e23566 Background: Advanced undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLS) are difficult to treat soft tissue sarcomas with response rates to first line systemic therapy between 10-30%. However, both UPS and DDLPS have been shown to have measurable tumor infiltrating lymphocyte (TIL) populations. LN-144 (lifileucel), an autologous TIL product derived from unresectable or metastatic melanoma, was shown to have an overall response rate (ORR) of 36% in heavily pretreated melanoma patients with a median DOR of 19.7 months. We hypothesized that generation and infusion of LN-145, an autologous TIL product from non-melanoma solid tumors, in this case UPS and DDLPS, would be both safe and feasible. Methods: NCT05607095 is a single center multi-cohort pilot trial with Cohort 2 enrolling patients with metastatic or unresectable UPS or DDLS to undergo autologous TIL therapy with LN-145. Eligible patients had to receive at least 1 prior line of systemic therapy, a lesion at least 1.5 cm in size available for TIL harvest, and adequate organ function and performance status (ECOG 0-1). After surgical excision of suitable tumor for TIL expansion, successful LN-145 product generation was determined by characteristics that meet pre-specified criteria in the LN-145 IND. Patients then underwent nonmyeloablative lymphodepletion with cyclophosphamide (60 mg/kg x 2 doses) and fludarabine (25 mg/m 2 x 5 doses). LN-145 was then infused and expanded with intravenous interleukin 2 (600,000 IU/kg up to 6 doses). Primary endpoints of the trial were feasibility, defined as ³6 of 10 harvested pts undergoing LN-145 therapy, and safety, defined by the incidence of Grade ³3 adverse events (AE) as measured by CTCAE v5.0. Key secondary endpoints included estimated LN-145 manufacture rates and efficacy (ORR) utilizing RECIST 1.1. Exploratory endpoints include persistence of LN-145 cells and immune correlates in tissue and peripheral blood and their potential association with objective response and toxicity. Safety and efficacy measures will be summarized using point estimates and a Clopper Pearson exact confidence interval will be used. The final results of the primary feasibility and safety endpoints and secondary feasibility endpoint for the first 10 enrolled patients as well as and preliminary secondary efficacy and exploratory correlative studies through week 12 for 7 treated patients will be reported as late-breaking abstract after data lock on March 1, 2026. Clinical trial information: NCT05607095 .

TPS9598 Background: Uveal melanoma (UM) is the most common primary intraocular malignancy, accounting for ~90% of ocular melanomas and 5% of all melanomas. Half of patients with UM develop metastases, most commonly in the liver (~90%). The prognosis for patients with metastatic UM (mUM) is poor, with a median overall survival (OS) of ~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 these often have increased toxicity. Tebentafusp is FDA-approved for mUM based on survival benefit but is restricted to patients who are HLA-A*02:01 positive, and only ~10% of patients 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 preliminary clinical data of intratumoral RP2 as monotherapy or in combination with nivolumab demonstrated a promising safety profile and anti-tumor activity with an overall response rate (ORR) of 29.4% and disease control rate of 58.8% in 17 patients with mUM, most of whom had received prior ICIs. This study will assess the efficacy and safety of RP2 + nivolumab vs ipilimumab + nivolumab in patients with ICI-naïve mUM. Methods: This is a multicenter, randomized, controlled, phase 2/3 study (NCT06581406; RP2-202). Key eligibility criteria include age ≥18 years and confirmed unresectable mUM with at least 1 lesion amenable to injection; up to 1 prior line of therapy in the metastatic setting is allowed. Patients with prior exposure to ICIs since the time of mUM diagnosis, >50% liver involvement, or previous selected liver-directed therapies are not eligible. Enrolled patients (N = ~280) will be randomized 1:1 to receive either RP2 + nivolumab or ipilimumab + nivolumab. In the RP2 + nivolumab arm, RP2 will be given intratumorally initially at 1 × 10 6 plaque-forming units (PFU)/mL, then every 2 weeks (Q2W) at 1 × 10 7 PFU/mL for 7 doses in combination with intravenous (IV) nivolumab (240 mg). In the ipilimumab + nivolumab arm, patients will receive IV ipilimumab (3 mg/kg) and IV nivolumab (1 mg/kg) Q3W for 4 doses. Patients in both arms may then receive IV nivolumab at 240 mg Q2W or 480 mg Q4W for up to 2 years. The co-primary endpoints are OS and progression-free survival by independent central review using RECIST 1.1. Secondary endpoints are ORR, 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 .

9507 Background: OBX-115 TIL are engineered to express mbIL15 under regulatory control of the small-molecule drug acetazolamide (ACZ); this engineering abrogates the need for toxic high-dose IL2 cytokine support after TIL infusion. Early data demonstrated differentiated safety and promising efficacy at the recommended phase 2 dose (RP2D; Chesney ASCO 2025). We report additional data evaluating OBX-115 in patients (pts) with advanced melanoma treated at the RP2D in the Agni-01 study. Methods: This single-arm, open-label, phase 1/2 study (NCT06060613) assesses safety, tolerability, and efficacy of the OBX-115 TIL cell therapy regimen in pts with advanced non-uveal melanoma and NSCLC (Shoushtari AACR 2025); eligibility was not restricted by LDH, HLA, or melanoma subtype. Phase 1 established an RP2D of OBX-115 1–100×10 9 cells, with ACZ 500 mg/d orally on Days 0–6 (Wk 1) and 14–20 (Wk 3). Phase 2 evaluates efficacy of the regimen at RP2D by RECIST v1.1 per investigator in pts with ≤2 prior lines of therapy. OBX-115 is manufactured from pt tumor tissue (core needle biopsy [CNB] or surgical excision) and infused after low-dose (Cy 750 mg/m 2 /d × 3; Flu 30 mg/m 2 /d × 4) lymphodepletion (LD). ACZ is redosed (7 d) after recovery from LD every 6 wks until Wk 24. Primary data cutoff is 19Dec2025; RECIST efficacy was updated on 22Jan2026. Results: OBX-115 was successfully manufactured (median dose 83.4×10 9 cells) and infused at RP2D schema for 15 pts with advanced melanoma progressing on/after ICI (doublet ICI in 93%); 6/8 pts (75%) with BRAF-mut disease had prior BRAF-/MEK-inhibitor exposure. 2 pts (13%) had tumor tissue procurement by CNB; 4 pts (27%) received outpatient LD. Confirmed ORR was 67% (1 CR, 9 PR, 4 SD; DCR 93%). At median study follow-up of 18.6 wks (range 10.1–73.4), median duration of response was not reached (range 4.6+ to 55.1+ wks). There was no dose-limiting toxicity, ICU transfer, or treatment-related mortality. Immune-related adverse events (AEs) included CRS (G3 n=1; G<3 n=4) and hypoxia (G3 n=1; G<3 n=2), which responded to short-course steroids; no ICANS was observed. 3 pts reported 4 OBX-115–related serious AEs. 13 pts were alive as of the datacut. Conclusions: OBX-115 TIL cell therapy at RP2D demonstrated encouraging efficacy in 2/3L advanced non-uveal melanoma, an area of unmet medical need. Unique aspects of the OBX-115 regimen, such as low-dose LD, ACZ-inducible mbIL15 expression, and CNB-enabled manufacturing, were associated with manageable side effects and compare favorably with other adoptive TIL approaches. Data support continued investigation of OBX‐115 in the ongoing phase 2 portion of Agni-01 and planned registrational study. Clinical trial information: NCT06060613 .

9519 Background: IO102-IO103 is an investigational cancer vaccine that targets both tumor and immune-suppressive cells in the tumor microenvironment. IO102-IO103 has demonstrated clinical activity in combination with anti-PD-1 monotherapy in advanced melanoma, with concordant clonal T cell expansion observed in the tumor and peripheral blood in patients with radiographic response. IO102-IO103 has not yet been assessed in combination with nivolumab-relatlimab (nivo-rela). Methods: In this multicenter, phase 2 trial (NCT05912244) patients with unresectable, previously untreated non-uveal melanoma were treated with subcutaneous IO102-IO103 and intravenous nivo-rela for up to two years. IO102-IO103 was administered every two weeks for eight weeks, and every four weeks thereafter. PD-L1 protein expression was assessed using the 28-8 pharmDx assay on pre-treatment tissue. The primary endpoint was best overall response rate (BORR) by RECIST v1.1, with a plan to reject the null hypothesis based on the proportion of patients with ≥1% membranous PD-L1 staining in the tumor compartment. Secondary endpoints included progression-free survival (PFS), safety assessed by Common Terminology Criteria for Adverse Events v 5.0, and duration of response (DOR). PFS and DOR were summarized using Kaplan-Meier methods. Bulk T cell receptor (TCR) sequencing was performed on peripheral blood mononuclear cells using an RNA-based assay at baseline, week 4 and week 8. Results: Among 43 evaluable patients, the BORR was 60% (95% confidence interval [CI]: 44-75%), including 19 patients with partial response and 7 patients with complete response. At database lock (Dec 1 2025), median follow up was 10.1 months (interquartile range 6.1-19.3). The median duration of response was not reached (95% CI: 14, NR) and median PFS was 8.2 months (95% CI 6.8, not reached [NR]). Among patients with PD-L1 negative tumors (n = 25), the BORR was 52% (95% CI 31-72%) and median PFS was 8.2 months (4.2, NR). Grade 3-4 treatment-related adverse events occurred in 9 patients (21%), including adrenal insufficiency (2 patients), acute kidney injury (2), aseptic meningitis (1), arthritis (1), maculopapular rash (1), myositis (1), neutropenia (1), and colitis (1). There were no treatment related deaths. T cell clonal expansion was observed at on-treatment time points compared to baseline in patients with and without radiographic response. Conclusions: IO102-IO103 in combination with nivo-rela was associated with a higher objective response rate compared to historical data for nivo-rela alone, meeting the trial’s primary endpoint. No unexpected safety signals were observed. These findings support the further clinical investigation of IO102-IO103 with nivo-rela as an initial treatment for unresectable melanoma. Clinical trial information: NCT05912244 .

9557 Background: While inpatient toxicity associated with tumor infiltrating lymphocyte (TIL) therapy and IL-2 administration is well characterized, risks facing patients after hospital discharge are less understood. Better characterization of outpatient adverse effects (AEs) could guide the optimal frequency and duration of follow up for this growing patient population. Methods: We conducted a retrospective analysis of all patients with advanced melanoma discharged from Memorial Sloan Kettering Cancer Center after receiving investigational or commercial lifileucel from October 2020 to October 2024. We reviewed incidence and timing of new Grade 3+ treatment-related AEs (TRAEs), blood product administration, and readmission among all patients from the time of hospital discharge to the time of the start of a subsequent systemic therapy or death. Results: Fifty-three patients successfully discharged after lifileucel administration were identified; patient demographics are included in Table 1 . The median follow up time from discharge in survivors was 5 months (interquartile range (IQR): 3, 18). Two patients (4%) developed new Grade 3+ TRAEs following hospital discharge, including new Grade 3 neutropenia 73 days after discharge and new Grade 3 hypoxia 104 days from discharge. Hypoxia was secondary to pleural effusions that developed in the setting of renal thrombotic microangiopathy. Four patients (7.5%) were readmitted for TRAEs including cytopenias, dyspnea, and syncope while 7 patients (13%) were readmitted for melanoma progression. Readmissions occurred a median of 85 (IQR: 39, 128) days after lifileucel infusion and 69 days (IQR: 19, 98) after initial discharge. Twelve patients (23%) received at least one outpatient blood product transfusion, including packed red blood cells (PRBCs; 10 patients) and platelets (6 patients). Within 30 days of initial discharge, six patients (11%) received at least one PRBC transfusion and 3 patients (5.7%) received at least one platelet transfusion. The median number of transfused PRBC units was 2 (IQR: 1,4) and the median number of platelet transfusions was 4 (IQR: 2, 4). Conclusions: Rates of new severe toxicity and treatment-related readmissions were low among patients discharged post-lifileucel. About one in four patients required blood products after discharge. Identification of risk factors for the development of outpatient TRAEs may inform personalized care following lifileucel administration. Patient demographics. Characteristic N = 53 1 Age at TIL infusion 61 (42, 66) Sex Male 29 (55%) Female 24 (45%) Melanoma subtype Cutaneous 19 (36%) Uveal 9 (17%) Acral 8 (15%) Unknown primary 8 (15%) Mucosal 5 (9.4%) Other 4 (7.5%) BRAF status Mutated 13/51 (25%) Wild type 38/51 (75%) Treatment setting Investigational 45 (85%) Standard of care 8 (15%) 1. N (%); Median (interquartile range).

9546 Background: Mucosal melanoma (MM) is a rare, aggressive melanoma subtype with poor survival. Prior to 2010, systemic therapy for MM was limited to chemotherapy, adjuvant interferon, and bolus interleukin-2; after 2015, immune checkpoint inhibitors (ICIs), specifically programmed cell death protein-1 (PD-1) based therapies, were widely adopted. The magnitude of overall survival (OS) benefit from ICIs in MM remains poorly defined. Methods: We conducted a retrospective cohort study of 8,125 patients with histologically confirmed MM from the National Cancer Database. Patients were stratified by diagnosis era (pre-ICI: diagnosed before 2010; post-ICI: diagnosed after 2015) and receipt of first-line systemic therapy (immunotherapy and/or chemotherapy versus none). Survival analysis was conducted using Kaplan-Meier methods and Cox proportional hazards models. Difference-in-differences (DID) models using Cox regression estimated survival improvements attributable to systemic therapy in the post-ICI era. Multivariable logistic regression was fitted to assess changes in the characteristics of patients receiving systemic therapy between eras. Subgroup analysis included metastatic patients and stratification by primary tumor site (genitourinary [GU], gastrointestinal [GI], head and neck [HN]). Covariates for multivariable models were selected a priori based on clinical relevance. Results: Median OS (mOS) significantly improved in the post-ICI era with covariate adjustment (36.2 vs. 25.0 months; HR: 0.63, 95% CI: 0.59-0.66). Adjusted DID analysis demonstrated survival benefits attributable to systemic therapy (HR: 0.86, 95% CI: 0.77-0.97). mOS of metastatic patients also improved in the post-ICI era (12.0 vs. 7.33 months; HR: 0.63, 95% CI: 0.54-0.73). All tumor sites demonstrated significantly longer mOS in the post-ICI era, with GU patients living the longest (49.5 months), followed by HN (34.5 months), and GI (24.4 months). Post-ICI systemic therapy recipients were more likely to be older and publicly insured, to have a high comorbidity burden (Charlson Deyo score), to be ineligible for surgery, and to receive immunotherapy alone compared to pre-ICI patients. Conclusions: Survival of MM patients has improved by 37% since the introduction of ICIs. While OS varies by tumor site, all sites showed relative improvement in the post-ICI era. DID analysis suggested that modern survival benefits are driven by ICIs despite an older and more clinically complex treatment population.

9555 Background: Mucosal melanoma (MM) is an aggressive subtype of melanoma with distinct biology, and outcomes in advanced disease are inferior compared with cutaneous melanoma. Frontline Chinese studies in MM have shown efficacy of combined VEGF/R and PD-1 blockade, but studies in more diverse populations and options in PD-1 resistance are lacking. Methods: We conducted a phase 2/1b single-center trial in patients (pts) with untreated, unresectable or advanced MM. Pts received standard nivolumab (nivo) plus axitinib (axi) 5mg PO twice daily. Primary endpoint of the phase 2 doublet arm was objective response rate (ORR) by RECIST 1.1 (H0=23%, Ha=48%). Clinical benefit rate (CBR) was defined as ORR or stable disease (SD) >6 months (mos). Upon progression with good tolerance, the phase 1b triplet arm pts received the addition of either stereotactic body radiotherapy (SBRT, 30Gy/5 fractions) or ipilimumab (ipi, 1mg/kg < 4 doses) to ongoing nivo + axi. The primary endpoint of the triplet was safety by CTCAE v5.0 and adverse events (AEs) of special interest (AESIs). Kaplan-Meier methods estimated time to event outcomes; ORR and AEs were reported as proportions with exact 95% confidence intervals. Results: N=21 pts were enrolled; N=20 were evaluable for efficacy. See Table for baseline population characteristics. Median follow up was 15 mos (IQR 6, 21), 45% of pts (95% CI: 23, 68) had an objective response; 3 complete and 6 partial responses. Median duration of response was 13 mos (8.6, not reached (NR)). SD persisted ≥ 6 mos in 2 of 7 pts; CBR was 55% (95% CI: 32,77). Median progression free survival (PFS) was 6.3 mos (3.5, NR), and 12-mos estimated PFS and overall survival was 37% (20,67) and 71% (52, 96), respectively. Rate of grade ≥3 treatment related AEs (TRAE) in the doublet arm (n=21) was 67% (95% CI: 43,85), most commonly hypertension & hepatitis, with two pt deaths; 1 nivo-related myasthenia gravis / myositis, and 1 nivo-related pancreatitis with steroid-related PJP pneumonia. 14 pts (70%) progressed on doublet therapy, of which 7 enrolled on the triplet arm. N=5 received ipi and N=2 SBRT (both to anorectal primaries and adjacent lymph nodes). There were 2 grade ≥3 TRAEs in the ipi triplet arm (hepatitis), 0 in the SBRT arm, no grade 5 events, and no AESIs. Zero of 4 evaluable pts in ipi triplet and 1 of 2 in the SBRT triplet responded (4+ mos, ongoing). Conclusions: The frontline combination of nivolumab and axitinib was effective in patients with unresectable or advanced outside of China, and a prospective global study randomized against immune checkpoint blockade is warranted. Adding either ipi or SBRT to nivo-axi appears safe in select pts with progressive disease and further studies are needed for pts with PD-1 resistant MM. Clinical trial information: NCT05384496 . Characteristic (n=21) N (%) Age (median) 73 years (IQR: 67, 82) Sex Female Male 13 (62%) 8 (38%) Race Caucasian Asian Black 16 (76%) 3 (14%) 2 (10%) Primary Site Anorectal Sinonasal Vulvovaginal 10 (48%) 8 (38%) 3 (14%) Stage Locoregionally advanced Metastatic 14 (67%) 7 (33%) LDH (median) 195 (IQR: 171,201)

This cohort study examines the response and survival rates associated with ipilimumab-nivolumab therapy in patients with progressive melanoma brain metastases after anti–programmed cell death 1 (anti–PD-1) therapy.

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.

Metastasis drives mortality and morbidity in cancer. While some patients develop broad metastatic disease across multiple organs, others exhibit organ-specific spread. To identify mechanisms underlying metastatic organotropism, we analyzed clinico-genomic data from over 7,000 patients with metastatic cutaneous melanoma in three independent cohorts (one primary discovery and two validation cohorts including a nationwide electronic health record-derived deidentified database), leveraging machine learning approaches to clinical data. We found that female sex and increased tumor mutational burden associate with decreased metastatic potential, while older age associates with more lung and adrenal metastases. Using unsupervised analyses, patients clustered into five metastatic patterns: a "highly metastatic" cluster characterized by involvement of many organs, a "low metastatic" cluster characterized by few metastatic sites (mostly lymph node metastases), and three additional clusters each characterized by metastasis to specific sites (brain, lung, liver). Mutations in B2M and PTEN associated with increased overall metastatic potential. PTEN mutations were also associated with brain metastases but were enriched only in the "highly metastatic" cluster and not the brain-specific cluster. Mutations in GNAQ or GNA11 (GNA) associated with increased liver metastasis. To validate this association, we tested and demonstrated liver tropism in two GNA-mutant genetically engineered cutaneous melanoma mouse models of metastasis. Overall, our study elucidates distinct phenotypes of metastasis in patients with melanoma and identifies novel clinical and genomic associations that illuminate the clinical drivers of metastatic organotropism.

1514 Background: There is growing interest to improve patient care transitions from hospital to home and to prevent readmissions but effective interventions are lacking. Methods: We conducted a randomized clinical trial among patients with cancer discharged after an unplanned hospital admission at a specialty cancer center. Hospitalized patients on medical oncology services were randomized at discharge to receive either a digital symptom monitoring and management intervention or to usual care. Patients randomized to the intervention received a daily electronic symptom assessment for 10 days post-discharge, consisting of 9 common symptoms from the National Cancer Institute Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events and an open-ended question to allow for patients to provide further symptom context and for two-way engagement with their clinical team. Patients also received customized self-management education delivered through the patient portal based on their reported symptoms. Primary oncologists received alerts through the portal for moderate and severe symptoms. Usual care consisted of symptom monitoring at the discretion of the primary clinical team, generally comprising an oncologist and an office practice nurse. The primary outcome was the 30-day readmission rate, analyzed using cumulative incidence functions and Gray’s test with death as a competing risk. Secondary endpoints included 90-day readmission rate and 30-day emergency room visit without admission rate. Results: Between 04/19 and 09/19/2024, 1,713 patients were randomized with median age 66 years (range: 19 – 99), 66% white, 12% African American, 11% Asian, and 11% Hispanic with 53% female. The most common cancer diagnoses were gastrointestinal (26%), thoracic (11%), genitourinary (10%), gynecologic (10%), leukemia (9%), and lymphoma (9%). In the intervention group, the most frequently reported moderate and severe symptoms were fatigue and pain. The two arms had roughly similar proportions of patients who died before a hospital readmission. The 30-day readmission rate was 30% in the intervention group compared to 37% in the usual care group (p = 0.001). The decrease in readmission rate was maintained at 90 days (45% vs. 52%, p = 0.002). Emergency room visits without admission at 30 days were also lower in the intervention group (12% vs. 17%, p = 0.007). Conclusions: Digital post-discharge symptom monitoring and customized patient self-management education for 10 days post discharge reduced hospital readmissions in patients with cancer. Further research is necessary to identify the precise mechanisms that contribute to the success of this 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.

Non-engineered TIL cell therapy was recently approved for patients with immune checkpoint inhibitor (ICI)-resistant melanoma (Chesney JITC 2022) and shows promising efficacy in non-small cell lung cancer ([NSCLC]; Creelan Nat Med 2021, Schoenfeld Cancer Discov 2024), but has a treatment-related mortality rate of 7.5% in melanoma and requires co-administration of systemic high-dose IL2, with well-described high-grade toxicity. OBX-115 TIL are expanded from patient tumor tissue and engineered with a transgene to express membrane-bound human IL15 (mbIL15), regulated by acetazolamide (ACZ), eliminating the need for IL2. A first-in-human single-institution study evaluating the safety of OBX-115 in metastatic melanoma has completed enrollment (NCT05470283; Amaria ASCO 2024). The current study (NCT06060613) is enrolling patients with melanoma and NSCLC at multiple US sites using centralized manufacturing. This phase 1/2, single-arm, open-label, nonrandomized, multicenter study will assess the safety, tolerability, and efficacy of the OBX-115 engineered autologous TIL cell therapy regimen in patients with unresectable Stage IIIC-IV metastatic melanoma (excluding uveal) with radiographic progression after systemic therapy containing PD-1-targeted ICI (≤2 prior lines; neoadjuvant/adjuvant considered prior line if progressed during treatment or within ≤12 weeks of last dose) OR metastatic NSCLC previously treated with an approved systemic therapy for metastatic disease (including an ICI-based regimen and/or targeted therapy where applicable) and progressed, no longer deriving benefit, or unable to continue due to treatment intolerance. Patients may have treated and asymptomatic brain metastases and must have ECOG PS of 0 or 1, life expectancy >∼6 months, ≥1 lesion suitable for OBX-115 manufacturing, and ≥1 RECIST v1.1-measurable lesion remaining after tumor tissue procurement. Primary objectives of Phase 1 are to characterize safety and tolerability and identify a recommended Phase 2 dose of OBX-115 + ACZ; Phase 2 will evaluate efficacy of the regimen (ORR using RECIST v1.1 per investigator). Melanoma RP2D has been determined and is in Phase 2; NSCLC is in Phase 1. Cryopreserved OBX-115 is generated from the patient’s own tumor tissue procured by surgical excision or core needle biopsy and is infused after standard- or low-dose lymphodepletion (cyclophosphamide and fludarabine) based on clinical status and prior treatments. No IL2 is administered. ACZ is administered at cohort-defined doses once daily starting day of OBX-115 infusion for ≤14 days (split into two ≤7-day periods within 28 days), with additional ACZ dosing for ≤7 days at weeks 5, 11, 17, and 23, or upon progression when new anticancer therapy is not immediately warranted. Eight sites are open and recruiting, with additional sites being activated. Alexander N. Shoushtari, Adam J. Schoenfeld, Kai He, Jason A. Chesney, Juan Carlos Varela, Justin T. Moyers, Gino K. In, Yazan Samhouri, Rodabe N. Amaria, Parameswaran Hari, Giridharan Ramsingh, Camille Renard, Prakash Prabhakar, Lauren Mclaughlin, Mercay Reuter, Allison Betof Warner. Trial in progress: Phase 1/2 study of OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT244.

Point mutations in genes of the mitogen-activated protein kinase (MAPK) pathway are the most frequent oncogenic drivers of melanocytic neoplasms, whereas gene fusions are comparatively rare. Kinase fusions are among the molecular alterations that characterize Spitz neoplasms; however, not all melanocytic tumors that harbor one as the main oncogenic driver conform to clinical and/or histomorphologic parameters associated with Spitz neoplasms. In this study, we describe the clinical, histopathologic, and molecular characteristics of 7 RAF1 and 23 BRAF fusion-positive melanomas of patients who presented with or later developed regional and/or distant metastases. We report that most tumors in this series arose in adult patients and lacked Spitz-like microscopic features. Awareness of the varied clinical and histopathologic presentation of RAF1 and BRAF fusion-positive melanomas is important as the protein products of these kinase gene fusions constitute potentially actionable therapeutic targets.

9509 Background: GNAQ/11 mutations occur in up to 95% of uveal melanomas (UM) and a subset of non-uveal melanomas. Cell surface PMEL17 (gp100) is highly and broadly expressed in melanoma (including UM). SDZ475 (FR900359) is a potent GNAQ/11 inhibitor, however in vivo toxicity has precluded clinical development. DYP688 is an antibody drug conjugate that binds to PMEL17 to deliver the payload SDZ475. Methods: This first-in-human, open-label, multicenter, single-arm study (NCT05415072) of DYP688 in patients (pts) with MUM and other GNAQ/11 mutant melanomas aimed to evaluate safety and tolerability, determine recommended dose(s) (RDs) of DYP688 (primary objective), and evaluate antitumor activity, pharmacokinetics (PK), and immunogenicity (secondary objectives). Here we present data from the ongoing Phase I dose-escalation. Results: As of 25 Oct 2024, 66 pts were treated with DYP688 at 4 (n=5), 8 (n=12), 12 (n=13), 16 (n=14), and 24 (n=11) mg/kg biweekly (Q2W) and at 12 (n=5) and 16 (n=6) mg/kg once weekly (QW) in 28-day cycles. Tumor types included MUM (n=60) and non-MUM (n=6). Of the 66 treated pts, 60 (90.9%) had prior antineoplastic therapy; 38 (57.6%) received ≥2 lines, and 22 (33.3%) received prior tebentafusp. The majority (n=57, 86.4%) of pts had liver metastases and elevated LDH (n=43, 65.25%) at baseline. Preliminary PK demonstrated a nearly dose-proportional exposure of total monoclonal antibody and active conjugated payload. Most treatment-related adverse events (TRAEs) were grade ≤2 with 4 grade 3 events: hypotension, hypercalcemia, anemia, and increased GGT. One dose limiting toxicity was reported (grade 3 hypotension at 24mg/kg Q2W). Most common TRAEs (all grades/doses, >15%) were hypercalcemia (22.7%), dry mouth (19.7%), fatigue (18.2%) and peripheral edema (16.7%). At data cutoff, 27 (40.9%) pts remained on study treatment and 39 (59.1%) pts had discontinued, mainly due to disease progression (PD) and none due to AEs. Of the 55 pts treated at doses ≥8 mg/kg Q2W who were eligible for RECIST v1.1 evaluation, confirmed objective responses were seen in 12 (21.8%) pts with 1/12 at 8 mg/kg (Q2W), 3/13 (1 complete response) at 12 mg/kg (Q2W), 5/8 at 16 mg/kg (Q2W), 2/5 at 12 mg/kg (QW) and 1/6 at 16 mg/kg (QW), with evidence of deepening response over time. Best response of PD was seen in 6/55 (10.9%) pts and stable disease in 35/55 (63.6%) pts. Median (range) duration of treatment by Kaplan Meier was 7.0 (<1 – 20.7) months. Analysis of mutational profiles from tissue and circulating tumor DNA is ongoing. Conclusions: DYP688 shows favorable safety and tolerability at all doses tested and promising preliminary clinical efficacy at doses ≥ 12mg/kg Q2W; the RDs for dose optimization are yet to be declared and dose exploration is ongoing. Clinical trial information: NCT05415072 .

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.

Programmed death ligand-1 (PD-L1) is an inducible protein heterogeneously expressed in melanoma. Assessment of PD-L1 expression is challenging and standard immunohistochemistry (IHC) requires biopsies and cannot capture heterogeneity of expression. Noninvasive imaging methods provide evaluation of expression across lesions in the body. We conducted a prospective pilot trial with PD-L1 PET imaging with [ 18 F]-BMS-986229 as a noninvasive approach to assess PD-L1 expression across lesions, in 10 patients with advanced melanoma, longitudinally during treatment with nivolumab and ipilimumab. PET imaging was performed at baseline and at 6 weeks after-initiation of treatment. We examined the relationship of PD-L1 PET uptake to radiographic clinical response. [ 18 F]-BMS-986229 uptake was variably seen across lesions in patients at baseline. All patients showed positive uptake in lesions at baseline PET with a median SUV max of 3.6 (range: 1.7–8.6). PD-L1 PET SUV max decreased in all but two lesions 6 weeks after treatment initiation. Four of five patients had a mean (SUV max ) greater than or equal to 3.00 in Response Evaluation Criteria in Solid Tumors (RECIST) evaluable lesions at baseline, and all had a RECIST response while all progressors ( n = 3) had baseline PD-L1 mean SUV max less than or equal to 2.60. A higher lesional baseline SUV max was associated with greater individual lesion reduction during treatment. The PD-L1 uptake in lesions showed a low correlation with baseline PD-L1 by IHC. In this small pilot study, PD-L1 PET imaging using [ 18 F]-BMS-986229 showed feasibility in noninvasively assessing lesion uptake and PD-L1 heterogeneity in patients receiving combination immunotherapy. Future exploration of this tracer in larger patient cohorts is necessary to delineate its use in managing immunotherapy treatments.