Role of Targeted Therapy in Metastatic Gallbladder Adenocarcinoma
Yes, targeted therapy has a definitive role in metastatic gallbladder adenocarcinoma, but only after molecular profiling identifies actionable alterations—patients should receive comprehensive genomic testing to guide treatment selection. 1
Mandatory Molecular Profiling
All patients with unresectable or metastatic gallbladder cancer must undergo molecular profiling to identify actionable alterations and support clinical trial enrollment. 1 This is a strong recommendation from the 2025 EASL guidelines for extrahepatic cholangiocarcinoma, which includes gallbladder cancer as part of the biliary tract cancer spectrum. 1
The rationale is clear: while gallbladder cancer shares molecular characteristics with other biliary tract cancers, actionable alterations occur at varying frequencies, and identifying them is essential for treatment selection. 1
FDA-Approved Targeted Therapies Applicable to Gallbladder Cancer
FGFR2 Alterations
- Futibatinib and pemigatinib have FDA and EMA approval for FGFR2 fusion/rearrangements in biliary tract cancers. 1
- However, FGFR2 fusions/rearrangements occur rarely in gallbladder cancer compared to intrahepatic cholangiocarcinoma. 1
- Despite rarity, case reports demonstrate sustained response with sequential FGFR inhibitor therapy in FGFR2-altered metastatic gallbladder adenocarcinoma, with overall survival approaching five years. 2
HER2 Amplification/Overexpression
- Zanidatamab (bispecific antibody) has FDA approval for HER2-positive (IHC 3+) biliary cancers with previously treated, unresectable or metastatic disease. 1
- Trastuzumab-deruxtecan received tumor-agnostic FDA approval for HER2-positive (IHC 3+) solid tumors after prior systemic treatment. 1
- The MyPathway trial demonstrated that pertuzumab plus trastuzumab achieved a 23% objective response rate in HER2-positive metastatic biliary tract cancers, with treatment well-tolerated and no treatment-related deaths. 3
IDH1 Mutations
- Ivosidenib has FDA approval based on phase III data for IDH1 R132 mutant biliary tract cancer. 1
- IDH1 mutations occur only rarely in gallbladder cancer. 1
BRAF V600E Mutations
- Dabrafenib plus trametinib has tumor-agnostic FDA approval for BRAF V600E-mutated solid tumors after prior treatment progression. 1
- Phase II data support BRAF V600E as a promising target in biliary tract cancers. 1
Rare Fusions
- NTRK fusions: Entrectinib, larotrectinib, and repotrectinib have entity-independent FDA/EMA approvals, though NTRK fusions are generally infrequent in cholangiocarcinoma. 1
- RET fusions: Selpercatinib has FDA/EMA approval for RET fusion-positive solid tumors, but these are also infrequent in biliary cancers. 1
Emerging Targets
- Basket trials have included KRAS G12C mutant biliary cancers and rare NRG1 fusions. 1
- Ongoing trials are addressing KRAS non-G12C alterations and FGFR2 amplifications. 1
Treatment Algorithm for Metastatic Gallbladder Cancer
First-Line Therapy
Cisplatin plus gemcitabine combined with durvalumab or pembrolizumab is the standard first-line treatment for inoperable gallbladder cancer. 1 Molecular profiling should be initiated at diagnosis to identify targetable alterations for subsequent lines. 1
When Targetable Alterations Are Present
Targeted therapies should be deployed when actionable alterations are identified, particularly after first-line chemotherapy progression. 1 The specific agent depends on the molecular alteration:
- FGFR2 fusions → Futibatinib or pemigatinib 1
- HER2 amplification/overexpression (IHC 3+) → Zanidatamab, trastuzumab-deruxtecan, or pertuzumab plus trastuzumab 1, 3
- BRAF V600E → Dabrafenib plus trametinib 1
- IDH1 R132 mutations → Ivosidenib 1
- NTRK fusions → Entrectinib, larotrectinib, or repotrectinib 1
- RET fusions → Selpercatinib 1
When No Targetable Alterations Are Present
FOLFOX is recommended as second-line systemic therapy in the absence of actionable alterations. 1 Alternative options include FOLFIRI or NalIRI+5FU, though evidence is more limited. 1
Critical Clinical Pitfalls
Frequency of Actionable Alterations
The major limitation is that actionable alterations occur at relatively low frequencies in gallbladder cancer. 1 Most evidence for precision oncology in biliary cancer stems from single-arm or basket phase II trials with small patient numbers. 1 However, when alterations are present, responses can be dramatic and durable. 2, 3
Timing of Molecular Testing
Do not delay molecular profiling until after multiple lines of chemotherapy—initiate testing at diagnosis of metastatic disease to have results available when first-line therapy fails. 1 Comprehensive genomic profiling takes time, and patients deteriorate rapidly with gallbladder cancer. 2
Distinguishing from Breast Cancer Treatment
Gallbladder cancer requires biliary tract/sarcoma-directed therapy, not breast cancer regimens, despite both potentially harboring HER2 alterations. 4 The biology and treatment paradigms differ fundamentally.
Clinical Trial Enrollment
Clinical trial enrollment is strongly recommended for all patients with metastatic gallbladder cancer, particularly for second-line and subsequent therapies. 1 Given the rarity of the disease and limited evidence base, trials offer access to novel agents and contribute to knowledge generation. 1
Evidence Quality Considerations
The 2025 EASL guidelines represent the most current and comprehensive guidance for biliary tract cancers including gallbladder cancer. 1 The strong recommendation for molecular profiling (Level of Evidence 2) reflects consensus that despite limited prospective randomized data, the potential for meaningful responses with targeted therapy justifies routine testing. 1
The MyPathway trial provides the highest-quality prospective evidence for HER2-targeted therapy in biliary tract cancers, demonstrating a 23% response rate with pertuzumab plus trastuzumab. 3 While not specific to gallbladder cancer alone, this multi-center phase 2a study enrolled patients with various biliary tract cancers and showed consistent benefit. 3