Targeted Treatments Shift the Paradigm of Advanced BTC

Biliary Tract Cancer | Image Credit:

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The management of advanced biliary tract cancer (BTC) hit a turning point in 2024 with the first approvals of targeted therapies fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and zanidatamab-hrii (Ziihera) for patients with HER2 positivity. However, the 5-year overall survival (OS) rate for patients with advanced BTC remains at less than 5%, underscoring the need for additional effective treatment options for these patients.1

“These are very aggressive cancers with median OS of approximately 12 months,” Haley Ellis, MD, said. “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 [GI] cancers, and we’ve seen some impressive survival data in some of these biomarker-driven tumors. [Although] this is still a challenging cancer with lots of room to improve, this rapidly evolving treatment landscape offers patients a lot of hope.”

During the 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI) in January, an OncLive Peer Exchange® featured insights from expert investigators in the field of BTC. They discussed the importance of early molecular testing, recent updates in the frontline setting, and the significance of targeted therapies moving into the second line and beyond.

New Standard Set By Targeted Agents In Frontline BTC

The panelists began their discussion by explaining the importance of early biomarker testing in informing treatment decisions in advanced BTC. They highlighted findings from an international real-world analysis of targeted therapy matched with molecularly actionable alterations in patients with advanced BTC following at least 30 days of palliative systemic treatment. The most common alterations included somatic BRCA1/2 mutations (n = 106), FGFR2 fusions (n = 61), HER2 amplification (n = 65), and IDH1 mutations (n = 38). Investigators used a Kaplan-Meier analysis to estimate OS from the start of frontline palliative systemic therapy until death or last follow-up.

Findings from the analysis demonstrated that matched patients (n = 135) achieved a median OS of 21.4 months (95% CI, 18.4-27.9). Comparatively, patients in the unmatched group (n = 231) and those without actionable alterations (n = 566) experienced a median OS of 14.6 months (95% CI, 12.8-17.6) and 17.2 months (95% CI, 15.5-19.0), respectively.

“Unfortunately, due to the rarity of the disease, there is not much [community] knowledge [in terms of] when we need to do biomarker testing. Tissue [supply] is always an issue [because] we have few cells to perform sequencing. In our practice, we [perform] both liquid biopsy and solid tumor next-generation sequencing [NGS] at the same time at the time of diagnosis,” Amit Mahipal, MD, said. “[The findings from this analysis] are very interesting; matched therapy is making a difference, and patients are living longer compared with unmatched [treatment]. 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].”

In the frontline setting of unresectable or metastatic BTC, durvalumab (Imfinzi) in combination with gemcitabine and cisplatin is a standard-of-care (SOC) option. The regimen was approved in September 2022 for treating adults with locally advanced or metastatic disease; the approval was supported by findings from the phase 3 TOPAZ-1 trial (NCT03875235).2 TOPAZ-1 compared durvalumab plus gemcitabine and cisplatin vs placebo with gemcitabine and cisplatin in patients with unresectable locally advanced or metastatic BTC.

Updated findings from TOPAZ-1 presented at the European Society for Medical Oncology Gastrointestinal Cancers Congress 2024 showed that at a median follow-up of 41.3 months (95% CI, 39.3-44.1) patients in the durvalumab arm (n = 341) achieved a median OS 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).3 The 36-month OS rates were 14.6% and 6.9%, respectively.

“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. There’s a huge ongoing effort to identify [which patients] are benefiting more. The toxicity was manageable. In general, there were no unexpected safety signals. For many of us in clinical practice in BTC, TOPAZ-1 has established the new SOC for first-line treatment.”

During ASCO GI, investigators presented findings from an exploratory analysis of clinically actionable alterations in TOPAZ-1 as a potential method to help guide treatment decisions.4 The findings showed that patients experienced an OS benefit with the addition of durvalumab to gemcitabine and cisplatin across all genetic mutation and wildtype subgroups examined, except for mutations in ARID1A and ERBB2. The most pronounced benefits were seen in patients with ARID1A (HR, 0.68; 95% CI, 0.56-0.81), KRAS (HR, 0.71; 95% CI, 0.59-0.85), and IDH1 wild-type (HR, 0.70; 95% CI, 0.59-0.84) disease. Progression-free survival (PFS) data also favored the durvalumab arm across all subgroups except for mutations in ARID1A, IDH1, and ERBB2.

Another FDA-approved first-line option for patients with advanced BTC is pembrolizumab (Keytruda) in combination with gemcitabine and cisplatin. In October 2023, the regimen was approved by the FDA for the treatment of patients with locally advanced unresectable or metastatic BTC.5 The approval was supported by findings from the phase 3 KEYNOTE-966 trial (NCT04003636), which compared pembrolizumab with placebo, both in combination with gemcitabine and cisplatin.

Updated findings from KEYNOTE-966 presented during the 2024 ASCO Annual Meeting showed that at a median follow-up of 36.6 months (range, 29.2-49.4), patients who received pembrolizumab (n = 533) achieved a median OS 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).6 The median PFS was 6.5 months (95% CI, 5.7-6.9) vs 5.6 months (95% CI, 4.9-6.5), respectively.

“Looking at both [TOPAZ-1 and KEYNOTE-966], it seems that [patients with] intrahepatic cholangiocarcinoma seemed to benefit more with the addition of immunotherapy compared with other subtypes, and [those with] gallbladder cancer do not tend to benefit as much with addition of immunotherapy,” Mahipal said. “These [subset findings] are hypothesis-generating; we should not change our treatment practice, but it’s interesting how the 2 studies are aligned.”

Targeted Therapeutics Move Into Pretreated BTC With a Focus on HER2

The panelists transitioned their discussion into the management of BTC in the second line and beyond by initially highlighting findings from a retrospective study presented during ASCO GI that aimed to characterize clinical and molecular outcomes associated with HER2 positivity in BTC.7 Patients were defined as being HER2 positive when they had an immunohistochemistry (IHC) of 3+ or 2+ in situ hybridization positive or by next-generation sequencing.

Findings from the analysis showed that 25.1% of patients with BTC included in the analysis (n = 310) were HER2 positive. The median OS for patients with HER2-positive disease was 13.7 months compared with 17.1 months for patients with HER2-negative disease (P = .084). Patients with HER2-positive disease who received an anti-HER2 agent experienced a median OS of 18.2 months, comparable to that of patients with HER2-negative disease (HR, 0.95; 95% CI, 0.71-1.27). Comparatively, patients with HER2-positive disease who did not receive a HER2-targeted agent experienced a median OS of 8.1 months.

One HER2-directed agent that has shown efficacy in BTC is the antibody-drug conjugate (ADC) T-DXd. T-DXd was examined in the phase 2 DESTINYPanTumor02 trial (NCT04482309) in patients with HER2-expressing solid tumors, including BTC.8 The primary end point was investigator-assessed overall response rate (ORR) per RECIST 1.1. Secondary end points included duration of response, disease control rate (DCR), PFS, OS, and safety.

Data from DESTINY-PanTumor02 showed that patients with BTC who received T-DXd (n = 41) experienced a confirmed ORR of 22.0% (95% CI, 10.6%-37.6%); notably, the ORR among patients with a HER2 IHC of 3+ (n = 16) was 56.3% (95% CI, 29.9%-80.2%). The median PFS 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. The respective median OS values were 7.0 months (95% CI, 4.6-10.2) and 12.4 months (95% CI, 2.8-not reached).

Findings from DESTINY-PanTumor02 partially supported the April 2024 FDA pan-tumor approval of T-DXd for adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.9

“At least for [patients with] HER2 IHC 3+ expression, if you have the [choice] of giving chemotherapy or unselected treatment vs T-DXd, [I believe] T-DXd would be a great option for these patients, keeping in mind that we do see interstitial lung disease with this drug,” Mahipal said.

The most recent agent to gain FDA approval for treating patients with BTC was the HER2-targeted bispecific antibody zanidatamab. In November 2024, the agent received accelerated approval in previously treated, unresectable or metastatic HER2-positive (IHC 3+) BTC.10 The regulatory decision was supported by findings from the single-arm, phase 2 HERIZON-BTC-01 study (NCT04466891), which showed that patients with unresectable or metastatic HER2-positive BTC who received at least 1 previous gemcitabine-containing regimen in the advanced disease setting (n = 62) achieved an ORR 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 [AEs] that we saw,[including] diarrhea and infusion reactions, were mostly grade 1 to 2,” Shubham Pant, MD, MBBS, noted. “That’s why [zanidatamab] is being combined with chemotherapy [in the phase 3 trial]. I wouldn’t think of combining an ADC with gemcitabine and cisplatin; that would be very challenging [for patients]. It’s a testament to this drug that it can be combined and that it’s tolerable in these patients.”

Darshil Shah, MD, MPH, added, “T-DXd is [similar to] chemotherapy in that we see neutropenia and other AEs that you do not see with the other HER2-targeted agents, [such as] trastuzumab [Herceptin], pertuzumab [Perjeta], or zanidatamab.”

In light of the positive findings from HERIZONBTC-01, investigators presented the design of the phase 3 HERIZON-BTC-302 study (NCT06282575) at ASCO GI, which is set to compare zanidatamab in combination with SOC gemcitabine and cisplatin vs SOC therapy alone, both with or without physician’s choice of pembrolizumab or durvalumab, in the first line of therapy.11 The ongoing study is enrolling adult patients with HER2-positive BTC who received up to 2 cycles of a gemcitabine-based regimen with or without a PD-L1 inhibitor for advanced, unresectable, or metastatic disease. The primary end point is PFS in the IHC 3+ population; secondary end points include OS and safety.

“HERIZON-BTC-302, the phase 3 confirmatory study of zanidatamab, is going to be very exciting,” Ellis said. “Hopefully, the paradigm is shifting for BTC; we know that targeting strong oncogenic drivers has clinical benefit in other cancers [such as] lung cancer when you treat these patients with targeted therapies in the frontline setting. It would be fantastic to see that mirrored in BTC.”

The panelists concluded their discussion by touching on other studies of interest in the BTC space presented during ASCO GI, including the phase 2 SIGNA (NCT06178588) and NIR-B trials (jRCT2011200023). SIGNA is an ongoing nonrandomized, open-label, single-arm study evaluating the TROP2-directed ADC sacituzumab govitecan-hziy (Trodelvy) in patients with locally advanced, recurrent, or metastatic cholangiocarcinoma with an ECOG performance status of 0 or 1 who have received at least 1 prior line of therapy.12 The primary end point is ORR per RECIST 1.1 criteria; secondary end points include OS, PFS, DCR, and safety.

During ASCO GI, investigators presented preliminary findings from NIR-B, which examined the PARP inhibitor niraparib (Zejula) in patients with BRCA-mutated unresectable or recurrent BTC, pancreatic cancer, and other GI malignancies who were refractory or intolerant to prior treatments.13 The primary end point was investigator-assessed ORR; key secondary end points included PFS, OS, DCR, and safety.

Patients in the BTC cohort (n = 26) experienced an ORR of 15.4% (95% CI, 8.4%-27.9%) and a DCR of 57.7% (95% CI, 36.9%-76.6%). The median PFS and OS were 2.7 months (95% CI, 1.5-4.1) and 7.8 months (95% CI, 5.9-9.8), respectively. Study authors noted that although data in terms of the primary end point did not reach statistical significance, evaluation of niraparib in other biomarker-selected patients beyond those with BRCA mutations or as a combination component could yield greater clinical activity in this disease setting.

“[I want to again] highlight the increasing importance of performing comprehensive molecular profiling,” Ellis said in her concluding remarks. “We recognize that tissue is often the issue with these difficult-to-access tumors, and tumor cellularity can [also] be an issue. However, 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.”

References

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2. FDA approves durvalumab for locally advanced or metastatic biliary tract cancer. FDA. September 2, 2022. Accessed February 19, 2025. https://www.fda.gov/drugs/resourcesinformation-approved-drugs/fda-approves-durvalumab-locallyadvanced-or-metastatic-biliary-tract-cancer
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10. FDA grants accelerated approval to zanidatamab-hrii for previously treated unresectable or metastatic HER2-positive biliary tract cancer. FDA. Updated November 21, 2024. Accessed February 19, 2025. https://www.fda.gov/drugs/resources-informationapproved-drugs/fda-grants-accelerated-approval-zanidatamabhrii-previously-treated-unresectable-or-metastatic-her2
11. Harding JJ, Macarulla T, Pant S, Wu X, Garfin PM, Okusaka T. HERIZON-BTC-302: a phase 3 study of zanidatamab with standard-of-care (SOC) therapy vs SOC alone for first-line treatment of human epidermal growth factor receptor 2 (HER2)positive advanced/metastatic biliary tract cancer (BTC). J Clin Oncol. 2025;43(suppl 4):TPS648. doi:10.1200/JCO.2025.43.4_ suppl.TPS648
12. Kasi A, Al-Rajabi RMT, Li H, et al. A phase II open-label study of sacituzumab govitecan in patients with previously treated locally advanced, recurrent, or metastatic cholangiocarcinoma (SIGNA). J Clin Oncol. 2025;43(suppl 4):TPS651. doi:10.1200/ JCO.2025.43.4_suppl.TPS651
13. Kawamoto Y, Morizane C, Komatsu Y, et al. Niraparib in patients with BRCA-mutated unresectable or recurrent biliary tract, pancreatic and other gastrointestinal cancers: an investigatorinitiated phase 2 trial (NIR-B trial). J Clin Oncol. 2025;43(suppl 4):589. doi:10.1200/JCO.2025.43.4_suppl.589