Dr Baretti on the Mechanisms of Resistance Associated With FGFR2+ Cholangiocarcinoma

Marina Baretti, MD, assistant professor, oncology, Johns Hopkins Medicine, discusses innate and acquired mechanisms of resistance in patients with unresectable, advanced, or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions or rearrangements.

Although previous data have demonstrated the efficacy of approved FGFR-targeted agents, such as pemigatinib (Pemazyre) and infigratinib (Truseltiq), in this patient population, a subset of patients will not initially respond to these therapies, Baretti begins. Moreover, the emergence of acquired resistance mechanisms can cause the efficacy of these agents to diminish over time, she states. Therefore, it is imperative to improve the identification of predictive biomarkers for response and resistance. Regarding innate resistance, growing evidence suggests that responses to FGFR inhibitors could be influenced by concurrent genetic alterations beyond FGFR alterations, Baretti explains. Initial data from the phase 2 FIGHT-202 study (NCT02924376) suggest that patients with mutations in tumor suppressor genes might benefit less from treatment with pemigatinib, she adds.

Similarly, subgroup analyses have shown futibatinib (Lytgobi) have not shown differences in outcomes based on the presence of concurrent TP53 gene mutations; however, data suggest that patients with mutations in other genes may experience less benefit with the agent, Baretti expands. She notes that these subgroup analyses include a limited number of patients, meaning it can be challenging to discern whether these effects should be attributed to the drug or are constrained by small sample sizes, she imparts.

As clinical experience with these FGFR-targeted agents increases, it's crucial to investigate how the spectrum of mutations influences the efficacy of these agents, Baretti notes. The emergence of secondary resistance is another challenge seen with the use of targeted therapy. The molecular basis for this acquired, on-target resistance has been well-documented, she says. Prolonged treatment with an FGFR inhibitor can cause a point mutation in the FGFR kinase domain, resulting in a conformational change that impedes proper drug binding, Baretti states. Secondary resistance is polyclonal, reflecting the heterogeneity of cholangiocarcinoma, she adds.

Leveraging liquid biopsies, such as circulating tumor DNA, can improve understanding of these secondary resistance mechanisms, Baretti continues. Current data suggests that various FGFR inhibitors may have distinct activity profiles against common secondary mutations, she says. For example, futibatinib appears to maintain efficacy against a variety of secondary point mutations; however, its activity can be limited by gatekeeper mutations, Baretti adds. Efforts are underway to overcome this challenge through the development of next-generation FGFR inhibitors, Baretti concludes.