A phase I dose-escalation and expansion study of HBM4003, an anti-CTLA-4 heavy chain only monoclonal antibody, in patients with advanced solid tumors.
Authors: Gu Shanzhi , de Souza Paul L. , Shi Yuankai , Han Weiqing , Luo SuXia , Chen Jing , Day Daphne , Frentzas Sophia , Park John J. , Shao Guoliang , Wu Shikai , Fang Meiyu , Haydon Andrew Mark , Sun Sanyuan , Lei Kaijian , Ding Luyin , Zuo Rui , Gan Xin , Zhao Yuansheng , Chen Xiaoxiang 
Published: June 2022

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Background: HBM4003 is a fully human heavy chain only monoclonal antibody (HCAb) to CTLA-4, which has been engineered to deplete Treg cells by enhanced antibody-dependent cellular cytotoxicity (ADCC) activity. In the Phase 1 dose escalation part, HBM4003 showed favorable safety and efficacy profile in patients (pts) with advanced solid tumors. Here, we present the updated data from the dose escalation part and most recent safety and clinical activity data from three expansion cohorts of pts with advanced hepatocellular carcinoma (HCC), melanoma, and renal cell carcinoma (RCC). Methods: In the dose-escalation part, pts were enrolled into 3 dose levels (DL): 0.3mg/kg QW (28-day cycle), 0.45mg/kg Q3W (21-day cycle), and 0.6mg/kg Q3W (21-day cycle). In the dose-expansion part, pts with advanced HCC, melanoma, and RCC received 0.45 mg/kg Q3W (21-day cycle). Tumor measurements were performed every 6 weeks for up to 12 months and subsequently every 12 weeks per RECIST v1.1. Results: In total 60 pts were included for this analysis, including 24 pts with advanced solid tumors in the dose escalation part and 36 pts in the dose expansion part: 18 pts with HCC, 4 pts with melanoma, and 14 pts with RCC, from 12 sites in mainland China, 5 sites in Australia, and 1 site in Hong Kong. 46 pts (77%) received ≥ 2 lines of previous systemic therapies and 37 pts (62%) received previous PD-1/PD-L1 treatment. For the HCC cohort, 19 pts were treated in dose-escalation (1 pt, 0.45 mg/kg Q3W) and dose-expansion parts. All 19 pts received previous PD-1/PD-L1 therapy. 12 pts were evaluable for efficacy. Two had stable disease (SD), 2 pts had partial response (PR) as best response. For 12 evaluable pts, ORR was 16.7% and disease control rate (DCR) was 33.3%. For the RCC cohort, 19 pts were treated in dose-escalation and dose-expansion parts; 18 pts were evaluable for efficacy. Eight had SD as best response; the DCR was 44.4%. Overall, the most common treatment-related adverse event (TRAE) (incidence ≥ 10%) of all grades was rash (16 [26.7%] pts). At the 0.45 mg/kg Q3W DL, the most common TRAE of all grades was hepatic function abnormalities (12 [27.9%] pts) and rash (12 [27.9%] pts). 30 (69.8%) pts reported Gr 1 or 2 TRAEs. Gr ≥3 TRAEs occurred in 4 (9.3%) pts. 1 pt reported Gr 4 TRAE: blood creatine phosphokinase increased. No Gr 5 TRAE was reported. TRAE leading to discontinuation occurred in 4 pts. In mouse model, only tumor infiltrating lymphocytes Treg was depleted upon HBM4003 treatment while no Treg change in blood and spleen. In pts, Treg depletion was observed only in tumor tissue on day 21 post dosing. Overall, HBM4003 demonstrated dose proportional pharmacokinetics and low immunogenicity. Conclusions: HBM4003 showed a favorable safety profile, promising antitumor activity and intratumoral Treg depletion in pts with advanced solid tumors at the 0.45 mg/kg Q3W DL. Clinical trial information: NCT04135261.