Treatment approaches for biliary tract cancers have undergone a significant transformation, moving beyond traditional cytotoxic chemotherapy to embrace precision medicine strategies based on molecular profiling. This evolution represents a paradigm shift in managing these rare but aggressive malignancies, offering new hope for patients with limited therapeutic options.
Evolution of First-Line Treatment Strategies
The standard of care for biliary tract cancers has traditionally centered on gemcitabine with cisplatin, which demonstrated superior outcomes compared with gemcitabine monotherapy and earned National Comprehensive Cancer Network Category 1 recommendation status. Recent advances have incorporated immunotherapy into frontline treatment, with chemo-immunotherapy combinations using gemcitabine and cisplatin as the backbone along with checkpoint inhibitors like durvalumab and pembrolizumab becoming preferred options for eligible patients.
Alternative first-line regimens include other gemcitabine-based combinations with partners like nab-paclitaxel, or fluoropyrimidine-based regimens such as FOLFOX and CAPOX. For patients with specific molecular alterations, targeted therapies may be considered in the first-line setting, including IDH inhibitors and potentially RET inhibitors for patients with mutation-positive disease.
FGFR2-Targeted Therapy: A Breakthrough in Biliary Tract Cancer
FGFR2-targeted therapy represents a particularly important treatment area unique to biliary tract cancers, with pemigatinib and futibatinib showing the most robust clinical data. Pemigatinib, a selective FGFR1-3 inhibitor, demonstrated a 35% overall response rate and 6.9-month median progression-free survival in the FIGHT-202 trial.
Futibatinib, an irreversible FGFR1-4 inhibitor, showed superior efficacy with a 42% objective response rate, 9.7-month median duration of response, and 9-month progression-free survival. These agents require careful monitoring for unique adverse effects, particularly hyperphosphatemia, dermatologic and nail toxicities, stomatitis, and rare ocular complications.
Comprehensive Biomarker Testing Drives Treatment Decisions
Biomarker analysis plays a crucial role in the management of biliary tract cancers, with comprehensive next-generation sequencing being the standard approach to identify actionable molecular alterations. The most clinically significant biomarkers include IDH1 and IDH2 mutations, FGFR2 fusions or rearrangements, and ERBB2 (HER2) amplifications and mutations.
These alterations demonstrate distinct patterns across different biliary tract cancer subtypes, with IDH1 and FGFR2 fusions being predominantly found in intrahepatic cholangiocarcinoma, while KRAS and TP53 mutations are more commonly observed in extrahepatic cholangiocarcinoma. ERBB2 alterations show particular prevalence in gallbladder cancers and extrahepatic cholangiocarcinoma.
Expanding Arsenal of Targeted Therapies
Second-line treatment options focus heavily on targeted therapies based on identified molecular alterations, with FOLFOX being a preferred chemotherapy regimen specifically studied in the subsequent-line setting. The targeted therapy landscape includes BRAF inhibitors for BRAF V600E mutations, multiple FGFR inhibitors for FGFR2 fusions, IDH inhibitors for IDH1 mutations, and HER2-directed therapies for ERBB2 alterations or amplifications.
Additional actionable alterations include BRAF V600E mutations, NTRK fusions, and DNA damage repair mutations such as BRCA, though these occur with significantly lower frequency. The National Comprehensive Cancer Network (NCCN) guidelines specifically recommend testing for IDH1/2 mutations, FGFR2 fusions, BRAF V600E mutations, and ERBB2 alterations as minimum requirements.
Clinical Trial Access Remains Critical
Despite comprehensive genomic profiling efforts, the rarity of biliary tract cancers presents unique challenges in treatment access and clinical trial enrollment. When patients harbor alterations for which FDA-approved therapies exist in other disease states but not specifically for biliary tract cancers, clinical trials become essential treatment options.
The scarcity of biliary tract cancer–specific clinical trials emphasizes the importance of identifying patients eligible for targeted therapy trials based on their molecular profiles, making biomarker testing not only diagnostically valuable but also critical for accessing experimental treatments that may offer improved outcomes.
