Introduction: Uveal melanoma (UM) metastasis follows variable temporal trajectories, with recurrences ranging from rapid onset to decades post primary therapy. Outcomes after metastasis also vary significantly. Predicting high-risk “early” progressors from “late” recurring phenotypes would facilitate tailored approaches to management. Methods: A literature review was conducted to synthesise clinicopathologic and molecular predictors of metastatic latency and their impact on survival outcomes in patients with UM. Results: Early dissemination is associated with older age, male sex, larger basal dimensions, and ciliary body involvement. Genetically, monosomy 3, 8q gain, and BAP1 loss drives a rapid-progression phenotype and poor survival. Conversely, SF3B1 mutations define a distinct late-onset cohort (median: >6 years) with persistent lifetime risk. PRAME expression significantly accelerates metastatic kinetics, even in gene expression profiling class 1 tumours. While early recurrence correlates with dismal outcomes, late-onset disease is associated with extended post-metastasis survival and greater eligibility for interventions like liver-directed therapy. Conclusion: Metastatic timing is related to biologic rather than stochastic determinants. Integrating molecular profiling with clinical staging and patient factors allows for more precise temporal risk stratification. These insights are essential for tailoring surveillance intensity and selecting candidates for emerging adjuvant therapies, such as tebentafusp and protein kinase C inhibitors.

Metastatic uveal melanoma (mUM) is an aggressive cancer with limited treatment options; 85-90% of tumors harbor activating GNAQ and GNA11 mutations. Uveal melanoma cells also express PMEL (also known as PMEL17 or gp100), a melanocyte lineage antigen. DYP688, a novel biology-matched antibody-drug conjugate, binds surface PMEL and delivers the potent Gαq/Gα11 (Gq/11) inhibitor SDZ475 as payload by internalization. This dose-escalating first-in-human phase 1 study of DYP688 in patients with metastatic uveal melanoma and other GNAQ/GNA11-mutant melanomas assessed safety as the primary endpoint and pharmacokinetics and preliminary antitumor activity as secondary endpoints. Sixty-six patients received varying DYP688 doses and schedules. Grade 3 treatment-related adverse events occurred in five patients (7.6%), including one dose-limiting toxicity of grade 3 hypotension. Objective responses were seen in 13 out of 66 patients (19.7%) and tumor reduction in 47 out of 66 patients (71.2%). Median progression-free survival was 7.2 (95% CI: 5.3-7.8) months. In summary, DYP688 was well tolerated and showed preliminary efficacy, supporting this novel therapeutic approach. ClinicalTrials.gov identifier: NCT05415072 .

Abstract Background: Colorectal liver metastases (CRLM) are the predominant cause of mortality in metastatic colorectal cancer (CRC). While immune checkpoint inhibitors have transformed outcomes for microsatellite instability-high (MSI-H) tumors, >95% of CRLM are microsatellite stable (MSS) and remain refractory to current immunotherapy approaches. The liver microenvironment uniquely drives immunotherapy resistance, partly through expansion of suppressive myeloid-derived suppressor cells (MDSCs) that limit T cell activation. Nelitolimod, a novel Class C TLR9 agonist, induces MDSC apoptosis, activates dendritic and B cells, and reprograms the tumor microenvironment (TME) toward immune activation. Additionally, regional administration using the FDA-approved TriNav Pressure-Enabled Drug Delivery (PEDD) catheter overcomes high hepatic interstitial pressures and minimizes drug reflux, enabling more effective intratumoral delivery and potentially restoring antitumor immunity. This investigator-initiated pilot trial tests feasibility and safety of neoadjuvant Nelitolimod delivered by PEDD in resectable MSS CRLM. Methods: This is a first-in-human single-arm, phase I feasibility and safety trial (NCT07172282). Ten adults with radiographically confirmed, resectable MSS CRLM will be enrolled. After standard chemotherapy, patients receive three weekly intrahepatic infusions of Nelitolimod via PEDD, followed by liver resection 2-6 weeks post-treatment. The 2mg dosage of Nelitolimod is based on prior experience with >400 prior regional infusions and an established safety profile. Patients are monitored for treatment-emergent adverse events (AEs), post-operative complications, and ability to complete planned resection. The primary endpoint is feasibility, defined as ≥8 of 10 patients proceeding to timely curative-intent liver resection. Secondary endpoints include safety (treatment-emergent AEs, surgical complications) and efficacy signals (R0 rate, tumor regression grade using the modified Rubbia-Brandt scoring system, mRECIST response, disease-free survival). Exploratory objectives include comprehensive immune cell profiling to assess treatment-induced modulation comparing pre and post- treatment intratumoral and peripheral immune cell populations and function, alongside tumor-informed circulating tumor DNA (ctDNA) dynamics and stool microbiome profiling. The study opened for enrollment September 2025 and has two patients enrolled. Citation Format: Nicholas J. Hornstein, Axel Grothey, Richard Carvajal, Codruta Chiuzan, Craig Devoe, Anna Levy, Gerardo Vitiello, David Tuveson, Danielle Deperalta, Matthew Weiss, Arvind Rishi, Igor Lobko, Jonathan Weinstein, Semir Beyaz, Peter Westcott, Sepideh Gholami. First-in-human study of neoadjuvant regional delivery of the TLR9 agonist Nelitolimod via pressure enabled drug delivery (PEDD) in resectable microsatellite stable colorectal liver metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT081.

Metastatic uveal melanoma (mUM) is an aggressive cancer with limited treatment options; 85-90% of tumors harbor activating GNAQ and GNA11 mutations. Uveal melanoma cells also express PMEL (also known as PMEL17 or gp100), a melanocyte lineage antigen. DYP688, a novel biology-matched antibody-drug conjugate, binds surface PMEL and delivers the potent G alpha q/G alpha 11 (Gq/11) inhibitor SDZ475 as payload by internalization. This dose-escalating first-in-human phase 1 study of DYP688 in patients with metastatic uveal melanoma and other GNAQ/GNA 11-mutant melanomas assessed safety as the primary endpoint and pharmacokinetics and preliminary antitumor activity as secondary endpoints. Sixty-six patients received varying DYP688 doses and schedules. Grade 3 treatment-related adverse events occurred in five patients (7.6%), including one dose-limiting toxicity of grade 3 hypotension. Objective responses were seen in 13 out of 66 patients (19.7%) and tumor reduction in 47 out of 66 patients (71.2%). Median progression-free survival was 7.2 (95% CI: 5.3-7.8) months. In summary, DYP688 was well tolerated and showed preliminary efficacy, supporting this novel therapeutic approach. ClinicalTrials.gov identifier: .

Supplementary Figures S1-S6 and figure legends.

PURPOSE:We conducted an integrated safety analysis from three clinical studies of tebentafusp, a first-in-class ImmTAC bispecific T-cell engager, which can redirect T cells to target glycoprotein 100-positive cells, in metastatic uveal melanoma. EXPERIMENTAL DESIGN:HLA-A*02:01-positive patients with unresectable or metastatic uveal melanoma enrolled in three clinical trials (IMCgp100-01, IMCgp100-102, and IMCgp100-202) who received ≥1 dose of tebentafusp were included. Safety data were pooled to evaluate the profile, onset, and management of treatment-related adverse events (TRAE). Adverse events of special interest included cytokine release syndrome (CRS), acute skin reactions (ASR), and liver function test elevations. Primary prophylaxis with medications was not permitted. RESULTS:Among 410 tebentafusp-treated patients, the most common TRAE were pyrexia (77%), pruritus (71%), and chills (53%). Most patients experienced CRS (88%), almost always mild (grade 1, 19%) to moderate (grade 2, 67%) in severity, with only 2% experiencing grade 3 (n = 6) or 4 (n = 1) CRS. Additionally, 92% had at least one ASR, primarily pruritus and rash, with 21% having a grade 3 event. Onset of CRS and ASR was within 1 to 2 days of infusion and generally reversible with standard interventions. Elevated liver function tests were generally mild and resolved without intervention. Most TRAE occurred following the first few infusions and diminished in frequency and severity with repeated dosing; no cumulative TRAE were detected. Discontinuations due to TRAE were rare (2%); there were no treatment-related deaths. CONCLUSIONS:TRAE were consistent with tebentafusp's mechanism of action, mostly occurred during dose escalation, and were predictable, reversible, and manageable with appropriate surveillance and intervention.

BACKGROUND:Tebentafusp has significantly improved overall survival in HLA-A*02:01+ metastatic uveal melanoma (mUM) patients even in those with a best objective response of progressive disease. Thus, strategies to maintain tebentafusp therapy are critical. Here, we examine the efficacy and safety of adding concurrent local therapy (CLT) to tebentafusp upon radiological progression with tebentafusp alone. PATIENTS AND METHODS:This multicenter retrospective study included mUM patients treated with tebentafusp and CLT, consisting of extrahepatic soft tissue irradiation and liver-directed therapies (LDTs). Efficacy of target and nontarget sites were assessed per RECIST version 1.1. PFS with tebentafusp alone (PFS1) was compared to that after adding CLTs to tebentafusp upon progression (PFS1+PFS2). ctDNA responses were explored. RESULTS:Of the 30 eligible patients, 21 (70%) received concurrent LDT, 7 (23%) had extrahepatic irradiation, and 2 (7%) had both. The objective response rate (ORR) was 12% (95% CI, 3-32) for tebentafusp alone and 28% (95% CI, 14-47) after adding CLTs. The disease-control rate with tebentafusp alone was 44% (95% CI, 25-65) vs 63% (95% CI, 44-78) after CLT. Median PFS1 was 5.8 months (95% CI, 2.8-13.4), while median PFS1+PFS2 was 14.8 months (95% CI, 9.2-NA). CLT thereby allowed treatment beyond progression with tebentafusp for approximately 9 months. Two patients (66%) had decreased ctDNA with tebentafusp alone, while 4 (100%) had decreased ctDNA after CLT. There were no treatment discontinuations due to toxicities from tebentafusp with CLT. CONCLUSIONS:CLT with tebentafusp was well-tolerated, extending the duration of tebentafusp benefit in a highly selected mUM population. This merits further studies to assess clinical utility.

PURPOSE:To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of ficerafusp alfa (BCA101), a first-in-class bifunctional protein targeting EGFR and TGF-β, as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors. PATIENTS AND METHODS:At escalating doses in a parallel 3 + 3 design, patients with EGFR-driven advanced solid tumors received weekly intravenous ficerafusp alfa as monotherapy (64-1,500 mg) or in combination (240-1,500 mg) with pembrolizumab (200 mg i.v. every 3 weeks). The primary objective was to determine safety/tolerability. Secondary objectives included assessment of pharmacokinetics, immunogenicity, and preliminary efficacy per investigator-assessed response. Exploratory analyses included pharmacodynamic biomarkers. RESULTS:Among 61 patients (monotherapy, n = 46; combination, n = 15), the most common treatment-related adverse events included acneiform dermatitis (46%) and fatigue (20%) with monotherapy and acneiform dermatitis (73%), fatigue (53%), pruritus (40%), epistaxis (40%), and maculopapular rash (40%) with combination therapy. One patient had a dose-limiting toxicity with 1,250-mg monotherapy (grade 3 anemia and hematuria). The MTD was not reached in either cohort. With monotherapy, objective response was observed in one of 42 evaluable patients and 16 (38%) achieved stable disease. With combination therapy, four of 13 evaluable patients (31%) had a confirmed response, including one with head and neck squamous cell carcinoma refractory to anti-PD-1 therapy and cetuximab. Prolonged neutralization of plasma TGF-β1 was observed at doses ≥500 mg. CONCLUSIONS:Ficerafusp alfa exhibited a manageable safety profile and clinical activity as monotherapy and in combination with pembrolizumab, with exposure increasing proportionally at anticipated therapeutic doses. See related commentary by Choudhury et al., p. 4617.

BackgroundThere is no neoadjuvant immunotherapy for early-stage oral cancer patients. We report a single-arm, open-label, pilot clinical trial assessing the efficacy and safety of topical toll-like receptor-7 (TLR-7) agonist, imiquimod, utilized in a neoadjuvant setting in early-stage oral squamous cell carcinoma (OSCC).MethodsThe primary endpoint is reduction in tumor cell counts assessed by quantitative multiplex immunofluorescence and the immune-related pathologic response. The secondary endpoint is safety.Results60% of patients experienced a 50% reduction or greater in tumor cell count post-treatment (95% CI = 32% to 84%). Similarly, 60% of patients had immune-related major pathologic response (irMPR) with two complete pathologic responses, and 40% had partial response (PR) with the percent residual viable tumor ranging from 25% to 65%. An increase in functional helper and cytotoxic T-cells significantly contributed to a reduction in tumor (R=0.54 and 0.55, respectively). The treatment was well tolerated with the application site mucositis being the most common adverse event (grades 1-3), and no grade 4 life-threatening event. The median follow-up time was 17 months (95% CI = 16 months - not reached), and one-year recurrence-free survival was 93% of evaluable patients.ConclusionNeoadjuvant imiquimod immunotherapy could be safe and promising regimen for early-stage oral cancer.Trial registrationClinicalTrials.gov, Identifier NCT04883645.

Abstract T-cell position in the tumor microenvironment determines the probability of target encounter and tumor killing. CD8+ T-cell exclusion from the tumor parenchyma is associated with poor response to immunotherapy, and yet the biology that underpins this distinct pattern remains unclear. Here we show that the vascular destabilizing factor angiopoietin-2 (ANGPT2) causes compromised vascular integrity in the tumor periphery, leading to impaired T-cell infiltration to the tumor core. The spatial regulation of ANGPT2 in whole tumor cross-sections was analyzed in conjunction with T-cell distribution, vascular integrity, and response to immunotherapy in syngeneic murine melanoma models. T-cell exclusion was associated with ANGPT2 upregulation and elevated vascular leakage at the periphery of human and murine melanomas. Both pharmacologic and genetic blockade of ANGPT2 promoted CD8+ T-cell infiltration into the tumor core, exerting antitumor effects. Importantly, the reversal of T-cell exclusion following ANGPT2 blockade not only enhanced response to anti-PD-1 immune checkpoint blockade therapy in immunogenic, therapy-responsive mouse melanomas, but it also rendered nonresponsive tumors susceptible to immunotherapy. Therapeutic response after ANGPT2 blockade, driven by improved CD8+ T-cell infiltration to the tumor core, coincided with spatial TIE2 signaling activation and increased vascular integrity at the tumor periphery where endothelial expression of adhesion molecules was reduced. These data highlight ANGPT2/TIE2 signaling as a key mediator of T-cell exclusion and a promising target to potentiate immune checkpoint blockade efficacy in melanoma. Significance: ANGPT2 limits the efficacy of immunotherapy by inducing vascular destabilization at the tumor periphery to promote T-cell exclusion.

Preclinical studies have shown that cyclin E overexpression enhances sensitivity to WEE1 inhibition in both in vitro and in vivo models. However, the molecular correlates of response to WEE1 inhibitors in patients with refractory solid tumors harboring CCNE1 amplifications remain poorly characterized. Patients with CCNE1 amplified solid tumors were enrolled a phase II trial of adavosertib (NCT03253679). Correlative blood and tumor tissues specimens were collected at the baseline and after the treatment initiation. Immunohistochemistry (IHC), RNA sequencing (RNA-seq) and whole exome sequencing (WES) were conducted to correlate with major clinical outcomes. Treatment with adavosertib did not consistently affect downstream protein levels in this heterogenous patient population. The median progression-free survival (PFS) in CCNE1 amplified patients with low CCNE1 protein expression or moderate CCNE1 gene amplificants (<20 copies of CCNE1) was numerically longer than those with high CCNE1 protein expression or super-amplificants (>20 copies), respectively. TP53 aberrations emerged as the most frequent concurrent genomic alterations. Compared with the baseline specimens, on-treatment tissues showed significant increases in the expression of the immunosuppressive genes such as FKBP5, TSC22D3, and PVALB. By pathway-level RNA-seq analyses, non-responders exhibited higher expression of the TGF-beta pathway, while responders showed elevated activity of the PI3K, JAK-STAT and NF-kB pathways. Immune-desert tumor microenvironment (TME) displayed rapid tumor progression in CCNE1 amplified patients treated with adavosertib. Biomarker analyses using IHC, RNA-seq and WES showed WEE1 inhibition induced significantly expression of the immunosuppressive genes. Patients with immune-desert TME at baseline or on treatment responded poorly to WEE1 inhibition, supporting further exploration of WEE1 inhibition in combination with TME-modulated immunotherapy for the treatment of patients with CCNE1 amplified malignancies. Siqing Fu, Camila Braganca Xavier, Khanda Keyomarsi, Yan Wang, Katherine Ferry-Galow, Deborah Wilsker, Francesca Paradiso, Vladimir Kushnarev, Yuan Yuan, Rebecca A. Previs, Anthony D. Elias, Richard Carvajal, Thomas J. George, Shuyang Yao, Ying Yuan, Ecaterina Ileana Dumbrava, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, Jordi Rodon Ahnert, Shannon Westin, Funda Meric-Bernstam. Biomarker analyses of WEE1 inhibition in patients with refractory CCNE1 amplified solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A006.

Metastatic uveal melanoma is an aggressive disease with poor outcome, which is refractory to immune checkpoint inhibitors. A T cell receptor (TCR)-based CD3 bispecific, tebentafusp, delivers clinical benefit in patients with metastatic uveal melanoma. Understanding the molecular basis for the anti-tumor activity of tebentafusp in an indication where checkpoint inhibitors are ineffective could aid in identification of other solid tumor indications where CD3 bispecifics may serve an unmet need. By analyzing tumor biopsies taken prior to treatment, early on-treatment, and at progression (NCT02570308), using RNA sequencing (RNA-seq) and immunohistochemistry (IHC), we show that expression of interferon-related genes in the tumor prior to treatment is associated with improved overall survival and tumor reduction on tebentafusp, that T cell recruitment occurs even in tumors with a low baseline level of T cell infiltration, and that durability of changes induced in the tumor microenvironment is key for survival duration.

TPS9597 Background: Uveal melanoma (UM) is the most common primary intraocular malignancy, accounting for nearly 90% of ocular melanomas and up to 5% of melanomas overall. Approximately 50% of patients (pts) with UM will develop metastatic disease, with the liver being the most common site of metastases (~90%). The prognosis for pts with metastatic UM (mUM) is poor, with a median overall survival (OS) of approximately 1 year. Effective treatment options for mUM are limited as it responds poorly to single-agent immune checkpoint inhibitors (ICIs; <10% response rate). Response rates are slightly higher with combination therapies (12%–18%), but often at the expense of increased toxicity. Tebentafusp is FDA approved for mUM based on survival benefit; however, its use is restricted to pts who are HLA-A*02:01 positive, and only ~10% of pts achieve an objective response. RP2 is a selectively replication-competent herpes simplex virus type 1–based oncolytic immunotherapy expressing GM-CSF, a fusogenic glycoprotein (GALV-GP-R–), and an anti–CTLA-4 antibody-like molecule. Prior phase 1 preliminary clinical data of RP2 as monotherapy or in combination with nivolumab (nivo) demonstrated a promising safety profile and anti-tumor activity with an ORR of 29.4% in 17 patients with mUM, most of whom had received prior ICIs. This study will assess the efficacy and safety of RP2 + nivo vs ipilimumab (ipi) + nivo in pts with ICI-naïve mUM (NCT06581406; RP2-202). Methods: This is a randomized, controlled, phase 2/3 study. Key eligibility criteria include age ≥18 years and confirmed unresectable mUM with lesions amenable to injection. Pts with metastatic disease who have had prior exposure to ICIs since the time of UM diagnosis, involvement of >33.3% of the liver, or a history of prior liver- or lesion-directed therapy are not eligible for enrollment. Enrolled pts (N = ~280) will be randomized 1:1 to receive either RP2 + nivo or ipi + nivo. In the RP2 + nivo arm, RP2 will be given intratumorally initially at 1 x 10 6 PFU/mL, then every 2 weeks (Q2W) at 1 x 10 7 PFU/mL for 7 doses in combination with intravenous (IV) nivo (240 mg). In the ipi + nivo arm, pts will receive IV ipi (3 mg/kg) and IV nivo (1 mg/kg) Q3W for 4 doses. Pts in both arms may then receive IV nivo at 240 mg Q2W or 480 mg Q4W for up to 2 years from the first dose. The co-primary endpoints are OS and progression-free survival by independent central review using RECIST 1.1. Secondary endpoints are overall response rate, duration of response, disease control rate, clinical benefit rate, duration of clinical benefit, and safety, including incidence of treatment-emergent adverse events (AEs), serious AEs, and immune-mediated AEs. Clinical trial information: NCT06581406 .

e23324 Background: Due to the hepatotropic pattern of metastasis in uveal melanoma (UM), liver directed therapies (LDT) are commonly used for the treatment of advanced disease. The PUMMA meta-analysis (Khoja et al, 2019) assessed patients (pts) with metastatic UM (mUM) treated on trials conducted from 2000-2016 and suggested improved outcomes for those treated with LDT. Methods: Using data from 7 centers in the US, Canada, the UK and Australia collected between as part of the Ocular Melanoma Natural History (OMNi) study, we assessed this finding in a more contemporary dataset and investigated potential global variations in practice patterns. Analysis was performed on data entered as of May 2024. Results: Of 985 pts enrolled, 283 developed mUM and received at least 1 line of treatment (tx; 77-US; 160-Canada; 30-UK; 16-Australia). 164 received regional (R) tx (LDT, surgery, radiation; 41% US pts, 35% Canadian pts, 46% UK pts, 55% Australian pts), with 130 treated in the first-line (1L) setting. 212 received systemic (S) tx (51% US pts, 55% Canadian pts, 51% UK pts, 55% Australian pts), with 137 treated in the 1L setting. Concurrent (C; any R tx delivered while a S tx was ongoing) was administered in 50 patients (18% US pts, 10% of Canada pts, 3% UK, pts 5% Australian pts), with 16 treated in the 1L setting. At the time of 1L tx, median age was 63 (range, 25-92), 62 (range, 24-88), and 64 (range, 42-83) years for those treated with S, R, and C tx, respectively. 47%, 50% and 25% were female of those treated with S, R, and C tx, respectively. Mean diameter of the largest tumor lesion and percentage of cases with stage M1b/c disease at time of 1L tx were 1.5cm and 20%, 1.1cm and 19%, and 0.6 cm and 0% for those treated with S, R or C tx, respectively. There was no significant difference in proportion of patients with liver-only disease who received 1L S or R/C tx (61 vs 62%, respectively). Median overall survival (OS) was 32, 24 and 32 months for those treated with S, R or C tx, respectively, with no significant difference observed across groups (p = 0.09). Conclusions: The use of C tx was more common in the US and Canadian centers when compared with those in the UK and Australia. Patient and tumor characteristics were similar between those treated with 1L S and R therapies, with no difference in OS observed in this dataset based upon initial tx strategy. Clinical trial information: NCT04588662 . Therapy Pts Receiving 1L Systemic Therapy (n = 137) Pts Receiving 1L Regional Therapy (n = 130) Pts Receiving 1L Concurrent Therapy (n = 16) Systemic Regional Checkpoint Blockade 104 (76%) n/a 10 (62%) n/a Targeted Therapy 22 (16%) n/a 6 (38%) n/a Other Systemic Therapy 11 (8%) n/a 0 (0%) n/a Surgery or Radiofrequency Ablation n/a 62 (48%) n/a 3 (18%) Radiotherapy n/a 22 (17%) n/a 4 (25%) Other Liver Directed Therapy n/a 34 (26%) n/a 6 (38%) Radioembolization or Chemoembolization n/a 9 (7%) n/a 2 (12%) Percutaneous Hepatic Perfusion n/a 3 (2%) n/a 1 (6%)

BACKGROUND:Intramedullary primary spinal melanoma (IPSM) is a rare tumor, with limited reports on its clinical presentation, radiographic features, histopathological and genetic factors, diagnosis, and management. OBSERVATIONS:A 49-year-old male presented with a 9-month history of intermittent, progressive left upper-extremity radiculopathy and left-sided numbness. Magnetic resonance imaging revealed an intramedullary tumor at the C6-T1 vertebral levels. Intraoperatively, upon opening the dura, the tumor was noted to be dark in appearance. Dorsal column mapping allowed for safe myelotomies above and below the tumor bulk, and a gross-total resection was achieved. The patient awoke with mild decreased lower-extremity sensation and proprioception but full motor strength. Surgical pathology was consistent with melanoma. Further workup ruled out the possibility of alternative primary neoplastic sites, and a diagnosis of IPSM was made. The patient was planned for radiation therapy (RT) and immune checkpoint inhibitor therapy in follow-up. LESSONS:Fewer than 40 cases of IPSM have been described in the literature. While patients with IPSM present with progressive symptomology and unique imaging findings, surgical pathology is required for a diagnosis. The optimal treatment paradigm likely includes resection, RT, and/or systemic therapies. Molecular and genetic markers might enable more efficient diagnosis and optimize therapy for these patients. https://thejns.org/doi/10.3171/CASE24732.

9537 Background: Tebentafusp, a bispecific soluble TCR specific for a gp100 peptide, is licensed for the treatment of metastatic uveal melanoma (mUM) in HLA-A*02:01+ individuals. 82% of patients (pts) with mUM in the IMCgp100-102 (previously treated; 2L+) and 61% in IMCgp100-202 (frontline; 1L) studies, respectively, had detectable baseline ctDNA. There is a strong relationship between decrease in ctDNA by 9 weeks and overall survival (OS) [Carvajal 2022; Hassel & Piperno-Neumann 2023]. Patients with undetectable baseline ctDNA had improved survival despite having macroscopic disease. In this study, we report the characteristics of baseline ctDNA undetectable vs detectable disease. Methods: Disease characteristics of 202 1L (Study 202) and 117 2L+ (Study 102) pts who had baseline undetectable or detectable ctDNA (unDNA vs detDNA) were compared in a post-hoc unplanned analysis. ctDNA detection was analysed at baseline and up to week 9 on tebentafusp using targeted mPCR-NGS assay for mutations in 15 genes including GNAQ, GNA11, SF3B1, CYSLTR2, PLCB4 and EIF1AX. Largest lesion size groups (≤ 3 cm, 3-8 cm, > 8 cm) were defined by American Joint Committee on Cancer 7 th Ed. Presence of oncogenic mutations in GNAQ, GNA11, SF3B1 and BAP1 were assessed by WES on metastatic tissue biopsies. Results: Baseline ctDNA levels increased in association with size of largest lesion regardless of number of prior therapies. However, there was an association between disease burden (defined by largest lesion size) and unDNA vs detDNA in both studies, with all pts with largest liver lesion > 8 cm having detDNA. In Study 202, % of the population with unDNA vs detDNA was 50% vs 50% for ≤ 3cm and 27% vs 73% for 3.1-8 cm. While OS was similar for unDNA & detDNA in pts with ≤ 3cm lesions, OS was longer for pts with unDNA vs detDNA who had baseline tumor size 3.1-8 cm in both studies (Table). Within this 3.1-8 cm group, pts with unDNA tended to have lower LDH, AST, and ALP. Initial analysis showed no difference in the frequency of GNAQ, GNA11, SF3B1 or BAP1 mutations between unDNA and detDNA groups. Further data on somatic mutation defined groups and RNAseq gene expression in unDNA and detDNA groups will be presented. Conclusions: Patients with unDNA were more likely to have smaller disease burden than those with detDNA; however, many pts with unDNA had a significant burden of metastatic disease. Baseline unDNA was associated with improved OS outcome vs detDNA in pts with 3.1-8 cm baseline metastatic deposits, but not in pts with ≤ 3cm disease. No association was seen between oncogenic background of GNAQ/GNA11/SF3B1/BAP1 and unDNA vs detDNA. Clinical trial information: NCT02570308 ; NCT03070392 . [Table: see text]

2622 Background: Immunotherapy (ICI) has shown limited survival benefit in patients (pts) with advanced HCC and intrahepatic cholangiocarcinoma (ICC). Nelitolimod (SD-101), a Class C toll-like receptor-9 (TLR-9 agonist), depletes MDSCs while broadly stimulating the tumor microenvironment. Given safety challenges with IV infusion and distribution limitations of needle injection, we studied hepatic arterial infusion (HAI) of nelitolimod with Pressure-Enabled Drug Delivery (PEDD) to enhance ICI responsiveness. Methods: Pts with advanced HCC or ICC were enrolled. Nelitolimod was dose-escalated without ICI (Cohort A), with pembrolizumab (Cohort B), or with nivolumab + ipilimumab (Cohort C). Nelitolimod administered with HAI for 2 cycles, with 3 weekly doses per cycle using the TriNav device. Primary endpoints included safety and optimal dose determination. Immune cells were examined in blood and tumor tissue using multiplex IF, flow cytometry, and Nanostring. Results: At data cutoff, 29 pts [70% ICC, 30% HCC] were enrolled, 23 received at least one dose of nelitolimod: 3 in Cohort A (4 mg), 8 in Cohort B (2 and 4 mg) and 12 in Cohort C (2 and 4 mg). Median age was 64.5. Only 1 pt was treatment-naïve; 4, 2L (17%); 5, 3L (22%); 14, > 4L (61%). 26% pts had > 10 liver tumors. 3 pts (13%) experienced serious treatment-related adverse events (AE); 1 pt dose-limiting toxicity. Five pts experienced LFT elevations, most G1 with 2 reported as G3. In cohort A, 1 of 3 evaluable pts had SD as best on-treatment response. In cohort B, 1 of 4 evaluable pts had SD as best on-treatment response, others experienced PD by RECIST 1.1. In cohort C 2 mg, 2 of 5 had SD reported at Day 53. At 4 mg dose in cohort C, 3 of 3 pts had disease control, with one CR in the liver (5L ICC) and 2 SD. Decreases were noted in the target liver lesion (31.3 to 17.5 mm), non-target liver lesion, and extra-hepatic lymph nodes on days 53 and 84 with complete response of target liver lesions and stability of extra hepatic nodal lesions reported on Day 154. Median PFS in the Cohort C 4 mg dose level is >120 days. Median OS for this group has not reached (range 120-170 days). Immune effects in cohort C 4 mg pts included increases in liver tumor CD4+ and CD8+ T cells, along with a decrease in the MDSC:CD8+ T cell ratio. Gene expression changes in cohort C 4 mg pts revealed increased Th1 programming in tumor tissue, with increased interferon, cytokine, TLR, Th1, and lymphocyte activation signals in surrounding normal liver. Changes among blood immune cells included increased IFNg and IL2-R expression, with decreased IL17A and VEGFA. Conclusions: HAI of nelitolimod has been well tolerated and associated with encouraging immunologic activity in HCC and ICC. Clinical and biologic activity in cohort C at 4mg is supportive of further enrollment in this cohort. Clinical trial information: NCT05220722 .