Background
Phase II open-label, single-arm, multicohort trial (FIGHT-202). Enrolled patients with previously treated, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements (Cohort A, N=107), other FGFR alterations (Cohort B, N=20), or no FGFR alteration (Cohort C, N=18). Primary analysis in Cohort A. Patients required ≥1 prior line of systemic therapy. Enrolled 2016–2018 across North America, Europe, and Asia.
Interventions and follow up
Regimen: Pemigatinib 13.5 mg PO QD on a 2-weeks-on/1-week-off schedule (21-day cycles), in 3 cohorts: A (FGFR2 fusions/rearrangements, n=107); B (other FGFR alterations, n=20); C (no FGFR alteration, n=18)
Primary endpoint: Objective response rate (ORR) in Cohort A by independent central review
Median follow-up: 15.4 months
Primary endpoint: Objective response rate (ORR) in Cohort A by independent central review
Median follow-up: 15.4 months
Results
ORR (Cohort A): 35.5% (38/107; 3 CR + 35 PR)
mDOR: 7.5 months
mPFS: 6.9 months
mOS: 21.1 months
ORR (Cohort B — other FGFR alterations): 0%
ORR (Cohort C — no FGFR alteration): 0%
mDOR: 7.5 months
mPFS: 6.9 months
mOS: 21.1 months
ORR (Cohort B — other FGFR alterations): 0%
ORR (Cohort C — no FGFR alteration): 0%
Adverse events
Most common grade ≥3: Hyponatremia 10%, stomatitis 9%, fatigue 9%, elevated lipase 8%, diarrhea 7%.
Class effects: Hyperphosphatemia any grade 60% (grade ≥3 only 3%, manageable with dietary phosphate restriction); dry eye/blurred vision any grade 23% (retinal pigment epithelium detachment risk).
Overall: Grade ≥3 AEs in 64% of Cohort A; dose reductions required in 38%.
Class effects: Hyperphosphatemia any grade 60% (grade ≥3 only 3%, manageable with dietary phosphate restriction); dry eye/blurred vision any grade 23% (retinal pigment epithelium detachment risk).
Overall: Grade ≥3 AEs in 64% of Cohort A; dose reductions required in 38%.
Conclusions
Pemigatinib produced a 35.5% ORR with durable responses (mDOR 7.5 months) in previously treated cholangiocarcinoma with FGFR2 fusions or rearrangements, with 0% ORR in non-FGFR2-altered cohorts confirming strict biomarker specificity. This was the first biomarker-selected targeted therapy approval in biliary tract cancer.
Key Limitations
Single-arm design — no randomized comparator; ORR and DOR cannot be reliably compared to historical controls. FGFR2 fusions are found in ~10–15% of cholangiocarcinoma and predominantly in intrahepatic CCA, limiting the eligible population. The 0% ORR in non-FGFR2-altered cohorts reinforces the need for molecular profiling. No head-to-head comparison with other FGFR inhibitors (infigratinib, futibatinib, tinengotinib). mOS of 21.1 months is unexpectedly long and may reflect patient selection bias inherent to molecular screening trials rather than true drug effect. Resistance mechanisms (FGFR2 kinase domain mutations) emerge in the majority of progressors, limiting duration of benefit. Slit lamp eye exams required due to retinal toxicity risk.
Clinical Context
FDA accelerated approval granted April 2020 for pemigatinib in adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or other rearrangements — the first targeted therapy approval in biliary cancer. Converted to regular approval in 2024. Other FGFR2-selective inhibitors (infigratinib, futibatinib) subsequently received FDA approval in overlapping indications. Comprehensive genomic profiling is now standard practice for all advanced BTC to identify FGFR2 fusions (10–15%), IDH1 mutations (13–20%), HER2 amplification (5–15%), BRAF V600E (5%), and NTRK fusions (rare). ESMO-MCBS not applicable (single-arm).