The management of advanced biliary tract cancer (BTC) reached a pivotal milestone in 2024 with the first FDA approvals of targeted therapies fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and zanidatamab-hrii (Ziihera) for patients with HER2-positive disease. However, the 5-year overall survival rate for patients with advanced BTC remains below 5%, underscoring the urgent need for additional effective treatment options.
"These are very aggressive cancers with median OS of approximately 12 months," said Haley Ellis, MD. "However, in recent years, we're moving the needle forward in a positive way with the incorporation of immunotherapy and targeted therapies for a growing number of genomic alterations. BTCs stand as a benchmark for precision medicine in gastrointestinal cancers, and we've seen some impressive survival data in some of these biomarker-driven tumors."
Real-World Evidence Supports Matched Targeted Therapy
An international real-world analysis presented at the 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium demonstrated the clinical impact of matched targeted therapy in advanced BTC. The study analyzed patients with molecularly actionable alterations following at least 30 days of palliative systemic treatment, with the most common alterations including somatic BRCA1/2 mutations (n = 106), FGFR2 fusions (n = 61), HER2 amplification (n = 65), and IDH1 mutations (n = 38).
Matched patients (n = 135) achieved a median overall survival of 21.4 months (95% CI, 18.4-27.9), significantly longer than the 14.6 months (95% CI, 12.8-17.6) observed in unmatched patients (n = 231) and 17.2 months (95% CI, 15.5-19.0) in those without actionable alterations (n = 566).
"Unfortunately, due to the rarity of the disease, there is not much [community] knowledge [in terms of] when we need to do biomarker testing," noted Amit Mahipal, MD. "It proves that we need to check for these actionable alterations and, when we do find them, [use] those therapies that could act on [those alterations]."
Immunotherapy Establishes New Frontline Standards
In the frontline setting, durvalumab (Imfinzi) combined with gemcitabine and cisplatin became a standard-of-care option following FDA approval in September 2022. The approval was supported by the phase 3 TOPAZ-1 trial, with updated findings showing patients in the durvalumab arm (n = 341) achieved a median overall survival of 12.9 months (95% CI, 11.6-14.1) compared with 11.3 months (95% CI, 10.1-12.5) in the placebo arm (n = 344; HR, 0.74; 95% CI, 0.63-0.87) at a median follow-up of 41.3 months.
"TOPAZ-1 was a landmark study," Ellis commented. "There is a notable tail effect on the survival curve, suggesting that there are durable responses in a subset of patients."
Similarly, pembrolizumab (Keytruda) in combination with gemcitabine and cisplatin received FDA approval in October 2023. Updated findings from the phase 3 KEYNOTE-966 trial showed patients who received pembrolizumab (n = 533) achieved a median overall survival of 12.7 months (95% CI, 11.5-13.6) compared with 10.9 months (95% CI, 9.9-11.6) in the placebo arm (n = 536) at a median follow-up of 36.6 months.
HER2-Targeted Therapies Lead Second-Line Advances
The treatment landscape for pretreated BTC has been transformed by HER2-directed therapies. A retrospective study presented at ASCO GI found that 25.1% of patients with BTC (n = 310) were HER2 positive. Patients with HER2-positive disease who received an anti-HER2 agent experienced a median overall survival of 18.2 months, comparable to patients with HER2-negative disease, while those who did not receive HER2-targeted therapy had a median overall survival of only 8.1 months.
T-DXd Shows Promise in HER2-Expressing Tumors
The antibody-drug conjugate T-DXd demonstrated efficacy in the phase 2 DESTINY-PanTumor02 trial in patients with HER2-expressing solid tumors. In the BTC cohort (n = 41), patients experienced a confirmed overall response rate of 22.0% (95% CI, 10.6%-37.6%). Among patients with HER2 IHC 3+ expression (n = 16), the response rate increased to 56.3% (95% CI, 29.9%-80.2%).
The median progression-free survival was 4.6 months (95% CI, 3.1-6.0) in the overall BTC cohort and 7.4 months (95% CI, 2.8-12.5) in the HER2 IHC 3+ subgroup. These findings supported T-DXd's April 2024 FDA pan-tumor approval for adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors.
Zanidatamab Receives Accelerated Approval
The HER2-targeted bispecific antibody zanidatamab received FDA accelerated approval in November 2024 for previously treated, unresectable or metastatic HER2-positive (IHC 3+) BTC. The approval was based on the single-arm, phase 2 HERIZON-BTC-01 study, which showed patients with unresectable or metastatic HER2-positive BTC who received at least one previous gemcitabine-containing regimen (n = 62) achieved an overall response rate of 52% (95% CI, 39%-65%) and a median duration of response of 14.9 months (95% CI, 7.4-not estimable).
"Interestingly, most adverse effects that we saw, [including] diarrhea and infusion reactions, were mostly grade 1 to 2," noted Shubham Pant, MD, MBBS. "That's why [zanidatamab] is being combined with chemotherapy [in the phase 3 trial]."
Expanding Therapeutic Targets
According to Tanios S. Bekaii-Saab, MD, approximately 30% to 40% of biliary tract cancers harbor actionable molecular alterations amenable to targeted therapy. In intrahepatic cholangiocarcinomas, FGFR2 fusions are present in approximately 5% to 7% of cases, with two FGFR inhibitors, pemigatinib (Pemazyre) and futibatinib (Lytgobi), demonstrating overall response rates of approximately 40%.
Additional actionable alterations include KRAS G12C mutations, for which adagrasib (Krazati) has been incorporated into treatment guidelines, and BRAF V600E mutations found in approximately 5% to 10% of biliary tract cancers, which respond to combined BRAF/MEK inhibition. IDH1 mutations, present in approximately 20% of intrahepatic cholangiocarcinomas, can be targeted with ivosidenib (Tibsovo).
Future Directions and Ongoing Studies
The phase 3 HERIZON-BTC-302 study is comparing zanidatamab in combination with standard-of-care gemcitabine and cisplatin versus standard-of-care therapy alone in the first-line setting. The study is enrolling adult patients with HER2-positive BTC, with progression-free survival in the IHC 3+ population as the primary endpoint.
Other ongoing investigations include the phase 2 SIGNA trial evaluating the TROP2-directed ADC sacituzumab govitecan-hziy (Trodelvy) in patients with locally advanced, recurrent, or metastatic cholangiocarcinoma, and the NIR-B trial examining the PARP inhibitor niraparib (Zejula) in patients with BRCA-mutated BTC.
"[I want to again] highlight the increasing importance of performing comprehensive molecular profiling," Ellis emphasized. "Making our best efforts to [perform] broad-based profiling, both DNA and RNA, tissue and/or liquid [biopsy] as early as possible in these disease courses is so critical to identify an increasing percentage of patients who can benefit from targeted therapies."
