First-line Trastuzumab, Gemcitabine, Cisplatin and Nivolumab in Advanced HER2- Positive Biliary Tract Cancer: a Multicenter, Open-label, Single-arm Phase Ib/II Trial (HERBOT)

Biliary tract cancer is a rare malignant neoplasm including intrahepatic cholangiocarcinoma (IhCCA), extrahepatic cholangiocarcinoma (EhCCA) and Gallbladder cancer (GBC). Survival outcome of advanced BTCs are still poor and heterogeneity of tissue and molecular differences between BTCs limit the clinical studies in BTCs. Combination therapy of Gemcitabine and Cisplatin has become the standard of care after the ABC-02 trial. This trial demonstrated that the addition of cisplatin to gemcitabine improved survival outcomes compared to that with gemcitabine alone. However, the median overall survival (OS) of Gem/Cis chemotherapy is only about one year. Anti-Program cell death-1 (anti-PD-1) inhibitor monotherapy including Nivolumab (OPDIVO) had shown efficacy in refractory, advanced BTC. Various ICIs combined with Gem/Cis as the 1st line treatment in BTCs are under the trials. Combination of Nivolumab and Gem/Cis showed improved overall survival (15.4 months) in a small sized study (n=30) with tolerable side effects in advanced BTC patients. Recently reported interim analysis of phase III TOPAZ-1 trial (NCT03875235) showed Durvalumab, anti-PD-L1 agent, combined with Gem/Cis showed improvement of overall survival. Considering other studies currently ongoing, ICIs combined with Gem/Cis are thought to be the future standard of care in 1st line treatment of advanced stage BTCs. HER2 amplification/overexpression is presented as many as 15% of total BTC patients. Basket trial of administration of pertuzumab and trastuzumab combination in previously treated HER2 positive advanced BTC patients showed promising overall response rate of 23%. Also, multicenter phase II study conducted by Korean investigators (KCSG-HB19-14) showed promising effect of Trastuzumab combined with modified FOLFOX in Gem/Cis refractory HER2 positive BTC patients with ORR of 29.4%. Moreover, preclinical data showed synergistic anti-cancer effect of trastuzumab combined with ICIs in HER2 positive cancers.