P1, N=95, Recruiting, Biohaven Therapeutics Ltd. | Not yet recruiting --> Recruiting

P1, N=95, Not yet recruiting, Biohaven Therapeutics Ltd.

IFN-γ levels correlated weakly with levels of anti-IFN-γ antibodies (Pearson's r = 0.22, p = 0.03). We conclude that the antibody repertoire of autoimmune SNN targets pathways of the innate and adaptive immune system, potentially reflecting key disease-related immune pathways and highlighting the systemic role of immune dysregulation in SNN.

TACSTD2/TROP2 and NECTIN-4/NECTIN-4 are widely expressed in aUC, independent of FGFR3 alterations or PD-L1 expression, thus representing a suitable target for ADC treatment in the majority of aUC. The expression loss was associated with aggressive morphomolecular aUC subtypes, i.e. neuroendocrine(-like) and sarcomatoid aUC.

AMB302/GR1017 showed robust anti-tumor efficacies in F3-T3 fusion and FGFR3 overexpression models derived from GBM and BC in vitro and in vivo. In addition, AMB302/GR1017 was well tolerated with no adverse effects in rodent model. Our data suggest AMB302/GR1017 has a potential therapeutic option as a first-in-class FGFR3 targeting ADC for GBM, BC, and other solid tumors with FGFR3 overexpression or alterations.

A clinical trial of nivolumab in an adjuvant setting (CheckMate 274) implied that immune-checkpoint inhibitors might be less efficacious in UTUC than in UBC...Clinical trials of enfortumab vedotin in a third-line setting (EV201 and EV301) implied that enfortumab vedotin might be less efficacious in UTUC than in UBC...Clinical differences in the effects of targeted drugs for UTUC and UBC may highlight the molecular differences between these diseases. The treatment strategy should be optimized based on further investigation of the molecular characteristics of UTUC.

Besides immunomodulative therapeutic options like anti-PD-(L)1 inhibitors and inhibitors targeting FGFR alterations, two new antibody-drug conjugates (ADC), sacituzumab govitecan (SG) and enfortumab vedotin (EV), have been approved for treatment. TACSTD2/TROP2 and NECTIN-4/NECTIN-4 are widely expressed in aUC, independent of FGFR3 alterations or PD-L1 expression. Expression loss is associated with aggressive morphomolecular aUC subtypes, i.e. neuroendocrine(-like) and sarcomatoid aUC. TROP2 and NECTIN-4 are widely expressed in aUC thus representing suitable targets for novel ADC treatment for the majority of aUC patients.

Novel targets, including cancer stem cells, DNA damage repair, antiapoptosis, drug metabolism and the tumour microenvironment, contribute to chemosensitization. Gene alteration-based drug selection and patient-derived xenograft- and organoid-based drug validation are the future for precision therapy.

However, activating mutations or fusions of FGFR2 and FGFR3 remains the only validated therapeutically actionable alteration, with erdafitinib as the only targeted agent currently approved for this group. Bladder cancer is characterized by genomic heterogeneity and a high tumor mutation burden. This review highlights the potential relevance of aberrations and discusses the current status of targeted therapies directed at them.

At current, erdafitinib, an inhibitor of FGFR1-4, is the only approved targeted therapy in metastatic UC following the BLC2001 study, which demonstrated a 49% overall response rate in patients with UC harboring an FGFR3 mutation. Additional FGFR-directed agents also continue to be investigated across multiple disease stages in FGFR-mutated UC including infigratinib, rogaratinib, and AZD4547, among others. Ongoing trials are combining these agents with immune checkpoint inhibitors and chemotherapy regimens. The precision medicine revolution has begun in UC, and FGFR3 inhibitors are leading the charge toward a more personalized, biomarker-driven treatment paradigm.