Bayer is looking to expand to treat other types of cancer that would require a more conventional path of labelling an isotope to a chelating agent which would be linked to an antibody expressed by the tumor of interest. Radium-223 is difficult to chelate. Thorium (Th227) looks like an attractive alternative since it could be supplied by the same production facility that supplied the Radium-223. The thorium labelled chelate (targeted thorium conjugate, TTC) is now in pre-clinical studies when linked to the HER2 antibody appropriate for a number of tumors including breast cancer. Phase I trials are ongoing with TTC-PMSA for prostate cancer, TTC-MSLN (mesothelioma, pancreatic, and ovarian cancer), and TTC-CD22 (non-Hodgkin lymphoma).
Dr. Morris described the possible use of TTC-PMSA in the treatment of both primary and metastatic prostate cancer. Previous radiotherapy with the beta-emitter Lu177-PMSA617 showed a number of adverse side effects including thrombocytopenia and xerostomia (dry mouth resulting from reduced or absent saliva flow). Some early studies with treatment of prostate cancer with Ac225-PMSA617 showed promising responses by PSA declines and reduction of tumor burden by PSMA imaging but xerostomia is still an issue.
Dr. Morris reported that Phase I clinical trials with TTC-PMSA are beginning now with an anticipated 108 patients. Goals of the study are establishing a safe starting dose and then studying dose escalation. Dr. Morris noted that TAT therapy is typically only begun in metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy and some combination of abiraterone, enzalutamide, or docetaxel (chemotherapy). Modern trends in prostate treatment indicate moving these later treatments earlier in the treatment cycle. He noted the importance of PSMA imaging which can show metastasis even when a bone scan appears clean. Dr. Morris also pointed out that these new trends could have the desired effect of increasing overall survival (OS) while that control of side effects becomes more important for patient quality of life. It is one thing to ask a patient to endure dry mouth at end of life and quite another to expect the patient to endure xerostomia for ten years.
Dr. Hassan spoke to the possible uses of TTC-MSLN in the treatment of mesothelioma, pancreatic, and ovarian cancers. It binds Mesothelin, which has been targeted in clinical trials with antibodies or antibody drug conjugates such as amatuximab or anetumabravtansine, respectively. Biodistribution studies show good tumor uptake. Preclinical colon cancer studies show tumor reduction when treated with conjugated TTC. The tumor reduction occurs even in patient-derived models resistant to chemotherapy. Tumor shrinkage can be enhanced with ATR or PARP repair inhibitors. Dr. Hassan also spoke to the advantages of imaging with Zr89-HOPO-MSLN. A Phase I clinical trial with TTC-MSLN is ongoing with 228 planned mesothelioma and ovarian cancer patients. It will start with an initial dose of 1.5 MBq and then escalate in steps of 1-1.5 MBq. TATs continue to be developed focused on improved patient outcomes.
Hartwig Hennekes, Ph.D., Global Program Head, Bayer AG Pharmaceuticals, Berlin, Germany
Michael J. Morris, MD, Medical Oncologist, Clinical Director, Genitourinary Medical Oncology Service & Prostate Cancer Section Head, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center
Raffit Hassan, MD, Senior Investigator, Thoracic and GI Malignancies Branch, National Institutes of Health, Bethesda, MD