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Phase I trial of KN046, a novel bispecific antibody targeting PD-L1 and CTLA-4 in patients with advanced solid tumors
BACKGROUND: KN046 is a novel bispecific antibody targeting programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). This multicenter phase I trial investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of KN046 in patients with advanced solid tu...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10254625/ https://www.ncbi.nlm.nih.gov/pubmed/37263673 http://dx.doi.org/10.1136/jitc-2022-006654 |
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author | Ma, Yuxiang Xue, Jinhui Zhao, Yuanyuan Zhang, Yang Huang, Yan Yang, Yunpeng Fang, Wenfeng Guo, Ye Li, Qun Ge, Xiaoxiao Sun, Jie Zhang, Bangyong Zhang, Yuhan Xiao, Jinyuan Zhang, Li Zhao, Hongyun |
author_facet | Ma, Yuxiang Xue, Jinhui Zhao, Yuanyuan Zhang, Yang Huang, Yan Yang, Yunpeng Fang, Wenfeng Guo, Ye Li, Qun Ge, Xiaoxiao Sun, Jie Zhang, Bangyong Zhang, Yuhan Xiao, Jinyuan Zhang, Li Zhao, Hongyun |
author_sort | Ma, Yuxiang |
collection | PubMed |
description | BACKGROUND: KN046 is a novel bispecific antibody targeting programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). This multicenter phase I trial investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of KN046 in patients with advanced solid tumors. METHODS: Patients who failed standard treatment were included. KN046 was administered at doses of 1, 3, and 5 mg/kg every 2 weeks (Q2W), 5 mg/kg every 3 weeks (Q3W), and 300 mg Q3W based on the modified toxicity probability interval method in the dose-escalation phase; the recommended dose was used in the expansion phase. Primary objectives were maximum tolerated dose (MTD) and recommended phase II dose (RP2D) in escalation and preliminary efficacy in expansion. Secondary objectives included PK, pharmacodynamics, safety, and tolerability of KN046. We also explored biomarkers based on PD-L1 expression, multiplex immunofluorescence (mIF) staining, and RNAseq-derived nCounter platform. RESULTS: Totally, 100 eligible patients were enrolled, including 59 with nasopharyngeal carcinoma (NPC), 36 with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), and those with other advanced solid tumors. The most common treatment-related adverse events (TRAEs) were rash (33.0%), pruritus (31.0%), and fatigue (20.0%). Grade ≥3 TRAEs were observed in 14.0% of participants. No dose-limiting toxicity occurred in the dose-escalation phase, and the MTD was not reached. The RP2D was determined as 5 mg/kg Q2W according to the pharmacokinetic–pharmacodynamic model, the preliminary exposure–response analysis, and the overall safety profile. Among 88 efficacy-evaluable participants, the objective response rate (ORR) was 12.5%, and the median duration of response was 16.6 months. In the NPC subgroup, the ORR was 15.4%, and the median overall survival (OS) was 24.7 (95% CI 16.3 to not estimable) months. In the EGFR-mutant NSCLC subgroup, the ORR was 6.3%. mIF analysis results showed patients with high CD8 expression showed longer median OS (27.1 vs 9.2 months, p=0.02); better prognosis was observed in patients with high CD8 and PD-L1 expression. CONCLUSIONS: KN046 was well tolerated and showed promising antitumor efficacy in advanced solid tumors, especially in patients with NPC. The combination of both CD8 and PD-L1 expression improved the prediction of KN046 response. TRIAL REGISTRATION NUMBERS: NCT03733951. |
format | Online Article Text |
id | pubmed-10254625 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-102546252023-06-10 Phase I trial of KN046, a novel bispecific antibody targeting PD-L1 and CTLA-4 in patients with advanced solid tumors Ma, Yuxiang Xue, Jinhui Zhao, Yuanyuan Zhang, Yang Huang, Yan Yang, Yunpeng Fang, Wenfeng Guo, Ye Li, Qun Ge, Xiaoxiao Sun, Jie Zhang, Bangyong Zhang, Yuhan Xiao, Jinyuan Zhang, Li Zhao, Hongyun J Immunother Cancer Clinical/Translational Cancer Immunotherapy BACKGROUND: KN046 is a novel bispecific antibody targeting programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). This multicenter phase I trial investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of KN046 in patients with advanced solid tumors. METHODS: Patients who failed standard treatment were included. KN046 was administered at doses of 1, 3, and 5 mg/kg every 2 weeks (Q2W), 5 mg/kg every 3 weeks (Q3W), and 300 mg Q3W based on the modified toxicity probability interval method in the dose-escalation phase; the recommended dose was used in the expansion phase. Primary objectives were maximum tolerated dose (MTD) and recommended phase II dose (RP2D) in escalation and preliminary efficacy in expansion. Secondary objectives included PK, pharmacodynamics, safety, and tolerability of KN046. We also explored biomarkers based on PD-L1 expression, multiplex immunofluorescence (mIF) staining, and RNAseq-derived nCounter platform. RESULTS: Totally, 100 eligible patients were enrolled, including 59 with nasopharyngeal carcinoma (NPC), 36 with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), and those with other advanced solid tumors. The most common treatment-related adverse events (TRAEs) were rash (33.0%), pruritus (31.0%), and fatigue (20.0%). Grade ≥3 TRAEs were observed in 14.0% of participants. No dose-limiting toxicity occurred in the dose-escalation phase, and the MTD was not reached. The RP2D was determined as 5 mg/kg Q2W according to the pharmacokinetic–pharmacodynamic model, the preliminary exposure–response analysis, and the overall safety profile. Among 88 efficacy-evaluable participants, the objective response rate (ORR) was 12.5%, and the median duration of response was 16.6 months. In the NPC subgroup, the ORR was 15.4%, and the median overall survival (OS) was 24.7 (95% CI 16.3 to not estimable) months. In the EGFR-mutant NSCLC subgroup, the ORR was 6.3%. mIF analysis results showed patients with high CD8 expression showed longer median OS (27.1 vs 9.2 months, p=0.02); better prognosis was observed in patients with high CD8 and PD-L1 expression. CONCLUSIONS: KN046 was well tolerated and showed promising antitumor efficacy in advanced solid tumors, especially in patients with NPC. The combination of both CD8 and PD-L1 expression improved the prediction of KN046 response. TRIAL REGISTRATION NUMBERS: NCT03733951. BMJ Publishing Group 2023-06-01 /pmc/articles/PMC10254625/ /pubmed/37263673 http://dx.doi.org/10.1136/jitc-2022-006654 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Clinical/Translational Cancer Immunotherapy Ma, Yuxiang Xue, Jinhui Zhao, Yuanyuan Zhang, Yang Huang, Yan Yang, Yunpeng Fang, Wenfeng Guo, Ye Li, Qun Ge, Xiaoxiao Sun, Jie Zhang, Bangyong Zhang, Yuhan Xiao, Jinyuan Zhang, Li Zhao, Hongyun Phase I trial of KN046, a novel bispecific antibody targeting PD-L1 and CTLA-4 in patients with advanced solid tumors |
title | Phase I trial of KN046, a novel bispecific antibody targeting PD-L1 and CTLA-4 in patients with advanced solid tumors |
title_full | Phase I trial of KN046, a novel bispecific antibody targeting PD-L1 and CTLA-4 in patients with advanced solid tumors |
title_fullStr | Phase I trial of KN046, a novel bispecific antibody targeting PD-L1 and CTLA-4 in patients with advanced solid tumors |
title_full_unstemmed | Phase I trial of KN046, a novel bispecific antibody targeting PD-L1 and CTLA-4 in patients with advanced solid tumors |
title_short | Phase I trial of KN046, a novel bispecific antibody targeting PD-L1 and CTLA-4 in patients with advanced solid tumors |
title_sort | phase i trial of kn046, a novel bispecific antibody targeting pd-l1 and ctla-4 in patients with advanced solid tumors |
topic | Clinical/Translational Cancer Immunotherapy |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10254625/ https://www.ncbi.nlm.nih.gov/pubmed/37263673 http://dx.doi.org/10.1136/jitc-2022-006654 |
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