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Background Several programmed cell death ligand 1 (PD‐L1)/programmed cell death protein 1 (PD‐1) antibodies have been approved for cancer treatment worldwide. Their pharmacokinetic and pharmacodynamic characteristics have been reported mainly in western countries, but related data in Chinese patients are limited. This study was conducted to investigate the safety, efficacy, pharmacokinetics, and pharmacodynamics of an anti‐PD‐1 antibody, toripalimab, in Chinese patients. Methods A single‐center phase I study was conducted in Sun Yat‐sen University Cancer Center. Eligible patients were adults with histologically confirmed, treatment‐refractory, advanced, solitary malignant tumors. Toripalimab was intravenously infused every 2 weeks in dose‐escalating cohorts at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg. The study followed standard 3 + 3 design. Results Between 15th March 2016 and 27th September 2016, 25 patients were enrolled, of whom 3 (12.0%), 7 (28.0%), 6 (24.0%), 6 (24.0%), 3 (12.0%) received 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg toripalimab, respectively. After a median follow‐up time of 5.0 months (range: 1.5‐19.8 months), we observed that the commonest treatment‐related adverse events (TRAEs) were fatigue (64.0%) and rash (24.0%). No grade 3 or higher TRAEs were observed. No dose‐limiting toxicity, treatment‐related serious adverse events (SAEs), or treatment‐related death occurred. Objective response rate was 12.5%. The half‐life of toripalimab was 150‐222 h after a single dose infusion. Most patients, including those from the 0.3 mg/kg group, maintained complete PD‐1 receptor occupancy (> 80%) on activated T cells since receiving the first dose of toripalimab. Conclusions Toripalimab is a promising anti‐PD‐1 antibody, which was well tolerated and demonstrated anti‐tumor activity in treatment‐refractory advanced solitary malignant tumors. Further exploration in various tumors and combination therapies is warranted.

Objectives This phase I study aimed to evaluate the antitumor effect and safety of programmed death‐ligand‐1 (PD‐L1)–targeting autologous chimeric antigen receptor T (CAR‐T) cells for patients with non‐small cell lung cancer (NSCLC). Methods Programmed death‐ligand‐1–specific CAR‐T cells were generated using lentiviral transduction. Four patients with NSCLC were recruited, but only one patient was finally involved. CAR‐T cells were infused on three different days (total dose during therapy, 1 × 106 CAR‐T cells kg−1 body weight). The date on which the patient received the first CAR‐T cell infusion was designated as Day 0. Results Circulating CAR‐T cells accounted for 3.30% of the patient’s peripheral blood T cells detected by FACS analysis during the first follow‐up (Day +29). The chest CT scan showed subtle tumor shrinkage (stable disease). On Day +43, the patient developed pyrexia without any known causes and dyspnoea that rapidly deteriorated to respiratory failure in 3 days. The chest X‐ray and CT scan showed bilateral extensive pulmonary infiltration in addition to the tumor silhouette on the left upper lung. The interleukin (IL)‐6 levels in serum dramatically increased (> 100‐fold). The patient was immediately transferred to the ICU where he received oxygen and intravenous infusions of tocilizumab and methylprednisolone. His symptoms rapidly improved and the pulmonary inflammation gradually resolved. Conclusion The clinical manifestations and test findings for this patient with NSCLC might represent unique clinical manifestations of solitary organ damage secondary to PD‐L1–specific CAR‐T cell therapy. The differential diagnosis, underlying mechanism and prevention and treatment strategies for such complications have also been discussed., We studied the circulating PD‐L1–specific CAR‐T cells in a patient with non‐small cell lung cancer. Circulating PD‐L1–specific CAR‐T cells accounted for 3.30% of the patient’s peripheral blood T cells detected by FACS in the first follow‐up (Day +29), and a chest CT scan showed subtle shrinkage of tumors (stable disease). However, the patient was immediately transferred to the ICU on Day +47 because he deteriorated quickly into respiratory failure in three days. This case might represent a unique clinical manifestation of solitary organ damage secondary to PD‐L1–specific CAR‐T cell therapy.

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.

Puquitinib mesylate (XC-302) is a new multiple-target anticancer inhibitor, which directly suppresses the activity of phosphatidylinositol 3-kinase (PI3K). This study was aimed to develop a sensitive and specific liquid chromatography electrospray ionization tandem mass spectrometry (HPLC–ESI MS/MS) method for the quantification and pharmacokinetic investigation of plasma puquitinib in cancer patients. The analytes of human plasma were prepared by liquid–liquid extraction using methyl-t-butyl ether (MTBE). The plasma analytes were separated by HPLC on Thermo ODS Hypersil column (2.1 × 150 mm; 3 μm) at 25 °C with 5 mmol/L ammonium acetate (A)-acetonitrile (B) (30:70, v/v) as the mobile phase. The total run time was 3.5 min and the elution of puquitinib was at 1.38 min. The detection were analyzed by multiple reaction monitoring (MRM) mode with positive-ion electrospray ionization (ESI) interface using the respective [M + H]+ ions: m/z 318.2 → 261.1 for puquitinib and m/z 258.2 → 121.0 for the internal standard (etofesalamide). The optimized method provided a good linear relation over the concentration range of 1.00-500.00 ng/mL (r = 0.9944) for puquitinib. The intra-day and inter-day precision (relative standard deviation [RSD%]) were within 9.83%, and the intra-day and inter-day accuracy ranged from 91.05 to 103.26%. The lower limit of quantitation (LLOQ) was 1.00 ng/mL. The absolute extraction recovery was on an average of 50.43% for puquitinib and 49.3% for internal standard. In addition, the maximum plasma concentration (Cmax) of puquitinib in dosage from 50 to 800 mg/m2 in the human study showed an increased linearly (57.1–1289.2 ng/mL), which displayed that the concentrations had reached effective levels. The optimized method was successfully applied to the pharmacokinetic profile study in human cancer patient plasma after the oral administration of puquitinib.

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.

The safety and pharmacokinetics assessment of antibodies targeting CD22 (e.g., epratuzumab) have been established in western Caucasian populations, but there are no reports of the effects in Chinese populations. This dose-escalation study examines the safety, pharmacokinetics and biologic effects of multiple doses of anti-CD22 human-murine chimeric monoclonal antibody SM03 in 21 Chinese patients with CD22-positive non-Hodgkin lymphoma. Most of drug-related adverse events (AEs) were mild and reversible. Two patients experienced serious AEs (hemorrhage); one patient had grade 4 neutropenia; one patient had asymptomatic grade III prolongation of activated partial thromboplastin time (APTT). Major AEs included fever (71%), prolongation of APTT (42.8%), leukocytopenia (44.4%), alanine transaminase elevation (28.6%), elevated serum creatinine (23.8%) and injection site skin redness (14.3%). Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. Pharmacokinetic data revealed that mean maximum observed SM03 concentration and mean AUC from time zero to infinity increased in a dose-dependent manner up to 360 mg/m (2) SM03. Mean clearance was similar at doses ≤ 360 mg/m (2) and decreased significantly at dose 480 mg/m (2), supporting saturation of B-cell binding at 360 mg/m (2). Across all dose levels and histologies, one patient achieved partial response at 480 mg/m (2) dose; 14 patients had stable disease as best response and four patients progressed. Overall, SM03 was tolerated at doses ranging from 60-480 mg/m (2) and had potential efficacy in Chinese patients with follicular lymphoma.

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