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

被引：165

作者：

Peng, Zhi ^{[1
]}

Liu, Tianshu ^{[2
]}

Wei, Jia ^{[3
]}

Wang, Airong ^{[4
]}

He, Yifu ^{[5
]}

Yang, Liuzhong ^{[6
]}

Zhang, Xizhi ^{[7
]}

Fan, Nanfeng ^{[8
]}

Luo, Suxia ^{[9
]}

Li, Zhen ^{[10
]}

Gu, Kangsheng ^{[11
]}

Lu, Jianwei ^{[12
]}

Xu, Jianming ^{[13
]}

Fan, Qingxia ^{[14
]}

Xu, Ruihua ^{[15
]}

Zhang, Liangming ^{[16
]}

Li, Enxiao ^{[17
]}

Sun, Yuping ^{[18
]}

Yu, Guohua ^{[19
]}

Bai, Chunmei ^{[20
]}

Liu, Yong ^{[21
]}

Zeng, Jiangzheng ^{[22
]}

Ying, Jieer ^{[23
]}

Liang, Xinjun ^{[24
]}

Xu, Nong ^{[25
]}

Gao, Chao ^{[26
]}

Shu, Yongqian ^{[27
]}

Ma, Dong ^{[28
]}

Dai, Guanghai ^{[29
]}

Li, Shengmian ^{[30
]}

Deng, Ting ^{[31
]}

Cui, Yuehong ^{[2
]}

Fang, Jianmin ^{[32
]}

Ba, Yi ^{[31
]}

Shen, Lin ^{[1
]}

机构：

[1] Peking Univ, Canc Hosp & Inst, Dept Gastrointestinal Oncol, Minist Educ,Key Lab Cancinogenesis & Translat Res, Beijing 100142, Peoples R China

[2] Fudan Univ, Affiliated Zhongshan Hosp, Dept Gastrointestinal Oncol, Shanghai 200032, Peoples R China

[3] Nanjing Univ, Nanjing Drum Tower Hosp, Affiliated Hosp, Dept Oncol,Med Sch, Nanjing 210008, Jiangsu, Peoples R China

[4] Weihai Municipal Hosp, Dept Oncol, Weihai 264299, Shandong, Peoples R China

[5] Anhui Prov Canc Hosp, Dept Oncol, Hefei 230031, Anhui, Peoples R China

[6] Xinxiang Med Coll, Affiliated Hosp 1, Dept Oncol, Xinxiang 453100, Henan, Peoples R China

[7] Subei Peoples Hosp, Dept Oncol, Yangzhou 225009, Jiangsu, Peoples R China

[8] Fujian Prov Canc Hosp, Dept Abdominal Oncol, Fuzhou 350014, Fujian, Peoples R China

[9] Henan Canc Hosp, Dept Gastrointestinal Oncol, Zhengzhou 450003, Henan, Peoples R China

[10] Linyi Canc Hosp, Dept Oncol, Linyi 276002, Shandong, Peoples R China

[11] Anhui Med Univ, Affiliated Hosp 1, Dept Oncol, Hefei 230022, Anhui, Peoples R China

[12] Jiangsu Canc Hosp, Dept Oncol, Nanjing 210009, Jiangsu, Peoples R China

[13] Peoples Liberat Army Gen Hosp, Med Ctr 5, Dept Oncol, Beijing 100039, Peoples R China

[14] First Affiliated Hosp Zhengzhou, Dept Oncol, Zhengzhou 450099, Henan, Peoples R China

[15] Sun Yat Sen Univ, Canc Ctr, Dept Oncol, Guangzhou 510060, Guangdong, Peoples R China

[16] Yantai Yuhuangding Hosp, Dept Oncol, Yantai 264099, Shandong, Peoples R China

[17] Xi An Jiao Tong Univ, Affiliated Hosp 1, Dept Oncol, Xian 710061, Shanxi, Peoples R China

[18] Jinan Cent Hosp, Dept Oncol, Jinan 250013, Shandong, Peoples R China

[19] Weifang Peoples Hosp, Dept Oncol, Weifang 261041, Shandong, Peoples R China

[20] Peking Union Med Coll Hosp, Dept Oncol, Beijing 100005, Peoples R China

[21] Xuzhou Cent Hosp, Dept Oncol, Xuzhou 221009, Jiangsu, Peoples R China

[22] Hainan Hosp, Affiliated Hosp 1, Dept Oncol, Haikou 570102, Hainan, Peoples R China

[23] Zhejiang Canc Hosp, Dept Abdominal Oncol, Hangzhou 310005, Zhejiang, Peoples R China

[24] Hubei Canc Hosp, Dept Oncol, Wuhan 430079, Hubei, Peoples R China

[25] Zhejiang Univ, Affiliated Hosp 1, Dept Oncol, Hangzhou 310003, Zhejiang, Peoples R China

[26] Xuzhou Med Univ, Affiliated Hosp, Dept Oncol, Xuzhou 221004, Jiangsu, Peoples R China

[27] Jiangsu Prov Hosp, Dept Oncol, Nanjing 210029, Jiangsu, Peoples R China

[28] Guangdong Prov Peoples Hosp, Dept Oncol, Guangzhou 510080, Guangdong, Peoples R China

[29] Chinese Peoples Liberat Army Gen Hosp, Dept Oncol, Beijing 100036, Peoples R China

[30] Hebei Med Univ, Hosp 4, Dept Gastrointestinal Oncol, Shijiazhuang 050011, Hebei, Peoples R China

[31] Tianjin Med Univ Canc Inst & Hosp, Dept Gastrointestinal Oncol, Tianjin 300181, Peoples R China

[32] RemeGen Ltd, Beijing 100020, Peoples R China

来源：

CANCER COMMUNICATIONS | 2021年 / 41卷 / 11期

基金：

中国国家自然科学基金;

关键词：

antibody-drug conjugate; gastric cancer; HER2-overexpressing; phase II clinical trial; RC48; third-line therapy; DOUBLE-BLIND; OPEN-LABEL; ADENOCARCINOMA; SURVIVAL; ANEMIA;

D O I：

10.1002/cac2.12214

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background Current treatment options for human epidermal growth factor receptor 2 (HER2)-overexpressing gastric cancer at third-line have shown limited clinical benefit. Further, there is no specific treatment for HER2 immunohistochemistry (IHC) 2+ and fluorescence in-situ hybridization-negative patients. Here, we report the efficacy and safety of a novel anti-HER2 antibody RC48 for patients with HER2-overexpressing, advanced gastric or gastroesophageal junction cancer. Methods Patients with HER2-overexpressing (IHC 2+ or 3+), locally advanced or metastatic gastric or gastroesophageal junction cancer who were under at least second-line therapy were eligible and received RC48 2.5 mg/kg alone every 2 weeks. The primary endpoint was the objective response rate (ORR) assessed by an independent review committee. Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to progression, disease control rate, and safety. Results Of 179 patients screened, 125 were eligible and received RC48 treatment. The ORR was 24.8% (95% confidence interval [CI]: 17.5%-33.3%). 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. The most frequently reported adverse events were decreased white blood cell count (53.6%), asthenia (53.6%), hair loss (53.6%), decreased neutrophil count (52.0%), anemia (49.6%), and increased aspartate aminotransferase level (43.2%). Serious adverse events (SAEs) occurred in 45 (36.0%) patients, and RC48-related SAEs were mainly decreased neutrophil count (3.2%). Seven patients had adverse events that led to death were not RC48-related. Conclusions RC48 showed promising activity with manageable safety, suggesting potential application in patients with HER2-overexpressing, advanced gastric or gastroesophageal junction cancer who have previously received at least two lines of chemotherapy.

引用

页码：1173 / 1182

页数：10

共 27 条

[11] Impact of preoperative anemia on outcomes in patients undergoing curative resection for gastric cancer: a single-institution retrospective analysis of 2163 Chinese patients [J].

Liu, Xuechao ;

Qiu, Haibo ;

Huang, Yuying ;

Xu, Dazhi ;

Li, Wei ;

Li, Yuanfang ;

Chen, Yingbo ;

Zhou, Zhiwei ;

Sun, Xiaowei .

CANCER MEDICINE, 2018, 7 (02) :360-369

[12] Regorafenib for the Treatment of Advanced Gastric Cancer (INTEGRATE): A Multinational Placebo-Controlled Phase II Trial [J].

Pavlakis, Nick ;

Sjoquist, Katrin M. ;

Martin, Andrew J. ;

Tsobanis, Eric ;

Yip, Sonia ;

Kang, Yoon-Koo ;

Bang, Yung-Jue ;

Alcindor, Thierry ;

O'Callaghan, Christopher J. ;

Burnell, Margot J. ;

Tebbutt, Niall C. ;

Rha, Sun Young ;

Lee, Jeeyun ;

Cho, Jae-Yong ;

Lipton, Lara R. ;

Wong, Mark ;

Strickland, Andrew ;

Kim, Jin Won ;

Zalcberg, John R. ;

Simes, John ;

Goldstein, David .

JOURNAL OF CLINICAL ONCOLOGY, 2016, 34 (23) :2728-+

[13] A Greenwood formula for standard error of the age-standardised relative survival ratio [J].

Pokhrel, Arun ;

Dyba, Tadeusz ;

Hakulinen, Timo .

EUROPEAN JOURNAL OF CANCER, 2008, 44 (03) :441-447

[14]

SAHIN U, 1990, CANCER RES, V50, P6944

[15] Lapatinib Plus Paclitaxel Versus Paclitaxel Alone in the Second-Line Treatment of HER2-Amplified Advanced Gastric Cancer in Asian Populations: TyTANA- A Randomized, Phase III Study [J].

Satoh, Taroh ;

Xu, Rui-Hua ;

Chung, Hyun Cheol ;

Sun, Guo-Ping ;

Doi, Toshihiko ;

Xu, Jian-Ming ;

Tsuji, Akihito ;

Omuro, Yasushi ;

Li, Jin ;

Wang, Jin-Wan ;

Miwa, Hiroto ;

Qin, Shu-Kui ;

Chung, Ik-Joo ;

Yeh, Kun-Huei ;

Feng, Ji-Feng ;

Mukaiyama, Akihira ;

Kobayashi, Mikiro ;

Ohtsu, Atsushi ;

Bang, Yung-Jue .

JOURNAL OF CLINICAL ONCOLOGY, 2014, 32 (19) :2039-U89

[16] Pretreatment anemia is associated with poorer survival in patients with stage I and II gastric cancer [J].

Shen, JG ;

Cheong, JH ;

Hyung, WJ ;

Kim, J ;

Choi, SH ;

Noh, SH .

JOURNAL OF SURGICAL ONCOLOGY, 2005, 91 (02) :126-130

[17] Open-label, Multicenter, Phase II Study of RC48-ADC, a HER2-Targeting Antibody-Drug Conjugate, in Patients with Locally Advanced or Metastatic Urothelial Carcinoma [J].

Sheng, Xinan ;

Yan, Xieqiao ;

Wang, Lin ;

Shi, Yanxia ;

Yao, Xin ;

Luo, Hong ;

Shi, Benkang ;

Liu, Jiyan ;

He, Zhisong ;

Yu, Guohua ;

Ying, Jianming ;

Han, Weiqing ;

Hu, Changlu ;

Ling, Yun ;

Chi, Zhihong ;

Cui, Chuanliang ;

Si, Lu ;

Fang, Jianmin ;

Zhou, Aiping ;

Guo, Jun .

CLINICAL CANCER RESEARCH, 2021, 27 (01) :43-51

[18] Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer [J].

Shitara, Kohei ;

Bang, Yung-Jue ;

Iwasa, Satoru ;

Sugimoto, Naotoshi ;

Ryu, Min-Hee ;

Sakai, Daisuke ;

Chung, Hyun-Cheol ;

Kawakami, Hisato ;

Yabusaki, Hiroshi ;

Lee, Jeeyun ;

Saito, Kaku ;

Kawaguchi, Yoshinori ;

Kamio, Takahiro ;

Kojima, Akihito ;

Sugihara, Masahiro ;

Yamaguchi, Kensei .

NEW ENGLAND JOURNAL OF MEDICINE, 2020, 382 (25) :2419-2430

[19] Trifluridine/tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial [J].

Shitara, Kohei ;

Doi, Toshihiko ;

Dvorkin, Mikhail ;

Mansoor, Wasat ;

Arkenau, Hendrik-Tobias ;

Prokharau, Aliaksandr ;

Alsina, Maria ;

Ghidini, Michele ;

Faustino, Catia ;

Gorbunova, Vera ;

Zhavrid, Edvard ;

Nishikawa, Kazuhiro ;

Hosokawa, Ayumu ;

Yalcin, Suayib ;

Fujitani, Kazumasa ;

Beretta, Giordano D. ;

Van Cutsem, Eric ;

Winkler, Robert E. ;

Makris, Lukas ;

Ilson, David H. ;

Tabernero, Josep .

LANCET ONCOLOGY, 2018, 19 (11) :1437-1448

[20] Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study [J].

Thuss-Patience, Peter C. ;

Shah, Manish A. ;

Ohtsu, Atsushi ;

Van Cutsem, Eric ;

Ajani, Jaffer A. ;

Castro, Hugo ;

Mansoor, Wasat ;

Chung, Hyun Cheol ;

Bodoky, Gyorgy ;

Shitara, Kohei ;

Phillips, Gail D. Lewis ;

van der Horst, Tina ;

Harle-Yge, Marie-Laurence ;

Althaus, Betsy L. ;

Kang, Yoon-Koo .

LANCET ONCOLOGY, 2017, 18 (05) :640-653

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