) results in substantially improved event-free survival. However, even with this regimen 41% of patients did not achieve a Major Pathologic Response (MPR), with 8% having a partial pathological response and 26.4% showing pathological non-response. Previous analyses have shown a ‘cold’ CD4-IL-2 signature being associated with no-response, which could be overcome by the addition of IL-2. MDNA11 is a long-acting engineered interleukin (IL)-2 albumin fusion protein, with enhanced affinity for IL-2 receptor β (IL-2Rβ/CD122) and no binding to IL-2Rα (CD25). This design enhances the stimulation of IL-2Rβ-expressing CD8+ T cells and NK cells whilst diminishing the activation of Tregs constitutively expressing the heterotrimeric receptor containing IL-2Rα. Thus, we hypothesize that MDNA11 combination with nivolumab +/- ipilimumab may further enhance clinical outcomes of neoadjuvant standard therapy. Methods: This is a phase Ib, prospective, open-label, randomised study where a 6- week neoadjuvant phase is followed by a 7-week surgery/post-surgery phase and a 49-week adjuvant phase as per clinical practice. The study population will include adult patients of either sex aged ≥ 18 years with surgically resectable stage IIIB/C/D cutaneous melanoma. Twenty patients will be enrolled in each arm for a total of up to 80 patients. The ARM A is the control one with Ipilimumab 80 mg plus Nivolumab 240 mg administered every 3 weeks for 2 cycles as for NADINA trial; the ARM B includes Nivolumab 240 mg every 3 weeks for 2 cycles plus MDNA11 at 30 μg/kg on week 0 followed by MDNA11 at 60 μg/kg on week 2 and week 4; the ARM C includes Ipilimumab 80 mg plus Nivolumab 240 mg administered every 3 weeks for 2 cycles plus MDNA11 at 30 μg/kg on week 0 followed by MDNA11 at 60 μg/kg on week 2 and week 4; the ARM D adds tocilizumab 4 mg/Kg on week 0 at the same schedule of the ARM C. The study’s primary endpoint is the Major Pathologic Response (MPR) rate at surgery, defined as ≤10% viable tumor in the treated tumor bed. Co-primary endpoints include the incidence, severity, and duration of treatment-related adverse events, particularly immune-related, as per CTCAE v5.0. Health-related quality of life will be analyzed using longitudinal models. Exploratory analyses will investigate biomarker associations with outcomes to generate hypotheses. Clinical trial information: 2024-519010-31-00.

AIMS:Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has demonstrated benefit for patients with advanced melanoma refractory to first-line immune checkpoint inhibitors (ICIs). However, predictive biomarkers for TIL therapy response are limited. Preclinical studies suggest that emotional distress (ED) may impair antitumor immune responses. We conducted a post-hoc analysis of the phase III TIL trial (NCT02278887) to evaluate the association between pretreatment ED and TIL therapy outcomes. METHODS:ED was evaluated using a composite score derived from the Impact of Event Scale and the emotional functioning subscale of the EORTC QLQ-C15-PAL. Patients were stratified into elevated ED (n = 32) or normal ED (n = 40) groups using a median split approach. To evaluate whether the obtained results were dependent on the ED classification method, a sensitivity analysis was conducted to compare TIL therapy outcomes between patients with composite ED scores in the lowest tertile (normal ED, n = 26) and highest tertile (elevated ED, n = 25). RESULTS:Elevated ED was associated with a reduced objective response rate (37 % vs. 69 %; adjusted odds ratio, 0.28; 95 % confidence interval [CI], 0.19-0.75; P = 0.013) and decreased progression-free survival rates at 1-year (31 % vs. 58 %) and 2-years (16 % vs. 35 %; adjusted hazard ratio, 1.84; 95 % CI, 1.03-3.26; P = 0.038). Sensitivity analysis using the tertile grouping method showed a similar trend (odds ratio, 0.35; 95 % CI, 0.11-1.08, P = 0.072). CONCLUSION:Our findings suggest that elevated ED before TIL therapy is associated with reduced therapeutic outcomes, underscoring the need for further investigation into the stress-immune-cancer axis.

Immunotherapy has become a fourth pillar of cancer therapy, alongside surgery, radiotherapy and chemotherapy. Cancer immunotherapy seems to be most effective in the context of low but not negligible tumour burden, thus in the neoadjuvant setting before curative intent surgery. Indeed, in the case of macroscopic stage III melanoma, a decade of clinical and translational research has led to conclusive evidence that neoadjuvant immunotherapy should be the clinical standard of care, although its adoption in different regions of the world is still ongoing. In this Perspective, we discuss the lessons learnt from neoadjuvant immunotherapy trials in melanoma and where the field is heading next. In the coming years, we believe that biomarker-driven personalization of the therapy, a deeper understanding of the role of immune education, and the ability to uncouple toxicity from efficacy will make neoadjuvant cancer immunotherapy safer and more effective, not only for melanoma but also for other types of cancer. Neoadjuvant (chemo)immunotherapy has become a new standard-of-care option for patients with cancer. This Perspective discusses the lessons learnt for neoadjuvant immunotherapy in the context of melanoma and where the field is heading next, particularly an increased understanding of the role of immune education in therapy resistance and the need for biomarker-driven therapy personalization to uncouple toxicity from efficacy.

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.

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.