Development of Possible Next Line of Systemic Therapies for Gemcitabine-Resistant Biliary Tract Cancers: A Perspective from Clinical Trials

Abstract

Biliary tract cancer (BTC) compromises a heterogenous group of tumors with poor prognoses. Curative surgery remains the first choice for localized disease; however, most BTC patients have had unresectable or metastatic disease. The gold standard therapy for these patients is chemotherapy with gemcitabine and cisplatin. There are no consensus guidelines for standard treatment in a second-line setting, although the data of the ABC-06 trial showed a slight survival benefit from oxaliplatin and 5-fluorouracil combination chemotherapy. Recent progress in comprehensive genomic profiling for advanced BTC (ABTC) has helped to clarify tumorigenesis and facilitate the coming era of precision medicine. Generally, targeted agents fail to show significant clinical benefits in unselected populations. Only fibroblast growth factor receptor 2 (FGFR2) fusion and isocitrate dehydrogenase (IDH)- and BRAF mutation-enriched populations have survival benefits from the corresponding inhibitors. Several interesting targeted agents for monotherapies or combination therapies with other compounds are currently ongoing or recruiting. Here, we review the published data from clinical trials of second-line therapies after the failure of gemcitabine-based chemotherapy in ABTC. The results were stratified by different genetic alternations, as well as by chemotherapy, targeted therapy and immunotherapy.

Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation

“…Gemcitabine (GEM)-based chemotherapy is the standard of care for patients with advanced CCA [6][7][8], but primary or acquired resistance to GEM compromises therapeutic efficacy [9][10][11]. Potential targets that have been identified based on tumor genomic profiling, including FGFR2 fusion, IDH1 mutation, NTRK fusion, and BRAF mutation, provide therapeutic options after intolerance to or failure of GEM-based chemotherapy [12]. Previous studies have shown that the infiltration of immunosuppressive immune cells is associated with poor prognosis in CCA patients [13].…”

Impaired Chromatin Remodeling Predicts Better Survival to Modified Gemcitabine and S-1 plus Nivolumab in Advanced Biliary Tract Cancer: A Phase II T1219 Study

“…Approximately 60% to 70% of advanced biliary tract cancer (ABTC) is diagnosed at an advanced stage with the historic 5-year survival rates of only 10% to 20% (2)(3)(4). Systemic therapy, including chemotherapy and targeted therapies based on genetic alternations, remains a standard treatment for ABTC (5).…”

Globo H Is a Promising Theranostic Marker for Intrahepatic Cholangiocarcinoma

“…( 4 ) In particular, two targeted agents, larotrectinib and pemigatinib, have been approved by the Food and Drug Administration for patients with cancers containing NTRK and FGFR2 fusion genes, respectively. ( 5 ) However, FGFR2 rearrangements occur in less than 20% of ICC cases, ( 6 ) and only 1 of 28 samples harbors the RABGAP1L‐NTRK1 gene fusion, ( 7 ) making FGFR2 and NTRK inhibitors clinically relevant only for a relatively small subset of patients. In addition, ivosidenib, a small‐molecule inhibitor of mutated IDH1, improved progression‐free survival of patients with ICC with IDH1 mutations; however, the IDH1 mutation was found in only approximately 13% of patients with ICC.…”