ESTRO 2025 - Abstract Book

S137

Invited Speaker

ESTRO 2025

Definitive radiation therapy combined with immune-checkpoint inhibitors such as anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody and/or programmed cell death (PD)/programmed cell death ligand 1 (PD-L1) antibody drugs has become the standard in the treatment for locally advanced NSCLC and randomized trials have been ongoing for esophageal cancer. Many studies have also shown that proton therapy reduces the incidence and severity of cardiopulmonary toxicities including radiation-pneumonitis after chest irradiation, which obstructs the continuation of immune-checkpoint inhibitors as adjuvant therapy. On the other hand, our multicenter, open-label, single-arm phase 2 study of bladder preservation therapy in combination with atezolizumab and radiation therapy showed a promisingly high interim clinical complete response (cCR) rate of 84.4% (38/45) and high complete remission (CR) rates of primary tumors were achieved in patients with high PD-L1-expressing tumors (95.8% vs 71.4%). Further analysis to identify potential tissue biomarkers for achieving cCR using tumor tissue samples of the bladder and blood samples collected from patients at baseline revealed that cCR rates of patients with the desert phenotype were as similarly high as patients with excluded/inflamed phenotypes (73.3% [11/15] vs 93.3% [14/15], P = .33) despite lower PD-L1 expression levels in the desert phenotype and increased CD8+ and CD204+ TIL infiltration, high CD8: forkhead box protein P3 ratios in the stroma of the excluded/inflamed phenotypes, and gene alterations, such as CDK12, GNAS, NOTCH2, and AR1D1A, were associated with a high cCR rate (93.3%). These potential subgroups could lead to the identification of good responders to a combination therapy of radiation therapy with immune-checkpoint inhibitor, and the findings should be viewed as hypothesis-generating and require further validation in larger studies. Future research will provide information regarding optimal patient selection and treatment schedule in combination therapy of immunotherapy and radiation therapy.

4886

Speaker Abstracts Radioligand therapy: Mechanism of action and current applications Felix M Mottaghy Nuclear Medicine, RWTH Aachen University Hospital, Aachen, Germany

Abstract: An overview of Radioligand Therapy (RLT) will be provided, focusing on its mechanism of action and current clinical applications. RLT is a form of targeted cancer therapy that combines a radioactive isotope with a ligand specifically designed to bind to receptors overexpressed on tumor cells. This approach allows for the direct delivery of radiation to malignant cells while sparing healthy tissue. First the pharmacological and radiobiological aspects of RLT will be explored. The ligand-receptor interaction is crucial, as it ensures specificity in targeting cancer cells. Once the radioligand binds to the receptor, the complex is internalized, and the radioactive isotope emits radiation that induces lethal DNA damage within the tumor cell. The concept of theranostics is introduced, as it is integral to RLT, where the same molecule can be used for both diagnostic imaging and therapeutic purposes by simply changing the radioactive isotope. This allows for personalized treatment planning and real-time monitoring of therapeutic efficacy. Then, highlights of the two currently approved radioligand therapies are presented, Peptide Receptor Radionuclide Therapy (PRRT) and Prostate-Specific Membrane Antigen (PSMA)-Targeted Therapy, including latest trial results. Finally also emerging therapies holding promise for treating various tumor entities will be touched. Advancements in radiochemistry and a deeper understanding of tumor biology are paving the way for the development of new radioligands and the expansion of RLT applications.