nofazinlimab (CS1003)

P1, N=91, Completed, CStone Pharmaceuticals | Phase classification: P1a/1b --> P1

CS1002 is a human immunoglobulin (Ig) G1 monoclonal antibody that blocks the interaction of CTLA-4 with its ligands and increases T-cell activation/proliferation. CS1003, now named nofazinlimab, is a humanized, recombinant IgG4 monoclonal antibody that blocks the interaction between human PD-1 and its ligands. In this original article, we determined the safety profile of CS1002 as monotherapy and in combination with CS1003. Furthermore, we explored the antitumor activity of the combination in anti-programmed cell death protein (ligand)-1 (PD-[L]1)-naive microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) pan tumors, and anti-PD-(L)1-refractory melanoma and hepatocellular carcinoma (HCC). CS1002 in combination with CS1003 had manageable safety profile across a broad dosing range and showed promising antitumor activities across CS1002 dose levels when combined with CS1003. This supports further assessment of CS1002 in combination with CS1003 for the treatment of solid tumors.

P3, N=534, Active, not recruiting, CStone Pharmaceuticals | Trial completion date: Jun 2023 --> Jun 2025 | Trial primary completion date: Jun 2023 --> Jun 2025

The antitumor activity of CS1003 + LEN combination as 1L treatment in Chinese pts with uHCC remains encouraging and durable through a longer follow-up period, and the safety profile is well tolerated and manageable. The PFS is longer and the ORR is higher compared to the data previously reported, which support further development as a combination treatment for improving outcomes in uHCC pts. The ongoing multi-regional, double-blinded, randomized, placebo-controlled, phase 3 trial (CS1003-305, NCT04194775) is currently recruiting and will further evaluate adding CS1003 to LEN as a 1L treatment in uHCC.

Multiple options are available for the treatment of metastatic HCC including atezolizumab, bevacizumab, nivolumab, pembrolizumab, ipilimumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab. Furthermore, other checkpoint inhibitors are being evaluated including durvalumab, tremelimumab, CS1003, sintilimab and camrelizumab. In this review article, we focus on the landscape of different immunotherapy strategies in the management of HCC and the combination of checkpoint inhibitors antibodies with antiangiogenics. In addition, we will address the limitation of cell therapies in advanced HCC and current strategies to improve efficacy.

Funding: CStone Pharmaceuticals (Su Zhou) Co., Ltd. Clinical trial identification: NCT03809767.

CS1003 blocked PD-1 interaction with its ligands, dose-dependently enhanced T cell proliferation and secretion of cytokines (IL-2 and IFN-γ) to the levels comparable to the reference antibody pembrolizumab. Pharmacokinetics (PK) study revealed a linear PK profile within the dose range of 2-18 mg/kg following single intravenous administration in cynomolgus monkey. These data provide a comprehensive preclinical characterization of CS1003 that supports its clinical development for cancer immunotherapy.