anbenitamab (KN026)

P1, N=48, Completed, Peking University | Active, not recruiting --> Completed

P1, N=63, Completed, Jiangsu Alphamab Biopharmaceuticals Co., Ltd | Active, not recruiting --> Completed

P2, N=45, Completed, Jiangsu Alphamab Biopharmaceuticals Co., Ltd | Unknown status --> Completed

Fully humanized, IgG1-like antibody binds to two distinct HER2 epitopes, the same domains as trastuzumab and pertuzumab. KN026 in combination with docetaxel is well tolerated and has shown promising clinical benefit as 1L treatment for HER2-positive BC. After 2.5 years follow-up, mPFS was 27.7 mons and the 24-months OS rate was 84.2%, which is very promising. No new safety signals were observed.

P2, N=18, Not yet recruiting, Peking University

P2, N=80, Not yet recruiting, Peking University Cancer Hospital & Institute

Fully humanized, IgG1-like antibody binds to two distinct HER2 epitopes, the same domains as trastuzumab and pertuzumab. After 2 years follow-up, mPFS was 25.4m and the 30-m OS rate was 83.7%, which is very promising. Robustness of efficacy and safety results will be further confirmed in an ongoing randomized phase 3 clinical trial with PTH as control.

Background Trastuzumab (H) plus Pertuzumab (P) combined with cytotoxic agents has been the SOC for Her2+BC across perioperative to late stage. Conclusions KN026 plus docetaxel as neoadjuvant treatment has shown promising clinical benefit and acceptable safety for pts with HER2+ early or LABC. Further validation in a large-scale randomized controlled trial is warranted.

P2, N=4, Terminated, Jiangsu Alphamab Biopharmaceuticals Co., Ltd | N=36 --> 4 | Trial completion date: Dec 2024 --> Mar 2023 | Recruiting --> Terminated | Trial primary completion date: Aug 2023 --> Mar 2023; Difficulty in completing enrollment within the planned time

P3, N=880, Not yet recruiting, Shanghai JMT-Bio Inc.

KN026 combined with KN046 treatment had demonstrated favorable efficacy and safety profile in HER2 positive other solid tumors (non-GC/GEJ and non-BC). Especially very promising efficacy were observed in ≥3 lines HER2 positive CRC. Based on these results, a pivotal study was planned to verify the efficacy and safety of KN026 and KN046 combo.

P1, N=48, Active, not recruiting, Peking University | Recruiting --> Active, not recruiting | N=24 --> 48

Trastuzumab deruxtecan (T-DXd) was approved in December 2022 by the FDA for patients with pretreated HER2- positive breast cancer based on the results of the phase III trial Destiny-Breast03 [3], showing an impressive improvement in progression-free survival with an hazard ratio of 0.33 (95% CI 0.26– 0.43, p-value<0.0001) compared to T-DM1, according to the last update presented at SABCS 2022 [4]...Besides T-DXd and SYD985, other ADCs have been or are under investigation, including, but not limited to, patritumab deruxtecan, disitamab vedotin, XMT-1522, MM-302, MEDI-4276, A166, ARX788, BAT8001 and PF-06804103...Several TKIs have been successfully developed, with tucatinib being the latest to enter clinical practice based on the results of the HER2CLIMB trial [7], with particular importance for patients with brain metastases. Other promising emerging treatments targeting HER2/3 receptors are the HER2- targeted bispecific antibodies (including, among others, KN026 and zanidatamab) and the anti-HER3 monoclonal antibodies; for both classes, clinical trials are ongoing...In the early setting, the first large, randomized, phase III trial testing the addition of an ICI (atezolizumab) to neoadjuvant dual-anti HER2 blockade and chemotherapy was negative [10]...In the phase Ib B-PRECISE-01 study (NCT03767335) the PI3 K inhibitor izorlisib (MEN1611) was tested in combination with trastuzumab ± fulvestrant in patients with HER2-positive/PIK3CA mutated metastatic breast cancer, showing a manageable safety profile with encouraging anti-tumor activity in heavily pre-treated patients (34.1% of partial responses, 2.4% complete response, 56.1% stable disease)...Thus, due to the close crosstalk between ER and HER2 receptor pathways, the simultaneous blockade of both signaling pathways represents a promising approach to prevent the onset of mechanisms of resistance. Large evidence supports the combination of endocrine and anti-HER2 therapies (often as maintenance treatment), while new strategies with novel agents (including novel SERDs, and CDK4/6i) are currently being investigated.

KN026 showed a favourable safety profile and promising anti-tumour activity. Our results support further studies evaluating KN026 and the combination treatment with other active drugs in patients with advanced gastric or gastroesophageal junction cancer having high-level HER2 expression.

The 3-drug combination therapy, trastuzumab, pertuzumab, and taxane chemotherapy is one of the standard treatment options for the first-line treatment of HER2- positive recurrent/metastatic breast cancer. KN026 in combination with docetaxel is well tolerated and has shown promising clinical benefit as a 1L treatment for HER2-positive advanced breast cancer. At data cut-off date (Mar 26, 2022)，median PFS was 19.3 months while 18-month OS rate was 88.3%, which is very encouraging. Efficacy and safety require large-scale phase III studies to verify.

KN026 is a bispecific monoclonal antibody that targets the distinct extra-cellular domains II (Pertuzumab binding site) and IV (Trastuzumab binding site) of HER2. KN026 and docetaxel as neoadjuvant treatment has shown promising clinical benefit for patients with HER2-positive early or locally advanced breast cancer with an acceptable and manageable safety profile. Further validation in a large-scale randomized controlled trial is warranted.

Background: KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes (two different HER2 epitopes shared by trastuzumab and pertuzumab). We identified a subpopulation of CD4-low and CD8-low T cells that may be associated with anti-HER2 resistance. And decreased of this subpopulation of T cells was associated with better ORR of KN046 in combination with KN026 treatment in heavily pretreated advanced HER2+ BC. Baseline CD8+ T/naïve T ratio in tumor is expected to be a predictor of ORR as well.

Conclusions KN026 combined with KN046 treatment had demonstrated outstanding efficacy and manageable safety in HER2 positive GC/GEJ patients without prior systemic treatment. It might be deserved to plan a randomized study to compare the KN026+KN046 treatment and the standard of care to further confirm the efficacy and safety.

P2/3, N=286, Recruiting, Shanghai JMT-Bio Inc.

P2, N=36, Recruiting, Jiangsu Alphamab Biopharmaceuticals Co., Ltd | Not yet recruiting --> Recruiting | Phase classification: PN/A --> P2 | N=66 --> 36 | Trial completion date: Apr 2022 --> Dec 2024 | Trial primary completion date: Apr 2022 --> Aug 2023

KN026 is a novel HER2-targeted bispecific antibody composed of VH regions of trastuzumab and pertuzumab, targeting the HER2 juxtamembrane domain (IV) and the dimerization domain (II) simultaneously. KN026 monotherapy yielded promising efficacy with mild to moderate toxicities in pts with previously treated, advanced GC/GEJC. Further investigation is warranted.

P1, N=24, Recruiting, Peking University | Trial completion date: Dec 2020 --> Dec 2023 | Trial primary completion date: Dec 2020 --> Dec 2022

This chemotherapy-free regimen of KN046 in combination with KN026 has shown promising clinical efficacy and manageable toxicity in HER2-positive non-breast and non-gastric solid tumors with ≥ 1 line prior systemic therapy.The trial is currently ongoing. ClinicalTrials.gov Number, NCT04521179

KN026, a HER2 bispecific antibody, was well tolerated and achieved comparable efficacy as trastuzumab and pertuzumab doublet even in the more heavily pretreated patients. Co-amplification of HER2/CDK12 may define patients who benefit more from KN026.

Here we reported the preliminary results from an ongoing phase II trial assessing the safety and efficacy for KN046 (a bispecific antibody blocks both PD-L1 interaction with PD-1/CD80 and CTLA-4 interaction with CD80/CD86) in combination with KN026 (a bispecific antibody that binds to two different HER2 epitopes shared by trastuzumab and pertuzumab) in HER2-positive metastatic breast cancer patients, who have progressed after prior anti-HER2 combinational therapies. The combination of KN046 and KN026, as a chemo free regimen, has shown favorable clinical efficacy with manageable side effects in heavily pre-treated patients with metastatic HER2-positive breast cancer. This trial is currently ongoing. ClinicalTrials.gov number, NCT04521179.

CONCLUSION KN026, a HER2 bispecific antibody, is well tolerated, with a favorable safety profile and promising anti-tumor activity in the context of its class in patients with HER2-positive breast cancer. Co-amplification of HER2/CDK12 may define patients who benefit more from KN026.

KN026 combined with KN046 as a chemo-free regimen was safe and demonstrated potential superior clinical benefit to available standard of care in both treatment-naïve and heavily pretreated HER2-postive gastrointestinal tumors. Pivotal trials in HER2-positive GC/GEJ are planned.

P2, N=30, Not yet recruiting, Jiangsu Alphamab Biopharmaceuticals Co., Ltd

P, N=66, Not yet recruiting, Jiangsu Alphamab Biopharmaceuticals Co., Ltd

P2, N=30, Recruiting, Jiangsu Alphamab Biopharmaceuticals Co., Ltd | Not yet recruiting --> Recruiting

18 pts had HER2-positive status (12 of 18 failed previous trastuzumab therapy), 2 pts had HER2 mutation and 5 pts had HER2 low expression (without FISH amplification). 2 death cases due to disease progression were reported, both only received one cycle of KN026 plus KN046 due to COVID-19 restriction. Conclusions KN026 combined with KN046 is well tolerated and has demonstrated preliminary albeit profound anti-tumor activity in HER2-positive solid tumors.

18 pts had HER2-positive status (12 of 18 failed previous trastuzumab therapy), 2 pts had HER2 mutation and 5 pts had HER2 low expression (without FISH amplification). 2 death cases due to disease progression were reported, both only received one cycle of KN026 plus KN046 due to COVID-19 restriction. Conclusions KN026 combined with KN046 is well tolerated and has demonstrated preliminary albeit profound anti-tumor activity in HER2-positive solid tumors.

15 pts had HER2-positive status (11 of 15 failed previous trastuzumab therapy), 1 pts had HER2 mutation and 5 pts had HER2 low expression (without FISH amplification). 2 death cases only received one cycle of KN026 plus KN046 due to COVID-19 restriction before died from clinical deterioration from underlying tumors. Conclusions KN026 combined with KN046 is well tolerated and has demonstrated profound anti-tumor activity in HER2-positive solid tumors.

15 pts had HER2-positive status (11 of 15 failed previous trastuzumab therapy), 1 pts had HER2 mutation and 5 pts had HER2 low expression (without FISH amplification). 2 death cases only received one cycle of KN026 plus KN046 due to COVID-19 restriction before died from clinical deterioration from underlying tumors. Conclusions KN026 combined with KN046 is well tolerated and has demonstrated profound anti-tumor activity in HER2-positive solid tumors.

The use of the modeling and simulation approach to aid decision in drug development has become a popular tool. Here we present a translational PK-PD modeling framework incorporating preclinical tumor growth data and clinical PK data to inform dose selection strategy for KN026 in patients with HER2-positive solid tumors. Furthermore, simulation results suggest that loading doses with higher dosing frequency will likely be beneficial.

Background: KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes, the same domains as trastuzumab (ECD4) and pertuzumab (ECD2). KN026 is well tolerated and has demonstrated encouraging anti-tumor activity in HER2-positive breast cancer patients who have failed standard anti-HER2 therapies. The recommended Phase 2 dose (RP2D) of KN026 were 20 mg/kg Q2W and 30 mg/kg Q3W. Phase II trials in various HER2-positive and HER2-low/intermediate solid tumors are currently ongoing.