Efficacy and safety of a novel anti‐HER2 therapeutic antibody RC48 in patients with HER2‐overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single‐arm phase II study

Peng, Zhi; Liu, Tianshu; Wei, Jia; Wang, Airong; He, Yong; Yang, Lu; Zhang, Xizhi; Fan, Nanfeng; Luo, Suxia; Li, Zhen; Gu, Kangsheng; Lu, Jianwei; Xu, Jianming; Fan, Qingxia; Xu, Rui‐hua; Zhang, Liangming; Li, Enxiao; Sun, Yehuan; Yang, Guohua; Bai, Chunmei; Liu, Yong; Zeng, Jiangzheng; Ying, Jieer; Liang, Xiaofeng; Xu, Nong; Gao, Chao; Shu, Yongqian; Ma, Dong; Dai, Guanghai; Li, Shengmian; Deng, Ting; Cui, Yuehong; Fang, Jianmin; Ba, Yi; Shen, Lin

doi:10.1002/cac2.12214

Cited by 116 publications

(95 citation statements)

References 23 publications

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“…The median PFS and OS were 4.1 months (95% CI: 3.7-4.9 months) and 7.9 months (95% CI: 6.7-9.9 months), respectively. Furthermore, the ORR of RC48-ADC in patients with HER2 IHC2+/FISH-(1/6, 16.7%) is lower than that in HER2-positive patients (20/76, 26.3%) (Peng et al, 2021). In June 10, , 2021, RC48-ADC was approved by the National Medical Products Administration for the treatment of locally advanced or metastatic GC with HER2 overexpression who had received at least second-line treatment of systemic chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…On one hand, the efficacy comparison of RC48-ADC, T-DM1, and DS-8201 in cell lines and PDXs was not conducted. From the results of phase II studies (NCT03556345 and NCT03329690), the ORR of RC48 (24.8%, 31/125) is relatively lower than that of DS-8201 (51%, 61/119) ( Shitara et al, 2020 ; Peng et al, 2021 ). Considering the differences in the baseline characteristics of the enrolled patients in the two studies, the difference in efficacy between RC48 and DS-8201a needs to be further explored.…”

Section: Discussionmentioning

confidence: 99%

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From AVATAR Mice to Patients: RC48-ADC Exerted Promising Efficacy in Advanced Gastric Cancer With HER2 Expression

Chen

Yuan

et al. 2022

Front. Pharmacol.

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RC48-ADC is a novel humanized antibody specific for human epidermal growth factor receptor 2 (HER2)in conjugation with a microtubule inhibitor via a cleavable linker. This study was to evaluate the antitumor activity and mechanism of RC48-ADC in gastric cancer (GC) and explore the population that may benefit from RC48-ADC treatment. Four human GC cell lines and nine patient-derived xenograft (PDX) models were exploited to evaluate the antitumor effect of RC48-ADC or trastuzumab treatment in vitro and in vivo. The expression and phosphorylation of HER2 were assessed by immunohistochemistry (IHC) staining. Critical molecules of downstream PI3K/AKT and cell cycle and apoptosis signaling pathways were detected and quantified by immunoblotting. Combined with preliminary results of preclinical research, three patients with IHC3+, IHC2+/FISH+, and IHC2+/FISH- of HER2 were enrolled to verify the efficacy of RC48-ADC treatment in advanced GC. In vitro, RC48-ADC had superior antiproliferative effects in a dose-dependent manner on GC cells, especially on HER2-positive cells. In vivo, RC48-ADC exceeded trastuzumab in GC PDX models with HER2 expression, even in models with moderate to low expression of HER2. Further exploration of mechanism showed that RC48-ADC exerted the antitumor effect by inhibiting phosphorylation of HER2, inducing G2/M phase arrest and cell apoptosis in HER2-expressed PDX models. In clinical practice, RC48-ADC had satisfactory efficacy in HER2-positive and HER2 moderately expressed GC patients and demonstrated promising efficacy in HER2-positive patients who have progressed after anti-HER2 therapy. In conclusion, RC48-ADC exerted promising antitumor activity in HER2-positive as well as score of 2+ in IHC and ISH-negative AGC patients after progression of systematic treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

From AVATAR Mice to Patients: RC48-ADC Exerted Promising Efficacy in Advanced Gastric Cancer With HER2 Expression

Chen

Yuan

et al. 2022

Front. Pharmacol.

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“…A total of 127 eligible GC/GEJC patients were recruited for an open-label, single-arm, multicenter Phase-II clinical study with clinical characteristics: HER2 status is IHC2+/3+, regardless of fluorescent in situ hybridization amplification (FISH) status, disease progression after conferring 2 prior therapies, of which including 60 patients who had endowed at least 3 lines previous therapies, patients agreed to receive accepted RC48 2.5 mg/kg every 2 weeks until disease progression or intolerable toxic side effects led to discontinuation or death, and the results indicated that ORR was 24.4%, accompanying median duration of response (DOR) was 4.7 months, meanwhile median progression-free survival (m-PFS) and overall survival (OS) were 4.1 months and 7.9 months, respectively (Peng et al., 2021 ).…”

Section: Therapeutic Efficacy Of Rc-48 Adc In the Clinical Studymentioning

confidence: 99%

Disitamab vedotin: a novel antibody-drug conjugates for cancer therapy

et al. 2022

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Human epidermal growth factor receptor 2 (HER2) regulates cell mitosis, proliferation, and apoptosis. Trastuzumab is a HER2-targeted monoclonal antibody (mAB), which can prolong the overall survival rate of patients with HER2 overexpression in later periods of gastric cancer and breast cancer. Although anti-HER2 monoclonal antibody has a curative effect, adjuvant chemotherapy is still necessary to upgrade the curative effect maximumly. Antibody-drug conjugate (ADC) is a kind of therapeutic drug that contains antigen-specific antibody and cytotoxic payload, which can improve the survival time of tumor patients. To date, there are several HER2-ADC products on the market, for which two anti-HER2 ADC (trastuzumab emtansine and trastuzumab deruxtecan) have been authorized by the FDA for distinct types of HER2-positive carcinoma in the breast. Disitamab vedotin (RC48) is a newly developed ADC drug targeting HER2 that is comprised of hertuzumab coupling monomethyl auristatin E (MMAE) via a cleavable linker. This paper aims to offer a general insight and summary of the mechanism of action and the currently completed and ongoing clinical studies of RC-48 in HER-2 positive solid tumors.

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“…A phase I study (NCT02881190) of single agent of RC48 was conducted in patients with advanced or metastatic HER2-positive solid carcinomas, which showed that RC48 had tolerable toxicity and substantial potency against HER2-positive solid tumors, especially in HER2-low expression gastric cancer ( Xu et al, 2021 ). Additionally, a phase II study (NCT03556345) of RC48 in patients with advanced or metastatic HER2-positive gastric or gastroesophageal junction cancer demonstrate a 24.8% objective response rate, a median progression-free survival of 4.1 months, and a median overall survival of 7.9 months ( Peng et al, 2021 ). Based on the results of this study, RC48 was granted conditional marketing approval by the NMPA of China for the treatment of patients with locally advanced or metastatic gastric or gastroesophageal junction cancer who have received at least two types of chemotherapy in June 2021.…”

Section: Introductionmentioning

confidence: 99%

Antibody-Drug Conjugates Targeting the Human Epidermal Growth Factor Receptor Family in Cancers

Tong

Yun

et al. 2022

Front. Mol. Biosci.

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Members of the human epidermal growth factor receptor (HER) family, which includes HER1 (also known as EGFR), HER2, HER3 and HER4, have played a central role in regulating cell proliferation, survival, differentiation and migration. The overexpression of the HER family has been recognized as one of the most common cellular dysregulation associated with a wide variety of tumor types. Antibody-drug conjugates (ADCs) represent a new and promising class of anticancer therapeutics that combine the cancer specificity of antibodies with cytotoxicity of chemotherapeutic drugs. Two HER2-directed ADCs, trastuzumane-emtansine (T-DM1) and trastuzumab-deruxtecan (DS-8201a), have been approved for HER2-positive metastatic breast cancer by the U.S. Food and Drug Administration (FDA) in 2013 and 2019, respectively. A third HER2-directed ADC, disitamab vedotin (RC48), has been approved for locally advanced or metastatic gastric or gastroesophageal junction cancer by the NMPA (National Medical Products Administration) of China in 2021. A total of 11 ADCs that target HER family receptors (EGFR, HER2 or HER3) are currently under clinical trials. In this review article, we summarize the three approved ADCs (T-DM1, DS-8201a and RC48), together with the investigational EGFR-directed ADCs (ABT-414, MRG003 and M1231), HER2-directed ADCs (SYD985, ARX-788, A166, MRG002, ALT-P7, GQ1001 and SBT6050) and HER3-directed ADC (U3-1402). Lastly, we discuss the major challenges associated with the development of ADCs, and highlight the possible future directions to tackle these challenges.

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Efficacy and safety of a novel anti‐HER2 therapeutic antibody RC48 in patients with HER2‐overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single‐arm phase II study

Cited by 116 publications

References 23 publications

From AVATAR Mice to Patients: RC48-ADC Exerted Promising Efficacy in Advanced Gastric Cancer With HER2 Expression

From AVATAR Mice to Patients: RC48-ADC Exerted Promising Efficacy in Advanced Gastric Cancer With HER2 Expression

Disitamab vedotin: a novel antibody-drug conjugates for cancer therapy

Antibody-Drug Conjugates Targeting the Human Epidermal Growth Factor Receptor Family in Cancers

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