Trastuzumab Deruxtecan Shows Promising Activity in HER2-Positive Biliary Tract Cancer: Annals of Oncology | August 2026

Introduction:

Advanced biliary tract cancer (BTC) and pancreatic cancer (PC) are highly aggressive malignancies with limited treatment options and poor survival after progression on standard therapy. Although HER2 overexpression occurs in a subset of these tumors, effective HER2-targeted therapies have been lacking. This subgroup analysis of the Phase II DESTINY-PanTumor02 trial evaluated the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with previously treated HER2-expressing BTC and PC.

Why was this study needed?

Advanced BTC and pancreatic cancer have very poor prognoses after failure of standard therapy.

HER2 overexpression represents a potential therapeutic target in a subset of these tumors.

Evidence supporting HER2-directed therapy in gastrointestinal cancers beyond gastric cancer has been limited.

Trastuzumab deruxtecan has demonstrated broad activity across multiple HER2-positive solid tumors.

Further evaluation was needed to determine its role in HER2-positive BTC and pancreatic cancer.

Results:

The analysis included 41 patients with biliary tract cancer and 25 patients with pancreatic cancer treated with trastuzumab deruxtecan after prior systemic therapy.

Biliary tract cancer demonstrated meaningful antitumor activity, with objective responses observed in approximately one-quarter of patients.

The greatest benefit was seen in patients with strong HER2 overexpression (IHC 3+), where response rates exceeded 50%, highlighting HER2 expression as an important predictive biomarker.

Most patients with BTC or pancreatic cancer achieved disease stabilization, suggesting additional disease-control benefit beyond objective tumor responses.

In contrast, pancreatic cancer showed only limited activity, likely reflecting the small number of patients with HER2 IHC 3+ tumors in this cohort.

Treatment responses in BTC were observed across multiple clinical and biomarker subgroups, supporting the broad activity of trastuzumab deruxtecan in HER2-positive disease.

The safety profile remained consistent with previous T-DXd studies, with interstitial lung disease (ILD)/pneumonitis remaining the most important adverse event requiring careful monitoring.

Clinical Impact:

This analysis further establishes trastuzumab deruxtecan as an important treatment option for previously treated HER2-positive biliary tract cancer, particularly in tumors with HER2 IHC 3+ expression. The findings reinforce the importance of routine HER2 testing in advanced biliary tract cancers, as identifying eligible patients may open access to an effective targeted therapy. While results in pancreatic cancer were less encouraging, the small sample size and low prevalence of HER2 overexpression limit definitive conclusions. Careful monitoring for ILD/pneumonitis remains essential during treatment.

Bottom Line:

Trastuzumab deruxtecan demonstrated clinically meaningful activity in previously treated HER2-positive biliary tract cancer, with the greatest benefit observed in HER2 IHC 3+ tumors. These findings support routine HER2 testing in advanced biliary tract cancer and further strengthen the role of T-DXd as a preferred targeted therapy for eligible patients, while its role in pancreatic cancer requires additional investigation.