A phase Ib study of porustobart (HBM4003), an anti-CTLA-4 heavy chain only monoclonal antibody, in combination with toripalimab in patients with hepatocellular carcinoma.
Authors: Zhang Ningning , Qin Shukui , Guo Yabing , Xu Zhongyuan , Zhang Yanqiao , Yao Jun , Gu Shanzhi , Shen Jie , Xu Aibing , Chen Yajin , Xin Guijie , Yu Ge , Wang Gang , Zhang Jingdong , Gardner Humphrey , Ding Luyin , Zhao Shuai , Yang Dian , Lu Wei , Hao Jihui 
Published: June 2023

e16106 Background: Porustobart (HBM4003) is a fully human heavy chain only monoclonal antibody (HCAb) targeting CTLA-4. In addition to blocking the CTLA-4 pathway, it has been shown to effectively deplete intratumoral Treg cells in patients due to its engineered enhanced antibody-dependent cellular cytotoxicity (ADCC). Toripalimab is a recombinant, humanized anti-PD-1 monoclonal antibody. Here we reported the results of a phase Ib study that evaluated porustobart plus toripalimab in patients with hepatocellular carcinoma (HCC). Methods: This is a phase Ib dose expansion study (NCT05149027). Patients with advanced HCC (n=28) received porustobart 0.45 mg/kg plus toripalimab 240 mg every three weeks (Q3W) in both Cohort 1 and Cohort 2. Cohort 1 recruited pts who failed previous anti-VEGFR multikinase inhibitor(s) treatment while have not received anti-PD-(L)1 treatment (n=16); Cohort 2 recruited patients who failed previous anti-PD-(L)1 and anti-VEGF(R) treatments (n=12). The primary endpoint was ORR per RECIST 1.1. Results: As of 9 Dec 2022, median follow-up time was 3.6 months (range: 1-7 months). In Cohort 1, ORR and DCR were 46.7% (95%CI: 21.3-73.4) and 73.3% (95%CI: 44.9-92.2) respectively in 15 patients with post-treatment tumor assessments. In Cohort 2, the ORR and DCR were 9.1% (95%CI: 0.2-41.3) and 54.5% (95%CI: 23.4-83.3) respectively in 11 patients with post-treatment tumor assessments. PFS or OS data were not mature by the cut-off date. Treatment-related adverse events (TRAEs) were reported in 89.3% (25/28) patients, and Grade 3 TRAEs were reported in 39.3% (11/28) patients. The most common (≥20%) TRAEs with all grades by pooled term were liver function test abnormal 46.4% (13/28), thrombocytopenia 42.9% (12/28), pyrexia 32.1% (9/28), asthenia 28.6% (8/28), anemia 25% (7/28), decreased appetite 25% (7/28), blood bilirubin increased 21.4% (6/28), leucopenia 21.4% (6/28), lymphopenia 21.4% (6/28), nausea 21.4% (6/28) and neutropenia 21.4% (6/28). TRAEs leading to permanent discontinuation of porustobart were reported in 3 (10.7%) patients. No Grade 4 or Grade 5 TRAE was reported. Porustobart promoted the clearance of Treg cells and the proliferation of CD4+ T cells and CD8+ T cells in peripheral blood that attested to its MOA. Greater effects were observed in Cohort 1. Taken together with the clinical observations these results suggested that PD-(L)1 inhibitor naïve patients have a larger available pool of effectors to induce anti-tumor activity in the presence of effective Treg depletion. No noticeable differences in PK between Cohort 1 and Cohort 2 were observed. Conclusions: Porustobart 0.45 mg/kg in combination with toripalimab 240mg Q3W showed promising anti-tumor activity in patients with advanced HCC, as well as an acceptable safety profile. Clinical trial information: NCT05149027 .