Citations

e13741 Background: The NCCN guidelines for first-line (1L) regimens in CLL have evolved over the past decade, shifting from ibrutinib (ibr) and chemoimmunotherapy (CIT) to second-generation BTK inhibitor and venetoclax combinations. We evaluated real-world use of preferred 1L treatment (tx) since 2016 in CLL patients (pts) in routine care to identify differences in prescribing based on race/ethnicity and practice type. Methods: This retrospective observational study utilized the US nationwide Flatiron Health electronic health record-derived de-identified database. Eligible pts had confirmed CLL and initiated 1L tx between 01/01/16-07/31/24. Primary outcome was receipt of preferred 1L tx defined by NCCN guidelines in four time periods by race/ethnicity (Hispanic, White, Black, Asian/Other). Odds ratios (ORs) were estimated using logistic regression, additionally adjusting for age, sex, ECOG performance status, IGHV, del17p/ TP53 mutation status, time period, and practice type. Results: A total of 7528 pts were included. Compared with White pts (n = 5472), Black pts (n = 640) were younger (median age at 1L: 68 vs 71). More Black and Hispanic (n = 290) pts were treated at community practices (86% vs 80% White). Of those pts tested, more Black pts had unmutated IGHV than White (77% vs 56%). Presence of del17p/ TP53 mutation was similar across races/ethnicities. The proportion of pts receiving preferred 1L tx based on the NCCN Guidelines significantly differed by race/ethnicity (Table) ( P = 0.0021). The proportion of Hispanic pts treated with preferred 1L tx was significantly lower than White (OR = 0.61; 95% CI: 0.47-0.79), but Black was similar to White (OR = 1.07; 95% CI: 0.89-1.30). Updates to NCCN guidelines were significantly associated with pts receiving preferred 1L tx by practice type ( P = 0.0005). In 2016-2018, 44% of community practices and 55% of academic centers adopted targeted therapies (TTs); in 2019, ibr use increased in both practices (77% vs 68%, respectively). Adherence to preferred tx improved across practices in 2020 but decreased with the prioritization of second-generation therapies. After the approval of zanu, use of TTs was 71% in community practices and 74% in academic centers. Conclusions: Inequities in pts with CLL receiving preferred 1L tx suggests disproportionate use of CIT and ibr by race/ethnicity. Use of preferred TTs also differed by practice type and time period, with increased adoption after pivotal trials. Time period % Pts receiving preferred tx by race a White Black Hispanic Asian/Other 2016-2018:Preferred tx ibr 46% 50% 43% 45% 2019(v2.2019: Jan 2019)Preferred tx ibr 76% 76% 67% 79% 2020-Jun 2022(v4.2020: Feb 2020)Preferred tx acala, VO, ibr 84% 84% 69% 83% Jul 2022-Jul 2024(v2.2023: Aug 2022)Preferred tx acala, VO, zanu 72% 66% 56% 73% VO, venetoclax + obinutuzumab. a By listing of NCCN preference (preferred vs other) among non-del17p and age >65.

e13738 Background: Persistent racial/ethnic and regional disparities in neoplasm mortality remain significant public health challenges. This study evaluates long-term trends in neoplasm mortality by race/ethnicity at the county level in the United States and examines the relationship between hospital density and mortality. Methods: Using data from the Global Burden of Disease Study (2000-2019), we analyzed age-standardized mortality rates (ASR) for neoplasms by ethnicity/raceHispanic (all races) and non-Hispanic American Indian or Alaska Native (AIAN), Asian or Pacific Islander (API), Black, and White. A joinpoint regression analysis was used to identify significant changes in the mortality trends, summarized as average annual percent change (AAPC). Correlation analysis evaluated the relationship between county-level hospital density and neoplasm mortality. Results: Neoplasm mortality rates declined across all racial/ethnic groups from 2000 to 2019, but disparities persisted. ASR per 100,000 population decreased from 240.5 (95% UI: 214.3–269.9) to 203.0 (180.8–228.3) for AIAN, 149.5 (144.9–153.9) to 115.3 (111.7–118.7) for API, 314.5 (312.1–317.0) to 218.7 (217.1–220.3) for Black, 168.4 (164.6–172.0) to 133.8 (131.0–136.4) for Latino, and 241.2 (240.5–242.0) to 187.5 (186.9–188.2) for White. AAPC from 2000 to 2019 ranged from -0.94% (AIAN) to -1.90% (Black). Gender-specific analyses revealed similar trends, with males showing slightly greater declines. Southeast states experienced slower declines compared to the Northeast. Some counties exhibited worsening mortality trends, particularly for AIAN, API, and Latino. The county-level hospital density (table) showed weak but statistically significant correlations in 2019 for AIAN (r = -0.35; p < 0.0001), White (r = -0.15; p < 0.0001), and Black (r = -0.18; p < 0.0001). No inverse correlation was observed for API (r = 0.07; p = 0.071) and Latino (r = 0.06; p = 0.012). Conclusions: While significant progress has been made in reducing neoplasm mortality, racial/ethnic and regional disparities persist, and health care access appears to contribute to this at least in part. Future analyses should evaluate mortality by cancer site and also account for broader clinical and public health infrastructure, as well as social determinants of health to better understand and address underlying disparities. The correlation between hospital density and age-standardized mortality rate from neoplasms by race/ethnicity in 2019. Correlation coefficient with mortality and hospital density AIAN API Black Latino White 2019 -0.35(-0.43 – -0.27) 0.069(-0.0058–0.14) -0.18(-0.23 –-0.13) 0.064(0.014–0.11) -0.15(-0.19 – -0.12)

e13718 Background: Oncology has evolved in the cyber era of medicine. The 21 st Century Cures Act mandated patient access to medical data (tests, provider notes) via patient portals connected to EHRs in order to facilitate patient engagement. Furthermore, the COVID-19 pandemic rapidly transformed patients’ interactions with portals by increasing reliance on telehealth and portal messaging. This shift has been well-documented in primary care, and emerging research suggests similar trends in oncology. More information is needed regarding how this has evolved post-pandemic. We present single academic institution real-world data (RWD) describing ongoing changes in patient messages and telephone calls in oncology. Methods: We quantified the changes (2019-2024) within oncology at Mayo Clinic Rochester campus including all care team, provider, nursing, and pharmacist visits, patient portal medical advice requests, patient calls, and messages sent to patients per year using Epic's SlicerDicer™ tool. Results: Patient visits/year dipped (-0.2%) from 2019 to 2020, but increased steadily from 2021 forward (Table 1). Patient portal advice requests increased significantly faster (Table 1); from 2019 to 2024, visits /year increased by 40%, while the number of advice requests increased by 131%. Patient calls/year increased more modestly (64%), while the number of messages sent to patients increased by 163% over this time. Conclusions: The transparency allowed by the Cures Act coupled with the impact of the pandemic has empowered patients to engage in their oncology care more proactively through the EHR. Patient-initiated portal messaging is increasing, with messages sent to patients from the oncology department similarly rising. Patient call volumes are also growing despite EHR messaging. Further research is necessary to better understand patterns of EHR use in oncology and explore ways to reduce clinician burnout that may arise from responding to this increased communication volume, as well as to understand the impact on patient satisfaction and outcomes. Changes in patient volume compared to patient calls and EHR messaging over time. Year Total Patient Visits Change in Patient Visits from Prior Year (%) Total Patient Medical Advice Messages Change in Patient Medical Advice Message Volume from Prior Year (%) Total Patient Calls Change in Patient Call Volume from Prior Year (%) Messages Sent to Patients Change in Patient Messages Sent to Patients from Prior Year (%) 2019 62,440 n/a 173,177 n/a 195,143 n/a 99,974 n/a 2020 61,959 -0.7 218,976 +26.5 240,833 +23.4 135,044 +35.1 2021 70,950 +14.5 276,561 +26.3 267,395 +11.0 165,293 +22.4 2022 74,961 +5.7 325,580 +17.7 263,732 -1.4 206,043 +24.7 2023 80,672 +7.6 349,756 +7.4 274,446 +4.0 214,257 +4.0 2024 87,605 +8.6 399,740 +14.3 319,963 +16.6 263,271 +22.9

e13701 Background: The optimal therapeutic strategy for advanced epithelial ovarian cancer (EOC) — primary debulking surgery (PDS) followed by adjuvant chemotherapy vs. neoadjuvant chemotherapy (NACT) followed by interval debulking surgery — remains debated. NACT is often chosen for unresectable disease, typically identified only during surgery. This study aims to develop a deep learning (DL) model to predict tumor resectability from pre-operative computed tomography (CT) scans. Methods: We retrospectively included EOC patients, FIGO stage III-IV, who underwent PDS between 01/ 2016 and 12/2023 at the European Institute of Oncology, Milan, Italy. The dataset included anonymized portal venous phase contrast-enhanced CT scans. Residual tumor (RT) annotations were extracted from operative reports and categorized as optimal RT (< 1cm) and suboptimal RT (≥1cm). A DL segmentation model (based on open-source TotalSegmentator) was used to identify pelvic/abdominal organ volumes and to remove couch artifacts. The dataset was split into training/validation (80%) and testing (20%) sets. A pre-trained Vision Transformer (ViT) encoder was adapted for 3D imaging, converting CT volumes into features refined by an attention mechanism and classified as optimal RT or suboptimal RT . We trained two ViT configurations (vit-base-patch16-224 and dinov2-small-imagenet1k-1-layer) and compared them with DenseNet121, a widely used Convolutional Neural Network (CNN) for image classification. Performance metrics included accuracy and F1 score. Results: Out of 521 patients, 416 (80%) had optimal RT and 105 (20%) suboptimal RT , the proportion being respected througouth the training/validation and testing groups. The median age at diagnosis was 60.0 years (IQR, 53.0-67.0). ViT models showed better performance compared to CNN in terms of accuracy (0.80 and 0.77 vs. 0.62) and F1 score (0.43 and 0.33 vs. 0.12). Conclusions: A pioneering ViT-based model was capable to predict tumor resectability from pre-operative CT scans in patients with advanced EOC. This improvement in performance, compared to CNN, might be due to the ViTs' ability to capture long-range dependencies and global context, which are crucial for predicting tumor resectability. In contrast, CNNs are limited by localized feature extraction and inductive bias, hindering their ability to capture the complex spatial relationships. By addressing the limitations of current radiological assessments, the model has the potential to serve as a clinical decision-support tool, enabling personalized management strategies for patients. Future work will focus on further improving the model performance.

e23101 Background: Liver cell carcinoma (LCC) and hepatic failure (HF) are major contributors to global adult mortality. Identifying trends and disparities in LCC and HF-related deaths is critical for addressing public health challenges and guiding prevention strategies. This study examines national trends in LCC and HF-related mortality from 1999 to 2023, with an emphasis on demographic, geographic, and temporal disparities in age-adjusted mortality rates (AAMRs). Methods: Using the CDC WONDER database (1999–2023), this descriptive study identified deaths attributed to LCC (ICD-10 code C22.0) and HF (ICD-10 code K72.9) among adults aged 25 and older. Mortality data were stratified by gender, race/ethnicity, census region, urban-rural classification, and state. Age-adjusted mortality rates (AAMRs) per 1,000,000 individuals were calculated, and trends were analyzed using Joinpoint regression to determine annual percent changes (APCs) with 95% confidence intervals (CIs). Statistical significance was set at p < 0.05, and the study followed STROBE guidelines. Results: From 1999 to 2023, there were 22,963 deaths attributed to LCC and HF (Men: 17,822; Women: 5,141). Overall, AAMRs declined from 1999 to 2007 (APC: -2.4), stabilized between 2007 and 2017 (APC: 0.2), and declined again from 2017 to 2023 (APC: -3.5). Men experienced a steady AAMR decline from 1999 to 2010 (APC: -2.1), followed by stabilization (2010–2017, APC: 0.7), and further decline (2017–2023, APC: -4.4). Women showed a sharp AAMR decrease from 1999 to 2006 (APC: -3.8) and a relatively stable trend thereafter (APC: -0.1). Non-Hispanic Blacks people experienced an overall AAMR decline from 1999 to 2020 (APC: -0.9). Among Non-Hispanic Whites people, AAMRs decreased initially (1999–2006, APC: -2.6), rose slightly (2006–2018, APC: 0.5), and declined further (2018–2020, APC: -7.3). Regional AAMRs varied, with the West having the highest overall AAMR (5.6; 95% CI: 5.4–5.7) and the Midwest the lowest (3.2; 95% CI: 3.1–3.3). Hawaii reported the highest state AAMR (10.3; 95% CI: 8.9–11.6), while Arkansas had the lowest (2.4; 95% CI: 2.0–2.9). Urban-rural disparities revealed a sharper AAMR decline in metropolitan areas (1999–2005, APC: -3.9) and the non-metropolitan areas showed a slight increase (1999–2020, APC: 1.3). Conclusions: LCC and HF-related mortality rates have shown significant declines over the past two decades, with variations across gender, race, and geographic locations. Men and urban populations experienced steeper reductions in AAMRs, while rural populations exhibited slower improvements or slight increases in mortality. These findings highlight the need for targeted public health interventions to address disparities and further reduce LCC and HF-related mortality in vulnerable populations.

e17617 Background: Abnormal uterine bleeding (AUB) is a cardinal symptom of endometrial cancer (EC). However, 90-95% of those with AUB will undergo invasive endometrial sampling with the finding of benign etiology. Our group has identified EC-related methylated DNA markers (MDMs) detectable in vaginal fluid obtained via self-collected tampon with high sensitivity to detect EC. To provide alternative vaginal fluid collection options, we compared total DNA recovery and detection of EC MDMs between tampon and swab collection methods. Methods: Patients ≥45 yrs with AUB or undergoing routine gynecologic care, and patients ≥18 yrs with biopsy-confirmed EC or atypical endometrial hyperplasia (AEH) were prospectively enrolled for paired vaginal fluid biospecimens collection. Participants self-collected vaginal fluid via tampon before provider-collected vaginal fluid sampling via swab immediately prior to clinically indicated endometrial sampling or hysterectomy. Cases (EC/AEH) and benign controls were determined by expert review. DNA was extracted from vaginal fluid. Bisulfite converted DNA was then used in long-probe quantitative amplified signal (LQAS) assays for 10 MDMs and 2 reference markers (RMs). Total DNA recovery using the RMs and detection of EC-specific MDMs were compared across sampling techniques. MDMs were standardized using the log of the ratio of the MDM and RM1. Standardized MDMs were compared between swabs and tampons using median and interquartile range (IQR). Results: A total of 40 eligible participants were evaluated in this study, 20 cases and 20 controls. Median time between tampon and swab collection was 27 hours (range 1-53). DNA quantity as measured using both RM1 and RM2 were comparable between swab and tampon in both cases and controls; MDM detection was also comparable between swab and tampon in both cases and controls (Table 1; 8 representative MDMs shown). Though not powered for sensitivity and specificity estimation, EC-related MDMs appear higher in EC cases vs controls, using either sample type. Conclusions: Sampling vaginal fluid with provider-collected swabs or self-collected tampons are both effective for detection of validated EC MDMs. Studies are ongoing to optimize an MDM panel to detect EC in vaginal fluid. Control Tampon Control Swab Case Tampon Case Swab RM1 3.5 [3.3-3.8] 4.2 [3.8-4.2] 3.6 [3.2-3.9] 4.2 [3.8-4.5] MDM1 0.5 [0.4-0.7] 0.4 [0.2-0.6] 1.3 [0.8-1.8] 1.1 [0.6-1.7] MDM2 1.5 [1.2-1.9] 0.9 [0.7-1.2] 3.2 [2.2-4.7] 2.9 [1.7-4.5] MDM3 0.5 [0.4-0.6] 0.4 [0.3-0.5] 1.5 [0.9-2.3] 1.0 [0.8-2.3] MDM4 0.9 [0.6-1.3] 0.5 [0.4-0.7] 2.3 [1.3-3.7] 1.9 [1.0-3.6] MDM5 1.3 [0.6-1.4] 0.8 [0.6-1.0] 3.3 [2.5-4.1] 3.1 [2.4-3.9] MDM6 1.6 [1.3-2.1] 1.2 [0.8-1.7] 3.3 [2.6-4.3] 3.1 [2.3-4.1] MDM7 1.5 [1.1-1.7] 1.0 [0.4-1.4] 3.5 [2.6-4.1] 3.3 [2.1-3.8] MDM8 0.5 [0.3-0.6] 0.5 [0.4-0.7] 1.8 [1.0-2.7] 1.7 [1.0-2.5] Median (IQR) for RM1 and 8 MDMs by case/control and sampling technique.

e16330 Background: Sarcomatoid hepatocellular carcinoma (SHC) is a rare and aggressive variant of hepatocellular carcinoma (HCC), accounting for less than 2% of all primary liver cancers. Characterized by the presence of both epithelial and mesenchymal components, SHC demonstrates a high degree of cellular plasticity, often associated with epithelial-mesenchymal transition. This phenotypic heterogeneity contributes to its aggressive clinical behavior, including rapid tumor progression, early metastasis, and poor response to conventional therapies. As a result, patients diagnosed with SHC typically have a median survival of less than 12 months, significantly lower than that observed in patients with conventional HCC. Methods: We conducted a retrospective study at the Mayo Clinic Comprehensive Cancer Center, focusing on patients diagnosed with SHC between April 2017 and December 2023. The data collected included demographics, performance status, underlying risk factors, alpha-fetoprotein (AFP) levels, next generation sequencing (NGS) testing, and the treatment received. Results: A total of ten patients with confirmed diagnoses of SHC were included, with median age at the time of diagnosis 63.5 years (37-77), predimonantly male (9 out of 10), and identifying white (8 out of 10). Alcoholic cirrhosis was identified as an underlying risk factor in three patients, NASH cirrhosis in two, and HCV in two patients. The majority (6 out of 10) of the patients had localized disease, with 4 patients having denovo metastatic disease with abdominal lymph node involvement. Five patients had NGS testing (Tempus, Guardant 360, and ProvsSeq523), with resultant pathogenic variants including TP53 in 3 patients, NTRK3 fusion, IDH2, EGFR, TERT, MLH1, ARIS1A, and PALB2. Four patients were treated with combined Yitrrium-90 and systemic therapy. Three patient started systemic therapy, and two patients underwent surgical resection. Systemic Therapy used included combined Atezolizumab/ Bevacizuamab, Pembrolizumab/ Lenvatinib, Gemcitabine/ Docetaxel, Gemcitabine/ Cisplatin, Cabozantinib, and pembrolizumab monotherapy. The median overall survival for this group was 11.5 months; 95% confidence interval (CI): 4.66-40.1 months. Seventy percent experienced progression, with a median progression-free survival after first line of treatment of 2.5 months; 95% CI: 1-15.3 months. Conclusions: Sarcomatoid HCC remains aggressive and difficult to treat cancer with limited overall survival. Immunotherapy based regimens have limited efficacy for this HCC variant.

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.