TQB2223 in Combination with Penpulimab in Patients with Relapsed or Refractory Lymphoma: Primary Analysis of an Open-Label Phase I Study

Introduction: Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor that downregulates T-cell activity and plays a role in regulating T-cell function. TQB2223 (Sym022) is a novel LAG-3 monoclonal antibody. Penpulimab is a programmed cell death protein 1(PD-1) inhibitor. Dual blockade of PD-1 and LAG-3 had demonstrated antitumor activity in patients with advanced melanoma. This is an open-label, phase I study investigated TQB2223 in combination with penpulimab to treat advanced tumors (NCT05894421). Here, we report the primary analysis results in patients with relapsed or refractory (RR) lymphoma. Methods: The study included a dose-escalation cohort and a dose-expansion cohort. Aged ≥18 years old, ECOG PS score of 0~1, and patients with advanced tumors who had failed standard treatment or had no effective treatment were enrolled. Eligible patients received escalating doses of TQB2223 at 5 mg/kg, 10 mg/kg and 600 mg in combination with a fixed-dose of 200 mg penpulimab. They were administered once every three weeks (Q3W) in a 21 day-cycle. A “3 + 3” design was used in the dose-escalation cohort. Treatment continued until progressive disease or unacceptable toxicity. The primary outcomes were the recommended Phase 2 dose (RP2D) and preliminary antitumor activity in both cohorts. Secondary endpoints were safety and pharmacokinetics (PK). Results: As of June 20, 2024, 21 patients with RR lymphoma were enrolled, including 14 with Hodgkin lymphoma (HL), 2 with primary mediastinal large B cell lymphoma (PMBCL), 2 with diffuse large B-cell lymphoma (DLBCL), 2 with NK/T cell lymphoma and 1 with eczema tuberculatum. The median age was 35 years, and 13 patients were male. 15 patients had an ECOG PS score of 1. The lugano stage of 11 patients was IV. Median number of prior therapies was 3 (IQR 2-4). Among 14 HL patients, 12 were previously treated with anti-PD-1/L1 and 7 were previously treated with Brentuximab vedotin. The number of patients enrolled was 3 per dose level. No dose limited toxicity (DLT) was found. The most common treatment-emergent adverse events (TEAEs) were hypothyroidism (42.86%), hyperthyroidism (28.57%), hypertriglyceridemia (28.57%), ALT increased (28.57%), AST increased (19.05%), lymphocyte count decreased (14.29%), hypercholesterolemia (14.29%), hyperuricemia (14.29%), pyrexia (14.29%), rash (14.29%), most of TEAEs was grade 1~2. Grade ≥3 TEAEs were reported in 2 (9.52%) patients, one with blood count decreased and one with pneumonia. There was no death happened. After dosing, the AUC increased proportionally from 5 mg/kg to 10 mg/kg. The elimination of TQB2223 was slow with t1/2 of 147 ~ 351 h. There was no accumulation with multiple dosing. The 600 mg dose level had similar pharmacokinetic parameters and receptor occupancy (RO) as the 10 mg/kg dose level. On the basis of tolerability, PK and RO, TQB2223 injection 600mg combination with penpulimab 200mg Q3W was identified as RP2D. With a median follow-up of 7 months for all lyphoma, the overall response rate (ORR) was 52.38%, the disease control rate (DCR) was 80.95%, the median progression free survival (mPFS) and median duration of response (mDOR) were not reached (NR), and 6-months PFS and DOR rate were 88.54% and 100%, respectively. With a median follow-up of 2.6 months for 12 HL patients previously treated with anti-PD-1/L1, ORR was 50%, DCR was 83.33%, mPFS and mDOR were both NR, and 6-months PFS rate were 100%. ORR was 100% in 2 patients with PMBCL. Conclusions: TQB2223 in combination with penpulimab was generally safe, well-tolerated and demonstrated encouraging efficacy in patients with lymphoma, especially in patients with Hodgkin lymphoma who has received extensive prior treatments including anti-PD-1/L1. A complex of TQB2223 and penpulimab was prepared and more clinical studies were planned.