Actionable alterations in BTC: Why genomic profiling can’t wait
Industry Buzz
The choice often comes down to institutional experience, formulary availability, and individual patient factors rather than clear superiority of one agent.
—Laura Vater, MD, MPH
Bile duct cancers arise inside the liver (intrahepatic) and outside the liver (extrahepatic), and treatment decisions depend on where the tumor started, whether it can be removed surgically, and whether the cancer carries a targetable mutation.
For patients with localized, resectable disease, the best chance at long-term control is surgical resection, followed by adjuvant capecitabine for 6 months, based on data from the BILCAP study showing a survival benefit in follow-up analyses.[] Liver transplantation can be considered in highly selected patients with perihilar disease after neoadjuvant chemoradiation.
For patients with unresectable or metastatic bile duct cancer who are well enough for systemic treatment, molecular profiling is crucial at diagnosis to identify actionable targets (such as FGFR2 fusions, IDH1 mutations, HER2 amplification, NTRK fusions) and guide therapy selection. It also facilitates enrollment in biomarker-driven trials and provides information on prognosis and resistance mechanisms.
First-line and maintenance therapy in advanced disease
For most patients with unresectable or metastatic disease, the backbone of first-line therapy is gemcitabine plus cisplatin, now often paired with an immune checkpoint inhibitor (ICI). The FDA has approved durvalumab with gemcitabine/cisplatin and also pembrolizumab with gemcitabine/cisplatin for advanced biliary tract cancer.
In practice, the choice between regimens is shaped by clinician preference, access, patient comorbidities, autoimmune history, and toxicity considerations. For some patients, especially those who are older, frailer, or have renal dysfunction, full-intensity cisplatin-based therapy may not be realistic, and treatment may need to be modified or de-escalated.
Due to cumulative toxicities from cisplatin, including nephrotoxicity, neurotoxicity, and myelosuppression, after 8 cycles of gemcitabine/cisplatin/ICI, cisplatin is usually stopped, and either gemcitabine with ICI continues or ICI is used alone.
If a patient progresses on first-line therapy, subsequent decisions are based on genomic testing. Because a substantial subset of biliary tract cancers harbor actionable alterations, broad molecular profiling should be performed early.
2L, targeted, and supportive care strategies
For patients with FGFR2 fusions or rearrangements in previously treated intrahepatic bile duct cancer, pemigatinib and futibatinib are FDA-approved options. Either agent is reasonable as first-line FGFR2 inhibitor therapy, as both have FDA approval along with NCCN preferred status, and demonstrate clinically meaningful benefit.
The choice often comes down to institutional experience, formulary availability, and individual patient factors rather than clear superiority of one agent.
—Laura Vater, MD, MPH
Pemigatinib is sometimes used first, as futibatinib can be used later to overcome some pemigatinib resistance mutations.
For patients with an IDH1 mutation, ivosidenib is FDA-approved for use after prior therapy. Tumor-agnostic options may also apply in the right molecular context, including immunotherapy for MSI-H/dMMR tumors, dabrafenib/trametinib for BRAF V600E, larotrectinib for NTRK fusions, selpercatinib for RET fusions, and zenocutuzumab-zbco for NRG1 fusions. For patients with HER2 (ERBB2) amplification (IHC3+), several options exist, including fam-trastuzumab deruxtecan-nxki, pertuzumab with trastuzumab, and tucatinib with trastuzumab.
Recognizing when to shift goals
Enrollment in clinical trials is strongly recommended for patients with biliary tract cancer.
A common chemotherapy-based second-line option for patients without actionable mutations is FOLFOX. The ABC-06 study established FOLFOX as the gold standard for second-line therapy, demonstrating improved median overall survival (6.2 vs 5.3 months) compared to active symptom control alone, though the absolute benefit was modest.[]
If a patient remains clinically well, subsequent third-line therapies often include irinotecan-based regimens such as FOLFIRI or fluorouracil/leucovorin/liposomal irinotecan.
The hardest pivot is the one from cancer-directed therapy to a primarily supportive-care-focused plan.
That pivot should be considered when the patient’s performance status is declining, time spent recovering from treatment exceeds time spent feeling well, infections or biliary complications recur, weight loss is accelerating, jaundice is not improving despite procedures, or each successive regimen produces more toxicity than benefit.
Palliative care should be integrated early for symptom control, goals-of-care conversations, and support for patients and families.
Related: Practice-changing signals amid evidence gaps: What’s driving your 2L decisions in HER2+ BTC?