Trastuzumab Plus Gemcitabine/Cisplatin in Advanced HER2-Positive Biliary Tract Adenocarcinoma

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In an Indian phase II trial reported in the Journal of Clinical Oncology, Ostwal et al found that trastuzumab plus gemcitabine/cisplatin was active in treatment-naive patients with advanced HER2-positive biliary tract adenocarcinoma.

Study Details

In the investigator-initiated multicenter trial, 90 patients enrolled between March 2020 and August 2022 were treated with 21-day cycles of trastuzumab at 8 mg/kg as an initial dose and then 6 mg/kg on day 1 in combination with gemcitabine at 1,000 mg/m2 and cisplatin at 25 mg/m2 on days 1 and 8. After 6 months of combination therapy every 3 weeks, modifications in dosing and scheduling of study drugs were permitted according to physician's choice. A total of 85 patients (94%) had metastatic disease, with 70 (78%) having two or more metastatic sites. The primary endpoint was 6-month progression-free survival, with the aim of increasing the previously observed rate of 40% with gemcitabine/cisplatin to 60% with the addition of trastuzumab.

Key Findings

At data cutoff (end of February 2023), median follow-up was 17.3 months (95% confidence interval [CI] = 15.2–19.3 months). Median progression-free survival was 7 months (95% CI = 6.2–7.8 months). Progression-free survival at 6 months was 75.6% (95% CI = 66.6–84.6%), exceeding the 60% threshold. The rate at 1 year was 17.6%.

The presence of isolated TP53 mutations was associated with poorer median progression-free survival compared with other mutations (eg, TERT promoter, HER2, PIK3CA) or no detected mutations (6.51 months vs 12.02 months vs 10.58 months; overall P < .001).

Median overall survival was 9.96 months (95% CI = 9.3–10.7 months), with rates at 6 and 12 months of 81.1% and 39.1%. Objective responses were observed in 50 patients (55.5%); an additional 22 patients (22.4%) had stable disease, yielding a disease control rate of 80%.

Grade ≥ 3 adverse events occurred in 56% of patients, most commonly anemia (29%), neutropenia (20%), increased aminotransferases (18%), and fatigue (17%). A decline of > 10% in ejection fraction was observed in two patients. Adverse events led to discontinuation of treatment in 7% of patients.

The investigators concluded, “The combination of gemcitabine/cisplatin and trastuzumab achieved its primary endpoint of improving progression-free survival compared with historical data in treatment-naive [patients with] HER2-positive biliary tract adenocarcinoma. Evaluating additional mutations such as TP53 and PIK3CA along with HER2 testing may help to preferentially select patients for anti-HER2 therapy in the future.”

Anant Ramaswamy, MD, DM, of the Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Cadilla Pharmaceuticals Limited and others. For full disclosures of the study authors, visit

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