Shanghai, China, November 22, 2024 - Shanghai Henlius Biotech, Inc. (2696.HK) announced that the first patient has been dosed in the phase 3 international multi-centre clinical trial (HLX22-GC-301) of HLX22, an innovative anti-HER2 monoclonal antibody (mAb) in combination with trastuzumab and chemotherapy for the first-line treatment of HER2-positive advanced gastric/gastroesophageal junction (G/GEJ) cancer. The leading principal investigator is Lin Shen from Peking University Cancer Hospital. Previously, the investigational new drug (IND) applications have received regulatory approvals in China, the U.S. and Japan for HLX22-GC-301. As of now, no similar dual HER2 blockade therapy for the treatment of HER2-positive gastric cancer has received approval for commercialization globally.
Until now, gastric/gastroesophageal junction (G/GEJ) cancer still constitutes a major global health problem. Globally, there were around 1 million new cases in 2022 [1]. While in China, the incidence and mortality of G/GEJ rank fifth and third among all malignant tumors, respectively, with over 358,600 new cases and 260,300 deaths in 2022 [1]. G/GEJ cancer generally carries a poor prognosis since it is often diagnosed at an advanced stage, with a 5-year relative survival rate of only 6% [2,3]. The reported rates of HER2 positivity in patients with gastric cancer range from 12% to 23%, and the prognosis for patients with HER2-positive disease used to be even worse than those with HER2-negative disease [2-4]. Currently, for patients with HER2-positive locally advanced/metastatic G/GEJ cancer, the current standard first-line treatment is trastuzumab plus chemotherapy. Immunotherapies are recommended to be added for tumours with PD-L1 expression levels by CPS (Combined Positive Score) of greater than 1. However, the effectiveness and prognosis for these treatments need to be further improved [5].
HLX22 is an innovative anti-HER2 mAb introduced from AbClon, Inc. and further investigated and developed by Henlius. HLX22 can bind to HER2 extracellular subdomain IV at a binding site different from that of trastuzumab, which allows simultaneous binding of HLX22 and trastuzumab to HER2 dimers (HER2 homodimer and HER2/EGFR heterodimer) on tumour cell surface, thereby promoting the internalisation and HER2 dimer degradation. Pre-clinical studies showed that the co-treatment with HLX22 and trastuzumab synergistically inhibited tumour cell proliferation and apoptosis, which led to enhanced anti-tumour activity in vitro and in vivo. A phase 1 clinical trial of HLX22 demonstrates that HLX22 was well tolerated and had a favorable safety profile. [6] Results from HLX22-GC-201, a phase 2 study of HLX22 in combination with trastuzumab injection (HLX02) and XELOX, as first-line therapy for HER2-positive locally advanced or metastatic gastric cancer patients were subsequently presented at the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI), 2024 ESMO Gastrointestinal Cancers Congress (ESMO GI) and on Med [10], a flagship medical journal by Cell Press, respectively. Updated results and study data showed that the addition of HLX22 to HLX02 (trastuzumab) plus chemotherapy as first-line therapy improved efficacy in HER2-positive G/GEJ cancer patients with manageable safety. [7-9]
HLX22-GC-301 is a double-blind, randomized, controlled multicenter phase 3 study aims to compare the efficacy and safety of HLX22 in combination with trastuzumab and chemotherapy versus trastuzumab and chemotherapy with or without pembrolizumab as first-line treatment in patients with human epidermal growth factor receptor 2 (HER2)-positive, locally advanced or metastatic gastric/gastroesophageal junction cancer. Eligible participants will be randomized at 1:1 to the experimental arm (treated with HLX22 (15 mg/kg, intravenous injection) plus trastuzumab and chemotherapy) or the control group (placebo plus trastuzumab and chemotherapy with or without pembrolizumab). The primary endpoints of this study are progression-free survival (PFS) accessed by independent radiology review committee (IRRC) per RECIST 1.1 and overall survival (OS), the secondary endpoints include investigator-assessed PFS, IRRC or investigator-accessed objective response rate (ORR), PFS2, duration of response (DOR), quality of life, safety, immunogenicity, and pharmacokinetic characteristics.
The HLX22-GC-301 clinical study has obtained IND approvals in China, the United States, and Japan. The company will continue to focus on patient needs and accelerate the advancement of the HLX22-GC-301 study in more countries, thus bringing hope to more patients.
【Reference】
[1] Bray F, Laversanne M, Sung H, et al. CA Cancer J Clin. 2024: 1-35.
[2] Ajani JA. et al. J Natl Compr Canc Netw 2022;20(2):167-92.
[3] Alsina M. et al. Nat Rev Gastroenterol Hepatol 2023;20(3):155-70.
[4] Gravalos C. et al. Ann Oncol 2008;19(9):1523-9.
[5] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Gastric Cancer V.1.2024
[6] Zhu X, Ding Y, Wang Q, Yang G, Zhou L, Wang Q. HLX22, an anti-HER-2 monoclonal antibody, in patients with advanced solid tumors overexpressing human epidermal growth factor receptor 2: an open-label, dose-escalation, phase 1 trial. Invest New Drugs. 2023;41(3):473-482. doi:10.1007/s10637-023-01338-7
[7] Jin Li et al., HLX22 plus HLX02 and XELOX for first-line treatment of HER2-positive locally advanced or metastatic gastric/gastroesophageal junction cancer: A randomized, double-blind, multicenter phase 2 study.. JCO 42, 354-354(2024).DOI:10.1200/JCO.2024.42.3_suppl.354
[8] J. Li et al., 422P HLX22 plus HLX02 and XELOX as first-line therapy for HER2-positive advanced gastric/gastroesophageal junction cancer: Updated results from a randomized, double-blind phase II study, Annals of Oncology,Annals of Oncology (2024) 35 (suppl_1): S162-S204. 10.1016/annonc/annonc1482
[9] Li N, Qiu M, Zhang Y, et al. A randomized phase 2 study of HLX22 plus trastuzumab biosimilar HLX02 and XELOX as first-line therapy for HER2-positive advanced gastric cancer. Med. 2024;5(10):1255-1265.e2. doi:10.1016/j.medj.2024.06.004
[10] Li N, Qiu M, Zhang Y, et al. A randomized phase 2 study of HLX22 plus trastuzumab biosimilar HLX02 and XELOX as first-line therapy for HER2-positive advanced gastric cancer. Med. 2024;5(10):1255-1265.e2. doi:10.1016/j.medj.2024.06.004