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Cholangiocarcinoma is a very heterogenous cancer and “target-rich” disease. While the current classifications are based on the anatomic location of these tumors (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), tumors within and across these disease groups have unique and often mutually exclusive molecular aberrations. Amongst these, fibroblast growth factor receptor 2 ( FGFR2 ) fusion is one of the first amongst the list of “actionable” targets for which the US Food and Drug Administration just approved pemigatinib. This is for patients with cholangiocarcinoma who have received prior treatment and have  FGFR2  fusion or another rearrangement. This was based on the results from the clinical trial FIGHT-202 (NCT02924376). At present, several  FGFR  inhibitors are actively being tested in several agnostic and tumor-specific clinical trials. Patients also have had the opportunity of getting access to some of these oral drugs through compassionate use programs. As a consequence, these patients have more options in addition to chemotherapy. These all tend to have “good” initial responses and improvement in performance status and later “acquired” mechanisms of resistance. The latter tend to often be gatekeeper mutations that bypass the inhibitory effects of these selective  FGFR  inhibitors and/or cause steric hindrance. These tumors, therefore, evolve on selective pressure (temporal heterogeneity). This can be captured noninvasively using “liquid biopsies” (circulating tumor DNA testing). Here we present cases (several years into treatment on average) showing the feasibility of using liquid biopsies (ctDNA testing) as well as the gain and later potential loss of intratumoral and temporal heterogeneity exhibited under selective pressure of these novel  FGFR  inhibitors, chemotherapy and/or locoregional therapies. Despite limitations in sample size and provider bias, it is important to identify these “exceptional responders” and/or better outcomes that may be inherent to the biology of  FGFR  fusion-positive cholangiocarcinomas.

Favorable Outcomes in FGFR Fusion-Positive Cholangiocarcinomas and Evolution on Treatment Noted on Circulating Tumor DNA Liquid Biopsies