Toripalimab in combination with HBM4003, an anti-CTLA-4 heavy chain-only antibody, in advanced melanoma and other solid tumors: an open-label phase I trial

Abstract

Background: HBM4003 is a novel anti-CTLA-4 heavy chain-only antibody, designed to enhance Treg ablation and antibody-dependent cell-mediated cytotoxicity while ensuring a manageable safety profile. This phase I trial investigated the safety, pharmacokinetics, immunogenicity and preliminary efficacy of HBM4003 plus with anti-PD-1 antibody toripalimab in patients with advanced solid tumors, especially focusing on melanoma.

Methods: The multicenter, open-label phase I trial was divided into two parts: dose-escalation phase (part 1) and dose-expansion phase (part 2). In part 1, HBM4003 was administered at doses of 0.03, 0.1, 0.3 mg/kg in combination with toripalimab with fixed dosage of 240 mg every 3 weeks. The recommended phase II dose (RP2D) was used in the expansion phase. Primary endpoints were safety and RP2D in part 1 and objective response rate (ORR) in part 2. Biomarkers based on cytokines and multiplex immunofluorescence staining were explored.

Results: A total of 40 patients received study treatment, including 36 patients treated with RP2D of HBM4003 0.3 mg/kg plus toripalimab 240 mg every 3 week. 36 participants (90.0%) experienced at least one treatment-related adverse event (TRAE), of which 10 (25.0%) patients experienced grade ≥3 TRAEs and 5 (12.5%) experienced immune-mediated adverse events (irAEs) with maximum severity of grade 3. No grade 4 or 5 irAEs occurred. Efficacy analysis set included 32 melanoma patients treated with RP2D and with available post-baseline imaging data. The ORRs of anti-PD-1/PD-L1 treatment-naïve subgroup and anti-PD-1/PD-L1 treatment-failed subgroup were 33.3% and 5.9%, respectively. In mucosal melanoma, the ORR of the two subgroups were 40.0% and 10.0%, respectively. Baseline high Treg/CD4+ratio in the tumor serves as an independent predictive factor for the efficacy of immunotherapy.

Conclusions: HBM4003 0.3 mg/kg plus toripalimab 240 mg every 3 week demonstrated manageable safety in solid tumors and no new safety signal. Limited data demonstrated promising antitumor activity, especially in PD-1 treatment-naïve mucosal melanoma.

Trial registration number: NCT04727164.

Keywords: Immunotherapy; Pharmacokinetics - PK; Solid tumor.

Figure 1. Study flow chart. IMGS, immunogenicity set; MTD, maximum tolerated dose; PKS, pharmacokinetic set; RP2D, recommended phase II dose.

Figure 2. Antitumor activity of HBM4003 combined with toripalimab. (A) Best percentage change from baseline in the sum of the longest diameters of target lesions in patients who had at least one assessable postbaseline tumor assessment (efficacy analysis set). (B) Swimmer plots of tumor responses in efficacy analysis set. PD, progressive disease; PR, partial response; SD, stable disease.

Figure 3. Effect of HBM4003/toripalimab on circulating T-cells. Quantification of peripheral Treg cells (A), Ki67+CD4+ T cells (B), and Ki67+CD8+ (C) by flow cytometry. (D) Representative multiplex immunofluorescence of tumor immune microenvironment before and 6 weeks after HBM4003/toripalimab treatment.

Figure 4. T-cell infiltration in association with response to HBM4003/toripalimab. (A) Baseline tumor-infiltrating T-cell density in patients with ORR and non-responders. (B) Baseline intratumoral Treg/CD4+ratio in patients with ORR and non-responders. (C) Kaplan-Meier plots of PFS stratified by quartile Treg/CD4+ratio. ORR, overall response rate; PFS, progress-free survival.