A phase 3 study of durvalumab with or without bevacizumab as adjuvant therapy in patients with hepatocellular carcinoma (HCC) who are at high risk of recurrence after curative hepatic resection

Introduction: Many patients with early-stage HCC undergo hepatic resection and ablation as the standard of care, but while potentially curative, the risk of cancer recurrence following resection is as high as 44-79% at 5 years (Bruix and Sherman 2005, Imamura, et al 2003, Kianmanesh et al 2003). Effective adjuvant therapy has not been demonstrated to date and the prevention and/or delay of recurrence of HCC after curative treatment presents a high unmet medical need. Adjuvant therapy given after resection or ablation has the potential to reduce the risk of relapse and is an effective therapeutic approach in the treatment of many solid tumors. There is encouraging evidence that adjuvant therapy involving agents that engage the immune response, including immunotherapy such as durvalumab (an anti PD-L1 antibody), can prolong recurrence-free survival (RFS) in patients with early-stage HCC (Yin et al 2013, Huang et al 2015, Xu et al 2015, Lee et al 2015). Other evidence shows that inhibiting the VEGF pathway may enhance the activity of PD-L1 blockade in more advanced HCC patients (Pishvaian et al 2018, Ikeda et al 2018). EMERALD-2 (NCT03847428) is a phase 3 randomized, double-blind, placebo-controlled study that will evaluate the efficacy and safety of durvalumab monotherapy and durvalumab combined with bevacizumab as adjuvant therapy in patients with HCC after curative resection or ablation who are at high risk of recurrence. Methods: Approximately 888 pts will be randomized 1:1:1 to either Arm A (durvalumab + bevacizumab), Arm B (durvalumab + placebo), or Arm C (placebo + placebo) following hepatic resection and ablation. Patients will be stratified based upon evidence of pathological microvascular invasion (assessed at study entry) and geographic region. Eligible pts must have confirmed HCC and have successfully completed curative therapy (resection or ablation) with imaging to confirm disease-free status ≤ 28 days prior to randomization, ECOG 0-1 and Child-Pugh score of 5 or 6. Patients will not be included in the study if they have known fibrolamellar HCC, sarcomatoid HCC or mixed cholangiocarcinoma and HCC, or any evidence of metastatic, macrovascular invasion or co-existing malignant disease on baseline imaging. Any patients with evidence of portal vein thrombosis or those on a waiting list for liver transplantation will be excluded. Prior systemic anticancer therapy for HCC is not allowed. Patients with hepatitis virus B or C (HBV, HCV) alone may be enrolled, but HBV+ pts must have adequately controlled viral suppression prior to enrollment and HBV/HCV replication will be monitored during the study and treated if appropriate. The primary endpoint is RFS as assessed by blinded independent central radiology review using RECIST v1.1. Secondary endpoints include 2- and 3-year RFS, time to recurrence, overall survival, health-related quality of life measures, and safety.