thorium (227Th) anetumab corixetan (BAY 2287411)

In the MSLN-expressing ST206B ovarian cancer patient-derived xenograft 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.

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.

These promising preclinical results supported the transition of BAY 2287411 into a clinical phase I program in mesothelioma and ovarian cancer patients (NCT03507452).

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.