Dr Goyal on the Safety Profile of Lirafugratinib in FGFR2-Altered Cholangiocarcinoma

“The question is, what tradeoffs are patients willing to have and oncologists willing to take in order for a chance at potentially better efficacy?... There is certainly more toxicity [with lirafugratinib compared with other FGFR inhibitors]."

Lipika Goyal, MD, an associate professor in the University Medical Line in the Division of Oncology of the Department of Medicine at Stanford University, as well as a member of the Stanford Cancer Institute, expanded on safety profile of lirafugratinib (RLY-4008) in FGFR2-altered cholangiocarcinoma (CCA), according to data from the phase 1/2 ReFocus trial (NCT04526106).

Drawing on findings from the pivotal cohort (n = 116) of ReFocus, Goyal explained that although the drug’s high potency against FGFR2 drives efficacy, it also introduces significant safety liabilities. The most frequent treatment-related adverse effects (TRAEs) of any grade included nail toxicities (87.9%), palmar-plantar erythrodysesthesia (PPE; 81.9%), and stomatitis (78.4%). Notably, grade 3 or higher TRAEs were observed in a substantial portion of the population, specifically in terms of PPE (32.8%), nail toxicities (12.1%), and stomatitis (12.1%).

Additionally, any-grade retinal pigment epithelial detachment was reported in 37.1% of patients. These toxicities led to high rates of clinical intervention, with 75.9% of patients requiring dose reductions and 82.8% experiencing dose interruptions; however, treatment discontinuation due to TRAEs remained low at 4.3%.

Goyal highlighted that lirafugratinib exhibits a more demanding safety profile than other approved FGFR inhibitors, such as futibatinib (Lygtobi) and pemigatinib (Pemazyre). For comparison, rates of PPE with futibatinib were approximately 13%—significantly lower than the 81.9% seen with lirafugratinib. Similarly, approximate retinal toxicity rates for futibatinib (8%) and pemigatinib (4%) were much lower than that observed with lirafugratinib in ReFocus.

Ultimately, Goyal emphasized the necessity of shared decision-making. She concluded that oncologists must work closely with patients to weigh the potential for enhanced efficacy against the increased risk of toxicity, ensuring the best therapeutic choice is made for each patient’s needs.