Background
Phase III open-label RCT, N=162 patients with advanced biliary tract cancer (intrahepatic CCA, extrahepatic CCA, gallbladder cancer) who had progressed on or after gemcitabine-based chemotherapy (gemcitabine alone or gemcitabine+cisplatin). Stratified by ECOG PS (0–1 vs 2), primary tumor type, and prior gemcitabine+cisplatin. Conducted across 20 UK centers. Enrolled 2014–2018.
Interventions and follow up
Arm A: FOLFOX (oxaliplatin 85 mg/m² + leucovorin 350 mg + 5-FU 400 mg/m² bolus then 2400 mg/m² CI over 46h, q2wk) + active symptom control (ASC)
Arm B: Active symptom control (ASC) alone
Primary endpoint: Overall survival (OS)
Median follow-up: 9.3 months
Arm B: Active symptom control (ASC) alone
Primary endpoint: Overall survival (OS)
Median follow-up: 9.3 months
Results
OS: 6.2 vs 5.3 months, HR 0.69 (95% CI 0.50–0.97), P=.031
ORR: 5% vs 1%
6-month OS rate: 50.6% vs 35.5%
12-month OS rate: 25.9% vs 11.4%
ORR: 5% vs 1%
6-month OS rate: 50.6% vs 35.5%
12-month OS rate: 25.9% vs 11.4%
Adverse events
Hematologic: Grade ≥3 neutropenia 15%.
Non-hematologic: Grade ≥3 fatigue 10%, peripheral neuropathy 6%, diarrhea 5%.
Overall: Grade ≥3 AEs 62% vs 39% (Arm A vs B); treatment discontinuation due to AE 29%.
Non-hematologic: Grade ≥3 fatigue 10%, peripheral neuropathy 6%, diarrhea 5%.
Overall: Grade ≥3 AEs 62% vs 39% (Arm A vs B); treatment discontinuation due to AE 29%.
Conclusions
FOLFOX plus active symptom control significantly improved OS compared to active symptom control alone (HR 0.69, P=.031) in advanced biliary tract cancer after progression on gemcitabine-based chemotherapy, establishing second-line chemotherapy as a standard option and providing the first randomized evidence for second-line treatment in BTC.
Key Limitations
Modest absolute OS benefit (0.9 months median), though landmark OS rates at 6 and 12 months show more meaningful separation (~15 percentage-point differences). Low ORR (5%) suggests disease control rather than tumor response as the mechanism of benefit. Open-label design required given active symptom control comparator. Trial enrolled before routine molecular profiling — FGFR2-mutated/IDH1-mutated/HER2-amplified patients may now preferentially receive targeted agents (pemigatinib, ivosidenib, trastuzumab deruxtecan) as second-line options, and applicability of ABC-06 findings to patients who received immune checkpoint inhibitors in first-line (TOPAZ-1/KEYNOTE-966 era) is uncertain. ECOG PS 2 patients included but represented a small fraction; generalizability to PS 2 remains uncertain.
Clinical Context
ABC-06 established FOLFOX as the second-line chemotherapy standard in advanced biliary tract cancer after gemcitabine-based first-line therapy — the first randomized evidence for second-line BTC. Prior to ABC-06, no RCT data existed for second-line BTC, and treatment was purely empirical. FOLFOX is now a guideline-recommended second-line option for unselected BTC patients. With introduction of targeted therapies (pemigatinib for FGFR2-fusion, ivosidenib for IDH1-mutant, trastuzumab deruxtecan/zanidatamab for HER2-amplified) and evolving post-IO second-line data, the second-line BTC landscape is rapidly evolving. FIGHT-202 (pemigatinib) and ClarIDHy (ivosidenib) offer biomarker-selected options preferred before FOLFOX in molecularly defined subsets.