At the 2025 Annual Cholangiocarcinoma Foundation Conference, Milind Javle presented on the next-generation fibroblast growth factor receptor (FGFR) inhibitor, tinengotinib, for the treatment of cholangiocarcinoma (CCA). FGFR alterations, particularly FGFR2 fusions and mutations, have emerged as actionable drivers in CCA, a rare and aggressive malignancy of the biliary tract. Although first-generation FGFR inhibitors such as pemigatinib and futibatinib have demonstrated efficacy in treating FGFR-altered tumors, resistance inevitably develops due to secondary mutations. Tinengotinib, a multikinase inhibitor, has been designed to overcome these resistance mechanisms, offering renewed hope for patients with refractory disease.
Tinengotinib has a novel binding mechanism; tinengotinib binds to an allosteric site located outside the deep pocket. This unique binding site allows tinengotinib to retain its inhibitory activity even in the presence of resistance mutations such as V564F and N549K, which often impair the efficacy of earlier inhibitors. By targeting the active conformation of FGFR with a high affinity, tinengotinib effectively blocks downstream signaling pathways, thereby inhibiting tumor growth and progression.
Preclinical models, including cell lines and patient-derived xenograft studies, have demonstrated tinengotinib’s robust activity against FGFR-resistant mutations. These findings validate its potential to address a critical unmet need in the treatment of advanced CCA.
Tinengotinib has been evaluated in phase 1 and 2 clinical trials involving nearly 100 patients with advanced CCA harboring FGFR alterations. The majority of patients had undergone multiple prior lines of therapy, including first-generation FGFR inhibitors. Despite this heavily pretreated population, tinengotinib demonstrated promising efficacy. In an analysis comprised of patients from 3 studies, phase 1 (NCT03654547), phase 1b/2 (NCT04742959), and phase 2 (NCT04919642), that included patients with CCA who had prior treatment with FGFR inhibitors, the overall response rate was 30%, with 93% of patients achieving disease control, defined as either tumor shrinkage or stabilization. Notably, the median progression-free survival (PFS) was 6 months, a significant improvement given the refractory nature of the disease. Some patients remained on treatment for >18 months, highlighting the durability of tinengotinib’s therapeutic effect. Tinengotinib’s safety profile was manageable, with hypertension emerging as the most common adverse event due to its vascular endothelial growth factor inhibitory effects. Generally, other side effects, such as mild diarrhea, fatigue, and occasional hand-foot syndrome, were less frequent compared with earlier FGFR inhibitors. Importantly, toxicities like hyperphosphatemia, often seen with first-generation agents, were rare with tinengotinib, making it a potentially better-tolerated option.
A pivotal phase 3 trial (NCT05948475) is currently underway to compare tinengotinib with physician’s choice of chemotherapy in patients with FGFR-altered and FGFR inhibitor-refractory CCA. This trial aims to confirm the efficacy and safety of tinengotinib on a larger scale, with PFS as the primary endpoint. If successful, tinengotinib could become a vital third-line therapy for patients with advanced CCA.
Tinengotinib represents a significant advancement in the treatment of FGFR-altered CCA, offering renewed hope for patients who develop resistance to existing therapies. Its innovative mechanism of action, promising clinical trial results, and manageable safety profile position tinengotinib as a potential game-changer in the evolving landscape of targeted therapies for rare cancers.
Javle M. CCF Webinar: Next Generation FGFR Inhibitor for Cholangiocarcinoma-Tinegotinib. Presented at: 2025 Annual Cholangiocarcinoma Foundation Conference. April 9-11, 2025; Salt Lake City, UT.
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