Gemcitabine and cisplatin plus durvalumab with or without tremelimumab in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, single-centre, phase 2 study
Mené sur 128 patients atteints d'un cancer des voies biliaires de stade avancé (durée médiane de suivi : 48,2 mois), cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité d'un traitement de première ligne combinant gemcitabine, cisplatine et durvalumab, avec ou sans trémélimumab
Background : Immunotherapies have shown clinical activity in patients with advanced biliary tractcancer, for which outcomes remain poor despite standard of care treatment with gemcitabine and cisplatin. We aimed to evaluate gemcitabine and cisplatin plus durvalumab withor without tremelimumab as first-line treatment in patients with advanced biliary tract cancer. Methods : This open-label, single-centre, phase 2 study was conducted at Seoul National UniversityHospital. Eligible patients were treatment-naïve adults aged 18 years or older with histologically proven unresectable or recurrent biliary tract cancer, at least onemeasurable lesion based on the Response Evaluation Criteria in Solid Tumors (version1.1), an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancyof 12 weeks or longer, and adequate healthy organ and bone marrow function. Initially,all patients received one 3-week cycle of gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) on day 1 and 8 followed by gemcitabine and cisplatin plus durvalumab (1120 mg) andtremelimumab (75 mg) on day 1 of each cycle, starting with the second cycle (chemotherapyfollowed by chemotherapy plus durvalumab and tremelimumab group). Following protocolamendment, patients were recruited to receive gemcitabine and cisplatin plus durvalumab,starting on day 1 of the first cycle (chemotherapy plus durvalumab group) or gemcitabineand cisplatin plus durvalumab and tremelimumab also from day 1 of the first cycle(chemotherapy plus durvalumab and tremelimumab group) in parallel and allocated usinga random block method. Assessors and patients were not masked to the treatment group.The primary endpoint was objective response rate, assessed in the efficacy population(ie, patients who were treated at least until the first tumour response assessment).This study is registered with ClinicalTrials.gov, NCT03046862 (active). Findings : Between March 2, 2017, and Feb 13, 2020, 128 patients were enrolled (32 in the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group, 49 in the chemotherapyplus durvalumab group, and 47 in the chemotherapy plus durvalumab and tremelimumabgroup). Four patients (two in the chemotherapy followed by chemotherapy plus durvalumaband tremelimumab group and two in the chemotherapy plus durvalumab group) were excludedand 124 were evaluable for tumour response. The median duration of follow-up was 48·2months (IQR 41·5–49·4) for the chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group, 26·6 months (19·0–27·9) for the chemotherapy plus durvalumab group, and 24·2 months (20·7–31·7) for the chemotherapy plus durvalumab and tremelimumabgroup. 82 (66%) of 124 patints achieved an objective response (15 [50%] of 30 inthe chemotherapy followed by chemotherapy plus durvalumab and tremelimumab group,34 [72%] of 47 in the chemotherapy plus durvalumab group, and 33 [70%] of 47 in thechemotherapy plus durvalumab and tremelimumab group). The most common grade 3 and4 adverse events were decreased neutrophil count (67 [53%] of 126), anaemia (50 [40%]),and decreased platelet count (24 [19%]), with no unexpected safety events. No adverseevents leading to discontinuation or death occurred. Interpretation : Gemcitabine and cisplatin plus immunotherapy showed promising efficacy and acceptable safety in patients with biliary tract cancer. Gemcitabine and cisplatin plus durvalumab are being evaluated in the phase 3, TOPAZ-1 study (NCT03875235) as first-line treatment in patients with advanced biliary tract cancer.