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Background: Anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody may enhance the efficacy of programmed cell death 1 (PD-1) inhibitor. QL1706 is a novel dual immune checkpoint blockade containing a mixture of anti-PD-1 IgG4 and anti-CTLA4 IgG1 antibodies produced by a single cell line. Here we reported the pooled data of the phase 1a/b trial. Methods: In the phase 1a dose escalation and expansion study (NCT04296994), dose escalation involved six levels (0.3, 1.0, 3.0, 5.0, 7.5, and 10.0 mg/kg, intravenously q3w) using an accelerated 3+3 design. The dose expansion cohorts received selected doses. In phase 1b (NCT05171790), patients with advanced solid tumors were given intravenous QL1706 5.0 mg/kg q3w according to the data in phase 1a. The primary objectives were to define the safety, tolerability, and recommended phase 2 dose (RP2D) of QL1706 in phase 1a, and to evaluate the preliminary efficacy in phase 1b. Results: As of Sept 30, 2021, totally 518 patients with multiple types of advanced cancer (99 in phase 1a and 419 in phase 1b) were enrolled, including lung cancer (175 [33.8%]), nasopharyngeal cancer (134 [25.9%]), cervical cancer (58 [11.2%]), liver cancer (34 [6.6%]), colorectal cancer (27 [5.2%]), and kidney cancer (18 [3.5%]), etc. 494 [95.4%] were previously treated, and 182 (35.1%) received previous immunotherapy. Two patients at 10 mg/kg suffered dose-limiting toxicity. The RP2D of QL1706 was defined as 5.0 mg/kg. After a median follow-up of 6.7 months, treatment-related adverse events (TRAEs) were observed in 374 patients (72.2%). 70 (13.5%) experienced grade ≥3 TRAEs. The most common TRAEs were rash (91 [17.6%]), pruritus (65 [12.5%]), hypothyroidism (60 [11.6%]), AST increased (48 [9.3%]), and hyperthyroidism (46 [8.9%]). The TRAEs that led to drug interruption and drug discontinuation were observed in 67 (12.9%) and 31 patients (6.0%), respectively. The immune-related TRAEs and treatment-related serious adverse events were observed in 223 (43.1%) and 59 patients (11.4%), respectively. 79 (16.9%) patients had a confirmed objective response, 237 (50.6%) patients had a confirmed disease control. Conclusion: QL1706 had a manageable safety profile. QL1706 still showed promising anti-tumor activity although over one-third of the patients received prior immunotherapy. These results supported further investigation of QL1706 for advanced solid tumors. Citation Format: Li Zhang, Hongyun Zhao, Yan Huang, Wenfeng Fang, Yuxiang Ma, Yang Zhang, Xiaoli Wei, Yanhua Yang, Wei Yang, Furong Liu, Zuan Lin, Jianing Li, Qianwen Liu, Benyan Zou, Kunlun Liao, qun Liu. The safety summary of the phase 1a/b trial of QL1706, a novel dual immune checkpoint blockade containing a mixture of anti-PD1 IgG4 and anti-CTLA4 IgG1 antibodies, for advanced malignant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT520.

Purpose: QL1706 (PSB205) is a novel biological entity consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1) that are expressed together in a fixed ratio from the same production cell line and manufactured as one product. In this Phase I, multiple-dose study (NCT04296994), the tolerability, safety, pharmacokinetics, and preliminary clinical activity of QL1706 in patients with advanced malignant tumors were evaluated. Experimental Design: Dose-escalation was based on an accelerated 3 + 3 design for doses of QL1706 from 0.3 to 10 mg/kg that was administered intravenously every 3 weeks (q3w). The expansion stage was carried out in selected dose cohorts. The primary objective of this study was to define the safety and tolerability of QL1706, and the recommended Phase 2 dose (RP2D) of QL1706 in patients that have advanced malignant tumors. Result: The trial is ongoing. By December 2020, 47 patients with solid tumors were enrolled, 16 patients in dose-escalation and 31 patients in expansion cohorts, respectively. Nineteen (40.4%) patients had previous immunotherapy, and the median lines of previous systemic therapy were 2 (0-5). QL1706 demonstrated a well-tolerated safety profile in the doses from 0.3 to 5 mg/kg. Two patients at 10 mg/kg experienced a dose-limiting toxicity, respectively. Due to the unique design, the clearance rate of anti-CTLA-4 antibody was faster than that of anti-PD-1 component of QL1706 in all dosage groups, and the elimination half-lives (t1/2) of anti-CTLA-4 antibody and anti-PD-1 component following single-dose administration were 4~5 days and 6~9 days, respectively. As a result, a much-reduced level of exposure was achieved for the anti-CTLA-4 antibody compared to the anti-PD-1 antibody. This unique feature may have contributed to the good overall safety profile of the product. Treatment related adverse events (TRAEs) occurred in 66.0% (31/47) of patients. Five (10.6%) patients in the 5 mg/kg and 10 mg/kg groups experienced grade 3 or higher TRAEs. The most common (≥10%) TRAEs were pruritus [23.4% (11/47)], rash [21.3% (10/47)], AST increased [14.9% (7/47)], fatigue [12.8% (6/47)], hyperthyroidism [10.6% (5/47)], and hypothyroidism [10.6% (5/47)]. Partial responses were observed in 10 out of 35 (28.6%) evaluated patients and the overall DCR was 48.6% (17/35) in the mixed population. The regime of 5 mg/kg q3w was recommended as the RP2D based on the overall assessment of tolerability, pharmacokinetics, and clinical activity. Significance: QL1706, a dual immune checkpoint pathways (PD-1 and CTLA-4) blockade product evaluated in this phase I dose-escalation and expansion study, showed an acceptable safety profile and early evidence of clinical activity in advanced solid malignancies. Citation Format: Li Zhang, Hongyun Zhao, Yuxiang Ma, Yan Huang, Yang Zhang, Xiaoli Wei, Yanhua Yang, Wei Yang, Furong Liu, Zhuan Lin, Jianing Li, Wenfeng Fang, Qianwen Liu, Benyan Zou, Kunlun Liao, Liuqun Liu. Development and preliminary clinical activity of QL1706 (PSB205), a combination of anti-PD1 and anti-CTLA-4 antibodies manufactured together as a single product [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT119.