Citations

e15046 Background: BRAF V600 is the most common driver mutation in melanoma, seen in ≈50% of patients. Recently, the use of liquid biopsy assays that are based on circulating tumor DNA (ctDNA) has become widespread for diagnosis and residual disease monitoring. We have previously reported on our droplet digital PCR (ddPCR) test as a liquid biopsy for BRAF mutant (BRAFm) melanoma. Here we report the correlation between clinical and radiological parameters and ddPCR test results. Methods: Using the department of laboratory medicine archives, we have identified all biopsy proven BRAFm melanoma patients that were tested with the BRAF V600 ddPCR assay at our institution over the years 2018-2024. All patients had blood samples collected, and cell free DNA (cfDNA) was extracted from plasma using the Qiagen QIAamp Circulating Nucleic Acid Kit. cfDNA was evaluated with a BioRad QX200 droplet digital PCR platform assessing for BRAF V600E/K mutations. Clinical and demographic data were collected from medical records. Radiometabolic features including volumetric data and FDG PET SUV values were collected and analyzed using the MIM software (MIM Software Inc., Beachwood, OH, USA). Univariate and multivariate analyses were used to assess correlations between baseline variables and test results. Results: 71 patients were identified. The median age was 59 (26-85), 54% were males. 46 patients (65%) had a positive test result which was based on a cut-off of ≥4 mutant copies per ml. 65 patients (92%) had active disease on imaging studies, of which those with a positive test result were younger (p = 0.047), had a higher proportion of osseous metastases (p = 0.02) and had a higher number of lesions (p = 0.006). There was no difference in the median overall survival between the groups (11 months vs. 33 months for positive and negative result respectively, log-rank test; p = 0.15). Total tumor volume on PET-CT (in ml) was predictive of the quantitative ddPCR test result (in copies per ml), with every increase in 10 ml of tumor leading to an expected increase of 370 copies per ml (p < 0.001). Multivariate models have failed to show a correlation between baseline parameters and the quantitative ddPCR test result. When performing the analyses using logistic regression models with the binary ddPCR test result as the outcome, osseous metastases were predictive in a univariate model (OR = 4.3, 95% CI 1.4-15.4). The best fit multivariate model showed that higher burden of disease with ≥6 lesions (OR = 6.57, 95% CI 1.24-44.3) and elevated LDH (OR = 8.8, 95% CI 1.83-56.91) were associated with an increased risk for a positive result, while younger age was associated with decreased risk for a positive result (OR = 0.92, 95% CI 0.86-0.97). Conclusions: The results of ddPCR testing for BRAF mutation are correlated with the radiological and volumetric extent of the disease. This test could be useful in patients presenting with high-burden disease when a fast turnaround time is needed.

e15045 Background: Increased cancer cell mitosis in tumor tissue is widely regarded as an indicator of aggressive disease, a predictor of shorter survival, and an indicator of response to specific anthracycline based chemotherapies. Circulating tumor cells (CTCs) are cancer cells that detach from primary tumors, enter the bloodstream, and seed metastatic sites, which in patients (pts) with metastatic breast cancer (mBC) are also predictors of poor prognosis and reduced therapy response. Furthermore, small preliminary studies have identified a specific subtype of mitotic CTCs that appears to correlate with poor survival rates compared to CTC detection alone. However, larger studies have yet to be conducted to validate the clinical utility of mitotic CTCs. In this large multi-institutional prospective study, we isolated CTCs from the blood of n = 155 mBC pts to subtype mitotic CTCs to assess progression-free survival (PFS) and overall survival (OS) over 2 years. Methods: Peripheral blood samples (7.5ml) were prospectively collected from n = 155 mBC pts progressing on systemic therapies and prior to new systemic therapy induction (i.e., chemotherapy n = 90, hormone therapy n = 13, immunotherapy n = 51, targeted therapy n = 62). Samples were processed using CellSieve microfilters to isolate CTCs via size exclusion and fluorescently stained for CD45, Cytokeratin, and DAPI. CTCs were imaged, enumerated, and subtyped based on the presence of ≥1 mitotic event, using established visual indicators. PFS and OS were assessed over 2 years by censored univariate and multivariate analyses. Results: CTCs were detected in ~45% (n = 70/155) of pts, while mitotic CTCs were identified in a subset of this group, ~23% (n = 35/155). The presence of any CTC was associated with poor outcomes (PFS HR = 2.16, 95%CI = 1.4-3.2, p = 0.0002 and OS: HR = 2.51, 95%CI = 1.5-4.0, p = 0.0002). The presence of mitotic CTCs correlated with significantly poorer outcomes (PFS: HR = 5.6, 95%CI = 3.1-10.2, p < 0.0001 and OS: HR = 7.3, 95%CI = 3.7-14.5, p < 0.0001). Overall, pts with no CTCs had a median PFS (mPFS) of 7 months and median OS (mOS) of 24 months, pts with non-mitotic CTCs had a mPFS of 6 months and mOS of 15 months; pts with both CTCs and mitotic CTCs had a mPFS of 3 months and mOS of 5 months. Notably, 97% of pts with a mitotic CTC progressed within 6 months, regardless of systemic therapy type. Interestingly at 2 years, a sole non-progressive pt with a mitotic CTC was receiving alpelisib (a specialized PI3KCA inhibitor). Conclusions: Overall, the detection of CTCs indicated poor outcomes in pts, with mitotic CTCs correlating with significantly more aggressive disease and further reduced survival rates regardless of systemic therapy type. This study highlights the need for larger, more comprehensive studies to expand upon and validate these findings.

e15024 Background: Anetumab ravtansine (AR) is an antibody-drug conjugate (ADC) containing the microtubule inhibitor DM4. ADC drugs have high interpatient variability in pharmacokinetics and pharmacodynamics (PK/PD), which raises concerns whether current dosing based on body weight (mg/kg) is optimal. Thus, we evaluated the effects of patient characteristics, including novel biomarkers of the innate immune system (IIS), on the PK/PD of AR. Methods: Studies were performed in patients in three clinical trials of different cancers with AR as part of treatment: 1) platinum-resistant or refractory high-grade ovarian cancer treated with AR at 2.2mg/kg IV weekly plus bevacizumab(N = 19); 2) pleural mesothelioma treated with AR at 6.5 mg/kg IV every 3 weeks plus pembrolizumab(N = 28); and 3) mesothelin-positive advanced pancreatic adenocarcinoma treated with AR at 5.5-6.5 mg/kg IV every 3 weeks plus nivolumab (and ipilimumab or gemcitabine, N = 27). Intensive plasma PK sampling was performed after the first dose to calculate clearance (CL), volume of distribution (Vd), and area-under-the-plasma-concentration-time curve (AUC 0-inf ). The relationship between biomarkers of FcɣRs (CD64, CD32, CD16) on IIS blood cells, total body weight (TBW), body surface area (BSA), lean body mass (LBM), and sex with PK parameters and clinical outcomes were evaluated by pearson correlation, t-test and multivariate regression analysis. Population PK (popPK) methods further evaluated patient covariates and variability in PK. Results: Patients with higher IIS FcγR CD64 and/or higher TBW or higher BSA had higher AR ADC CL (p < 0.05). AR ADC CL was lower in females (0.030 ± 0.007 L/h) versus males (0.042 ± 0.006 L/h) (p < 0.05). Patients with stable disease and partial response had higher AR ADC AUC 0-inf versus patients with progressive disease AR ADC disposition was described by linear CL with two pathways for the release of the payload DM4, hydrolysis and the IIS. A time-varying drug-to-antibody ratio predicted the release of the DM4 payload. In the PopPK model, LBM and albumin were associated with CL of the AR ADC, LBM and IIS FcγR CD64 were associated with the Vd of the AR ADC, and LBM and age were associated with the CL of the released DM4. Conclusions: These results suggest that TBW-based dosing of AR ADC is not optimal, whereas precision dosing of antibodies and ADCs based on the use of novel metrics of body habitus, IIS biomarkers, and sex may be more appropriate to reduce PK variability and improve response.

e15003 Background: Antibody-drug conjugates (ADCs) have shown substantial promise as therapies for metastatic breast cancer (mBC). However, direct comparisons of different ADC-based regimens are limited. We assessed survival outcomes in mBC patients treated with ADCs. Methods: Randomized controlled trials (RCTs) published before October 2024 were searched in Medline, Embase, ClinicalTrials.gov, and Cochrane Library. Progression-free survival (PFS) and overall surcvival (OS) outcomes were extracted from the most updated publications. Participants were stratified based on molecular subtypes, hormone receptor (HR) status, duration of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) treatment, and sensitivity to endocrine therapy (ET). Bayesian frameworks were deployed, presenting the synthesized outcomes of indirect comparisons using the surface under the cumulative ranking curve (SUCRA), hazard ratio (HR), and 95% credible interval (Crl). This study was prospectively registered on the International Platform of Registered Systemic Reviews and Meta-analysis Protocols (INPLASY) (INPLASY2024110021). Results: A total of 6449 patients from 12 RCTs of ADCs ado-trastuzumab emtansine (T-DM1), sacituzumab govitecan (SG), trastuzumab deruxtecan (T-DXd), and datopotamab deruxtecan (Dato-DXd) were included in the analysis. Compared to chemotherapy, T-DXd significantly improved PFS (HR 0.35, 95% Crl 0.15-0.84) and OS (HR 0.56, 95% Crl 0.32-1.0). SG also significantly extended OS (HR 0.65, 95% Crl 0.43-0.97) but not PFS. In HER2+ mBC, pooled analyses revealed T-DXd was the most effective treatment in terms of PFS, with a SUCRA of 94.2%, followed by T-DM1 (58.9%), and chemotherapy with HER2-directed therapy (34.2%). Synthesized outcomes of OS mirrored the PFS outcomes. In HR+/HER2- mBC (some of which was HER2-low), Dato-DXd (76.1%) showed slightly superior efficacy over SG (67.4%) for PFS, while SG (85.1%) was advantageous over Dato-DXd (49.1%) in terms of OS. Among patients with HR+/HER2+ mBC, T-DXd (80.0%), SG (55.5%), and chemotherapy with HER2-directed therapy (53.1%) were the most effective therapies for prolonging PFS. Regarding OS, SG (70.3%) and T-DM1 (60.3%) were the most effective, with comparable efficacy observed between chemotherapy with HER2-directed therapy (52.1%) and T-DXd (52.0%). In HR-/HER2+ mBC, T-DXd (78.1%), SG (56.1%), and T-DM1 (51.5%) significantly prolonged PFS, while SG (69.4%) had the most substantial benefit for OS, followed by T-DXd (62.8%) and chemotherapy with HER2-directed therapy (57.6%). Dato-DXd showed an advantage over SG in mBC patients received CDK4/6i for > 12 months. Conclusions: This network meta-analysis showed prominent survival benefits with ADC-containing regimens for mBC. Our results provide valuable insights into personalized treatment strategies for mBC patients.

e16265 Background: The pivotal TOPAZ-1 trial established durvalumab plus gemcitabine and cisplatin (GC) as a new first-line standard of care for advanced biliary tract cancer (ABTC). However, weekly administration of GC can lead to significant toxicity limiting its tolerability in clinical practice. Based on previous studies, we implemented biweekly regimen of GC on days 1 and 15 together with durvalumab on day 1 of each 28-day cycle to optimize the treatment delivery and improve tolerability. Here, we report the Mayo Clinic experience with biweekly GC with monthly durvalumab in patients with ABTC. Methods: At our three-site institution, we retrospectively identified patients with ABTC between January 2021 and August 2024, who received biweekly GC with monthly durvalumab. Patient demographics, tumor characteristics, treatment details - treatment related adverse events (trAEs) graded according to the NCTCAE V5.0 were collected. Outcomes included median progression-free survival (mPFS), median overall survival (mOS) and clinically assessed overall response rate (ORR) and disease control rate (DCR). Results: 57 patients were included in our analysis, median age was 68 years (range 35-90), and 57.9% were females. 91.2% of patients had ECOG performance status of 0-1. 71.9% had intrahepatic cholangiocarcinoma, 19.3% extrahepatic cholangiocarcinoma and 8.7% gallbladder carcinoma. 70.2% had metastatic disease, 21 % locally advanced unresectable disease and 8.7% recurrent metastatic disease. Patients were followed for a median of 9.1 months (2.3-28.5). 91.2% of the patients received biweekly GC plus monthly durvalumab while 8.8% switched from weekly to biweekly GC plus monthly durvalumab due to treatment toxicities. Median number of treatment cycles was 5. Maintenance regimens included durvalumab (19.3%), gemcitabine/durvalumab (8.8%) and GC/durvalumab (8.8%). Median duration of follow up was 9.1 months (range 2.3 – 28.5). ORR was 36.9% and DCR was 72% (complete response 5.3%, partial response 31.6% and stable disease 35.1%). mPFS was 7.2 months, while mOS was 16 months. Grade(G) 3 or 4 trAEs included abnormal liver function tests (15.7%), infections (11.5%), anemia (8.7%), thrombocytopenia (5.2%), peripheral neuropathy (1.7%), acute kidney injury (1.7%). Immune-related AEs were noted in 6 patients (10.5%) including colitis, gastritis, hepatitis, myocarditis and hypothyroidism. There was no patient with severe neutropenia or febrile neutropenia. Only 5 patients (8.8%) stopped treatment due to trAEs. Conclusions: Biweekly GC on days 1 and 15 plus durvalumab on day 1 of each 28-day cycle is associated with a more favorable toxicity profile while maintaining efficacy similar to that observed in the TOPAZ-1 trial indicating that a de-escalation strategy is feasible with improvement in patient centered outcomes.

9037 Background: Efficient dissemination of research findings is critical in oncology, where timely access to new knowledge impacts clinical care and outcomes. This study analyzes publication timelines of high-impact oncology journals to identify patterns and determinants, including research categories and study designs. Methods: This is a retrospective observational study. Journals with the highest impact factors and available publication timeline data were included: Journal of Clinical Oncology, Molecular Cancer, Clinical Cancer Research, and Cancer Discovery. All articles published in 2023 were analyzed for submission-to-acceptance, acceptance-to-publication, and total publication times. Data were processed using SPSS, and statistical comparisons were made with the Kruskal-Wallis test (significance: p<0.05). Results: A total of 875 articles were analyzed. The overall median total publication time (TT) was 7.1 months (IQR: 5.7–8.9), with submission-to-acceptance (AT) and acceptance-to-publication (PT) medians of 4.8 months (IQR: 3.5–6.3) and 2.2 months (IQR: 1.6–2.6), respectively. Among journals, Molecular Cancer exhibited the shortest TT (median: 4.7 months; IQR: 3.1–6.6), while Cancer Discovery had the longest TT (median: 8.8 months; IQR: 6.8–10.6). Similarly, Molecular Cancer achieved the fastest AT (median: 3.9 months; IQR: 2.2–5.4) and PT (median: 0.6 months; IQR: 0.4–1.1). Conversely, Cancer Discovery recorded the slowest AT (median: 6.0 months; IQR: 4.5–7.8) and PT (median: 2.8 months; IQR: 2.4–3.2). In terms of research categories, blood cancer articles accounted for the largest proportion of publications (14.4%), followed by gastrointestinal cancer (13.9%). Articles in genitourinary (median TT: 6.4 months; IQR: 5.5–8.8) and cardiac cancer (median TT: 6.5 months; IQR: 5.9–6.9) categories had the shortest TT, while endocrine (median TT: 7.9 months; IQR: 5.6–10.9) and immunotherapy (median TT: 9.1 months; IQR: 6.8–10.5) categories exhibited the longest TT (p<0.05). Clinical trials were the most common study design (37.6%), followed by cross-sectional studies (19.5%). Systematic reviews had the shortest TT (median: 2.4 months; IQR: 1.9–9.2), while proof-of-concept studies required the longest TT (median: 9.5 months; IQR: 8.7–10.7) (p<0.05). Systematic reviews and database studies also had the shortest PT (median: 1.5 months), whereas proof-of-concept studies had the longest PT (median: 2.8 months; p<0.001). Conclusions: Publication timelines in oncology journals vary significantly by journal, research category, and study design. Molecular Cancer demonstrates the fastest publication processes, while Cancer Discovery exhibits the slowest. Genitourinary and dermatologic oncology categories, as well as systematic reviews, achieve the most expedited timelines, emphasizing the need to consider category and study design in publication planning.

9029 Background: Addressing guideline concordant FP and TPP with cancer is challenging, especially for OT. SIM, a well-known education tool, has not been traditionally used to teach these topics. As part of the hematology/oncology fellowship curriculum, we designed a SIM applying LSP to bridge this educational gap. Methods: Applying LSP of contrasting cases, elaboration, feedback, generation and just-in-time telling, chief OTs and faculty designed a SIM with 3 clinical scenarios (CS) and 3 standardized pts (SP): FP for a female pt hospitalized for acute lymphoblastic leukemia tx, FP for a male pt in clinic for germ cell tumor tx, and breast cancer tx for a pregnant pt in 2 nd trimester. OT received written educational materials (WEM) and attended a lecture 1 week and 1 day pre SIM, respectively. OT were split into 2 groups; 1 started in the FP CS and 1 in the TPP CS, and then they switched. To reduce cognitive overload, each OT participated in 1 of 2 FP CS: half in the female FP CS and half in the male. Faculty and chiefs led debriefing sessions after all CS. The FP debrief ended with a special “learner as a teacher” part, where OT who attended the female CS taught those from the male CS about their topic and vice versa. The SIM concluded with "take-home" points. Pre (after having WEM) and post SIM anonymous surveys and verbal feedback assessed OT comfort, perceptions, and knowledge. Results: A 3 hour SIM with 14 OT and 5 faculty was completed successfully. SIM ended with all OT verbally sharing a learning point and positive feedback. All OT filled pre and post SIM surveys. Pre SIM, 17% reported having prior FP education, and 42% had prior TPP education. However, only 8% and 25% felt adequately prepared for FP and TPP discussions, respectively. Post SIM survey showed major improvement in comfort and knowledge about FP and TPP (see table 1). 75% of OT favored a combination of SIM and learning by teaching over other SIM formats. 83% supported having a TPP lecture before SIM. 100% reported satisfaction with FP and TPP SIM’s quality and wanted similar activities in the future. 92% were satisfied with the learner as a teacher tool. 100% felt education about FP and TPP with cancer should be part of fellowship training. Moral/cultural concerns were discussed as possible challenges in FP education. Conclusions: The application of LSP through SIM significantly increased OTs’ comfort discussing FP and TPP with cancer, and objectively enhanced their knowledge on these topics compared to after reading WEM. The SIM was largely perceived as a successful activity to educate about challenging topics and should become part of fellowship curriculum. Pre SIM % Post SIM % Comfortable addressing FP 17 92 Comfortable addressing TPP 8 100 Correct answers about female FP 63 83 Correct answers about male FP 67 94 Correct answers about TPP with cancer 68 98

5555 Background: Platinum-resistant/refractory ovarian cancer presents a significant therapeutic challenge and despite several attempts, immunotherapies have not delivered satisfactory results to be approved. Identifying biomarkers of response to novel therapies is crucial for personalizing treatments and improving patient outcomes, especially since certain patients do experience long term benefit after the treatment with pembrolizumab and igrelimogene litadenorepvec (TILT-123; an oncolytic adenovirus coding for TNF and IL-2). Methods: Tumor biopsies (n=62), ascites (n=8) and blood (n=234) were collected from 15 patients treated in the PROTA trial (Phase I, NCT05271318). These patients received pembrolizumab intravenously plus igrelimogene litadenorepvec intravenously, followed by local administration intratumorally or intraperitoneally. Sampling took place prior to therapy, during therapy and after it. Tumor proteome (IHC, mIF) and transcriptome was analyzed to assess immune changes and virus presence. Ascites and blood samples were assayed to measure cell counts, phenotypes, cytokine and protein counts, as well as for the presence of antiviral neutralizing antibodies (NAbs). Biological parameters were correlated with overall survival (OS), RECIST 1.1 evaluations and tumor size changes. For analysis of OS, logrank test was used. For group comparisons two-tailed Mann-Whitney U-test was used. Pearson or Spearman tests were used for correlations. Results: Patients experiencing a drop in circulating lymphocytes 8-24 hours after treatment were more likely to experience longer OS (p=0.044). Additionally, patients with a higher lymphocyte count at baseline experienced similar OS benefit (p=0.018) plus a positive correlation with disease control (p=0.023). Most patients (11/15) showed antiviral immunity at baseline but eventually all patients developed neutralizing activity, and the same was observed in ascites. The presence of NAbs at baseline as well as development of highest titers were positively correlated with longer OS (p=0.004) and disease control (p=0.003). Conclusions: Igrelimogene litadenorepvec and pembrolizumab are therapies designed to attract, activate and/or protect lymphocyte-mediated antitumor activity. These findings suggest that having a fit immune system able to mobilize effector immune cells as well as responding to immunostimulant agents increases therapeutic success. As a disease with few therapeutic options, ovarian cancer patients often receive multiple lines of chemotherapy that might decrease the efficacy of immediate immunotherapies. The potential use of these biomarkers will be studied in larger studies to validate their utility in guiding the use of immunotherapy in this challenging patient population. Clinical trial information: NCT05271318 .

5515 Background: Clear cell ovarian carcinoma (CCOC) is a chemoresistant subtype of ovarian cancer. Immune checkpoint inhibitors have been reported to have clinical activity in CCOC. Additionally, CCOC harbors molecular alterations suggesting a role for anti-angiogenic agents. We therefore conducted a single-arm two-stage phase 2 trial to investigate the clinical activity of the combination of the PD-1 inhibitor pembrolizumab with the anti-angiogenic tyrosine kinase inhibitor lenvatinib in patients (pts) with CCOC. Methods: Pts with CCOC and measurable disease received pembrolizumab 200 mg IV every 3 weeks and lenvatinib 20 mg daily. Pts could have received an unlimited number of prior therapies; prior bevacizumab and immune checkpoint inhibitors were allowed, but prior lenvatinib was exclusionary. Malignant bowel involvement was not allowed. Co-primary endpoints were objective response rate (H 0 5%; H a 25%) and rate of PFS at 6 months (mo) per RECIST v1.1 (H 0 10%; H a 30%), restricting the probabilities of type I and type II errors to 10% and 10%, respectively. Two pts with objective responses or 3 pts progression-free and alive at 6 mos were needed to proceed from stage 1 (n=18) to stage 2 (n=13); 5 pts with objective responses or 6 pts progression-free and alive at 6 mos were needed to declare the combination worthy of further study. Results: Data cut-off occurred 22-Oct-2024. Of 30 enrolled pts, 83.3% were white; the mean age among all pts was 54.1 years. 30% of pts (9/30) experienced a confirmed response (2 CR, 7 PR); an additional 3 pts (10%) experienced unconfirmed PRs and 4 pts (13.3%) had SD ≥6 mo. As of data cut-off, 3 pts (10%) had not yet reached their first radiographic assessments, and 17 pts were still receiving study therapy. With a median of 9.72 mo of follow up, 16 pts were alive and progression-free at 6 months. The estimated 6-month PFS was 75.96% (95% CI 53.82-88.51%). Median PFS was 10.9 mo. The estimated 12-month PFS was 48.86% (95% CI 23.67-70.04%). The most common any-grade TRAEs were hypertension (71%), hypothyroidism (66%), and fatigue (60%). There were no unanticipated TRAEs. Conclusions: The combination of pembrolizumab/lenvatinib demonstrates encouraging evidence of clinical activity in CCOC, with 9 pts experiencing a confirmed response and 16 pts alive and progression-free at 6 months. As both co-primary endpoints of the study were met, enrollment closed with 30 pts. Updated data for all pts will be reported. There were no new safety signals. Clinical trial information: NCT05296512 .

3099 Background: Immune checkpoint inhibitors (ICI) are effective in melanoma, but many patients experience progression on or after approved ICI +/- MAPK inhibitor therapy. Melanocortin-1 receptor (MC1R) is a novel target for radiopharmaceutical therapy (RPT) and is highly expressed on melanoma tumor cells. VMT01 is an MC1R-targeted RPT that can be radiolabeled with either 203 Pb (patient selection and dosimetry assessments) or 212 Pb (alpha particle therapy). Here, we present data on the first in-human evaluation of [ 203 Pb/ 212 Pb]VMT01 in patients with metastatic melanoma. FDA granted Fast Track Designation to the product on the bases of preclinical experiments combining [ 212 Pb]VMT01 with immunotherapy. Methods: This is a first-in-human dose-finding study to determine the safety, pharmacokinetics, dosimetry and preliminary efficacy of [ 212 Pb]VMT01 in subjects with MC1R-positive metastatic melanoma who progressed on at least 1 approved first-line therapy (NCT05655312). Phase 1 of the trial includes escalating dose cohorts. The first two cohorts incorporate dosimetry evaluations (reported separately) with the imaging surrogate [ 203 Pb]VMT01 prior to receiving up to 3 treatment cycles of [ 212 Pb]VMT01 therapy (injected activity of 111 MBq (3 mCi) or 185 MBq (5 mCi) for Cohort 1 and 2, respectively). Participants are evaluated for any DLT for the first 6 weeks after cycle one. Efficacy is assessed by RECIST 1.1 criteria by the investigator. Following the start of the study the anticipated combination arm with nivolumab was opened as an amendment. Results: Cohort 1 (DCO 04Sep24) was completed with 3 enrolled participants who received 3 treatment cycles without any DLTs or SAEs. Cohort 1 participants showed prolonged stabilization of disease from start of treatment (mean: 11.1 months); one participant developed a confirmed objective response (PR) after completion of all three [ 212 Pb]VMT01 administrations and is still on trial after 13.1 months from start of treatment. Cohort 2 has completed with 7 enrolled participants. No DLTs or related SAEs have been observed. All participants in this Cohort progressed after either the first cycle (3 participants) or the second cycle (4 participants).Based on these preliminary results showing anti-tumor effect at the lower dose, additional cohorts for both monotherapy and in combination with nivolumab were introduced at a de-escalated dose of 55.5 MBq (1.5 mCi). Both cohorts are now open for enrollment. Updated safety and efficacy data will be analyzed and presented at ASCO. Conclusions: At 111 MBq and 185 MBq activity levels, [ 212 Pb]VMT01 was safe and well-tolerated. An objective response and prolonged stabilization of disease were observed at the 111 MBq activity level while no effect was seen at 185 MBq. The study will continue to explore potentially immunostimulating lower doses of administered activity of [ 212 Pb]VMT01 either as a monotherapy or in combination with nivolumab. Clinical trial information: NCT05655312 .