Citations

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.

See the Reply by Semla and Steinman in this issue.

IVC filters (IVCF) perform an important function in select patients that have venous blood clots. However, they are usually intended to be temporary, and significant delay in removal can have negative health consequences for the patient. Currently, all Interventional Radiology (IR) practices are tasked with tracking patients in whom IVCF are placed. Due to their small size and location deep within the abdomen it is common for patients to forget that they have an IVCF. Therefore, there is a significant delay for a new healthcare provider to become aware of the presence of a filter. Patients may have an abdominopelvic CT scan for many reasons and, fortunately, IVCF are clearly visible on these scans. In this research a deep learning model capable of segmenting IVCF from CT scan slices along the axial plane is developed. The model achieved a Dice score of 0.82 for training over 372 CT scan slices. The segmentation model is then integrated with a prediction algorithm capable of flagging an entire CT scan as having IVCF. The prediction algorithm utilizing the segmentation model achieved a 92.22% accuracy at detecting IVCF in the scans.