In an adult with intra‑hepatic cholangiocarcinoma harboring an FGFR2 fusion who has progressed after first‑line gemcitabine plus cisplatin, what is the recommended next‑line therapy?

FGFR Inhibitors Are the Recommended Next-Line Therapy

For an adult with intrahepatic cholangiocarcinoma harboring an FGFR2 fusion who has progressed after first-line gemcitabine plus cisplatin, FGFR inhibitors (pemigatinib, futibatinib, or infigratinib) should be initiated immediately as second-line therapy. This represents a strong recommendation with Level 2 evidence from multiple international guidelines. 1

Specific FGFR Inhibitor Options

The following three agents have demonstrated meaningful clinical activity and are FDA/EMA approved for this indication:

Futibatinib (First Choice Based on Efficacy Data)

• Highest objective response rate at 41.7% with median progression-free survival of 9.0 months and overall survival of 21.7 months in the FOENIX-CCA2 trial 1, 2
• Covalent, non-ATP-competitive FGFR1-4 inhibitor with activity against acquired resistance mutations that emerge with ATP-competitive inhibitors 2
• FDA-approved for previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma with FGFR2 fusions or rearrangements 3
• Dosed at 20 mg orally once daily continuously 3, 2
• Common grade 3+ adverse events: hyperphosphatemia (30%), elevated AST (7%), stomatitis (6%), fatigue (6%) 2

Pemigatinib

• Objective response rate of 35.5% with median PFS 6.9-9.0 months and OS 12.2-21.7 months 1
• ATP-competitive FGFR1-3 inhibitor 1
• Grade 2+ recommendation with strong agreement from French guidelines 1

Infigratinib

• Objective response rate of 23.1% with similar PFS/OS ranges 1
• ATP-competitive inhibitor 1
• Grade 2+ recommendation with strong agreement 1

Critical Evidence Supporting This Recommendation

The EASL-ILCA 2023 guidelines provide a strong recommendation (Level 2 evidence, strong consensus) that FGFR inhibitors should be used for patients with FGFR2 fusions or rearrangements after progression on standard first-line chemotherapy. 1 This recommendation is echoed by the 2024 French Association for the Study of the Liver guidelines with Grade 2+ strength and strong agreement. 1

All three pivotal trials were large, multicenter phase II studies in patients with advanced cholangiocarcinoma harboring FGFR2 fusions/rearrangements who had progressed on at least one prior line of standard chemotherapy. 1 Subanalyses consistently showed that response rates and survival outcomes were highest in patients with only one or two prior lines of therapy, making immediate use after first-line failure optimal. 1

Why FGFR Inhibitors Over Chemotherapy

While no head-to-head randomized trials compare FGFR inhibitors directly to second-line chemotherapy in FGFR2-fusion positive disease, the clinical outcomes with FGFR inhibition are substantially superior to historical second-line chemotherapy data in unselected cholangiocarcinoma populations. 1

For context, FOLFOX chemotherapy (the standard second-line option for patients without actionable mutations) achieves more modest outcomes in unselected populations. 1 The consistent 23-42% objective response rates and 9-22 month overall survival with FGFR inhibitors represent a meaningful therapeutic advance. 1

Important Caveats and Pitfalls

Confirm FGFR2 Fusion/Rearrangement Specifically

• FGFR inhibitors show no meaningful benefit in patients with other FGFR2 alterations (mutations, amplifications) 1
• In the pemigatinib trial, patients with FGFR2 mutations had median PFS of only 2.1 months and OS of 6.7 months, with zero objective responses 1
• Use NGS-based RNA panel to detect fusion transcripts reliably 1

Hyperphosphatemia Management

• Occurs in 72% of patients (16-30% grade 3+) across all FGFR inhibitor trials 4, 2
• Requires phosphate-restricted diet and phosphate binders 5
• May necessitate dose reduction but rarely requires permanent discontinuation 5, 2

Resistance Mechanisms

• Acquired gatekeeper mutations can emerge under selective pressure of FGFR inhibitors 6
• Futibatinib's covalent binding mechanism may overcome some ATP-competitive inhibitor resistance 2
• Liquid biopsy (circulating tumor DNA) can detect evolving resistance patterns noninvasively 6

Performance Status Matters

• These recommendations apply to patients with good performance status (ECOG 0-1) 1
• For ECOG 2 patients, consider fluoropyrimidine monotherapy instead 1
• For ECOG 3-4 patients, supportive care only is recommended 1

Alternative Second-Line Options (If FGFR Inhibitors Unavailable)

If FGFR inhibitors are not accessible, the treatment algorithm should prioritize:

1. FOLFOX chemotherapy (Grade 1+ recommendation, strong agreement) 1
2. Clinical trial enrollment is strongly encouraged for all patients with advanced cholangiocarcinoma 7

Molecular Testing Timing

Comprehensive molecular profiling should be performed at first-line treatment initiation, not delayed until progression, to enable rapid transition to targeted therapy. 1 Testing should include NGS-based RNA panel for FGFR2 fusions, plus evaluation for IDH1 mutations, BRAF V600E, HER2 amplification, NTRK fusions, and MSI/dMMR status. 1, 8