Advances in antibody-drug conjugates for endometrial cancerTu, Li, Zou
et alMol Cancer Ther (2025)
Abstract: The treatment of advanced endometrial cancer is clinically challenging, prompting the exploration of innovative therapeutic strategies such as antibody-drug conjugates (ADCs). ADCs, which include monoclonal antibodies, cytotoxic components, and linkers, demonstrate robust targeting, cytotoxicity, and manageable adverse effects. To provide a thorough understanding of the status of research, this review elucidates promising therapeutic targets in endometrial cancer, such as HER2, FRα, and TROP-2, and summarizes preclinical and clinical trial data on related ADC drugs in endometrial cancer. We also discuss the toxicity of ADC drugs. Most adverse events arise from cytotoxic components such as microtubule inhibitors and topoisomerase inhibitors. The ocular toxicity may be mainly related to off-target effects of MMAF/DF4 payloads. Interstitial lung disease (ILD) is a serious adverse event, mainly caused by antibodies, and most of them are grade 1-2 toxicity. Among them, anti-HER2 ADC induced interstitial pneumonia is commonly dose dependent. Moreover, we identified potential new targets for endometrial cancer treatment and explored strategies to overcome ADC resistance, such as choosing combination therapy or developing a new generation of ADC drugs. Continuous research and innovation in this field hold promise for improving the survival and overall quality of life of patients with advanced endometrial cancer.
Spatial expression of HER2, NECTIN4, and TROP-2 in Muscle-Invasive Bladder Cancer and metastases: Implications for pathological and clinical managementDernbach, Eich, Dragomir
et alMod Pathol (2025)
Abstract: Muscle-invasive bladder cancer (MIBC) presents significant treatment challenges. Antibody-drug conjugates (ADCs) targeting HER2, TROP-2, and NECTIN4 offer promising therapeutic options. This study examined the spatial expression of HER2, TROP-2, and NECTIN4 in MIBC and metastases, their association with molecular subtypes, and clinical outcomes. Formalin-fixed, paraffin-embedded (FFPE) tissue samples from 251 MIBC patients were analyzed using immunohistochemistry and tissue microarrays (TMA). Expression patterns between the tumor front (TF) and center (TC) were compared, and statistical analyses assessed associations with molecular subtypes and clinical parameters. Additionally, 67 matched lymph node metastases and a secondary cohort comprising 16 distant metastases, including seven matched primary tumors, were examined to explore the expression patterns in advanced tumor stages. In primary tumors, HER2 was predominantly negative (83%) but showed higher positivity in the TC. TROP-2 exhibited high overall expression (58% score 3+), while NECTIN4 displayed significant heterogeneity with stronger expression in the TC. Spatial overexpression of TROP-2 and NECTIN4 at the tumor front relative to the tumor center was associated with a better disease free survival. Accurate assessment required four biopsies for HER2 and NECTIN4 and three for TROP-2. HER2 expression was associated with urothelial-like and genomically unstable molecular subtypes, whereas TROP-2 was widely expressed except in the mesenchymal-like subtype. NECTIN4 showed absence of staining in basal, mes-like and Sc/Nec-like subtypes. Paired lymph node metastases showed higher expression scores for all three markers, while distant metastases showed reduced NECTIN4 expression. Additionally, lymph node metastases revealed a considerable heterogeneity for HER2 compared to their matched primary tumors. The spatial heterogeneity of HER2, TROP-2, and NECTIN4 expression necessitates multiple biopsies, particularly from the TC, for accurate evaluation. These findings underscore the need for personalized treatment strategies in MIBC, considering the increased risk of relapse associated with HER2 and NECTIN4 overexpression in the TC. Implementing a multi-biopsy approach is critical to enhance diagnostic accuracy.Copyright © 2025. Published by Elsevier Inc.
The PESGA Trial: A Prospective, Open-Label, Single-Arm, Phase II Study to Evaluate First Line Therapy for Extensive-Stage Small Cell Lung Cancer (ES-SCLC) Patients, Treated by Induction Carboplatin/Etoposide/Pembrolizumab Followed by Maintenance of Pembrolizumab/ Sacituzumab GovitecanRoisman, Mann, Basel
et alClin Lung Cancer (2025)
Abstract: Despite recent advances in immunotherapy combinations for extensive-stage small cell lung cancer (ES-SCLC), rapid disease progression following chemotherapy discontinuation remains a significant challenge. While the addition of pembrolizumab to platinum-etoposide has demonstrated a modest improvement in progression-free survival (PFS), there is an urgent need for more effective maintenance strategies. Sacituzumab govitecan (SG), an antibody-drug conjugate targeting Trop-2, has shown promising activity in pretreated ES-SCLC. This phase II study evaluates the efficacy and safety of adding SG to pembrolizumab maintenance therapy following chemoimmunotherapy induction in treatment-naïve ES-SCLC patients.In the PESGA trial, a prospective, open-label, single-arm phase II trial, patients with previously untreated ES-SCLC will receive induction therapy consisting of pembrolizumab (200 mg Q3 W) plus carboplatin (AUC 5) and etoposide (100 mg/m² Days 1-3) for 4 cycles. This will be followed by maintenance therapy combining pembrolizumab (200 mg Q3 W) with SG (10 mg/kg on Days 1 and 8 of 21-day cycles) for up to 31 cycles. The primary endpoint is PFS from the start of induction treatment. Secondary endpoints include overall survival, duration of response, and safety. Exploratory analyses will investigate molecular resistance mechanisms through sequential liquid and tissue biopsies and evaluate correlations between tumor Trop-2 expression and clinical outcomes. The study plans to enroll 21 patients over 18 months, with an estimated total study duration of 54 months. Results will be analyzed after 50% of patients have achieved PFS.The PESGA study design builds upon the KEYNOTE-604 regimen by incorporating SG into the maintenance phase, potentially addressing the challenge of early progression in ES-SCLC. The study may provide valuable insights into novel maintenance strategies and molecular mechanisms of treatment resistance in ES-SCLC.Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
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