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8618 Background: Telisotuzumab vedotin (Teliso-V) is a c-Met–directed antibody-drug conjugate comprising the mAb telisotuzumab and the microtubule polymerization inhibitor monomethyl auristatin E. In the phase 2 LUMINOSITY trial (NCT03539536), Teliso-V monotherapy 1.9 mg/kg showed durable responses and a generally manageable safety profile in patients (pts) with c-Met protein–overexpressing (OE) non-squamous (NSQ) EGFR -wildtype (WT) non-small cell lung cancer (NSCLC). Herein we present an analysis of efficacy outcomes according to prior platinum or prior platinum and immune checkpoint inhibitor (ICI)-based therapies. Methods: Pts (≥18 years) with locally advanced/metastatic c-Met protein–OE NSQ EGFR -WT NSCLC who had ≤2 prior lines of therapy, including ≤1 line of chemotherapy, were treated with 1.9 mg/kg Teliso-V Q2W. c-Met protein overexpression (by immunohistochemistry clinical trial assay for MET [SP44] [Roche]) was defined as ≥25% tumor cells with 3+ staining intensity (high: ≥50% 3+; intermediate [int]: 25 to <50% 3+). The primary endpoint was overall response rate (ORR) by independent central review per RECIST v1.1. Results: As of 21 Feb 2024, 172 pts received ≥1 dose of Teliso-V and 168 pts were included in efficacy analyses (c-Met high, n=84; c-Met int, n=84). In the c-Met OE total population, 97.6% of pts received prior platinum and 78.6% received prior platinum + ICI. Efficacy data for pts with prior platinum and platinum + ICI therapies are shown in the Table. Among the 172 dosed pts, the most common any-grade treatment-related adverse events (TRAEs) were peripheral sensory neuropathy (31%), peripheral edema (16%), and fatigue (14%). The most common grade ≥3 TRAE was peripheral sensory neuropathy (7%). Conclusions: This analysis demonstrated that Teliso-V elicited durable responses in pts with c-Met protein–OE NSQ EGFR -WT NSCLC regardless of whether they had received prior platinum or platinum + ICI therapies; the efficacy outcomes in these subgroups were consistent with those in the overall pt population. Clinical trial information: NCT03539536 . Platinum Platinum + ICI Overall ORR, a n/N (%) [95% CI] c-Met OE total c-Met high c-Met int 48/164 (29.3) [22.4, 36.9]28/81 (34.6) [24.3, 46.0]20/83 (24.1) [15.4, 34.7] 38/132 (28.8) [21.2, 37.3]22/67 (32.8) [21.8, 45.4]16/65 (24.6) [14.8, 36.9] 49/168 (29.2) [22.4, 36.7]29/84 (34.5) [24.5, 45.7]20/84 (23.8) [15.2, 34.3] Median DOR, a mo [95% CI] c-Met OE total c-Met high c-Met int 7.2 [5.5, 11.3]9.0 [3.8, 12.0]7.2 [4.7, 11.5] 7.2 [5.5, 11.0]9.0 [3.8, 11.3]7.2 [5.3, 11.5] 7.2 [5.5, 11.0]7.2 [4.2, 12.0]7.2 [4.7, 11.5] a Per independent central review. DOR, duration of response.

e14545 Background: Next generation sequencing (NGS) identifies genomic alterations in DNA obtained from tissue biopsies and/or blood [circulating tumor (ct)DNA]. We anticipate a lower rate of copy number loss (CNL) in ctDNA compared to tissue, as lower ctDNA tumor fraction may limit the ability to detect a deletion. However, we observed several instances of a CNL in ctDNA that was not identified in a tissue specimen, prompting this systematic evaluation of an institutional dataset. We focused on BRCA1/2 pathogenic variants (PVs) given their therapeutic implications and coverage across testing platforms. Methods: Using an IRB-approved protocol, we evaluated an institutional repository of NGS results performed across the Mayo Clinic Enterprise. We focused on patients (pts) who had both tissue and blood NGS testing performed. We further narrowed this cohort to those with a BRCA1/2 PVs, somatic and/or germline, as determined by testing performed at Guardant Health, Tempus, or Foundation Medicine. We abstracted information about each variant, including type of alteration classification and functional impact. Demographic information, cancer characteristics, and germline testing information was collected. Fisher’s exact test was used to compare alteration frequencies in ctDNA vs tissue using GraphPad Prism v 10.1. Results: From Dec 2015-Sept 2024, we identified 158 unique pts with BRCA1/2 PV who had NGS results for both tissue and ctDNA. The median age at first reporting BRCA1/2 variant was 67 years (range: 29-98 years). 48% of pts were female, and the most common cancer type sites were lung (23%), colorectal (20%), and pancreaticobiliary (20%). We identified 198 unique pathogenic genomic alterations; 71 in BRCA1 & 127 in BRCA2 . Most common alteration was an SNV or indel (127/198), followed by CNL (n = 63), splice site variants (n = 5), fusions (n = 2), and rearrangements (n = 1). Of the 126 SNV or indels, 50 (39.7%) were identified in both ctDNA and tissue, 40 (31.7%) were detected in blood only, 36 (28.6%) identified only in tissue (p < 0.0001). Amongst the 63 CNL, only 3 (4.8%) were identified in both ctDNA and tissue; 41(65.1%) were only identified in ctDNA, and 19 (30.2%) in tissue only (p < 0.0001). In the 19 tissue-only CNL tests, 12/19 noted one or more additional pathogenic SNV/Indel in BRCA1/2. In the 41 ctDNA-only CNL tests, 1/41 noted one or more additional pathogenic SNV/Indel in BRCA 1/2 . Germline testing was available in 41/63 pts with copy number loss. 3/41 deletions were identified in germline (2 in ctDNA, 1 in tissue). Conclusions: We observed a low degree of concordance in CNL between tissue and ctDNA for BRCA1/2 . CNL detection in ctDNA that could not be confirmed in germline or with a second alteration warrants further attention. In particular, clinicians should be cautioned when interpreting ctDNA reports noting BRCA1/2 CNL without clarity if this represents biallelic loss or a synchronous loss of function.

6008 Background: ATC patients present with advanced, often surgically unresectable disease with historically dismal prognosis. Median PFS and OS of DT without pembrolizumab were 6.7 and 13.5 months, respectively, in the ROAR trial. Neoadjuvant DTP achieved locoregional control without radical surgery in a retrospective series of BRAF m-ATC patients, providing rationale to evaluate efficacy and safety in a phase 2 prospective trial. Methods: In this single-arm multicenter phase 2 trial, patients with BRAF m-ATC stage IVB/IVC were enrolled in 5 US centers. Following a 3-6 week run-in with D (150 mg BID) and T (2 mg daily), P (200 mg Q3W) was added, with restaging every three (21-day) cycles. Post-operatively, patients continued P (or DTP) with radiotherapy or transitioned directly to adjuvant DTP (up to 26 cycles). Primary endpoints included R0/R1 resection rate (historically 5%) and overall survival (OS). Secondary endpoints included RECIST 1.1 response after DTP and progression-free survival (PFS). Results: Between 9/2021-1/2025, 42 patients were enrolled; 36 are included in the current analysis (3 not evaluable, 3 pending surgery) (Table). Patients received median 4 (range: 2-7) neoadjuvant DTP cycles, with 26 (72%) achieving radiographic PR/CR. 30 patients (83%) had surgery after neoadjuvant DTP, achieving R0/R1 resection in 29/30 (97%). Mean surgical morbidity score (0-4 scale, 4=unresectable) improved from 3.3 to 1.6 after DTP (p<0.01). Complete ATC pathologic response occurred in 20/30 patients (67%), while 10/30 (33%) had residual ATC in the surgical specimen. Postoperatively, 11/30 (37%) received adjuvant neck radiation, and 28/36 (78%) completed a median of 11 (range: 1-26) adjuvant DTP cycles. With median follow up 18 months, 15/36 (42%) patients died. Median OS was 20 months (95% CI: 12.6-NR); 1- and 2-year OS were 71% and 48%. Complete pathologic responders had better 2-year OS than those with residual ATC (69% vs. 22%, p=0.02). Median PFS was 13.9 months (95% CI, 7.5-NR); 1- and 2-year PFS were 57% and 36%. Grade 5 adverse events occurred in 8 patients (22%), including one possible (duodenal perforation), one probable (kidney injury with sepsis), and 6 unlikely/unrelated treatment-related deaths. Conclusions: Neoadjuvant DTP enables surgical resection in BRAF m-ATC compared with historical controls, and leads to improved PFS and OS. This approach should now be considered a standard of care for BRAF m-ATC. Clinical trial information: NCT04675710 . Total N=36 Age (y), median (range) 67 (46-86) Stage IVB/IVC, n (%) 15 (42%)/21 (58%) Best RECIST response neoadjuvant phase, n (%) CR 2 (6%) PR 24 (67%) SD 6 (17%) PD 4 (11%) Percent change target lesion diameter, mean (95% CI) -44% (-54%, -34%) Surgical morbidity score change, mean (95% CI) -1.7 (-2.1, -1.3)

6002 Background: There is a need for continued improvement in outcomes with systemic therapy for advanced cSCC. Pre-clinical data suggest immunologic synergy between IgG1 mAb therapy targeting EGFR and PD-1:PD-(L)1 blockade. Methods: Alliance A091802 is a randomized phase II trial of avelumab (AV) (800 mg) plus cetuximab (C) (500 mg/m2) vs. AV alone every 2 weeks for up to 2 years (yrs). C was given for 1 yr in the AV+C arm. Crossover at progression to AV+C was allowed in the AV arm. Randomization was 1:1 and stratified by PD-L1 [+(>1%) vs. -] and HIV status (+ vs. -). Eligible patients (pts) had distant metastatic or unresectable locally advanced cSCC, anti-PD-1/PD-L1 mAb naive, no prior cetuximab in the advanced setting, ECOG PS 0-2, HIV+ if CD4 >200 and VL <200. Pts with CLL, immunosuppression, or active autoimmune diseases were excluded. The primary endpoint was progression-free survival (PFS) (Ho: Median=12 mo vs Ha: 21 mo or a 75% improvement, power of 80% with one-sided alpha 0.2, n=57, 37 PFS events required). Secondary endpoints were overall survival (OS), confirmed response rate (ORR), clinical benefit rate, and toxicity. After 31/37 events, an early unplanned analysis (along with sensitivity analyses) was performed because it became apparent that 37 events would not be reached. These results were submitted to the Alliance Data and Safety Monitoring Board, which recommended releasing the data. Data cutoff was 1/16/25. Results: 60 pts were enrolled between 2019-2023; 57 pts were evaluable. Median age was 72 yrs (41‒93), 96.5% were white, 91.2% male, all HIV-; 75.4% PD-L1+. 84.2% were head/neck origin, 47.1% had distant metastasis, and there were no differences in baseline characteristics by arm. AV+C significantly improved PFS compared to AV [median 11.1 months (mo) (7.6‒not reached (NR)) vs. 4.8 mo (2.8‒NR) hazard ratio (HR) 0.53 95% CI (0.26‒1.09), one-sided p=0.041]. The median OS of AV+C vs. AV was NR (25.2‒NR) vs. 35.8 mo (18.6‒NR) HR 0.77 (0.33‒1.78) p=0.267. ORR was 31.0% in the AV+C arm and 21.4% in the AV arm. Treatment-related adverse events (TRAE) of any grade (G) occurred in 93% and 78.6%, respectively, and were G>3 in 48.3% and 21.5% of pts in the AV+C [most common G3 TRAEs were rash (20.7%) and infusion-related reaction (20.7%)] and AV arms, respectively. There were no G5 events. Outcomes after crossover and by PD-L1 status will be presented subsequently. Conclusions: Avelumab plus cetuximab significantly improved PFS vs. avelumab alone in advanced cSCC pts, without unexpected toxicity. Alliance A091802 supports a larger confirmatory study with combination cetuximab and PD-1:PD-(L)1 blockade. Support: U10CA180821, U10CA180882, U24CA196171; U10CA180868 (NRG Oncology); U10CA180888 (SWOG); https://acknowledgments.alliancefound.org . EMD Serono CrossRef Funder ID: 10.13039/100004755. Clinical trial information: NCT03944941 .

Abstract Ischemic cardiomyopathy (ICM) is a leading cause of heart failure characterized by extensive remodeling of the cardiac extracellular matrix (ECM). While initially adaptive, ECM deposition following ischemic injury eventually turns maladaptive, promoting adverse cardiac remodeling. The strong link between the extent of fibrosis and adverse clinical outcomes has led to growing interest in ECM targeted therapies to prevent or reverse maladaptive cardiac remodeling in ICM; yet, the precise composition of the ECM in ICM remains poorly defined. In this study, we employed a sequential protein extraction enabled by the photocleavable surfactant Azo to enrich ECM proteins from left ventricular tissues of patients with end-stage ICM (n=16) and nonfailing donor hearts (n=16). High-resolution mass spectrometry-based quantitative proteomics identified and quantified over 6,000 unique protein groups, including 315 ECM proteins. We discovered significant upregulation of key ECM components, particularly glycoproteins, proteoglycans, collagens, and ECM regulators. Notably, LOXL1, FBLN1, and VCAN were among the most differentially expressed. Functional enrichment analyses revealed enhanced TGFβ signaling, integrin-mediated adhesion, and complement activation in ICM tissues, suggesting a feedback loop driving continued ECM deposition in the end-stage failing heart. Together, our findings provide a comprehensive proteomic landscape of ECM alterations in the end-stage ICM myocardium and identify promising molecular targets for therapeutic intervention.

e20551 Background: Lung cancer is leading cause of cancer related mortality globally, with non-small cell lung cancer (NSCLC) comprising approximately 80% of all cases. The combination of immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or its ligand (PD-L1), specifically Durvalumab, and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors, such as Tremelimumab has demonstrated clinical efficacy in both adjuvant and neoadjuvant settings. However, a comprehensive systematic review of the available data is currently lacking. This study aims to assess the therapeutic efficacy of Durvalumab combined with Tremelimumab in NSCLC focusing on key end points including progression-free survival, overall survival, overall response rate, and safety, with particular attention to any adverse events and mortality. Methods: A comprehensive literature search was performed to identify relevant studies published until March 2024 across PubMed, Google Scholar, and Embase databases. Outcomes were pooled using the random effects DerSimonian-Laird model and reported as hazard ratio (HR) with a 95% confidence interval. A p-value of less than 0.05 was considered statistically significant. Results: A total of 1600 patients with NSCLC were included in the analysis, with 825 patients receiving Durvalumab plus Tremelimumab, and 775 patient receiving Standard chemotherapy across four studies. For Efficacy, following parameters were statistically significant: Progression Free Survival HR 0.75, 95%CI: 0.59, 0.92; Overall Survival HR 0.8, 95%CI: 0.58, 0.99; Overall Response Rate HR: 0.68, 95%CI: 0.47, 0.88, Mean Duration of Response was 12.23 month. Safety outcomes revealed that Durvalumab plus Tremelimumab versus Standard chemotherapy were comparable in mean percentage in terms of following parameters: Any Adverse Event (85.1% vs 92.8%), Any Serious Adverse Event (28.9% vs 17.75%), any mortality (6.35% vs 3.4%), Adverse Event leading to discontinuation (11.6% vs 10.13%), Any treatment related adverse event (69.96% vs 85.6%) and Any Treatment Related Death (0.9% vs 0.3%). Conclusions: Efficacy outcomes in patients treated with Durvalumab plus Tremelimumab demonstrated clinically meaningful improvements while the safety profile was comparable to that of Standard chemotherapy. Given the increasing use of this combination therapy as adjuvant and neoadjuvant treatment for NSCLC, further clinical trials are warranted to confirm and validate these findings.

e19554 Background: Adding daratumumab to standard multiple myeloma (MM) regimens improves response rates and clinical outcomes. Systematic reviews (meta-analyses) allow further evaluation of its effectiveness in MM patients with high-risk cytogenetic factors but are limited by model assumptions. his study addresses these limitations using a novel synthetic individual patient data (SynIPD) generation algorithm to enable a more robust analysis. Methods: Advances in AI have enabled the creation of synthetic data that mimics the statistical properties of real patient data, empowering aggregated analyses of clinical trials. This study focuses on newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) patients with high-risk cytogenetic profiles. Six studies were included: ALCYONE, CASSIOPEIA, and MAIA for NDMM, and CANDOR, CASTOR, and POLLUX for RRMM. Large language models extracted clinical evidence, and SynIPD was generated, incorporating cytogenetic profiles. Random-effects meta-analyses were conducted, and results were compared with pooled analyses using synthetic data. Results: Synthetic data were generated for three studies for NDMM (ALCYONE, CASSIOPEIA, MAIA) and three studies for RRMM (CANDOR, CASTOR, POLLUX). The generated hazard ratios (HRs) for each study closely aligned with reported HRs for high-risk patients, with a maximum relative error of less than 2%. By pooling these datasets, we obtained synthetic datasets for NDMM and RRMM patients. Stratified Cox regression analyses yielded HRs (95% confidence interval) of 0.764 (0.529-1.104) for NDMM and 0.431 (0.294-0.613) for RRMM. Random-effects meta-analyses showed HRs (95% confidence interval) of 0.764 (0.529-1.104) for NDMM and 0.425 (0.287-0.621) for RRMM. Compared with traditional meta-analysis techniques, the synthetic data approach provides additional clinical insights that were not available in the original publications. For instance, the clinical results for the three NDMM studies are summarized as KM curves in Figure 1, which were not reported in the original studies. Conclusions: Our results suggest that the addition of daratumumab to standard regimens improves PFS for RRMM patients with high-risk cytogenetic factors, although its benefit for NDMM patients is not statistically significant. Pooling synthetic data enhances the robustness of conventional meta-analysis outcomes. The identification of HRs and corresponding confidence intervals through SynIPD improves the credibility of our proposed method, offering a reliable approach to evaluating the efficacy of daratumumab in high-risk patients. Since SynIPD includes individual covariate information, it provides deep clinical insights beyond merely enhancing meta-analysis. In other words, any statistical results derived from the original IPD can be effectively approximated using SynIPD.

e19545 Background: Cytogenetic abnormalities (CA) at diagnosis are important prognostic factors in multiple myeloma (MM), but there is limited information on how these abnormalities evolve at first relapse and their significance. Methods: This retrospective study included patients aged ≥18 years, with a confirmed diagnosis of MM who experienced at least one disease relapse and had fluorescence in situ hybridization analysis within six months of both diagnosis and relapse. Data on CA and clinical outcomes were collected. High-risk (HR) secondary CA were defined as the presence of deletion of chromosome 17p (del17p) or gain or amplification of chromosome 1q. The primary objective was to evaluate changes in HR secondary CA at first relapse, while the secondary objective was to assess the impact of the cytogenetic changes on overall survival (OS) from diagnosis. Based on the presence or absence of HR secondary CA, patients who were tested for HR secondary CA at both time points were classified into four groups: 1) persistent absence of HR secondary CA, 2) emergence of HR secondary CA at relapse, 3) persistent presence of HR secondary CA, and 4) loss of HR secondary CA at relapse. Results: A total of 233 patients diagnosed between 2004 and 2023 were included. HR secondary CA were tested in 98.7% (n= 230) of patients at diagnosis, with 24.8% (n=57) testing positive. At first relapse, testing for HR secondary CA was performed in 97.4% (n=227) of patients, of whom 23.8% (n=54) tested positive. Del17p was evaluated in 98.3% (n=229) of patients at baseline and 95.7% (n=223) at relapse, with positivity increasing from 10.9% (n=25) to 15.3% (n=34). Gain or amplification of chromosome 1q was evaluated in 49.4% (n=115) at baseline and 25.5% (n=60) at relapse, with positivity rate rising from 28.7% (n=33) to 38.3% (n=23). There were no differences in overall response rate or very-good-partial-response-or-better rates to the initial therapy at diagnosis between the groups. (Table) Emergence/persistence of HR CA were associated with lower OS from diagnosis. Conclusions: Emergence of HR secondary CA at first relapse in MM has prognostic significance. These findings highlight the importance of serial cytogenetic testing for risk stratification. Response rate to initial line of therapy and overall survival from diagnosis among patients tested for HR secondary CA both at diagnosis and first relapse (n=224). Outcome Persistent absence of HR secondary CA(n=142) Emergence of HR secondary CA at relapse (n=25) Persistent presence of HR secondary CA (n=27) Loss of HR secondary CA at relapse(n=30) p-value Overall response rate a 75% (106) 76% (19) 63% (17) 67% (20) 0.5 b Very-good-partial response or better response rate 43% (61) 36% (9) 44% (12) 40% (12) >0.9 b Median (95% CI) OS from diagnosis in years 11.3 (9.7-13.4) 7.5 (5.1-12.1) 6.1 (4.2-9.4) 10.1 (6.5-14.1) <0.0001 c a Partial response or better; b Chi-square test; c Log-rank test.

3520 Background: Recent analyses highlight nonhierarchical outcomes using the 8 th Edition AJCC staging system for CC. For instance, the 5-year survival rate for stages I and IIIa patients (pts) closely align. Additionally, tumor deposits (TDs) have been established as significant prognostic indicators. The AJCCCCEP commissioned this study to develop an updated pathological staging system for CC focused specifically on pts without distant metastasis (M0), while retaining the existing stage IV classification. Methods: Individual patient data (IPD) from pts diagnosed with cc (2010- 2017) in the NCDB were divided into training (70%) and internal validation (30%) datasets. External validation used IPD from clinical trials. The primary endpoint was overall survival (OS). Risk classification development for M0 pts incorporated ungrouped data on pathologic T categories, the number of involved regional lymph nodes (LN+), and TD counts. Recursive partitioning and regression tree analyses were applied to construct hierarchical staging levels. Pre-specified criteria required survival probabilities to be consecutive and show clear separations using Kaplan-Meier (KM) estimates with pairwise log-rank test P of < 0.005 for the training and < 0.05 for validation analyses. Results: Data from 281,997 pts (median age 67 years, 50% male, 81% white, 55% T3, 19% T4, 44% N+, 26% M+, and 11% with ≥1 TD) were analyzed, with a median follow-up of 7.3 years. The updated staging system (Table) met pre-specified criteria, with all observed pairwise P < 0.0001 in the development and internal validation sets. KM OS curves displayed a hierarchical separation across all sub-levels after the 1 st year of diagnosis. Consistent results were seen in pts treated with adjuvant chemotherapy in 4 trials (all pair-wise P < 0.0001). Conclusions: The proposed pathological staging system for M0 pts fulfills pre-specified criteria for hierarchical risk stratification, validated both internally and externally, and provides an evidence-based update. Pending review process, the AJCCCCEP will recommend that these changes be made to the Version 9 staging protocol for colon cancer to improve prognostication for CC pts. Stage T, # of LN+, # of TD M % of pts 1y OS (CI), % 3y OS (CI), % 5y OS (CI), % I T1, 0, 0 0 5 96 (95-97) 91 (90-92) 84 (83-86) IIa T2, 0, 0 0 10 95 (94-95) 88 (88-89) 80 (79-81) IIb T1, 0, 1+T1, 1+, 0T2, 0, 1+T2, 1-4, 0T3, 0, 0 0 27 93 (92-93) 84 (84-85) 75 (75-76) IIIa T1, 1+, 1+T2, 1-4, 1+T2, 5+, 0T3, 0, 1+T3, 1-4, 0 0 14 92 (91-92) 80 (80-81) 71 (70-72) IIIb T2, 5+, 1+T3, 1-4, 1+T3, 5+, 0T4a, 0-4, 0T4b, 0-2, 0 0 13 86 (86-87) 69 (68-70) 58 (57-59) IIIc T3, 5+, 1+T4a, 0-4, 1+T4a, 5+, anyT4b, 0-2, 1+T4b, 3+, any 0 5 78 (77-80) 53 (51-54) 40 (38-41) IVa Any 1a 19 59 (58-60) 28 (28-29) 17 (16-18) IVb Any 1b 7 43 (42-44) 14 (13-14) 6 (6-7) CI: 95% confidence internal; Peritoneum involvement data were not available before 2018 in NCDB. Thus, IVa/b were based on 7 th Edition.

TPS9607 Background: The majority of 100,000 annual new U.S. cases of mel consist of localized early-stage disease that undergo wide local excision (WLE) +/- SLN biopsy (SLNB). The tumor draining lymph node is the initial site of immune response including formation of tumor mediated immune suppression and pre-metastatic niches. SLN positivity is a key prognostic factor in early stage mel. Thus, the SLN is a target for local immune intervention to boost the antitumor response. Vusolimogene oderparepvec (RP1) is an intratumorally administered oncolytic immunotherapy with unique potential for neo-adjuvant therapeutic application. RP1 is constructed from a high potency HSV1 strain (RH018A) modified to replicate selectively in tumors (deletion of neurovirulence factors ICP34.5 and ICP47). RP1 encodes GM-CSF and a fusogenic GALV-GP R- protein to maximize oncolytic potency and induce immunogenic cell death. Preclinical and clinical data demonstrate robust antitumor efficacy (including non-injected lesions) of RP1 alone and in combination with checkpoint inhibitors in advanced mel. This trial addresses a crucial gap in understanding the impact of RP1 on SLN dynamics and preventing disease recurrence in high-risk patients (pts). We hypothesize that in pts with high risk, clinically node negative mel (pT3b-T4b), RP1 will reduce rates of SLN positivity as compared to a historic control by favorably reshaping the immune landscape of the primary tumor, SLN, and the peripheral blood. Methods: This is an investigator-initiated, single arm phase 1/2 trial (NCT06216938) designed to assess efficacy and safety of neo-adjuvant RP1 in high-risk, clinically node-negative, non-uveal mel. Eligibility criteria: pT3b, T4a, or T4b non-uveal mel with visible residual tumor or positive biopsy margins, ECOG ≤1, and no prior oncolytic virus therapy. Pts receive 3 doses of neo-adjuvant RP1 (10e6 PFU day 1, 10e7 PFU on days 15 and 21), injected at the primary tumor site followed by standard WLE and SLNB within 35 days of dose 1. Biopsy of residual tumor or archival tumor tissue is obtained pre-RP1 and archival tissue from WLE and SLNB is obtained post-RP1. Blood samples are obtained with each RP1 dose and 3 months post-therapy. Pts are followed for 3 years. Primary endpoint: rate of SLN positivity in the overall cohort. Secondary endpoints: treatment related adverse events (per CTCAE), recurrence free survival, and overall survival. Exploratory endpoints: immunophenotype and microenvironment of the primary tumor, SLN and peripheral blood pre- and post- RP1 (via IHC, IF, and flow cytometry). The observed rate of SLN positivity will be compared to the predicted rate (Melanoma Institute of Australia Prediction Tool for SLN metastatic risk) with a one-sided, one-sample proportion test. Kaplan-Meier estimates will be provided for survival endpoints. The trial is active with 13 of 25 pts enrolled in January 2025. Clinical trial information: NCT06216938 .