Esfahani, Shadi A.

292 Background: Fibroblast activation protein (FAP) has high expression in cancer associated fibroblasts (CAFs) in the tumor microenvironment of many solid tumor malignancies. [ 18 F]FAPI-74 is a fluorine-18 labeled FAP-targeting PET imaging tracer with promising characteristics for detection of malignant disease in a variety of cancers. In this multicenter prospective Phase 2 trial, we hypothesized that [ 18 F]FAPI-74 PET would have a high positive predictive value (PPV) for detecting FAP-expressing tumor tissue in a variety of gastrointestinal (GI) malignancies. Methods: This Phase 2 multicenter trial was conducted in the United States at MGH, MSKCC, BAMF, Northwell, UCLA and Mayo (NCT05641896). Eligible GI cancers in the study included hepatocellular carcinoma, cholangiocarcinoma, gastric, esophageal, pancreatic, and colorectal cancer. Each subject underwent one [ 18 F]FAPI-74 PET scan, and a tissue sample was obtained by biopsy and/or surgical resection. The imaging reads were performed centrally by experienced PET readers. The primary objective was to evaluate the PPV of [ 18 F]FAPI-74 PET in detecting FAP-expressing cells from patient collected tissues using centrally evaluated immunohistochemistry (IHC) with positivity defined by the sponsor as an H score higher than 50. The secondary objective was to evaluate the safety profile of [ 18 F]FAPI-74 and its PPV in detecting the presence of GI malignancies using histopathology as the standard of truth. Results: The trial was activated in May 2023, with the last patient imaged in Jan 2025. Of 103 subjects with GI malignancies, the primary site was gastroesophageal in 46 (45%), pancreatic in 22 (21%), colorectal in 17 (17%), hepatobiliary in 10 (10%) and of other GI origin in 8 (8%) cancers. 60 participants were male and 43 female. In total, 60 patients had viable and representative tissue data for efficacy analysis of primary and secondary endpoints. No serious adverse events were reported because of the investigational product. The PPV of [ 18 F]FAPI-74 PET to detect FAP-expressing cells using IHC was 100% (52/52). The sensitivity and specificity for the detection of FAP were 90% (52/58) and 100% (2/2) respectively. The PPVs of [ 18 F]FAPI-74 PET to detect cancer using histopathology as truth standard was 94% (49/52). The sensitivity for the detection of disease was 91% (49/54). Conclusions: The Phase 2 study in GI cancers demonstrates that [ 18 F]FAPI-74 PET detects FAP expression and presence of disease in cancers of the GI tract. PPV of 100% for primary objective and 94% for secondary objective were determined. These results support initiation of a Phase 3 study of [ 18 F]FAPI-74 PET in patients with GI cancers. In addition, [ 18 F]FAPI-74 PET’s reliability in visualizing FAP expression cells in the tumor microenvironment supports a further role in selection of patients for FAP-directed therapies. Clinical trial information: NCT05641896 .

Introduction: Mitral valve transcatheter edge-to-edge repair (M-TEER) has emerged as a minimally invasive option for high-risk surgical candidates with severe and symptomatic mitral regurgitation (MR), but post-procedure residual mitral valve (MV) dysfunction remains a significant concern. This study evaluates the clinical utility of combining artificial intelligence applied to electrocardiograms (ECG-AI) for diastolic dysfunction (DD) grading and the echocardiography-derived velocity time integral of the MV and left ventricular outflow tract ratio (VTIMV/LVOT) in predicting prognosis in patients post-M-TEER. Methods: A retrospective analysis of patients who underwent M-TEER between 2014 and 2021 was conducted. Patients were categorized based on VTIMV/LVOT and ECG-AI scores into three groups: both normal parameters, either abnormal parameter, or both abnormal parameters to compare outcomes (mortality, major adverse cardiovascular events [MACE], and the need for subsequent MV reintervention) using Kaplan–Meier analysis, multivariable Cox regression models, and net reclassification improvement. Results: Overall, 250 patients were included; the median age was 79.5 (IQR: 73.1, 84.6) and 66.4% were male. The combined abnormal VTIMV/LVOT (≥2.5) and ECG-AI score for DD (>1) was associated with higher risk of one-year mortality (adjusted HR: 4.56 [1.04–19.89], p = 0.044) and MACE (adjusted HR: 3.72 [1.09–12.72], p = 0.037) compared to patients with both normal parameters. Conclusions: This study highlights the potential additive value of integrating VTIMV/LVOT and ECG-AI scores as a prognostic tool for a personalized approach to the post-operative evaluation and risk stratification in M-TEER patients.

Abstract Background: Fibroblast activation protein (FAP) is a type II integral membrane glycoprotein, highly expressed on the cell surface of cancer-associated fibroblasts (CAFs) present in the tumor microenvironment of most epithelial cancers and showing limited expression in normal tissues. Given this expression profile, FAP appears to be a promising target for radioligand therapy that has pan-cancer potential. [177Lu]Lu-NNS309 is a FAP-targeted radiopharmaceutical that shows improved tumor retention and demonstrates promising anti-tumor activity in translationally relevant preclinical models (e.g., PDAC, NSCLC) where FAP is expressed on CAFs. Methods: CFXX489A12101 (NCT06562192) is a first-in-human phase I, open-label, multi-center study of [177Lu]Lu-NNS309 in patients with pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), breast cancer (BC), and colorectal cancer (CRC). The study includes a dose escalation part followed by a dose expansion part. Key eligibility criteria include prior treatment for locally advanced unresectable or metastatic disease and having all measurable lesions (per RECIST 1.1) showing [68Ga]Ga-NNS309 uptake on positron emission tomography/computed tomography (PET/CT). Patients who are eligible for treatment receive one dose of [177Lu]Lu-NNS309 on day 1 of each cycle. A 6-week and a 4-week dosing schedule will be explored. Dosimetry data will be obtained from patients in the dose escalation part after the first dose and will be used to calculate the cumulative radiation exposure. Dose escalation will be guided by a Bayesian hierarchical logistic regression model with overdose control (EWOC) principle, and assessment of all relevant data available from all dose levels including safety, tolerability, clinical dosimetry, pharmacodynamics, and preliminary efficacy. Once the recommended dose(s) (RD) and schedule(s) of [177Lu]Lu-NNS309 are determined, the expansion part may open and will include patients with locally advanced or metastatic PDAC (n∼20), locally advanced or metastatic NSCLC (n∼20), HR+/HER2- ductal BC (n∼15), HR+/HER2- lobular BC (n∼15), and triple negative BC (; n∼24).The primary objectives of the study are to evaluate the safety and tolerability of [177Lu]Lu-NNS309 and to identify the RD(s) and regimen(s) of [177Lu]Lu-NNS309 for further clinical evaluation. Secondary objectives of the study are to evaluate the preliminary anti-tumor activity of [177Lu]Lu-NNS309, characterize the pharmacokinetics of [177Lu]Lu-NNS309 in blood and urine, the radiation dosimetry for organs and tumor lesions, and to evaluate the safety and imaging properties of [68Ga]Ga-NNS309. Conclusion: The study is currently enrolling in the dose escalation part. Citation Format: Ravit Geva, Daniel Juneau, Shadi Abdar Esfahani, Cristiano Ferrario, Farshad Moradi, Amir Iravani, Jordi Ahnert, Ivan Manuel Victoria Ruiz, Thibaud Koessler, Aitana Calvo Ferrandiz, Bernard Doger de Speville, Patrick Flamen, Albiruni Razak, Desiree Deandreis, Laure Al-Mansour, Niklaus Schaefer, James Nagarajah, Hilde Nienhuis, Marco Maccauro, Angelina Filice, Jonathan Goldman, Ken Herrmann, Matthias Eiber, Alexander Drzezga, Martin Heuschkel, Jonathan McConathy, Johnson Geoffrey, Ephraim Parent, Yasutoshi Kuboki, Shizuka Origuchi, Xuan Mai Couillebault, Elisa Garcia Garayoa, Jayarama Naidu Roopa, Christopher Straub, Dominik Hainzl, Xinyu Chen, Fang Yang, Eirini Pectasides, Brandon Mancini. Phase I open-label, multi-center study to evaluate the safety, tolerability, dosimetry, and preliminary activity of FXX489 ([177Lu]Lu-NNS309) in patients with pancreatic, lung, breast and colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT112.