Ado-trastuzumab emtansine (T-DM1; Kadcyla) has shown limited efficacy in improving progression-free survival (PFS) in patients with previously treated HER2-positive biliary tract adenocarcinoma, according to findings from a phase 2 trial (CTRI/2023/07/055785) presented at the 2025 Gastrointestinal Cancers Symposium. While the treatment was tolerable, the study did not meet its primary endpoint of statistically significant PFS improvement compared to historical controls.
The single-arm, phase 2 trial enrolled 40 patients between July 2023 and July 2024. The median age of participants was 50.5 years, and 78% were female. The majority (90%) had stage IV disease at diagnosis, and 98% had an ECOG performance status of 0 to 1. All patients had progressed on gemcitabine-based first-line therapy or relapsed within 6 months of stopping gemcitabine when used as adjuvant therapy and were HER2-positive by immunohistochemistry.
Efficacy and Outcomes
The primary endpoint of the study was PFS. Secondary endpoints included overall response rate, disease control rate, overall survival (OS), and the incidence of grade 3/4 treatment-related adverse effects (AEs). The median follow-up was 7.1 months (95% CI, 5.1-9.1).
Results indicated that the 3-month PFS was 51.2% (95% CI, 33.4%-69.0%), with a median PFS of 3.1 months (95% CI, 2.3-3.8). The 6-month OS was 56.5% (95% CI, 36.5%-76.5%), and the median OS was 7.1 months (95% CI, 5.1-9.1). A partial response was observed in 12.5% of patients, 20% had stable disease, and the disease control rate was 32.5%.
Notably, a subgroup of patients (40%) who did not experience rapid progression on prior systemic therapy showed a more favorable outcome, with a 3-month PFS of 70% (95% CI, 44.8%-95.2%) and a median PFS of 4.9 months (95% CI, 2.9-6.9).
Safety and Tolerability
T-DM1 was administered intravenously at a dose of 3.6 mg/kg on a 21-day schedule until disease progression, unacceptable toxicity, or patient withdrawal. Treatment-related AEs of grade 3 or higher included anemia (13%) and thrombocytopenia (3%), indicating a manageable safety profile.
Expert Commentary
Vikas Ostwal, MD, a professor at Tata Memorial Care in Mumbai, noted that patients without rapid progression on prior therapy seemed to have better survival outcomes. "Patients who did not have rapid progression on prior systemic therapy appeared to have a more favorable survival in comparison with rapid progressors and the role of T-DM1 in such favorable cohorts can be expected in larger studies," Dr. Ostwal wrote in the poster presentation.
Implications for HER2-Positive Biliary Tract Cancer
HER2 amplification is a therapeutic target of interest in advanced biliary tract cancer. This study provides insights into the potential role of T-DM1 in this setting, particularly in patients who do not exhibit rapid progression on initial therapies. Further research is warranted to identify predictive biomarkers and optimize treatment strategies for this patient population.
