Molecular profiling and targeted therapies in biliary tract cancer—a short review

Fusions or gene rearrangements of FGFR2 are oncogenic drivers that result in constitutive activation of FGFR2 signaling, promoting tumor cell proliferation [8].

Two FGFR kinase inhibitors have gained approval for previously treated FGFR2 fusion-positive cholangiocarcinoma: pemigatinib and futibatinib. Pemigatinib was the first to be approved (by the US Food and Drug Administration [FDA] in 2020 and the European Medicines Agency [EMA] in 2021) after demonstrating clinical benefit in the phase II FIGHT-202 trial. In FIGHT-202, pemigatinib achieved an objective response rate (ORR) of 35.5% (95% CI: 26.5–45.4%) in patients with FGFR2 fusion-positive CCA, whereas no responses were seen in patients without FGFR2 alterations. The median progression-free survival (PFS) was 6.9 months in the FGFR2 fusion cohort [8].

Subsequently, the irreversible covalent pan-FGFR inhibitor futibatinib (TAS-120) showed even higher efficacy in a similar population. In the FOENIX-CCA2 trial, futibatinib achieved an ORR of 42% in previously treated FGFR2-rearranged iCCA, with a median PFS of 8.9 months [9].

Mutations in IDH1, typically the R132C or R132L substitutions, occur in about 15% of intrahepatic cholangiocarcinoma cases. These IDH1 mutations result in the production of an oncometabolite (2-hydroxyglutarate) that drives epigenetic dysregulation and cholangiocarcinoma development. Ivosidenib is an oral IDH1 inhibitor that became the first molecularly targeted drug approved for cholangiocarcinoma (FDA 2021, EMA 2023). Approval of ivosidenib was based on the phase III ClarIDHy trial, which enrolled patients with advanced IDH1-mutated cholangiocarcinoma who had progressed on prior therapy. Ivosidenib significantly prolonged PFS compared to placebo: median PFS 2.7 months vs. 1.4 months, respectively (hazard ratio [HR]: 0.37, P < 0.0001). Although the objective response rate was low (approximately 2% with ivosidenib vs. 0% with placebo), a large proportion of patients achieved stable disease, leading to a disease control rate ~51%. Importantly, there was a trend toward improved overall survival (OS). In the final analysis adjusting for crossover, ivosidenib was estimated to improve median OS from 5.1 months on placebo to 10.3 months, roughly halving the risk of death (HR: ~0.49; [10]).

While no HER2-targeted agent has received broad formal approval yet, specifically in BTC, clinical trials and real-world studies have shown clear benefit, and treatment guidelines recommend HER2-directed therapy for advanced BTC that overexpresses HER2. One approach is to use combinations of monoclonal antibodies against HER2. The phase II MyPathway basket study evaluated dual HER2 blockade (trastuzumab + pertuzumab) in patients with HER2-altered BTC. In that trial, among 39 BTC patients the ORR was 23% with a median PFS of 4.0 months [11].

A more potent strategy has been the use of antibody–drug conjugates (ADCs) targeting HER2. Trastuzumab deruxtecan (T-DXd), an ADC comprising an anti-HER2 antibody linked to a topoisomerase inhibitor payload, has demonstrated robust activity in HER2-expressing BTC. In the single-arm HERB trial from Japan, T‑DXd was given to patients with advanced, refractory BTC who were HER2-positive (IHC 3+ or IHC 2+ with gene amplification). The results showed an ORR of 36.4% in HER2-positive BTC. Median PFS was about 5.1 months in the HER2-positive group. Moreover, the global phase II DESTINY-PanTumor02 study recently reported an ORR of 56.3% in HER2 3+ BTC treated with T‑DXd, with a median PFS of 7.4 months [12].

Another novel agent is zanidatamab, a bispecific antibody that binds two distinct HER2 epitopes. In the phase IIb HERIZON-BTC-01 trial, zanidatamab showed an ORR of 41% in previously treated HER2-positive BTC, with a median PFS of 5.5 months [13].

The efficacy of dabrafenib + trametinib in BTC was shown in the ROAR basket trial, which included 43 patients with BRAF V600E-mutated biliary tract cancers. Among these patients (most of whom had iCCA), the ORR was 51% (95% CI: 36–67%), with durable responses. The median PFS was around 9.0 months, and 30% of patients remained progression-free at 1 year. Median overall survival was ~14 months [14].

KRAS G12C is also an interesting target for targeted therapy, actionable by sotorasib and adagrasib [15, 16].

Integrating molecular profiling into routine BTC care can benefit from a proactive and structured approach. The following recommendations may help optimize its implementation: