Promising efficacy of next-generation FGFR1-3 inhibitor, Tienegotinib, in heavily pre-treated cholangiocarcinoma patients

FGFR fusions are found in 10% to 15% of cholangiocarcinoma patients. While several FGFR inhibitors have gained FDA approval for treating cholangiocarcinoma patients with FGFR2 fusion, FGFR mutations may arise as a mechanism of acquired resistance. Unlike first-generation FGFR inhibitors that target the inner pocket of the ATP-binding site where most acquired mutations occur, tinengotinib binds to a site away from the inner pocket to reduce the impact of mutations. It binds specifically to the active configuration of FGFR2 with high affinity through three hydrogen bonds. Preclinical studies have demonstrated tinengotinib's remarkable potency against FGFR kinase domain mutations. In phase 2 trials, patients with FGFR alterations exhibited objective response rates (ORR) of 26.3% and disease control rates (DCR) of 94.7%, respectively. Among patients with acquired resistance to prior FGFR inhibitors, the ORR and DCR were 40% and 90%, respectively. The toxicity and side effects were well-managed and tolerable. These promising findings suggest that tinengotinib could serve as a viable option for cholangiocarcinoma patients resistant to FGFR inhibitors.

Reference:

1. Piha-Paul SA, Goel S, Liao C-Y, et al. Preliminary safety and efficacy of tinengotinib tablets as monotherapy and combination therapy in advanced solid tumors: A phase Ib/II clinical trial. JCO 41(suppl 16):3019(2023).
2. Milind M. Javle et al. Efficacy and safety results of FGFR1-3 inhibitor, tinengotinib, as monotherapy in patients with advanced, metastatic cholangiocarcinoma: Results from phase II clinical trial. JCO 42, 434-434(2024).

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