Novel Approaches to Overcome FGFR Resistance

In a Cholangiocarcinoma (CCA) Foundation meeting session titled “Targeted Therapies and Overcoming Resistance,” Dr Francesco Facchinetti from the Gustave Roussy Cancer Campus discussed novel approaches to overcome FGFR resistance in FGFR-altered CCA.

Established concepts in FGFR resistance include (1) mutations in the target preclude target-drug binding, (2) drug binds to target but may bypass target activation, and (3) lesser-known mechanisms such as epigenetic regulation.

In FGFR-altered CCA, increasing data confirm the presence of polyclonal secondary mutations in FGFR that drive acquired mutations following FGFR-targeted therapy.^1,2

There is a need for novel FGFR inhibitors that can overcome on-target resistance. In this context, RLY-4008 is a next-generation irreversible FGFR2 selective inhibitor that is showing activity in pan-FGFR inhibitor–resistant CCA regardless of FGFR2 resistance mutation.³ Emerging data suggest a potential role for EGFR inhibition to overcome resistance in FGFR-positive CCA.⁴

In the context of polyclonality, it is not known if all mutations detected in patients generate the same degree of resistance to inhibitors. Dr Facchinetti shared that early preclinical data suggest that the mutations are different in terms of conferring resistance, and that the potency of selective FGFR inhibitors against the resistance mutations is also variable.

The integration of several lines of evidence is crucial for the understanding of the biology of resistance. Dr Facchinetti shared that his group, in collaboration with Dr Lipika Goyal, are initiating a trial in 77 patients with CCA whose disease is progressing on FGFR inhibitors to specifically acquire an in-depth understanding of the biology of resistance. This landscape approach will include pharmacokinetic analysis of FGFR inhibitors, ctDNA longitudinal monitoring, rapid autopsy programs, patient-derived models, engineered cell-line models, and 3D modeling.

In conclusion, Dr Facchinetti stated that “resistance in FGFR-altered cholangiocarcinoma is complex and unique.”

References

1. Goyal L, Saha SK, Liu LY, et al. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma. Cancer Discov. 2017;7:252-263.
2. Varghese AM, Patel J, Janjigian YY, et al. Noninvasive detection of polyclonal acquired resistance to FGFR inhibition in patients with cholangiocarcinoma harboring FGFR2 alterations. JCO Precis Oncol. 2021;5:PO.20.00178.
3. Goyal L, Borad M, Subbiah V, et al. First results of RLY-4008, a potent and highly selective FGFR2 inhibitor in a first-in-human study in patients with FGFR2-altered cholangiocarcinoma and multiple solid tumors. Mol Cancer Ther. 2021;20(12_Suppl):P02-02.
4. Wu Q, Zhen Y, Vu P, et al. EGFR inhibition potentiates FGFR inhibitor therapy and overcomes resistance in FGFR2 fusion-positive cholangiocarcinoma. https://scholar.harvard.edu/mjwu/publications/egfr-inhibition-potentiates-fgfr-inhibitor-therapy-and-overcomes-resistance-fgfr2. Accessed April 21, 2022.