Protocol of notable-HCC: a phase Ib study of neoadjuvant tislelizumab with stereotactic body radiotherapy in patients with resectable hepatocellular carcinoma

Abstract

Introduction Liver resection is the mainstay of curative-intent treatment for hepatocellular carcinoma (HCC), but the postoperative 5-year recurrence rate reaches 70%, and there are no adjuvant or neoadjuvant therapies recommended by major HCC guidelines that can reduce the risk of recurrence. In the recent decade, significant progress has been achieved in the systemic treatment of HCC, mainly from immune checkpoint inhibitors (ICIs) and targeted therapy. In other malignancies, ICIs in the neoadjuvant setting have shown better outcomes than in the adjuvant setting. On the other hand, the addition of radiation to ICIs incrementally improves the systemic response to ICIs. Neoadjuvant therapy of ICIs plus stereotactic body radiotherapy (SBRT) has shown promising results in several types of solid tumours but not HCC. Methods and analysis Here, we describe a phase Ib clinical trial of neoadjuvant SBRT plus PD-1 (tislelizumab) prior to hepatic resection in HCC patients. Prior to resection, eligible HCC patients will receive 8 Gy×3 fractions of SBRT together with two cycles of tislelizumab with an interval of 3 weeks. HCC resection is scheduled 4 weeks after the second dose of tislelizumab, followed by adjuvant tislelizumab for 1 year. We plan to enrol 20 participants in this trial. The primary study endpoints include the delay of surgery, tumour response and safety and tolerability of the sequential SBRT/tislelizumab. Other endpoints are the disease-free survival and overall survival rates every 3 or 6 months after the surgery. Ethics and dissemination This trial was approved by the Ethics Committee of Shandong Cancer Hospital and Institute (SDZLEC2022-021-01). The final results of this trial will be published in a peer-reviewed journal after completion. Trial registration number NCT05185531 .

Neoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable hepatocellular carcinoma: the Notable-HCC phase 1b trial

“…This trial was registered with ClinicalTrial.gov, NCT05185531 , on 11 January 2022, and is ongoing but closed to accrual. The study protocol has been published previously 46 and a synopsis is also available in the Supplementary Information file. There is a lack of data on the treatment of neoadjuvant anti-PD-1 monoclonal antibody plus SBRT in early-stage resectable HCC patients in previous studies.…”

Combined radiotherapy and immune checkpoint inhibition for the treatment of advanced hepatocellular carcinoma

“…The proposed mechanism involves creation of reactive oxygen species, and expression of PD-L1 leading to T-cell suppression ( 103 ). Among patients with HCC, EPCs produce artemin, a glia cell derived neurotrophic factor that stimulates HCC growth in animal models ( 104 , 105 ). Combination RT and ICI therapy, particularly anti-PD-L1 could disrupt this pathway by inhibiting accumulation of splenic EPCs.…”

Neoadjuvant and Adjuvant Systemic Therapies in Loco-Regional Treatments for Hepatocellular Carcinoma: Are We at the Dawn of a New Era?

“…Li et al [57] are, instead, analyzing the safety and efficacy of the combination scheme lenvatinib plus sintilimab plus radiotherapy as neoadjuvant treatment regimen in patients with HCC and portal vein tumor thrombus (NCT05225116). Finally, there is an ongoing evaluation by Zhang et al [58] of the efficacy of neoadjuvant tislelizumab with stereotactic body radiotherapy in patients with resectable HCC (NCT05185531).…”