First-line Trastuzumab Plus Chemoimmunotherapy for Biliary Tract Cancer (HERBOT Trial)
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. Similar data are reported in HER2 positive gastric cancer that phase II and phase III clinical data showed 1st-line ICIs combined with trastuzumab and cytotoxic chemotherapy showed promising overall survival outcomes. In treating HER2-positive advanced BTC, the triple combination of nivolumab, trastuzumab, and cytotoxic chemotherapy (Gem/Cis) may overcome innate resistance and activate an immune response to cancer along with inhibiting oncogenic signal from HER2 pathway, resulting in a synergistic effect with a longer response.
• Subjects with histologically- or cytologically-confirmed biliary tract cancer (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gall bladder cancer)
• HER2 positive biliary tract cancer (IHC 3+ or 2+ with ISH + (HER2/CEP17≥2.0) or ERBB2 gene copy number ≥ 6.0 by NGS)
• Age (at the time of informed consent): 20 years and older
• Previously untreated if unresectable/metastatic at initial diagnosis; or recurrent disease \>6 months after curative surgery or adjuvant therapy (allow up to 1 cycle of gemcitabine-based chemotherapy for advanced/unresectable or metastatic cholangiocarcinoma prior to enrollment)
• Explicit and voluntary consent to participate in the study obtained using a signed and dated informed consent form clearly and fully describing the purpose, potential risks, and any other critical issues regarding the study
• Subject with measurable lesions according to RECIST v. 1.1
• ECOG Performance Status Score 0 or 1
• Patients with a life expectancy of at least 3 months
• Patients whose latest laboratory data meet the below criteria within 14 days before enrollment.
• White blood cells ≥2,000/mm3 and neutrophils ≥1,500/mm3 Platelets ≥100,000/mm3 Hemoglobin ≥9.0 g/dL AST (GOT) and ALT (GPT) ≤3.0-fold the upper limit of normal (ULN) of the study site (or ≤5.0-fold the ULN of the study site in patients with liver metastases) Total bilirubin ≤1.5-fold the ULN of the study site Creatinine ≤1.5-fold the ULN of the study site or creatinine clearance (either the measured or estimated value using the Cockcroft-Gault equation) \>45 mL/min INR ≤1.5-fold or prothrombin time ≤1.5-fold the ULN of the study site aPTT ≤1.5-fold the ULN of the study site
⁃ Women of childbearing potential (including women with chemical menopause or no menstruation for other medical reasons) #1 must agree to use contraception#2 from the time of informed consent until 5 months or more after the last dose of the investigational product. Also, women must agree not to breastfeed from the time of informed consent until 5 months or more after the last dose of the investigational product.
⁃ Men must agree to use contraception#2 from the start of study treatment until 7 months or more after the last dose of the investigational product.
∙ 1\. Women of childbearing potential are defined as all women after the onset of menstruation who are not postmenopausal and have not been surgically sterilized (e.g., hysterectomy, bilateral tubal ligation, bilateral oophorectomy). Postmenopause is defined as amenorrhea for ≥12 consecutive months without specific reasons. Women using oral contraceptives, intrauterine devices, or mechanical contraception such as contraceptive barriers are regarded as having childbearing potential.
‣ 2\. The subject must consent to use any of the following methods of contraception: vasectomy or condom for patients who are male or female subject's partner and tubal ligation, contraceptive diaphragm, intrauterine device, spermicide, or oral contraceptive for patients who are female or male subject's partner.
⁃ EF ≥ 50% via Transthoracic echocardiography or MUGA scan
⁃ Subjects willing to provide tumor biopsy tissue or excisional biopsy tissue.
⁃ Subjects with adequate organ function