Spotlight: FGFR Inhibitors in Biliary Tract Cancer - The Truth is Out There!
Biliary cancer is a notoriously difficult-to-treat malignancy. Between insidious symptoms, a high rate of de novo metastatic disease (resectability rate ~30%), and sparse therapeutic options, the prognosis of advanced biliary cancers has always lagged behind breast, melanoma, lung and prostate. According to one review, 5-year survival rates with advanced biliary tract cancer are as low as 2.5%.
The most significant recent addition to standard practice is the addition of durvalumab to cisplatin and gemcitabine following the publication of the TOPAZ-1 trial in 2022. Even then, the median overall survival remains relatively poor at 12.9 months, a survival improvement of less than two months compared with placebo (11.3 months). As a result, identifying and targeting specific molecular targets remain the brightest therapeutic hope for patients with this lethal disease.
A review article by Dr Nicole Farha and colleagues provides an in-depth assessment of the state of play of precision medicine in biliary tract cancer. In this edition of the OftiM Newsreel, we will focus on the exciting early data surrounding FGFR inhibitors, but a summary of other targets, including IDH, HER2, BRAF/MEK, and many others, is present in the full article (link below):
Fibroblast Growth Factor Receptors (FGFR):
Fibroblast growth factors and their associated receptor mediate cellular proliferation, differentiation, survival and angiogenesis. If an alteration in FGFR occurs, usually in the form of a point mutation or rearrangement, the affected sell can potentially proliferate without the usual safety checks, leading to oncogenesis.
The most common FGFR alteration in solid organ malignancies is FGFR1 fusions, accounting for 49% of all FGFR changes. In biliary tract cancers, however, FGFR2 changes are more common, occurring in 10-15% of intrahepatic cholangiocarcinomas, though they are rare in extrahepatic cholangiocarcinomas. There is a significant but subtle difference between fusions and alterations in the FGFR landscape: fusions are more likely to be activating than alterations and correspond to a higher response rate to treatment.
Two agents that have shown promise in this area are pemigatinib and futibatinib. Both are non-selective inhibitors of FGFR; pemigatinib inhibits FGFR1-3 and futibatinib inhibits FGFR1-4. Both have phase 2 evidence of benefit in the FIGHT-202 and FOENIX-CCA2 trials, respectively, demonstrating objective response rates (ORR) of >30%. Overall survival data for FIGHT-202 remain immature, while the final data for FOENIX-CCA2 demonstrated median overall survival (mOS) of 20 months. Abnormal phosphate levels, ocular toxicity, hand-foot syndrome, onycholysis and stomatitis characterise both agents’ toxicity profiles. Both agents are currently being evaluated for efficacy when compared to first-line treatment with gemcitabine and cisplatin.
A third agent, tentatively called RLY-4008, is a highly specific FGFR2 inhibitor designed to minimise toxicity and overcome FGFR2 resistance mechanisms. Initial data from the phase 1/2 ReFocus trial demonstrated an ORR of 88% in 17 patients. Adverse events appeared to be less significant when compared with pemigatinib and futibatinib, with stomatitis, hand-foot syndrome, dry mouth and ocular toxicity being the most common side effects. The study is ongoing.
The Bottom Line:
FGFR inhibitors represent a ray of light in the dark night of advanced biliary cancer, with exciting early-phase data that may soon outstrip the rather antiquated cytotoxic chemotherapy-focused approach. However, it is far from the only target in development. For a full, deep dive into the state of precision oncology in biliary tract cancers, check out the full article below:
Farha, N.; Dima, D.; Ullah, F.; Kamath, S. Precision Oncology Targets in Biliary Tract Cancer. Cancers2023,15,2105. https:// doi.org/10.3390/cancers15072105. Available from: https://www.mdpi.com/2072-6694/15/7/2105
