Do Fibroblast Growth Factor Receptor (FGFR) inhibitors offer a survival benefit in advanced gallbladder carcinoma?

FGFR Inhibitors in Advanced Gallbladder Carcinoma

FGFR inhibitors are NOT routinely recommended for advanced gallbladder carcinoma (GBC), as the evidence base is extremely limited and primarily derived from cholangiocarcinoma (CCA) studies where GBC represents only a small minority of patients. However, in the rare GBC patient with documented FGFR2 fusions or rearrangements who has progressed on first-line chemotherapy and lacks other therapeutic options, FGFR inhibition may be considered based on extrapolation from CCA data and limited case reports 1.

Critical Context: The Evidence Gap

The major guidelines addressing FGFR inhibitors in biliary tract cancers focus predominantly on intrahepatic cholangiocarcinoma (iCCA), where FGFR2 fusions occur in approximately 5-10% of cases 1. Gallbladder carcinoma is fundamentally different from cholangiocarcinoma in its molecular landscape:

• HER2 amplification is the more relevant target in GBC, occurring in up to 20% of gallbladder cancers compared to only 5-10% of CCAs 1
• FGFR2 alterations are significantly less common in GBC than in iCCA
• The ESMO and EASL-ILCA guidelines make strong recommendations for FGFR inhibitors specifically in cholangiocarcinoma with FGFR2 fusions, not gallbladder cancer 1

When FGFR Inhibitors Might Be Considered in GBC

If comprehensive genomic profiling identifies FGFR2 fusions or rearrangements in a GBC patient, FGFR inhibitors may be considered after progression on first-line chemotherapy, based on:

Available FGFR Inhibitors and Their Efficacy Data (from CCA studies):

• Pemigatinib: ORR 35.5%, median PFS 6.9-9.0 months, median OS 12.2-21.7 months (FDA and EMA approved) 1, 2
• Infigratinib: ORR 23.1%, median PFS 6.9-9.0 months, median OS 12.2-21.7 months (FDA approved only) 1
• Futibatinib: ORR 41.7%, median PFS 6.9-9.0 months, median OS 12.2-21.7 months (FDA approved only) 1

Important Caveats:

• These response rates are from phase II trials in CCA patients, not randomized controlled trials, and lack direct comparison to chemotherapy 1
• Patients with only 1-2 prior lines of therapy had better outcomes than those with more extensive prior treatment 1
• FGFR2 fusions/rearrangements are required—other FGFR2 alterations showed minimal benefit (median PFS 2.1 months, median OS 6.7 months, with no objective responses) 1

Case Report Evidence in GBC

One case report describes sustained response in metastatic GBC with FGFR2 S252W mutation treated with sequential FGFR inhibitors, achieving nearly 5 years overall survival 3. While encouraging, a single case report cannot establish standard practice, but it supports the biological rationale for testing FGFR inhibitors in molecularly selected GBC patients.

Practical Algorithm for Advanced GBC

For patients with advanced gallbladder carcinoma:

1. First priority: Obtain comprehensive genomic profiling before or during first-line chemotherapy to identify actionable alterations 1

2. First-line treatment: Gemcitabine-cisplatin with durvalumab (where available) 1

3. At progression, prioritize molecular targets in this order:

   • HER2 amplification (more common in GBC): Consider pertuzumab-trastuzumab (ORR 23%, median PFS 4 months, median OS 10.9 months) 1
   • FGFR2 fusions/rearrangements (if present): Consider FGFR inhibitors as described above
   • IDH1 mutations: Ivosidenib 1
   • BRAF V600E mutations: Dabrafenib-trametinib 1
   • MSI-H/dMMR: Immune checkpoint inhibitors 1

4. If no actionable alterations: Second-line chemotherapy (FOLFOX or 5-FU based regimens) 1

Key Pitfalls to Avoid

• Do not assume GBC and CCA are interchangeable—they have different molecular profiles and treatment priorities 1
• Do not use FGFR inhibitors without documented FGFR2 fusions/rearrangements—other FGFR alterations show no meaningful benefit 1
• Do not delay molecular profiling—obtain it early to guide second-line decisions 1
• Be aware of resistance mechanisms: Secondary FGFR2 mutations and EGFR feedback activation can limit FGFR inhibitor efficacy; re-biopsy or circulating tumor DNA analysis may identify resistance mechanisms 1, 4

Toxicity Considerations

The most common adverse events with FGFR inhibitors include hyperphosphatemia (60%), with grade 3+ events in 64% of patients, most frequently hypophosphatemia (12%), arthralgia (6%), and stomatitis (5%) 2. These are generally manageable but require monitoring.