Practice-changing signals amid evidence gaps: What’s driving your 2L decisions in HER2+ BTC?
Industry Buzz
Several HER2-directed treatments are in active development for BTC, with the most impactful being phase 3 trials that could shift HER2-targeted therapy from second-line to first-line use.
—Laura Vater, MD, MPH
The treatment landscape for biliary tract cancers has evolved with the growing recognition of HER2 as a therapeutic target. While standard second-line chemotherapy has historically offered limited benefit, HER2-directed therapies are emerging as important options for a subset of patients with HER2-positive disease.
Although definitive phase 3 evidence is still pending, several agents have demonstrated clinically meaningful activity and are increasingly incorporated into practice.
As HER2-targeted therapies gain traction in BTC, translating evolving data into practical second-line treatment decisions is becoming increasingly critical. Ahead, we break down the currently available HER2-directed options and what their efficacy and safety profiles mean for real-world use.
HER2-directed second-line therapy options
Although randomized phase 3 data are still emerging for HER2-targeted therapies in BTC, multiple agents have demonstrated clinically meaningful activity and are now incorporated into treatment pathways.
In current US practice, zanidatamab is FDA-approved for previously treated unresectable or metastatic HER2-positive BTC, defined as IHC 3+ by an FDA-approved test, and trastuzumab deruxtecan also has a tumor-agnostic approval for previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors when no satisfactory alternatives are available.
Zanidatamab is a bispecific antibody and was approved under accelerated approval based on ORR (52% in IHC 3+ patients) and duration of response (median 14.9 months) from HERIZON-BTC-01, and continued approval is contingent on the results of the confirmatory phase 3 HERIZON-BTC-302 trial.[] The main toxicities of zanidatamab are diarrhea and infusion reactions, which are generally manageable.
Trastuzumab deruxtecan is FDA-approved for previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors when there is no satisfactory alternative treatment option. It demonstrated a 36.4% ORR in HER2-positive BTC in the HERB trial (n=22).[] Of note, it carries a risk of interstitial lung disease (ILD).
Pertuzumab plus trastuzumab is a widely available combination, familiar to oncologists, and has shown positive outcomes in the phase 2a setting, but the combination is not FDA-approved for BTC, requiring off-label justification. The same is true for tucatinib with trastuzumab, which has phase 2 data demonstrating clinically meaningful activity but is not yet approved for BTC.
Several HER2-directed treatments are in active development for BTC, with the most impactful being phase 3 trials that could shift HER2-targeted therapy from second-line to first-line use.
Baseline assessment before starting HER2-directed therapy
Before initiating HER2-directed therapy, it is important to obtain a cardiac assessment to determine baseline LVEF.
The safety of zanidatamab has not been established in patients with a baseline LVEF below 50%. For HER2-targeted therapies, guidelines typically recommend LVEF measurements every 3 months during therapy. Echocardiogram is preferred.
If trastuzumab deruxtecan is the selected agent, additional baseline pulmonary assessment is often warranted, given the risk of ILD, including a chest CT and baseline pulse oximetry.
Prior authorization considerations
Providing the following information often speeds up approvals:
A pathology report indicating HER2 IHC 3+.
Diagnosis and stage documentation showing unresectable or metastatic BTC.
A prior-treatment summary demonstrating progression after a gemcitabine-based regimen, or previous systemic therapy with no satisfactory alternatives.
A recent oncology note stating current disease status, intended line of therapy, and ECOG performance status.