A phase I open-label, dose escalation of YH003, an anti-CD40 monoclonal antibody, in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors

2603 Background: YH003, a recombinant, humanized agonistic anti-CD40 IgG2 monoclonal antibody (mAb) specifically recognizes and agonizes CD40 on the antigen-presenting cells to enhance immune responses. Preclinical data have shown potent anti-cancer activity when combined with anti-PD-1 antibodies. Methods: This is an ongoing phase 1 dose-escalation study conducted in Australia using an accelerated "3+3" design. Patients (pts) with advanced solid tumors receive YH003 by IV administration Q3W as monotherapy at 0.03 to 3.0 mg/kg for the first cycle (21 days) then in combination with Toripalimab at 240 mg Q3W for the 4 subsequent cycles. Treatment continuation beyond cycle 4 is possible if subject is deriving an ongoing clinic benefit. The safety, tolerability and preliminary efficacy data will be analyzed. Results: Between 29 Jul 2020 and 30 Dec 2021, a total of 20 patients with various advanced solid tumors were enrolled including 0.03 mg/kg (n = 3), 0.1 mg/kg (n = 3), 0.3 mg/kg (n = 3), 1.0 mg/kg (n = 8) and 3.0 mg/kg (n = 3). The median age was 60 years (range 33-75). Baseline ECOG scores were 0 (13 pts) and 1 (7 pts). 8 pts had received prior immunotherapy (anti-PD-1/PD-L1 or anti-PD-1+CTLA-4mAb). Dose escalation has been completed and only one dose-limiting toxicity relating to YH003 was observed at 1.0 mg/kg (grade 3 transaminitis). The maximum tolerated dose (MTD) was not reached. 13 (65%) pts experienced any grade treatment related adverse events (TRAEs). The most common (≥ 10%) TRAEs were infusion reaction, pyrexia, fatigue, nausea, diarrhea, transaminitis. Most TRAEs were grade 1 or 2. Only 3 (15.0%) pts experienced Grade 3 TRAEs including one each of neutropenia (YH003 0.3 mg/kg), transaminitis (YH003 1.0 mg/kg) and elevated lipase (Toripalimab 0.1 mg/kg). Only 2 pts have permanently discontinued treatment due to TRAEs including grade 3 transaminases increased and grade 2 hepatitis. There were no ≥grade 4 TRAEs and drug related serious adverse events (SAEs) were not observed. Among 14 pts assessable for response, the overall response rate (ORR) was 14.3% (2/14) and disease control rate (DCR) was 35.7% (5/14). One partial response (PR) occurred in a pt with anti-PD1/anti-CTLA4 refractory ocular melanoma with liver metastases (YH003 0.1 mg/kg) who continued on treatment for > 1 year. The other PR occurred in a pt with Non-Small Cell Lung Carcinoma (YH003 1.0 mg/kg) who continued on treatment for almost 9 months. Conclusions: YH003 was well tolerated up to 3.0 mg/kg dose levels when combined with Toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04481009.