Notable-HCC: A phase Ib trial of neoadjuvant tislelizumab with stereotactic body radiotherapy in patients with early stage resectable hepatocellular carcinoma
Authors: Zhao Lei , Li Zhongchao , Liu Jing , Zhang Bo , Yue Jinbo , Shi Xuetao , Cui Kai , Liu Zhaogang , Chang Zhibin , Sun Zhicheng , Li Mingming , Yang Yue , Ma Zhao , Li Lei , Zhang Chengsheng , Sun Pengfei , Zhong Jingtao 
Published: January 2024

Abstract
Background
Hepatocellular carcinoma (HCC) is highly invasive, even for early stage HCC, the 1-year post-operative recurrence rates were over a quarter; so far no standard neoadjuvant therapy (NAT) is recommended by major guidelines. NAT with immune checkpoint inhibitors (ICIs) has been tried in varying solid tumors including HCC; radiotherapy showed immuno-modulating effect in the treatment of some malignancies. So we aimed to evaluate the safety, tolerability and preliminary effectiveness of neoadjuvant anti-programmed cell death protein-1(PD-1) monoclonal antibody plus stereotactic body radiotherapy (SBRT) in early stage resectable HCC.
Methods/Procedures
Notable-HCC (NCT05185531) is a single-center phase Ib trial; in this pilot study, patients with resectable HCC of Barcelona Clinic Liver Cancer (BCLC) stage 0 to A planned to receive three fractions of 8 Gy SBRT on day 1, 3 and 5, and two cycles of tislelizumab, an anti-PD-1 monoclonal antibody, 3 weeks apart at a dose of 200mg. Curative liver resection of HCC was scheduled on day 50. Adjuvant therapy was tislelizumab every 3 weeks for up to 1 year. The primary endpoints were the surgery delay over 6 weeks, objective response rate (ORR) after the neoadjuvant therapy, pathological response rates, and the safety and tolerability of the combination neoadjuvant therapy as well as the adjuvant therapy. Secondary endpoints were 1-, 3- and 5-year disease-free survival (DFS) and over survival (OS) rates assessed every 3 or 6 months after hepatic resection. Exploratory endpoints included patients’ immune response, incidence of surgical complications, and mortality rate.
Results
Between Mar 22, 2022, and Jul 17, 2023, 22 patients were screened and 20 were enrolled. During the neoadjuvant therapy period, treatment-related adverse events (TRAEs) of any grade occurred in all 20 patients (100%), eight patients (40%) had grade 3 TRAEs, the most common grade 3 TRAEs were decreased lymphocyte count (n = 3, 15.0%) and decreased neutrophil count (n = 3, 15.0%); no grade 4 to 5 TRAE occurred. All adverse events resolved spontaneously without the need for corticosteroids treatment. Per RECIST v1.1, ORR was 42.1% (8/19), all were partial response (PR) and no patients achieved complete response (CR), and other 11 (57.9%) patients were stable disease (SD), so the disease control rate (DCR) was 100%. While per mRECIST, the ORR was 63.2% (12/19), with 3 CR and 9 PR, the DCR was also 100%. All patients had radiographic tumor regression in varying degree. Two (10.5%) patients achieved complete pathological response (pCR), and 6 (31.6%) reached major pathological response (MPR). No patient had surgery delay over 6 weeks due to any reason. One patient had radiofrequency ablation, other 19 patients achieved curative R0 resection. The neoadjuvant therapy did not increase the difficulty of surgical resection, nor did it increase the incidence of post-operative complications. TRAEs of any grade occurred in all 17 patients who received adjuvant tislelizumab after the R0 HCC resection, with the vast majority were grade 1 to 2. The three most common types TRAEs were decreased lymphocyte count (n = 13, 76.5%), decreased platelet count (n = 12, 70.6%) and decreased white blood cell (n = 7, 41.2%). Three patients experienced grade 3 TRAEs, which were decrease lymphocyte count (n = 3, 17.6%) and decreased platelet count (n = 1, 5.9%), all TRAEs during the adjuvant therapy were asymptomatic and no corticosteroids treatment was needed, no grade 4 or 5 TRAE occurred. Median time from enrollment to data cutoff (Dec 1, 2023) for the preliminary analysis was 6.1months (IQR 5-12.5). The median cycle of adjuvant tislelizumab in 15 patients who received regular adjuvant treatment was 4 (range, 2–16). With a median follow-up of 4.0 months since the resection (range, 2.2–18.8), disease recurrence developed in only 1 out of 19 patients (5.3%). The neoadjuvant therapy of tislelizumab plus SBRT effectively activated the immune system, indicated by the increases of both adaptive and innate immune-related cell populations, upregulation of T cell activation-related gene expression, the gene signatures of tumor-reactive T cells and cytotoxic cells, enhanced expression of HLA class I and II genes, as well as a larger proportion of newly generated TCR clonotypes after the neoadjuvant therapy, and the immuno-enhancing effects were more significant in patients with better radiographic tumor responses.
Conclusion
In patients with early stage resectable HCC, the combination neoadjuvant therapy with anti-PD-1 monoclonal antibody (tislelizumab) and SBRT appears to be safe and well-tolerated, and achieves significant tumor responses as well as anti-tumor immunity. Our pilot results warrant further studies of neoadjuvant therapy with ICI plus radiotherapy in resectable HCC.