thorium (227Th) anetumab corixetan (BAY 2287411) / Bayer - LARVOL DELTA

A targeted thorium-227 conjugate demonstrates efficacy in preclinical models of acquired drug resistance and combination potential with chemotherapeutics and antiangiogenic therapies. (PubMed, Mol Cancer Ther) - "In the MSLN-expressing ST206B OvCa PDX model, MSLN-TTC accumulated specifically in the tumor, which combined with pegylated liposomal doxorubicin (doxil), docetaxel, bevacizumab, or regorafenib treatment induced additive-to-synergistic antitumor efficacy and substantially increased response rates compared with respective monotherapies. The combination treatments were well tolerated and only transient decreases in white and red blood cells were observed. In summary, we demonstrate that MSLN-TTC treatment shows efficacy in p-gp-expressing models of chemoresistance and has combination potential with chemo- and antiangiogenic therapies."

Journal • Preclinical • Cervical Cancer • Gynecologic Cancers • Oncology • Solid Tumor • MSLN

Zr-3,2-HOPO-mesothelin antibody PET imaging reflects tumor uptake of mesothelin targeted Th-conjugate therapy in mice. (PubMed, J Nucl Med) - "Rationale: Mesothelin targeted thorium-227 conjugate (Th-MSLN) is a novel targeted alpha therapy developed to treat mesothelin overexpressing cancers... Zr-MSLN PET imaging reflected mesothelin expression and matched with Th-MSLN tumor uptake, biodistribution, and antitumor activity. Our data support the clinical exploration of Zr-MSLN PET imaging together with Th-MSLN therapy, both using the same antibody-chelator conjugate."

Journal • Preclinical • Oncology • Pancreatic Cancer • MSLN

First-in-human Study of BAY2287411 Injection, a Thorium-227 Labeled Antibody-chelator Conjugate, in Patients With Tumors Known to Express Mesothelin (clinicaltrials.gov) - P1 | N=36 | Completed | Sponsor: Bayer | Active, not recruiting ➔ Completed

Trial completion • Gastrointestinal Cancer • Lung Cancer • Mesothelioma • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Immunostimulatory effects of targeted thorium-227 conjugates as single agent and in combination with anti-PD-L1 therapy. (PubMed, J Immunother Cancer) - "These in vitro and in vivo data on MSLN-TTC demonstrate that the MoA of TTCs involves activation of the immune system. The findings are of relevance for other targeted radiotherapies and may guide clinical combination strategies."

Combination therapy • Journal • Immune Modulation • Inflammation • Oncology • CCL20 • CD8 • CXCL10 • IL6 • ITGAE • MSLN • STING

First-in-human Study of BAY2287411 Injection, a Thorium-227 Labeled Antibody-chelator Conjugate, in Patients With Tumors Known to Express Mesothelin (clinicaltrials.gov) - P1; N=36; Active, not recruiting; Sponsor: Bayer; N=228 ➔ 36

Enrollment change • Gastrointestinal Cancer • Lung Cancer • Mesothelioma • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

First-in-human Study of BAY2287411 Injection, a Thorium-227 Labeled Antibody-chelator Conjugate, in Patients With Tumors Known to Express Mesothelin (clinicaltrials.gov) - P1; N=228; Active, not recruiting; Sponsor: Bayer; Recruiting ➔ Active, not recruiting; Trial completion date: Nov 2024 ➔ Mar 2022; Trial primary completion date: Dec 2023 ➔ May 2021

Clinical • Enrollment closed • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Lung Cancer • Mesothelioma • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Mesothelin-targeted thorium-227 conjugate (MSLN-TTC): Preclinical evaluation of a new targeted alpha therapy for mesothelin-positive cancers. (PubMed, Clin Cancer Res) - P1 | "These promising preclinical results supported the transition of BAY 2287411 into a clinical phase I program in mesothelioma and ovarian cancer patients (NCT03507452)."

Journal • Preclinical • Breast Cancer • Gastrointestinal Cancer • Gynecologic Cancers • Hepatology • Lung Cancer • Mesothelioma • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • Thoracic Cancer

[VIRTUAL] MSLN-targeted thorium-227 conjugate demonstrates increased antitumor activity in combination with bevacizumab and regorafenib (AACR-II 2020) - "In summary, MSLN-TTC effectively reduced the growth of primary tumors in the ST206B ovarian cancer model which was further enhanced by addition of bevacizumab and regorafenib. Further studies are needed to investigate the underlying molecular mechanisms."

Combination therapy • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • CD31 • MSLN

[VIRTUAL] Targeted thorium-227 conjugates demonstrate synergistic activity in combination with PD-L1 inhibitors (AACR-II 2020) - "In the present work, the immunostimulatory effects of the mesothelin (MSLN) targeted thorium-227 conjugate (MSLN-TTC) was studied in immunocompetent mice, bearing human MSLN-transfected MC38 cells, in monotherapy and in combination with the PD-L1 inhibitor (PD-L1i) atezolizumab. These results suggest that the efficacy of MSLN-TTC may involve activation of CD8+ T cells. These findings support the hypothesis that upon binding to antigen-positive cancer cells, TTC treatment induces DNA double strand breaks, leading to apoptosis and potentially immunogenic cell death, resulting in activation of the adaptive immune system."

Combination therapy • IO Biomarker • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CALR • CD8 • HSP90AA1 • IFNAR1 • MSLN

Synergistic Effect of a Mesothelin Targeted Thorium-227 Conjugate in Combination with DNA Damage Response Inhibitors in Ovarian Cancer Xenograft Models. (PubMed, J Nucl Med) - "Further, in vivo anti-tumor efficacy of the MSLN-TTC in combination with ATRi or PARPi was investigated in the OVCAR-3 and OVCAR-8 xenograft models in nude mice, demonstrating synergistic anti-tumor activity for the ATRi combination at doses demonstrated to be non-efficacious when administered as monotherapy. The presented data support the mechanism-based rationale for combining the MSLN-TTC with DDR inhibitors as new treatment strategies in MSLN-positive ovarian cancer."

Combination therapy • Journal • Preclinical • Ataxia • CNS Disorders • Gastrointestinal Cancer • Gynecologic Cancers • Lung Cancer • Mesothelioma • Movement Disorders • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • Thoracic Cancer

First-in-human Study of BAY2287411 Injection, a Thorium-227 Labeled Antibody-chelator Conjugate, in Patients With Tumors Known to Express Mesothelin (clinicaltrials.gov) - P1; N=228; Recruiting; Sponsor: Bayer; Trial completion date: Feb 2023 ➔ Nov 2024; Trial primary completion date: Jun 2022 ➔ Dec 2023

Clinical • Trial completion date • Trial primary completion date