Trastuzumab plus FOLFOX for HER2-positive bile duct cancer refractory to gemcitabine and cisplatin: a phase 2 multi-institutional trial from the Korean Cancer Study Group (KCSG-HB19–14)


Overexpression or amplification of HER2, which is present in 15% of all cases of bile duct cancer, has been identified as a molecular drug target by genomic profiling. In the Phase 3 ABC-06 trial, the folinic acid, fluorouracil, and oxaliplatin (FOLFOX) regimen showed a survival advantage over active symptom control as a treatment for second line of cancer of the bile ducts. Our objective was to evaluate the clinical activity of FOLFOX plus trastuzumab, an anti-HER2 antibody, as a second- or third-line treatment for HER2-positive bile duct cancer.


This study was an open-label, non-randomized, single-arm, multi-institutional, investigator-initiated Phase 2 trial in participants 19 years of age or older with HER2-positive (defined as immunohistochemistry 3+ or immunohistochemistry 2+ and positive in situ hybridization or ERBB2 gene copy number ≥6 0 by next-generation sequencing) bile duct cancer (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer) that progressed on chemotherapy containing gemcitabine and cisplatin (with one or two lines previous authorized chemotherapy). During the first cycle, patients received trastuzumab-pkrb intravenously at 6 mg/kg on day 1, and FOLFOX (compound oxaliplatin intravenously [85 mg/m2]intravenous leucovorin [200 mg/m2]and fluorouracil [400 mg/m2 bolus] every day 1, and fluorouracil [2400 mg/m2 infusion] on days 1-2. During the second cycle, participants received trastuzumab-pkrb intravenously at 4 mg/kg and FOLFOX every 2 weeks until unacceptable toxic effects or disease progression. The primary endpoint of the study was objective response rate based on RECIST version 1.1, assessed in participants who completed at least one study cycle. The response rate threshold for a positive objective response rate was 25%. This trial is registered with (NCT04722133) and is ongoing.


34 participants were enrolled between June 26, 2020 and September 1, 2021. At the time of data cutoff on May 1, 2022, the median follow-up was 13 0 months (IQR 11 0–16 9), with three participants remaining on treatment. Ten patients had a partial response and 17 had stable disease; the overall response rate was 29.4% (95% CI 16.7–46.3) and the disease control rate was 79.4% (95% CI 62.9–89, 9). The median progression-free survival was 5.1 months (95% CI 3.6–6.7); median overall survival was 10·7 (95% CI 7·9–not achieved). The most common grade 3 or 4 treatment-related adverse events were neutropenia (ten
[29%] 3rd and 9th year participants [26%] grade 4), grade 3 anemia (five
[15%] participants), and grade 3 peripheral sensory neuropathy (four [12%] attendees). There were no cardiac toxic effects or treatment-related deaths. The global health assessment score (EuroQoL-VAS) did not change significantly throughout treatment. Symptoms of sensory and motor neuropathy, as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Chemotherapy-Induced Peripheral Neuropathy Questionnaire, did not change from significantly over time.


For HER2-positive bile duct cancer, the second- or third-line biosimilar trastuzumab plus FOLFOX showed promising activity with acceptable toxicity, warranting further investigation.


Boryung Pharmaceutical, Celltrion, National Research Foundation of Korea, National R&D Program for Cancer Control through the National Cancer Center, Yonsei University College of Medicine.

About Hector Hedgepeth

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