Aaron S. Mansfield

Evaluation of Innate Immune System, Body Habitus, and Sex on the Pharmacokinetics and Pharmacodynamics of Anetumab Ravtansine in Patients With Cancer

ABSTRACTAnetumab ravtansine, like other ADC drugs, has high inter‐patient variability in its pharmacokinetic (PK) and pharmacodynamic (PD) outcomes, which raises concerns about whether current dosing regimens are optimal for patients. The objective of this study was to evaluate covariates, especially body habitus and the innate immune system (IIS), which may affect anetumab ravtansine PK and PD as part of two clinical trials in patients with ovarian cancer and mesothelioma. Biomarkers of Fcγ receptors(FcγR) CD64 on IIS cells, total body weight (TBW), body surface area (BSA), and other covariates, such as sex and age, were analyzed for an association with anetumab ravtansine PK. Higher FcγR CD64, TBW, and BSA were associated with higher clearance (CL) of anetumab ravtansine (p < 0.05). However, there was no relationship between TBW or BSA and FcγR CD64. Female patients had a lower anetumab ravtansine CL (0.030 ± 0.007 L/h) compared to male patients (0.042 ± 0.006 L/h) (p < 0.05). In both studies, patients with stable disease (SD) and partial response (PR) had higher anetumab ravtansine AUC0‐inf compared to patients with progressive disease (PD). Individualizing the dose of anetumab ravtansine and potentially other ADCs based only on TBW is not optimal, whereas precision dosing of an ADC based on the inclusion of novel metrics of IIS biomarkers, body habitus, and sex may be more appropriate to reduce variability in PK exposure, reduce toxicity, and improve response.

Repurposing Ceritinib Induces DNA Damage and Enhances PARP Inhibitor Responses in High-Grade Serous Ovarian Carcinoma

Abstract PARP inhibitors (PARPi) have activity in homologous recombination (HR) repair-deficient, high-grade serous ovarian cancers (HGSOC). However, even responsive tumors develop PARPi resistance, highlighting the need to delay or prevent the appearance of PARPi resistance. Here, we showed that the ALK kinase inhibitor ceritinib synergizes with PARPis by inhibiting complex I of the mitochondrial electron transport chain, which increases production of reactive oxygen species (ROS) and subsequent induction of oxidative DNA damage that is repaired in a PARP-dependent manner. In addition, combined treatment with ceritinib and PARPi synergized in HGSOC cell lines irrespective of HR status, and a combination of ceritinib with the PARPi olaparib induced tumor regression more effectively than olaparib alone in HGSOC patient-derived xenograft (PDX) models. Notably, the ceritinib and olaparib combination was most effective in PDX models with preexisting PARPi sensitivity and was well tolerated. These findings unveil suppression of mitochondrial respiration, accumulation of ROS, and subsequent induction of DNA damage as novel effects of ceritinib. They also suggest that the ceritinib and PARPi combination warrants further investigation as a means to enhance PARPi activity in HGSOC, particularly in tumors with preexisting HR defects. Significance: The kinase inhibitor ceritinib synergizes with PARPi to induce tumor regression in ovarian cancer models, suggesting that ceritinib combined with PARPi may be an effective strategy for treating ovarian cancer.

Prognostic value of perioperative circulating tumor DNA (ctDNA) in endometrial cancer with high-risk features: a prospective observational study.

Although circulating tumor DNA (ctDNA) has emerged as a promising prognostic tool in various malignancies, evidence in endometrial cancer at high risk of recurrence is limited. This study evaluated the association of pre- and post-surgical ctDNA with advanced-stage disease, disease-free and overall survival in endometrial cancer with high-risk features. This prospective observational study was conducted at Mayo Clinic (7/2016-6/2021). Patients with endometrial cancer at preoperative biopsy, confirmed by final pathology, were included. Blood samples were collected before and 10 weeks after surgery. Tumor-specific junctions identified in pathology specimens and blood samples were used to detect ctDNA. Associations between pre- and post-surgical ctDNA and advanced-stage disease, recurrence, and death were evaluated using logistic regression [odds ratio (OR) and 95 % confidence interval] and Cox proportional hazards [hazard ratio (HR) and 95 % confidence interval]. Thirty-six patients were included: 6 (16.7 %) intermediate risk, 1 (2.8 %) high-intermediate risk, 28 (77.8 %) high risk, and 1 (2.8 %) advanced metastatic. Detection of pre- or post-surgical ctDNA was not significantly associated with advanced disease (pre-surgical OR 5.69 [0.88-66.02]; post-surgical OR 5.86 [0.83-72.68]). Pre-surgical ctDNA did not significantly predict recurrence (HR 0.99 [0.30-3.23]) or death (HR 3.23 [0.40-25.91]). In contrast, post-surgical ctDNA was associated with increased risk of recurrence (HR 3.32 [1.05-10.51]) and death (HR 5.97 [1.11-36.08]). Post-surgical ctDNA detection was associated with poor outcomes in patients with endometrial cancer. These findings support the potential of ctDNA as a biomarker to personalize surveillance and guide post-surgical treatment strategies.