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PRELIMINARY SAFETY, EFFICACY AND PHARMACOKINETICS (PK) RESULTS OF KN026 (A HER2 BISPECIFIC ANTIBODY) MONOTHERAPY IN ADVANCED SOLID TUMOR PATIENTS WITH HER2 EXPRESSION
BACKGROUND: KN026 is a novel bispecific antibody and simultaneously binds to two distinct HER2 epitopes which are the same domains as trastuzumab (ECD4) and pertuzumab (ECD2). It showed higher maximal binding than monospecific HER2 antibodies and favors that crosslinking of HER2 receptors could enha...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10370438/ http://dx.doi.org/10.1093/abt/tbad014.006 |
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author | Xu, Ting Lv, Yuan Sun, Jie Peng, Jianjian Li, Jingqiu Li, Xionghui Guo, Baohong |
author_facet | Xu, Ting Lv, Yuan Sun, Jie Peng, Jianjian Li, Jingqiu Li, Xionghui Guo, Baohong |
author_sort | Xu, Ting |
collection | PubMed |
description | BACKGROUND: KN026 is a novel bispecific antibody and simultaneously binds to two distinct HER2 epitopes which are the same domains as trastuzumab (ECD4) and pertuzumab (ECD2). It showed higher maximal binding than monospecific HER2 antibodies and favors that crosslinking of HER2 receptors could enhance the receptors internalization in preclinical studies. KN026 significantly inhibited the growth of human cancer cell lines and demonstrated obviously antitumor activity against different xenografts models. The encouraging efficacy and manageable safety of KN026 were reported in Chinese cancer patients (pts) with HER2 expression and ph3 study is ongoing in gastric cancer (NCT05427383). METHODS: The late line solid tumor pts with HER2 expression who were refractory to or ineligible for standard therapy were recruited in this phase I dose-escalation study in US (NCT03847168). All pts intravenously received KN026 monotherapy at ascending dose of 10 mg/kg (QW), 20 mg/kg (Q2W) or 30 mg/kg (Q3W). Dose escalation followed standard “3 + 3” design. Expansion was determined by Safety Monitoring Committee (SMC). The primary objectives were to evaluate safety and tolerability of KN026 and determine the MTD and/or RP2D. Safety was evaluated according to CTCAE v 5.0, and efficacy was assessed by RECIST 1.1. RESULTS: A total of 22 pts with median 4 lines prior treatment were enrolled, including 5 breast cancer pts, 3 gastric or gastroesophageal junction cancer pts and 14 other solid tumor pts. 21 pts were included in the efficacy analysis. The median age was 57.0 (47-79), with 8 males and 14 females and most of pts were Caucasian (72.7%). 3, 10 (7 at expansion phase), and 9 (6 at expansion phase) pts were treated at 10mg/kg, 20mg/kg, 30mg/kg, respectively. No dose-limiting toxicities (DLTs) were observed and MTD wasn’t reached. 20 pts (90.9%) occurred TRAEs and the common (≥20%) TRAEs were diarrhea (45.5%), fatigue (40.9%), chills (36.4%) and nausea (27.3%). Most of TRAE were Gr 1-2, and only 3 pts (13.6%) experienced ≥ Gr3 TRAE (anemia, fatigue and pneumonitis) without treatment discontinuation and death caused by KN026. 4 of 21 pts (1 at 10mg/kg, 2 at 20 mg/kg, 1 at 30mg/kg) achieved objective response (ORR 19.0%, 95% CI: 5.5, 41.9), and DCR was 61.9% (95% CI: 38.4, 81.9). The exposure of KN026 and T(1/2) increased with dose escalation. Accumulation ratio of C(max) and AUC was 1.18-1.42 and 1.14-1.71. The concentration of Ctrough was over 20μM at all dose levels. There was only one positive ADA sample in 20 mg/kg group in C1D1. And the RP2D was 20mg/kg Q2W or 30mg/kg Q3W. CONCLUSION: KN026 was well tolerated and showed the promising anti-tumor activity in US pts with HER2 expression. Besides, KN026 has well pharmacokinetic profile and favorable immunogenicity. |
format | Online Article Text |
id | pubmed-10370438 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-103704382023-07-27 PRELIMINARY SAFETY, EFFICACY AND PHARMACOKINETICS (PK) RESULTS OF KN026 (A HER2 BISPECIFIC ANTIBODY) MONOTHERAPY IN ADVANCED SOLID TUMOR PATIENTS WITH HER2 EXPRESSION Xu, Ting Lv, Yuan Sun, Jie Peng, Jianjian Li, Jingqiu Li, Xionghui Guo, Baohong Antib Ther Abstract BACKGROUND: KN026 is a novel bispecific antibody and simultaneously binds to two distinct HER2 epitopes which are the same domains as trastuzumab (ECD4) and pertuzumab (ECD2). It showed higher maximal binding than monospecific HER2 antibodies and favors that crosslinking of HER2 receptors could enhance the receptors internalization in preclinical studies. KN026 significantly inhibited the growth of human cancer cell lines and demonstrated obviously antitumor activity against different xenografts models. The encouraging efficacy and manageable safety of KN026 were reported in Chinese cancer patients (pts) with HER2 expression and ph3 study is ongoing in gastric cancer (NCT05427383). METHODS: The late line solid tumor pts with HER2 expression who were refractory to or ineligible for standard therapy were recruited in this phase I dose-escalation study in US (NCT03847168). All pts intravenously received KN026 monotherapy at ascending dose of 10 mg/kg (QW), 20 mg/kg (Q2W) or 30 mg/kg (Q3W). Dose escalation followed standard “3 + 3” design. Expansion was determined by Safety Monitoring Committee (SMC). The primary objectives were to evaluate safety and tolerability of KN026 and determine the MTD and/or RP2D. Safety was evaluated according to CTCAE v 5.0, and efficacy was assessed by RECIST 1.1. RESULTS: A total of 22 pts with median 4 lines prior treatment were enrolled, including 5 breast cancer pts, 3 gastric or gastroesophageal junction cancer pts and 14 other solid tumor pts. 21 pts were included in the efficacy analysis. The median age was 57.0 (47-79), with 8 males and 14 females and most of pts were Caucasian (72.7%). 3, 10 (7 at expansion phase), and 9 (6 at expansion phase) pts were treated at 10mg/kg, 20mg/kg, 30mg/kg, respectively. No dose-limiting toxicities (DLTs) were observed and MTD wasn’t reached. 20 pts (90.9%) occurred TRAEs and the common (≥20%) TRAEs were diarrhea (45.5%), fatigue (40.9%), chills (36.4%) and nausea (27.3%). Most of TRAE were Gr 1-2, and only 3 pts (13.6%) experienced ≥ Gr3 TRAE (anemia, fatigue and pneumonitis) without treatment discontinuation and death caused by KN026. 4 of 21 pts (1 at 10mg/kg, 2 at 20 mg/kg, 1 at 30mg/kg) achieved objective response (ORR 19.0%, 95% CI: 5.5, 41.9), and DCR was 61.9% (95% CI: 38.4, 81.9). The exposure of KN026 and T(1/2) increased with dose escalation. Accumulation ratio of C(max) and AUC was 1.18-1.42 and 1.14-1.71. The concentration of Ctrough was over 20μM at all dose levels. There was only one positive ADA sample in 20 mg/kg group in C1D1. And the RP2D was 20mg/kg Q2W or 30mg/kg Q3W. CONCLUSION: KN026 was well tolerated and showed the promising anti-tumor activity in US pts with HER2 expression. Besides, KN026 has well pharmacokinetic profile and favorable immunogenicity. Oxford University Press 2023-07-24 /pmc/articles/PMC10370438/ http://dx.doi.org/10.1093/abt/tbad014.006 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Antibody Therapeutics. All rights reserved. For Permissions, please email: journals.permissions@oup.com https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Abstract Xu, Ting Lv, Yuan Sun, Jie Peng, Jianjian Li, Jingqiu Li, Xionghui Guo, Baohong PRELIMINARY SAFETY, EFFICACY AND PHARMACOKINETICS (PK) RESULTS OF KN026 (A HER2 BISPECIFIC ANTIBODY) MONOTHERAPY IN ADVANCED SOLID TUMOR PATIENTS WITH HER2 EXPRESSION |
title | PRELIMINARY SAFETY, EFFICACY AND PHARMACOKINETICS (PK) RESULTS OF KN026 (A HER2 BISPECIFIC ANTIBODY) MONOTHERAPY IN ADVANCED SOLID TUMOR PATIENTS WITH HER2 EXPRESSION |
title_full | PRELIMINARY SAFETY, EFFICACY AND PHARMACOKINETICS (PK) RESULTS OF KN026 (A HER2 BISPECIFIC ANTIBODY) MONOTHERAPY IN ADVANCED SOLID TUMOR PATIENTS WITH HER2 EXPRESSION |
title_fullStr | PRELIMINARY SAFETY, EFFICACY AND PHARMACOKINETICS (PK) RESULTS OF KN026 (A HER2 BISPECIFIC ANTIBODY) MONOTHERAPY IN ADVANCED SOLID TUMOR PATIENTS WITH HER2 EXPRESSION |
title_full_unstemmed | PRELIMINARY SAFETY, EFFICACY AND PHARMACOKINETICS (PK) RESULTS OF KN026 (A HER2 BISPECIFIC ANTIBODY) MONOTHERAPY IN ADVANCED SOLID TUMOR PATIENTS WITH HER2 EXPRESSION |
title_short | PRELIMINARY SAFETY, EFFICACY AND PHARMACOKINETICS (PK) RESULTS OF KN026 (A HER2 BISPECIFIC ANTIBODY) MONOTHERAPY IN ADVANCED SOLID TUMOR PATIENTS WITH HER2 EXPRESSION |
title_sort | preliminary safety, efficacy and pharmacokinetics (pk) results of kn026 (a her2 bispecific antibody) monotherapy in advanced solid tumor patients with her2 expression |
topic | Abstract |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10370438/ http://dx.doi.org/10.1093/abt/tbad014.006 |
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