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186 Background: INCA33890 is an anti–PD-1/TGFβR2 bispecific antibody designed to antagonize TGFβR2/PD-1 signaling in immune cells co-expressing both targets. In the INCA33890-101 study (NCT05836324), patients (pts) with refractory non-MSI-H mCRC were treated with INCA33890 monotherapy at 3 expansion doses. Responses were observed in pts with and without active liver metastases. Here, we analyze associations between baseline biomarkers and clinical outcomes. Methods: Fresh or archival (≤3 years from study registration) baseline biopsies were required in the dose expansion part and assessed using immunohistochemistry (IHC) for CD8 and PD-L1 (SP263) and whole transcriptome and next-generation sequencing for DNA aberrations (both Tempus xT). Baseline ctDNA was analyzed using Predicine Atlas during dose escalation and expansion. Efficacy was assessed by investigators per RECIST v1.1. Results: As of July 25, 2025, efficacy data with INCA33890 monotherapy were available from 105 pts; 16 pts (15.2%) had a partial response (PR), including pts with liver and peritoneal metastases (Table). Of the 78 pts with evaluable baseline biopsies for IHC analysis, pts with PR or stable disease (SD) showed greater PD-L1 tumor area positivity scores than those with progressive disease (PD) (nominal p<0.05). mRNA expression of inflammatory genes (IFN-γ, CXCL9, CXCL10 and T-cell inflamed signature) were higher in pts with PR/SD vs PD. Pts with blood tumor mutation burden (bTMB) >20 mut/MB had a trend towards higher ORR (33.3%) vs pts with bTMB <20 mut/MB (12.5%). Consensus molecular subtypes (CMS) were assessed in 44 pts. Although CMS 4 is commonly associated with the presence of TGF-β, it was not associated with a higher ORR (7.7% [1/13]). Responses were also observed in CMS 2 (21.7% [5/23]) and CMS 1 (50% [1/2]), but not in CMS 3 (n=6). There was no relationship with tumor mRNA expression of TGFβ or TGFβ-associated signatures with clinical outcomes. In addition, SMAD4 mutations, determined by ctDNA, were present in both responders and non-responders. Mutations in KRAS (64%), TP53 (72%), and APC (47%) were the most common aberrations and had no impact on clinical outcomes. Conclusions: INCA33890 demonstrated preliminary efficacy in pts with non-MSI-H mCRC across a variety of subgroups. Higher baseline PD-L1 expression and mRNA expression of inflammatory genes enriched for clinical benefit while overexpression of TGF-β did not seem to enhance efficacy. Updated data will be presented. Clinical trial information: NCT05836324 . Efficacy across subgroups. N ORR, % DCR, % Overall 105 15.2 28.6 With/without Liver Metastases 75/30 12.0/23.3 20.0/50.0 Peritoneal Metastases 40 10.0 20.0 No Liver or Peritoneal Metastases 20 30.0 60.0 PD-L1 TAP <1% 22 9.1 22.7 PD-L1 TAP >1% 56 17.9 25.0 PD-L1 TAP >5% 13 38.5 61.5 bTMB high >20 mut/MB 15 33.3 40.0 bTMB <20 mut/MB 64 12.5 28.1

To explore the role of large language models (LLMs), such as ChatGPT, in enhancing radiology reporting and patient interaction, highlighting their benefits, limitations, and ethical implications. The integration of ChatGPT into radiology can potentially streamline workflows by providing succinct impressions and extracting longitudinal patient information from electronic medical records (EMR), thereby increasing efficiency and workflow for radiologists. It helps facilitate patient understanding by simplifying complex medical information, fostering better engagement and understanding. Despite their promise, ChatGPT face substantial limitations, particularly in accurately contextualising intricate medical data and performing abstract clinical reasoning—areas where human expertise is indispensable. Ethical considerations include ensuring transparency, accountability, and the reduction of inherent biases to safeguard patient care. Additionally, the current medicolegal frameworks are insufficient in addressing the liability of errors or misinterpretations generated by AI. LLMs such as ChatGPT can serve as valuable adjuncts in radiology, enhancing report drafting and patient communication. However, responsible integration requires rigorous validation, ethical oversight, and adherence to updated regulatory standards. Radiologists' expertise remains essential to ensure precise, contextually accurate reporting and maintain high-quality patient care. Continuous research and policy development are needed to optimize and safely harness the potential of LLMs in medical practice.

3012 Background: VLS-1488 is an oral small molecule inhibitor of KIF18A, a mitotic kinesin protein important for successful division of cancer cells with chromosomal instability (CIN) but not required for mitosis in normal cells. Preclinical studies of VLS-1488 showed dose-dependent inhibition of tumor growth in CIN models. Methods: VLS-1488-2201 is a phase I/II study of patients (pts) with advanced solid tumors consisting of two parts, Dose Escalation and Dose Expansion. During Dose Escalation, a Bayesian Optimal Interval design was utilized to enroll pts to dose escalation cohorts with additional pts enrolled to backfill cohorts at dose levels (DLs) that did not meet de-escalation/elimination rules. Primary objective was to assess safety/tolerability of VLS-1488 at various DLs to determine the Maximum Tolerated Dose (MTD). Secondary objectives included evaluating preliminary efficacy and pharmacokinetics (PK). Eligible pts had exhausted standard of care treatments and had measurable disease per RECIST v1.1. Pts received VLS-1488 once daily, orally for 28-day cycles until disease progression, unacceptable toxicity or other stopping criteria. Results: 52 pts (ITT) were enrolled across 5 DLs including 50mg (n = 4), 100mg (n = 12), 200mg (n = 14), 400mg (n = 12) and 800mg (n = 10). Tumor types were high grade serous ovarian (HGSOC; n = 20), colorectal (n = 14), triple negative breast (n = 7), squamous lung (n = 3), endometrial (n = 3), ovarian carcinosarcoma (n = 2), esophageal (n = 2) and bladder (n = 1). The median number of prior lines was 4 (range 1-8). As of data cutoff, 52 pts (100%) received >1 dose of VLS-1488. No dose-limiting toxicities (as assessed during the first 28 days) were observed and MTD was not reached. Treatment-related AEs (TRAEs) occurred in 22 pts (42%), with fatigue (17.3%; G1 13.5%, G2 3.8%), aspartate aminotransferase increased (13.5%; G1 7.7%, G2 1.9%, G3 3.8%) and rash (11.5%; G1 3.8%, G2 1.9%, G3 5.8%) observed in >10% of pts. 6 pts (12%) experienced G3 TRAEs and no > G3 TRAEs were observed. Drug exposures exceeded preclinically defined efficacious thresholds and were approximately dose proportional at analyzed DLs. 41 pts (79%) were evaluable for response per RECIST v1.1. In the 16 HGSOC pts evaluable for response (where the median number of prior lines was 4.5; range 2-8), 3 partial responses (PRs; including 2 pts with sustained PR >24 weeks) and 6 with stable disease (SD; including 4 pts with tumor reductions) were observed across multiple DLs, with 5 pts continuing with study treatment. Conclusions: VLS-1488 was found to be safe and tolerable, with encouraging anti-tumor activity observed in heavily treated HGSOC pts. VLS-1488 will be evaluated further in the Dose Expansion phase of the study. Clinical trial information: NCT05902988 .

105 Background: SEZ6 is a potential neuroendocrine lineage marker that is expressed in small cell lung cancer (SCLC) and high-grade neuroendocrine neoplasms (NENs). NENs have a significant unmet need for novel effective targeted therapies. ABBV-706, a unique antibody-drug conjugate comprising a SEZ6-directed antibody conjugated to a potent topoisomerase 1 inhibitor payload, is being evaluated in a phase 1 study (NCT05599984) in patients (pts) with advanced solid tumors. Preliminary results from ABBV-706 monotherapy dose escalation showed a manageable safety profile with promising efficacy in SCLC and NENs ( J Clin Oncol 2024;42[suppl 16]: abs 3001). Herein, updated safety and efficacy of ABBV-706 monotherapy in NENs are presented. Methods: Pts (≥18 yr) with relapsed/refractory high-grade NENs (well-differentiated grade [G] 3 neuroendocrine tumors [G3 NETs] and poorly differentiated neuroendocrine carcinomas [NECs]), atypical lung carcinoid, and medullary thyroid cancer (MTC) were enrolled in dose-escalation and -expansion cohorts of a phase 1, open-label study. Pts received ABBV-706 monotherapy IV at 1.3–3.5 mg/kg once every 3 weeks. Primary study objectives are assessment of safety, PK, and efficacy. SEZ6 expression is evaluated retrospectively. Results: As of Aug 27, 2024, 191 pts were enrolled overall, including 64 with NENs. In the NEN cohort, median age was 63 yr (range 33–86) and pts had received a median of 3 (range 1–8) prior therapies. NEN histologies were large cell NEC (LCNEC; 22%, n=14), gastro-enteropancreatic NEC (GEPNEC; 19%, n=12), MTC (9%, n=6), neuroendocrine prostate carcinoma (NEPC; 8%, n=5), G3 NETs (8%, n=5), and other NECs (34%, n=22). The safety profile for ABBV-706 was similar across NEN subtypes and aligned with the entire study population. For the overall study population, TEAEs occurred in 184 (96%) pts and G≥3 in 134 (70%). Most frequent hematologic TEAEs were anemia (58%; G≥3: 45%), neutropenia (44%; G≥3: 33%), and thrombocytopenia (35%; G≥3: 21%). Most frequent nonhematologic TEAEs were fatigue (45%; G≥3: 3%) and nausea (38%; G≥3: 2%). Unadjudicated pneumonitis/interstitial lung disease rate was 4% (G≥3 in 2 pts). For the entire NEN cohort, the objective response rate (ORR) was 31.3% (20/64) and the clinical benefit rate was 92.2% (59/64). ORR by NEN type was: LCNEC, 28.6% (4/14); GEPNEC, 16.7% (2/12); NEPC, 60.0% (3/5); G3 NET, 60% (3/5); MTC, 16.7% (1/6); other NEC, 31.8% (7/22). The median duration of response was 5.59 mo (95% CI: 4.24, not estimable) and median progression-free survival was 6.80 mo (95% CI: 5.45, 7.75). Correlation analysis of efficacy with SEZ6 expression is ongoing. Conclusions: ABBV-706 showed preliminary efficacy in several high-grade NENs with a high unmet need, supporting its further development in specific subtypes. Clinical trial information: NCT05599984 .

3023 Background: Folate receptor alpha (FRα) is overexpressed in several solid tumors. LY4170156 is an Fc-silent, FRα specific humanized IgG1 ADC linked to exatecan, a topo-I inhibitor, via a novel cleavable polysarcosine linker at a homogenous DAR of 8. LY4170156 demonstrated in vivo preclinical efficacy in tumor models, across all FRα expression levels. Methods: This is a multicenter, open-label, first-in-human phase 1a/b study of LY4170156 in patients (pts) with advanced FRα-expressing ovarian, endometrial, cervical, and other solid tumors. Pts with prior ADCs targeting FRα with payloads other than topo-I (including mirvetuximab soravtansine-gynx [mirv]) were allowed. Dose escalation followed the mTPI-2 method. LY4170156 was administered Q3W IV (dose range of 2-6 mg/kg); dose limiting toxicity (DLT) evaluation period was 21 days. Dose escalation included a randomized dose optimization cohort in PROC. Key endpoints were safety, PK, and antitumor activity per RECIST v1.1. Efficacy evaluable pts were those who had a post baseline response assessment or discontinued treatment prior to the response assessment. Results: As of 27 Nov 2024, 45 pts were treated with LY4170156. Median age was 63 yrs (range, 24-85), 100% had ECOG PS 0-1, and 32 (71%) had high-grade serous ovarian cancer (HGSOC). Among the HGSOC pts (32), median lines of prior therapy was 5 (range, 1-10), 19% had received prior mirv, and 44% had FRα expression < 75% by local or central testing. PK of LY4170156, total antibody, and exatecan were linear and dose-proportional within the tested dose range. Unconjugated payload release from ADC at C max was < 4% at 4 mg/kg; median half-life of LY4170156 was 5.7-7.0 days and exatecan was 7.2-8.6 days. Main toxicities were myelosuppression and GI-related, as expected from an exatecan payload. Across all doses, the most common treatment-emergent adverse events (TEAEs; ≥15%) were nausea (58%, 2% gr 3), fatigue (44%, 0% gr 3-4), anemia (33%, 24% gr 3), vomiting (27%, no gr 3-4), diarrhea (22%, 4% gr 3), and neutropenia (20%, 11% gr 3-4). Febrile neutropenia (FN) was observed in 3 pts (7%). To date, no pulmonary or ocular toxicity were noted. Two DLTs were observed (1 gr 3 FN [6 mg/kg]; 1 gr 3 anemia [2 mg/kg]); no MTD has been established to date. Among 13 efficacy evaluable HGSOC pts (6 FRα ≥75%; 6 < 75%; 1 pending data), 9 showed reduction in target lesions; preliminary ORR was 38% (n = 5) with 1 CR, 4 PR, and 4 SD across all dose levels. Combined ORR for 4 and 6 mg/kg dose levels was 55%. All responses were unconfirmed and ongoing at the time of data cutoff. Three of 5 responders had FRa expression < 75% and two ≥75% including 1 who was mirv refractory. Conclusions: LY4170156 was well-tolerated with encouraging clinical activity among HGSOC pts, including those with FRα expression < 75% and those with prior mirv. Randomized dose optimization is ongoing and updated data will be presented. Clinical trial information: NCT06400472 .

BackgroundNemvaleukin alfa (nemvaleukin) is a novel engineered cytokine with antitumor activity both as monotherapy and in combination with pembrolizumab in multiple solid tumors when administered intravenously (IV) at 6 μg/kg once daily, days 1–5 in a 21-day cycle (q5d).1 ARTISTRY-3 (NCT04592653) is a phase 1/2, open-label study evaluating less frequent IV dosing (LFD) of nemvaleukin in advanced solid tumors. With both q5d and LFD regimens, nemvaleukin expands CD8+ T and NK cells in peripheral blood with minimal expansion of Tregs. Similarly, administration of nemvaleukin monotherapy q5d regimen in a cutaneous melanoma patient increased GZB+CD8+ T cells with minimal expansion of Treg in the tumor microenvironment (TME).2 Here, we report modulation of the TME in ovarian cancer and mucosal melanoma patients dosed with 3 different schedules in ARTISTRY-3.MethodsAt the time of this abstract, screening and on-treatment (Cycle 2 Day 8) biopsies were available from five subjects (30ug/kg D1 in 21-d cycle, N=2, 1 ovarian cancer (OC) and 1 mucosal melanoma (MM); 15ug/kg D1+D4 in 21-d cycle, N=2, 1 OC and 1 MM (vulvar); and 25ug/kg D1+D8 in 21-d cycle, N=1 OC). We performed deep immune profiling using a 14-marker multiplex immunofluorescence panel encompassing various activation states of NK, CD8+ T, CD4+ T, and Treg cells, plasma cells, macrophages, and tumor markers. CD8/NK:Treg densities in whole tissue from all subjects and immune densities in distinct TME regions along with spatial analytics (nearest neighbor distance, neighborhood analysis) from 4 of 5 subjects are reported here.ResultsImmune activation was demonstrated with nemvaleukin LFD by increased on-treatment density of NK and CD8+T cell subsets (figure 1). Ratios of CD8:Treg and NK:Treg were favorable and increased on treatment in 4 of 5 subjects (table 1). Nearest neighbor analysis revealed a shorter distance from tumor to GZB+NK cells in 4 of 4 subjects in on-treatment biopsies. Neighborhood analysis revealed increased proportions of GZB+NK and GZB+CD8+ T cells in tumor neighborhoods in on-treatment biopsies in 2 of 4 subjects. Data from additional subjects will be available at the time of this presentation.ConclusionsHere we report the first data describing tumor site pharmacodynamics of nemvaleukin LFD. These findings are consistent with nemvaleukin’s peripheral immune dynamics and proposed mechanism of action. Collectively, we demonstrate tumor-site immune activation and a shift towards a proinflammatory immune milieu dominated by cytolytic effector NK cells and CD8+ T cells in subjects treated with nemvaleukin LFD.Trial RegistrationNCT04592653.ReferencesUlka N Vaishampayan, et al. Nemvaleukin alfa monotherapy and in combination with pembrolizumab in patients (pts) with advanced solid tumors: ARTISTRY-1. Jour Clin Oncology 2022;40:2500–2500.Winer I, Gilbert L, Vaishampayan U, et al. Clinical outcomes of ovarian cancer patients treated with ALKS 4230, a novel engineered cytokine, in combination with pembrolizumab: ARTISTRY-1 trial. Journal for ImmunoTherapy of Cancer 2020;8:doi: 10.1136/jitc-2020-SITC2020.0347Ethics ApprovalMultiple ethics committees and IRBs were involved and the trial protocol was approved by the institutional review boards/independent ethics committees at each site. Institution details for each site are available at the ARTISTRY-3 clinicaltrials.gov trial page: ‘https://clinicaltrials.gov/study/NCT04592653?term=artistry-3&rank=1#contacts-and-locations.’ 217 Figure 1Treg, CD8+, and NK and subsets densities (#/mm2) within and surrounding tumor parenchyma 217 Table 1Ratios of CD8+ T cells and NKp46+NK cells to Treg in pre-treatment and on-treatment tumor biopsies (whole tissue values)

IntroductionADCs represent an important class of cancer therapies. Combining ADCs with chemotherapy has historically been challenging due to overlapping toxicities. UpRi is a NaPi2b-directed ADC designed with a high DAR and a proprietary AF-HPA microtubule inhibitor payload with controlled bystander effect. UPGRADE was a Ph1 dose escalation/expansion study to evaluate the combination of UpRi/carboplatin followed by UpRi maintenance.MethodsUPGRADE enrolled pts with recurrent PSOC, 1-3 prior LoT. Primary objective was to determine the MTD/RP2D for the combination. Secondary objectives included safety and preliminary efficacy. The combination UpRi/carboplatin (AUC5) was dosed Q4W up to 6 cycles, followed by UpRi monotherapy. Here we report results from DES.Results15 pts enrolled at UpRi dose levels 20-36 mg/m2. DLTs assessed during cycle 1. One DLT observed (20 mg/m2; G3 AKI due to dehydration). At data cut (Oct 3, 2023) fatigue (86.7%), nausea (73.3%), platelet count decrease (66.7%; G3/4 33.3%), diarrhea (66.7%; G3 20%) and anemia (60%; G3/4 33.3%) were the most common TEAEs. Severe overlapping toxicities observed with other standard of care chemotherapy combinations such as peripheral neuropathy, alopecia and mucositis were not observed. 14 patients were evaluable for response; ORR was 71.4% (10/14) regardless of NaPi2b status, including 4 CR.Conclusion/ImplicationsThese emerging data suggest that UpRi/carboplatin was well tolerated and showed encouraging activity. While development of UpRi has been discontinued by the sponsor due to portfolio reprioritization considerations, the combination demonstrates the potential for the AF-HPA payload to achieve a differentiated tolerability profile and enable potential combinations with platinum without significant overlapping toxicities.