Rogaratinib (BAY-1163877): A Comprehensive Monograph on a Pan-FGFR Inhibitor in Oncology

Executive Summary

Rogaratinib, also known by its development code BAY-1163877, is an orally bioavailable, potent, and selective small molecule inhibitor of fibroblast growth factor receptors 1 through 4 (FGFR1-4). Developed by Bayer, this investigational agent has been evaluated for the treatment of various advanced solid tumors.[1] As a therapeutic agent, Rogaratinib functions as an adenosine triphosphate (ATP)-competitive inhibitor, designed to reversibly occupy the kinase domain of the FGFRs. This action effectively blocks receptor autophosphorylation and subsequent activation of downstream signaling cascades, most notably the FGFR/ERK pathway, which are critical for the proliferation, survival, and angiogenesis of many cancer types.[1]

The clinical development of Rogaratinib has been extensive and has yielded a complex set of outcomes that provide significant learnings for the field of targeted oncology. The drug has been investigated across a spectrum of malignancies, including urothelial carcinoma (UC), non-small cell lung cancer (NSCLC), breast cancer, and various sarcomas.[3] The results have been mixed, underscoring the challenges of targeting the FGFR pathway. A key Phase II study in squamous NSCLC (SAKK 19/18) was terminated early for lack of efficacy, leading to the discontinuation of development in that indication.[5] Similarly, the pivotal Phase II/III FORT-1 trial, which evaluated Rogaratinib as a monotherapy in previously treated, FGFR mRNA-positive UC, was halted before progressing to Phase III after an interim analysis showed non-superiority over standard chemotherapy.[6] In stark contrast, the Phase Ib/II FORT-2 trial demonstrated highly promising results, where Rogaratinib in combination with the PD-L1 inhibitor atezolizumab yielded a high response rate in first-line, cisplatin-ineligible UC patients, suggesting a powerful synergi