Citations

e13615 Background: Bacillus Calmette-Guérin (BCG) remains the standard intravesical therapy for high-risk non-muscle-invasive bladder cancer (NMIBC), but weekly clinic-based instillations create substantial travel, time, and indirect costs that may threaten adherence. Therefore, we proposed a pilot trial of delivering BCG at Home as a prospective, single-center pilot testing a pharmacy-to-home pathway with digital patient-reported outcome (PRO) monitoring. Methods: BCG at Home is a prospective, single-center pilot evaluating feasibility and safety of home delivery of induction BCG for treatment-naïve, high-grade T1 and/or carcinoma in situ NMIBC. Dose 1 is administered in clinic to confirm tolerability and catheterization feasibility; doses 2-6 are administered at home by Penn Medicine at Home nurses after a 3 month training and proctorship program in intravesical therapy and exposure precautions. To enable transport beyond conventional short post-preparation windows, the pharmacy prepares BCG using a closed system transfer device (CSTD); bench testing demonstrated stability and sterility for 24 hours after connection. A medical courier delivers the prepared medication to the patient’s home, where the nurse receives the delivery and performs the instillation. The primary endpoint is induction adherence (completion of all recommended doses). Secondary endpoints include PROs (EORTC QLQ-C30/QLQ-NMIBC24), satisfaction, and acute care utilization. PROs are captured before and after treatment using a conversational chatbot; domain summaries are assessed at baseline, 6 weeks, and 12 weeks. Results: The pilot began enrollment in June 2025 (planned sample size: 20). To date, eight participants have enrolled and completed induction. Median age was 76 years (range 41-88); 50% were female and 25% were Black/African American. Participants lived a mean of 30 miles from the treating facility. Forty home instillations were delivered, and all participants completed all recommended induction doses (100% adherence). Median nurse time in the home was 40 minutes. Five episodes of hematuria were self-limited; one urinary tract infection resolved with antibiotics. Self-efficacy improved from a median of 3 pre-treatment to 7 post-treatment. The median COST-FACIT score was 30 (scale 1-44). Mean EORTC QLQ-C30 global health status was 71 (0-100). EORTC QLQ-NMIBC24 averages showed urinary symptoms rising during induction (23 at baseline to 30 at 6 weeks) with improvement by 12 weeks (18) and future worries decreasing (33 to 25); intravesical treatment issues remained low (5 to 2). Conclusions: BCG at Home is, to our knowledge, the first prospective trial to administer intravesical BCG in the home setting using a standardized pharmacy-to-home pathway. Early results support feasibility, complete adherence, and an acceptable short-term safety profile. Clinical trial information: 07048496 .

9567 Background: Resected stage IIB/C and microscopic stage IIIA/B/C/D melanoma presents a significant risk of recurrence risk of 37 to 62% at 5 years (yrs). While 1 year of adjuvant PD1 therapy reduces this risk by approximately half, the individual patient’s baseline risk without treatment and their specific benefit from adjuvant PD1 remain unknown. We aimed to generate two separate predictive models for recurrence – one for untreated and one for treated pts - to calculate the individualised benefit of adjuvant PD1. Methods: Pts with resected stage IIB/C or microscopic stage IIIA/B/C/D melanoma, either treated with adjuvant PD1 or untreated at 13 major melanoma centres, and with at least 2 years of follow-up from surgery were included. We analysed pts demographics, disease characteristics, blood parameters, pathological and imaging data at baseline, and clinical outcomes. Propensity scores were estimated using logistic regression with covariates associated with treatment in univariate screening (p<0.05). Separate penalised multivariable logistic regression models were built to predict recurrence for treated and untreated pts. A tool based on these models was created to calculate the individual patient benefit from adjuvant PD1. Results: A total of 3560 pts was included, divided into untreated (discovery n=2384 and validation n=597) and treated (discovery n=404 and validation n=175) cohorts. The model for untreated pts included age, gender, primary site, histological subtype, Breslow thickness, ulceration, mitosis, number and site of regional lymph nodes (LN), mutation status and LDH (AUC 0.70 in discovery, 0.69 in validation). The model for treated pts included age, gender, Breslow thickness, site of regional LN, and mutation status (AUC 0.69 in discovery, 0.61 in validation). ADAPT-M (ADjuvant Anti-PD-1 Tool for Melanoma) calculates the individualized benefit of adjuvant PD1. For example, patient A, a woman ≤45 years old with a primary head & neck melanoma (superficial spreading, thickness >1-2 mm, no ulceration, 1 mitosis/mm 2 ), 2 clinically occult LN metastases in the neck, NRAS mutant, and normal LDH, has a 12-month recurrence risk of 21.9% untreated vs 2.3% treated (benefit 19.6%), and a 24-month risk of 41.1% untreated vs 6.4% treated (benefit 34.7%). While, patient B, a man ≤45 years old with a primary melanoma in the lower limb (nodular, thickness >1-2 mm, no ulceration, 1 mitosis/mm 2 ), 2 clinically occult LN metastases in the groin, BRAF V600 mutant, and normal LDH, has a 12-month recurrence risk of 14.2% untreated vs 11.8% treated (benefit 2.5%), and a 24-month risk of 28.0% untreated vs 30.1% treated (no benefit). Conclusions: ADAPT-M, a clinical tool that estimate individualized recurrence risks with and without adjuvant anti-PD1 therapy, quantifies the absolute benefit of treatment for pts with high-risk resected melanoma, facilitating personalized adjuvant therapy decisions.

9524 Background: Unresectable melanoma in-transit metastases (ITM) can pose a significant clinical challenge. Our recently published data comparing first-line treatments for ITM, isolated limb infusion or perfusion (ILI/ILP), immune checkpoint inhibitors (ICI) and intralesional talimogene laherparepvec (TVEC), found superior outcomes with TVEC. However, TVEC was used more often in patients with lower disease burden and earlier stage (IIIB vs. IIIC/D). Therefore, we sought to better investigate these differences with a propensity score-matched (PSM) analysis. Methods: A multi-institutional, international IRB- approved retrospective analysis was conducted for unresectable melanoma ITM from 2016-2022. PSM analysis comparing first-line ILI/ILP, ICI, and TVEC for was performed. Patients were matched for stage, number of ITM, anatomical site, CLND status, gender and age. Kaplan-Meier curves (OS, PFS, DMFS) and Cumulative incidence function (MSS) were used to visualize time-to-event outcomes in the PSM cohort, though both methods do not account for the matched structure. Results: 274 patients were identified, 120 female/154 male; 96 treated with ILI/ILP, 111 with ICI, and 67 with TVEC. Median follow-up was 40 months (range, 1-80). PSM was performed and identified 36 TVEC–ICI pairs and 27 TVEC–ILI pairs. These were combined resulting in a final cohort of 108 observations (45 TVEC, 36 ICI and 27 ILI). The groups were well balanced. No statistical difference was found for metastasis-free survival (DMFS), progression-free survival (PFS), melanoma-specific survival (MSS), and overall survival (OS) between treatment modalities. TVEC was associated with significant improvement in local PFS (median was 2.2 years (y) for ILI/ILP, 1.5y for ICI and not reached for TVEC, p=0.048). While not statistically significant, a clinical benefit was seen in PFS being longer for TVEC (2.1y for TVEC vs. 1.2y for ILI/ILP and 1.1y for ICI; p=0.2) and OS (not reached vs 2.9y for ILI/ILP and 5.2y for ICI; p=0.2). On mixed effect Cox regression proportional hazard model using the matched data set, there were no significant differences in any of the survival and recurrence outcomes. Conclusions: When patients are propensity-matched, there were no significant differences in first-line treatment modalities for unresectable melanoma ITM. Treatment with TVEC did result in clinically meaningful improved overall and local PFS and OS. This supports that selection of ITM therapy should incorporate an individualized approach, incorporating disease distribution, stage, burden, treatment side effects and patient priorities.

9523 Background: Primary Central Nervous System (CNS) Melanoma is a rare and aggressive malignancy, comprising 1% of melanoma cases and 0.07% of brain tumors. Due to its rarity, its natural history, molecular features and optimal management remain poorly defined. Methods: We retrospectively reviewed patients at our institution between January 1998 and October 2025 with primary CNS melanoma or melanocytoma with melanoma transformation. Clinical characteristics, molecular profiling, treatments and survival outcomes were collected. Overall survival (OS) and progression free survival (PFS) were estimated using Kaplan-Meier curves. Results: Nineteen patients were identified, including eight (42%) with melanocytoma to melanoma transformation. Median time of transformation was 34.4 months. Thirteen (68%) patients were female with a median age at diagnosis of 59.3 years. Common presenting symptoms were sensory disturbances (58%), pain (53%), motor deficits (37%) and nausea or vomiting (32%). At diagnosis, location of disease was spinal (n=12), intracranial (n=6) and multifocal (n=1). Thirteen patients had leptomeningeal involvement. Molecular profiling was performed in 15 patients, revealing mutations in GNAQ (n=7), GNA11 (n=3), CKIT (n=2), BAP1 (n=1), EIF1AX (n=1), and BRAF v600 (n=1). Thirteen (68%) patients underwent subtotal resection (STR), five (26%) gross total resection (GTR) and one radiation only. Median resected tumor size was 1.7 cm. Seventeen (94%) patients had recurrence at a median of 9.1 months, and four patients underwent repeat surgery. Fourteen (74%) patients received adjuvant radiation and 14 (74%) received immunotherapy, most commonly ipilimumab with nivolumab (71%). Nine patients received chemotherapy: temozolomide (n=5), bevacizumab (n=2) and one each of intrathecal IL-2, tebentafusp, imatinib and encorafenib with binimetininb. Four patients received chemotherapy before immunotherapy. Median OS from diagnosis of CNS melanocytoma or melanoma was 50.9 months (13.4 – 80). Median OS from time of transformation to melanoma or CNS melanoma diagnosis was 24.0 months (11.9 – NA). One-, three- and five-year OS rates were 73%, 53% and 40% respectively. GTR was associated with increased median OS compared to STR (80.0 vs 19.7 months, p= 0.02). Age at diagnosis, immunotherapy, chemotherapy, adjuvant radiation, STR with or without radiation, disease location, leptomeningeal involvement, tumor size >3cm and presence of GNAQ mutation were not associated with survival. Median PFS was 3 months with chemotherapy and 5.7 months with immunotherapy. Conclusions: To our knowledge, this is the largest single center study of primary CNS melanoma. Outcomes remain poor, with survival primarily associated with GTR. The predominance of GNAQ and GNA11 alterations with rare BRAF v600 mutations highlight the distinct biology of primary CNS melanoma and need for novel targeted therapies.

9535 Background: MUM carries a poor prognosis with few effective treatments, especially for HLA-A*02:01-negative pts. While a subset of MUM pts responds to immune checkpoint inhibitors, the comparative efficacy of IPI+PD1 versus PD1 monotherapy is unclear. This study compares objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety between these regimens in MUM. Methods: MUM pts treated with PD1 or IPI+PD1 at 15 major melanoma centres (from Australia, Europe, United States and Israel) were included. Demographics, patient and disease characteristics, and clinical outcomes were examined. Univariate and multivariate (MVA) analyses were performed to identify clinical predictors of response and survival. Results: Of 412 MUM pts treated, 150 (36%) had PD1 and 262 (64%) received PD1+IPI. Compared to the PD1 group, PD1+IPI-treated pts were younger (64 vs. 70 years; p<0.001), had higher rate of elevated LDH (44% vs. 31%; p=0.037), and more frequently had prior treatment with tebentafusp (6.5% vs. 1.3%; p=0.031). Median follow-up from commencement of PD1+/-IPI was 4.9 years (95% CI 4.7 – 6.1). ORR was higher in IPI+PD1 group (18%) vs. PD1 (9%) (p=0.008), particularly in males (p=0.009), patients with liver metastases (p=0.018) and with lung metastases (p=0.011), with elevated LDH (p=0.047) and with no prior treatment with tebentafusp (p=0.007). PFS and OS at 1 and 2 years were numerically higher with IPI+PD1 (1- and 2-year PFS: 23% and 15%; 1- and 2-year OS: 63% and 39%) vs. PD1 (1- and 2-year PFS: 17% and 11%; 1- and 2-year OS: 54% and 36%), but these differences were not statistically significant (p>0.05). On MVA, adjusting for predefined variables (age, gender, ECOG PS, LDH, presence/absence of liver/lung metastases, prior treatment with tebentafusp), IPI+PD1 was associated with higher ORR (OR 2.71, 1.30 – 6.05; p=0.01) but not with PFS or OS compared to PD1. Presence of liver metastases (ORR [OR 0.28; 95% CI 0.13 - 0.64], PFS [HR 1.61; 95% CI 1.11 - 2.34], OS [HR 2.02; 95% CI 1.32 - 3.10]), ECOG PS≥2 (PFS [HR 1.82; 95% CI 1.07 - 3.10], OS [HR 2.24; 95% CI 1.25-4.01]), elevated LDH (PFS [HR 1.66; 95% CI 1.30 - 2.11], OS [HR 2.39; 95% CI 1.84-3.10]) and prior tebentafusp treatment (OS [HR 2.36; 95% CI 1.21-4.59]) were also independent predictors of response and/or survival. A higher percentage of pts experienced grade ≥3 immune-related adverse events (irAEs) in the IPI+PD1 group compared to the PD1 group (34% vs 13%, p<0.0001). Most pts ceased treatment due to progression (234, 57%), and more pts stopped due to toxicity in the IPI+PD1 vs. PD1 group (25% vs. 9%, p<0.0001). Conclusions: In pts with MUM, IPI+PD1 demonstrated a higher ORR but did not improve survival compared with PD1 alone. IPI+PD1 was more toxic, leading to early treatment discontinuation in one-quarter of pts. These findings may help guide treatment selection in MUM.

7501 Background: AL amyloidosis is a plasma cell dyscrasia (PCD) characterized by κ or λ Ig light chain amyloid fibrils that deposit in vital organs. Anselamimab is an investigational mAb designed to complement anti-PCD therapy through accelerated removal of amyloid fibrils. Cardiac Amyloid Reaching for Extended Survival (CARES) studies (NCT04512235 and NCT04504825) investigated the efficacy and safety of anselamimab compared with placebo, in addition to anti-PCD therapy. Methods: Alongside anti-PCD therapy with CyBorD (daratumumab was permitted) newly diagnosed patients with European modification of Mayo stage IIIa or IIIb AL amyloidosis were randomized 2:1 to receive anselamimab (1000 mg/m 2 ) or placebo (normal saline) IV every 7 days for 4 weeks followed by every 14 days for the remainder of the blinded study (18 months after the last participant enrolled). The primary endpoint was a hierarchical combination of time to all-cause mortality (ACM) and frequency of adjudicated cardiovascular hospitalizations (CVH) using the Finkelstein-Schoenfeld test and win-ratio in the combined study population. Subgroup analysis by involved κ or λ free light chain (iFLC) was prespecified. Results: 271 patients were randomized to receive anselamimab and 135 placebo. Baseline characteristics were similar between treatment arms. The median duration of treatment was 21.4 months and 21.1 in the anselamimab and placebo arms, respectively. Daratumumab was used in 79.3% and 83.7% of the anselamimab and placebo arms, respectively. Results of the primary efficacy analyses are shown in the table. Anselamimab-treated patients with κ iFLC had a 62% reduction in ACM (HR = 0.38; 95% CI, 0.17, 0.86; nominal P = 0.012) and a 71% reduction in risk for CVH (estimated CVH rate ratio = 0.29; 95% CI, 0.10, 0.87; nominal P = 0.028). Patients with λ iFLC had a 10% reduction in risk for CVH; none in ACM. Safety data were comparable between both treatment arms. In anselamimab-treated patients, safety findings were similar between κ subgroup and full population. Conclusions: Anselamimab, a κ light chain–directed anti-fibril monoclonal antibody used alongside standard of care chemotherapy, offers a first-in-class, new therapeutic option for patients with newly diagnosed κ AL amyloidosis. Clinical trial information: NCT04512235 and NCT04504825 . Summary of primary efficacy endpoints. Endpoint Overall κ Isotype λ Isotype Anselamimab (N=271) Placebo (N=135) P -value Anselamimab (N=48) Placebo (N=24) P -value Anselamimab (N=219) Placebo (N=109) P -value ACM and CVH win ratio (95% CI) 1.1 (0.8, 1.5) 0.332 2.06 (0.98, 4.31) 0.100 0.9 (0.6, 1.3) 0.848 ACM n (%) 90 (33.2) 52 (38.5) 15 (31.3) 14 (58.3) 73 (33.3) 37 (33.9) HR (95% CI) 0.8 (0.6, 1.1) 0.290 0.38 (0.2, 0.9) 0.012 1.0 (0.7, 1.5) 0.647 CVH Frequency/year (95% CI) 0.6 (0.4, 0.8) 0.9 (0.6, 1.4) 0.145 0.41 (0.2, 0.8) 1.4 (0.6, 3.4) 0.028 0.7 (0.4, 1.0) 0.8 (0.4, 1.3) 0.664 Incidence risk ratio (95% CI) 0.7 (0.4, 1.2) 0.29 (0.1, 0.9) 0.9 (0.5, 1.7)

625 Background: I-SPY 2 is a multicenter phase II adaptive platform trial evaluating novel agents for stage II-III high-risk breast cancer using response-predictive subtypes (RPS) and a sequential neoadjuvant treatment design of up to three blocks (A/B/C). Investigational regimens are given in Block A, followed by response-guided escalation to standard-of-care (SOC) therapy (tx) in subsequent blocks or early surgery for responders. Topoisomerase I (TOPO1) inhibition plus PARP inhibition may enhance DNA damage and tumor response. DAN-222 is a tumor-targeted polymeric camptothecin conjugate designed to improve the therapeutic index of TOPO1 inhibition. Based on favorable phase 1 safety and preliminary activity in metastatic breast cancer, DAN-222 plus niraparib was evaluated as Block A tx in HER2− disease. Notably, the neoadjuvant regimen used a higher dose of niraparib (200 mg daily) than the prior phase 1 metastatic study. Methods: Patients (pts) with HER2− breast cancer were randomized to DAN-222 plus niraparib for up to 12 weeks in Block A. Response was assessed by serial MRI and biopsy. Inadequate responders escalated early to SOC tx in Blocks B/C. Primary endpoint was pathologic complete response (pCR). Secondary endpoints included residual cancer burden, safety, early discontinuation, and treatment-strategy performance versus subtype-specific SOC tx controls. Given established PARPi sensitivity in BRCA mut disease, the key objective was to assess clinically meaningful activity of DAN-222 plus niraparib in BRCA wt pts. Accordingly, a prespecified Bayesian interim futility analysis focused on BRCA wt and tested the probability of the true pCR rate after Block A alone exceeded 15% after 50 pts. Results: Fifty pts enrolled from Sep to Dec 2024. In BRCA wt (n=47), estimated Block A pCR was 3%, with posterior probability of 0.02 that that true pCR exceeded 15%, meeting futility criteria and prompting arm closure. Across all blocks, pCR rate was 57% (8/14) for HR-HER2−; 11% (4/36) for HR+ HER2−, largely after SOC tx. 2/3 BRCA mut pts achieved pCR. Treatment strategies initiating with DAN-222 plus niraparib underperformed subtype-specific controls. 68% discontinued Block A early, mainly due to toxicity. Grade ≥3 cytopenias were common: neutropenia (n=25; 50%), anemia (24%), and thrombocytopenia (18%). Cystitis occurred in 36% (1 grade ≥3). Conclusions: Neoadjuvant DAN-222 plus niraparib showed insufficient activity and no treatment-strategy benefit in BRCA wt HER2− breast cancer, underscoring challenges for TOPO1–PARP inhibitor combinations. Although not supported for further development in this setting, these results highlight the strength of I-SPY 2 in rapidly enrolling patients and quickly distinguishing ineffective from promising therapeutic strategies to accelerate progress toward improved outcomes for patients with curable breast cancer. Clinical trial information: NCT01042379 .

4614 Background: Enfortumab vedotin (EV) + pembrolizumab (pembro) is the established first-line standard of care for locally advanced/metastatic urothelial carcinoma and represents a novel neoadjuvant and adjuvant treatment strategy for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy. The randomized phase 3 KEYNOTE-B15/EV-304 study (NCT04700124) evaluates neoadjuvant EV + pembro followed by radical cystectomy plus pelvic lymph node dissection (RC + PLND) and adjuvant EV + pembro vs neoadjuvant chemotherapy followed by RC + PLND in participants (pts) with MIBC who are eligible for cisplatin-based therapy. Methods: Pts with clinical stage T2-T4aN0M0 or T1-T4aN1M0 MIBC (confirmed by central pathology and central imaging assessment) who were eligible for cisplatin-based chemotherapy and RC + PLND were randomized 1:1 to receive either 4 cycles neoadjuvant EV 1.25 mg/kg IV on days 1 and 8 + pembro 200 mg IV on day 1 Q3W, followed by RC + PLND, and adjuvant 5 cycles EV + 13 cycles pembro (EV + pembro arm) vs 4 cycles neoadjuvant gemcitabine 1000 mg/m 2 on days 1 and 8 + cisplatin 70 mg/m 2 on day 1 Q3W, followed by RC + PLND (cis + gem arm). The primary endpoint was event-free survival (EFS) by blinded independent central review. Key secondary endpoints were pathological complete response (pCR) rate by blinded central pathological review and overall survival (OS). Safety was a secondary endpoint; AEs of special interest were based on distinct prespecified lists for each drug. Results: A total of 405 and 403 pts were randomized to EV + pembro and cis + gem, respectively. Median time from randomization to the data cutoff date of October 27, 2025 was 33.6 months (range, 22.5–53.6). Baseline characteristics were generally balanced between groups. EV + pembro significantly improved EFS (median NR vs 48.5 mo; 24-mo estimated EFS rate 79.4% vs 66.2%; HR 0.53, 95% CI 0.41–0.70; 1-sided P <.0001), OS (median NR vs NR; 24-mo estimated OS rate 86.9% vs 81.3%; HR 0.65, 95% CI 0.48–0.89; 1-sided P =.0029), and pCR rate (55.8% vs 32.5%; estimated difference 23.4%, 95% CI 16.7–29.8; 1-sided P <.0001) vs cis + gem. Grade ≥3 treatment-emergent AEs occurred in 75.7% of pts with EV + pembro and 67.2% with cis + gem. Most common grade ≥3 drug-related AE of special interest for EV was skin reactions (14.1%); most common grade ≥3 AE of special interest for pembro was severe skin reactions (13.9%). Conclusions: Neoadjuvant and adjuvant EV + pembro significantly improved EFS, OS, and pCR rate compared with neoadjuvant gem + cis in pts with MIBC who were eligible for cisplatin-based chemotherapy. The safety profile of EV + pembro was consistent with prior experience with the combination. These results support EV + pembro as an effective perioperative treatment option in this setting. Clinical trial information: NCT04700124 .

4013 Background: Pancreatic ductal adenocarcinoma (PDAC) is driven predominantly by oncogenic KRAS signaling, yet prior attempts to target the MAPK pathway have been limited by toxicity and emergence of resistance. Atebimetinib is a next-generation, deep cyclic inhibitor (DCI) of MEK designed to achieve pulsatile pathway inhibition with improved tolerability. We report a Phase 2a cohort evaluating atebimetinib in combination with modified gemcitabine/nab-paclitaxel (mGnP) in the first-line treatment of advanced or metastatic PDAC (NCT05585320). Methods: In this multicenter, open-label, nonrandomized Phase 2a study, patients with previously untreated advanced or metastatic PDAC were eligible for participation and were treated with orally administered atebimetinib daily in combination with mGnP (modification: every other week dosing). The primary endpoint was objective response rate (ORR) per investigator assessment using RECIST 1.1 criteria in response-evaluable patients. The cohort was powered (~80%, one sided alpha 0.05) using an optimal Simon’s 2-stage design. Results: Fifty-five patients were enrolled and treated with 320 mg atebimetinib daily + mGnP. ECOG performance status was 0-1 (100%); median age was 68 years (range 42-85 years), 62% were ≥65 years, and 55% were male. No grade 5 treatment-related adverse events (AE) were observed. No AE related to atebimetinib were higher than grade 3. Grade 3 AE related to atebimetinib occurred in 29% of participants, with the most frequent being rash (5%), ALT increased (5%), and AST increased (5%). Among the 50 response-evaluable patients, best overall response (BOR) achieved were 21 PR, 21 SD, 7 PD, 1 NE. The ORR was 42%, and DCR was 84%. With a median follow-up of 10.4 months (data cutoff Jan 7, 2026), 6- and 9-month OS rates were 88% and 79%, respectively; median PFS was 8.3 months and median OS was not reached. Conclusions: Atebimetinib in combination with mGnP demonstrated favorable safety and promising efficacy compared to historic standard-of-care (SoC) GnP. 1 A phase 3 registrational trial is planned to start in mid-2026 for evaluation of atebimetinib + mGnP versus SoC GnP. 1. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med . 2013;369(18):1691-1703. doi:10.1056/NEJMoa1304369 (PMID: 24131140). Clinical trial information: NCT05585320 .

3146 Background: The MTA-cooperative PRMT5 inhibitor BMS-986504 selectively binds to the PRMT5-MTA complex, a synthetic lethal target in MTAP -del cancer cells, while sparing MTAP –wild-type normal cells. In the phase 1 CA240-0007 study, BMS-986504 was well tolerated and had antitumor activity in pts with MTAP -del advanced solid tumors (ORR, 23%; median DOR, 10.5 mo). BMS-986504 also demonstrated dose-dependent reductions in plasma symmetric dimethylarginine (SDMA) levels, a PD biomarker of PRMT5 inhibition. Here, we report expanded PD and genomic analyses and initial results of exploratory proteomic analyses from CA240-0007. Methods: Pts with advanced, unresectable, or metastatic solid tumors with homozygous MTAP -del received BMS-986504 (50–800 mg) in 3-wk cycles. Analyses of SDMA levels and proteomic profiles from paired plasma samples (baseline and C2D1) were performed using mass spectrometry and SomaScan 11K, respectively. Tumor genomic information was extracted from local pathology reports. ORR was assessed per RECIST v1.1. Results: Among 78 pts with paired samples at data cutoff (22 Sept 2025; median f/u, 15.9 mo), dose-dependent reductions were seen in plasma SDMA levels, with the greatest reductions at 400 mg QD (median, 60.3%; n = 31) and 600 mg QD (median, 60.3%; n = 23). Proteomic pathway enrichment analysis demonstrated downregulation of PI3K/Akt/mTOR, Myc target, cell cycle, and DNA damage repair (DDR) pathways with BMS-986504 on C2D1 (n = 87), consistent with the expected effect of PRMT5 inhibition; a trend toward deeper modulation of PRMT5-regulated pathways was observed at higher doses. No proteins at baseline (n = 94) were found to be significantly associated with ORR (false discovery rate > 0.05). Responses in clinically evaluable pts with NSCLC (n = 33) or PDAC (n = 35) were observed regardless of EGFR , KRAS , or TP53 status. In pts with NSCLC, STK11 and SMARCA4 alterations were numerically higher in nonresponders. No gene alterations were associated with response in PDAC, except GABRA6 alterations (n = 2, both responders). A trend toward higher ORRs was seen in pts with alterations in DDR genes ( CHEK2, FANCD2, XRCC4 , and/or MSH2 ), consistent with the role of PRMT5 in DDR via regulation of mRNA splicing. ctDNA analysis will be presented. Conclusions: BMS-986504 demonstrated robust dose-dependent PD effects in pts with advanced solid tumors in plasma SDMA and proteomic analyses. Downregulation of PRMT5-regulated pathways was observed with BMS-986504 treatment. Response was seen regardless of EGFR, KRAS , and TP53 alterations in NSCLC or PDAC, and DDR gene alterations were associated with improved response. These findings further support the MOA of BMS-986504 and its ongoing investigation in the phase 2/3 MountainTAP-9, -29, and -30 studies as a potential treatment option in pts with MTAP -del advanced solid tumors. Clinical trial information: NCT05245500 .