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北京大学学报（医学版） ›› 2022, Vol. 54 ›› Issue (5): 971-980. doi: 10.19723/j.issn.1671-167X.2022.05.026

• 论著 • 上一篇    下一篇

阿替利珠单抗治疗中国晚期实体瘤患者的开放标签Ⅰ期临床试验

张力1,龚继芳2,潘宏铭3,白玉贤4,刘天舒5,程颖6,陈亚池7,黄佳莹8,许婷婷8,葛飞娇8,许婉玲9,施佳10,胡夕春11,*(),沈琳2,*()   

  1. 1. 中山大学附属肿瘤医院肿瘤内科, 广州 510060
    2. 北京大学肿瘤医院暨北京市肿瘤防治研究所消化肿瘤内科, 恶性肿瘤发病机制及转化研究教育部重点实验室, 北京 100142
    3. 浙江大学医学院附属邵逸夫医院肿瘤内科, 杭州 310020
    4. 哈尔滨医科大学附属肿瘤医院肿瘤内科, 哈尔滨 150081
    5. 复旦大学附属中山医院肿瘤内科, 上海 200032
    6. 吉林省肿瘤医院肿瘤内科, 长春 130012
    7. Clinical Pharmacology, Genentech, Inc., South San Francisco, CA 94080, USA
    8. 罗氏全球药品开发中国中心临床科学部, 上海 201203
    9. 罗氏全球药品开发中国中心统计部, 上海 201203
    10. 罗氏全球药品开发中国中心安全部, 上海 201203
    11. 复旦大学附属肿瘤医院肿瘤内科, 上海 200032
  • 收稿日期:2022-07-08 出版日期:2022-10-18 发布日期:2022-10-14
  • 通讯作者: 胡夕春,沈琳 E-mail:xchu2009@hotmail.com;linshenpku@163.com

Atezolizumab therapy in Chinese patients with locally advanced or metastatic solid tumors: An open-label, phase Ⅰ study

Li ZHANG1,Ji-fang GONG2,Hong-ming PAN3,Yu-xian BAI4,Tian-shu LIU5,Ying CHENG6,Ya-chi CHEN7,Jia-ying HUANG8,Ting-ting XU8,Fei-jiao GE8,Wan-ling HSU9,Jane SHI10,Xi-chun HU11,*(),Lin SHEN2,*()   

  1. 1. Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
    2. Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education; Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
    3. Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310020, China
    4. Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China
    5. Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
    6. Department of Medical Oncology, Jilin Cancer Hospital, Changchun 130012, China
    7. Clinical Pharmacology, Genentech, Inc., South San Francisco, CA 94080, USA
    8. Oncology, Roche Product Development Shanghai, Shanghai, 201203, China
    9. Department of Statistics, Roche Product Development Shanghai, Shanghai 201203, China
    10. Portfolio Clinical Safety, Roche Product Development Shanghai, Shanghai 201203, China
    11. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
  • Received:2022-07-08 Online:2022-10-18 Published:2022-10-14
  • Contact: Xi-chun HU,Lin SHEN E-mail:xchu2009@hotmail.com;linshenpku@163.com

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摘要：

目的: 观察程序性细胞死亡配体1(programmed death-ligand 1，PD-L1)抑制剂阿替利珠单抗在中国高发实体瘤，包括食管癌(esophageal cancer，EC)、胃癌(gastric cancer，GC)、肝细胞癌(hepatocellular carcinoma，HCC)、鼻咽癌(nasopharyngeal cancer，NPC)和非小细胞肺癌(non-small cell lung cancer，NSCLC)患者中的药代动力学(pharmacokinetics，PK)、疗效和安全性数据。方法: 本研究为开放标签的Ⅰ期临床试验，于2016年8月4日至2019年4月15日在中国6个研究中心进行。入组患者年龄≥18岁，患有经组织学证实的无法治愈或转移性的实体瘤，且既往抗肿瘤治疗失败。PK阶段研究了阿替利珠单抗单药治疗的PK和安全性；扩展阶段研究了阿替利珠单抗单药治疗(入组EC、GC、HCC、NPC患者)和联合化疗(入组NSCLC患者)的安全性和有效性。结果: 共入组120例患者(PK阶段20例；扩展期每队列20例)。阿替利珠单抗单药组患者(n=100)中有42例(42.0%)为PD-L1阳性，9例(9.0%)为微卫星高度不稳定性。阿替利珠单抗的清除率为0.219 L/d，重复给药6~9周(2~3个周期)后达到稳态。EC、GC、HCC、NPC和NSCLC的客观缓解率(objective response rate，ORR)分别为10.0%、15.0%、10.0%、5.0%和40.0%。在PD-L1阳性的肿瘤患者中，阿替利珠单抗的ORR为11.9%，阿替利珠单抗联合吉西他滨和顺铂的ORR为46.2%。2例GC患者在假性进展后获得了持久的肿瘤缩小。阿替利珠单抗单药组最常见的治疗相关不良事件是疲劳、贫血、发热和白细胞计数减少，联合组最常见的治疗相关AE是贫血、白细胞计数减少和食欲下降。本试验没有发现新的安全信号。结论: 中国患者应用阿替利珠单抗的PK、疗效和安全性与之前研究中入组的全球患者的数据相似。

关键词: 阿替利珠单抗, 药代动力学, 中国, 肿瘤

Abstract:

Objective: To evaluate pharmacokinetics (PK), efficacy, and safety of atezolizumab (anti-PD-L1) in high interest cancers in China, including esophageal cancer (EC), gastric cancer (GC), hepatocellular carcinoma (HCC), nasopharyngeal cancer (NPC), and non-small cell lung can-cer (NSCLC). Methods: This phase I, open-label study was conducted at 6 Chinese sites from August 4, 2016 to April 15, 2019. The patients were ≥18 years old with a histologically documented incurable or metastatic solid tumor that was advanced or recurrent and had progressed since the last anti-tumor the-rapy. The PK phase characterized PK and safety of atezolizumab following multiple-dose administration when atezolizumab was administered as a single agent. The extension phase studied safety and efficacy of atezolizumab, as monotherapy (EC, GC, HCC, NPC) and with chemotherapy (NSCLC). Results: This study enrolled 120 patients (PK phase: n=20; extension phase: n=20/cohort). Fourty-two patients (42.0%) were PD-L1 positive in atezolizumab monotherapy group (100 patients), of the 9 patients (9.0%) with microsatellite instability-high (MSI-H) tumors. Atezolizumab clearance was 0.219 L/d, and steady state was reached after 6 to 9 weeks (2-3 cycles) of repeated dosing. Objective response rates (ORRs) in EC, GC, HCC, NPC, and NSCLC were 10.0%, 15.0%, 10.0%, 5.0%, and 40.0%, respectively. In the patients with PD-L1 positive tumors, ORR was 11.9% with atezolizumab and 46.2% with atezolizumab plus gemcitabine and cisplatin. Two GC patients achieved durable response after pseudo-progression. The most common treatment-related adverse events in the atezolizumab monotherapy group were fatigue, anemia, fever, and decreased white blood cell count. The most common treatment-related adverse events in the combination group were anemia, decreased white blood cell count, and decreased appetite. No new safety signals were identified. Conclusion: Atezolizumab's PK, efficacy, and safety were similar in Chinese patients vs. global patients in previous studies.

Key words: Atezolizumab, Pharmacokinetics, China, Neoplasms

中图分类号: 

  • R730.51

图1

研究流程图"

表1

入组患者的一般基线特征"

Items Atezolizumab (n=100) Atezolizumab+gemcitabine+cisplatin (n=20)
Age/years, median (range) 55.0 (19.0-77.0) 60.0 (38.0-77.0)
Age < 65 years, n(%) 81 (81.0) 14 (70.0)
Male, n(%) 80 (80.0) 18 (90.0)
Weight/kg, Median (Range) 60.0 (33.0-96.0) 64.5 (47.0-94.0)
Study cohort
  EC (PD-L1+/PD-L1-), n 20 (10/10) NA
  GC (PD-L1+/PD-L1-/EBV+/MSI-H), n 20 (6/14/10/5) NA
  HCC (PD-L1+/PD-L1-), n 20 (8/12) NA
  NPC (PD-L1+/PD-L1-), n 20 (15/5) NA
  NSCLC (PD-L1+/PD-L1-), n NA 20 (13/7)
  PK (NSCLC/CRC/GC/UC/EC/HCC/BTC/NET)，n 20 (7/4/4/1/1/1/1/1) NA
ECOG performance score, n(%)
  0 21 (21.0) 0
  1 79 (79.0) 20 (100.0)
PD-L1+a, n(%) 42 (42.0) 13 (65.0)
PD-L1 IC scoreb, n(%)
  IC0 63 (63.0) 10 (50.0)
  IC1 26 (26.0) 6 (30.0)
  IC2 3 (3.0) 2 (10.0)
  IC3 5 (5.0) 1 (5.0)
  Unknown 3 (3.0) 1 (5.0)
PD-L1 TC scorec, n(%)
  TC0 81 (81.0) 13 (65.0)
  TC1 5 (5.0) 1 (5.0)
  TC2 10 (10.0) 1 (5.0)
  TC3 1 (1.0) 4 (20.0)
  Unknown 3 (3.0) 1 (5.0)
Tobacco use, n(%)
  Current 6 (6.0) 0
  Previous 40 (40.0) 14 (70.0)
  Never 54 (54.0) 6 (30.0)
Alcohol use, n(%)
  Current 5 (5.0) 0
  Previous 32 (32.0) 11 (55.0)
  Never 63 (63.0) 9 (45.0)
Prior radiotherapy, n(%) 43 (43.0) 4 (20.0)
MSI-H (all cancer types), n(%) 9 (9.0) 0
Prior therapy for recurrent/metastatic disease, n(%) 91 (91.0) 1 (5.0)

图2

阿替利珠单抗在PK组的血药浓度"

表2

阿替利珠单抗PK组患者在第1周期获得的血浆PK参数(n=20)"

Items Cmax/(mg/L) Cmin/(mg/L) AUC0-21/[d·(mg/L)] AUC0-∞a/[d·(mg/L)] CLb/(mL/d)
n 20 20 20 13 13
Mean (CV) 542 (22.3%) 102 (26.0%) 4 510 (16.6%) 5 710 (19.6%) 219 (21.2%)
SD 121 26.5 749 1 120 46.4
Minimum 377 56.1 2 970 3 780 165
Median 520 105 4 530 5 970 201
Maximum 887 143 6 100 7 280 317
GM (CV) 530 (20.9%) 98.7 (28.7%) 4 450 (17.2%) 5 600 (20.7%) 214 (20.7%)

表3

不同组间患者的治疗疗效汇总"

Items Atezolizumab (n=100) Atezolizumab+ gemcitabine+ cisplatin (n=20)
EC (n=20) GC (n=20) HCC (n=20) NPC (n=20) PK (n=20) NSCLC (n=20)
ORR (95%CI)/% 10.0 (1.23-31.70) 15.0 (3.21-37.89) 10.0 (1.23-31.70) 5.0 (0.13-24.87) 10.0 (1.23-31.70) 40.0 (19.12-63.95)
  CR, n(%) 0 0 0 0 0 0
  PR, n(%) 2 (10.0) 3 (15.0) 2 (10.0) 1 (5.0) 2 (10.0) 8 (40.0)
  SD, n(%) 6 (30.0) 7 (35.0) 10 (50.0) 12 (60.0) 7 (35.0) 10 (50.0)
  DCRa, n(%) 8 (40.0) 10 (50.0) 12 (60.0) 13 (65.0) 9 (45.0) 18 (90.0)
  PD, n(%) 7 (35.0) 7 (35.0) 7 (35.0) 7 (35.0) 11 (55.0) 1 (5.0)
  NE, n(%) 0 0 0 0 0 0
  Missing, n(%) 5 (25.0) 3 (15.0) 1 (5.0) 0 0 1 (5.0)
Median DOR (95%CI)/months 14.4 (8.0-20.8) 18.4 (NE) NE (6.9-NE) 8.3 (NE) NA NE (5.6-NE)
Median PFS (95%CI)/months 1.4 (1.4-2.8) 2.7 (1.4-4.4) 2.8 (1.4-7.8) 3.5 (1.4-7.0) NA 5.8 (5.5-9.6)
Median OS (95%CI)/months 4.8 (2.1-10.9) 9.7 (3.7-27.6) 7.8 (4.7-NE) 13.9 (8.2-21.3) NA NE (9.6-NE)
6-month OS rate (95%CI)/% 40 (19-61) 52 (29-75) 61 (39-84) 90 (77-100) NA 89 (74-100)
1-year OS rate (95%CI)/% 25 (6-44) 37 (13-61) 43 (19-66) 57 (34-80) NA 66 (27-100)
Duration of follow-up/months, M (Range) 4.76 (0.3-29.9) 7.41 (1.2-29.2) 12.16 (0.7-29.2) 14.93 (1.7-26.3) 15.21 (2.4-27.5) 6.95 (0.8-14.6)

表4

不同生物标志物表达组间患者疗效汇总"

Items PD-L1+ (n=55) PD-L1- (n=62) MSI-H (n=9)
Atezolizumab (n=42) Atezolizumab + gemcitabine + cisplatin (n=13) Atezolizumab (n=56) Atezolizumab + gemcitabine + cisplatin (n=6) Atezolizumab (n=9)
ORR (95%CI)/% 11.9 (3.98-25.63) 46.2 (19.22-74.87) 8.9 (2.96-19.62) 33.3 (4.33-77.72) 11.1 (0.28-48.25)
  CR, n(%) 0 0 0 0 0
  PR, n(%) 5 (11.9) 6 (46.2) 5 (8.9) 2 (33.3) 1 (11.1)
  SD, n(%) 16 (38.1) 5 (38.5) 25 (44.6) 4 (66.7) 4 (44.4)
  DCRa, n(%) 21 (50.0) 11 (84.6) 30 (53.6) 6 (100.0) 5 (55.6)
  PD, n(%) 17 (40.5) 1 (7.7) 21 (37.5) 0 4 (44.4)
  NE, n(%) 0 0 0 0 0
  Missing, n(%) 4 (9.5) 1 (7.7) 5 (8.9) 0 0
Median DOR (95%CI)/months 20.8 (6.9-20.8) NE (5.6-NE) 17.1 (8.0-NE) NE (NE) NE
Median PFS (95%CI)/months 2.8 (1.4-4.4) 6.9 (5.5-NE) 2.7 (1.4-3.8) 5.8 (3.3-NE) 4.2 (1.4-15.0)
Median OS (95%CI)/months 14.9 (6.1-29.9) NE (9.6-NE) 9.7 (6.6-13.2) NE (3.8-NE) 15.0 (9.7-NE)
6-month OS rate (95%CI)/% 67 (52-82) 100 (100-100) 64 (52-77) 67 (29-100) 78 (51-100)
1-year OS rate (95%CI)/% 50 (34-67) 75 (33-100) 39 (26-52) NE (NE) 65 (32-97)
Duration of follow-up/months, M (Range) NA NA NA NA NA

表5

阿替利珠单抗单药或联合化疗治疗患者的安全性数据汇总"

Items Atezolizumaba (n=100) Atezolizumab+gemcitabine+cisplatina (n=20)
Patients with ≥1 AE, n(%) 98 (98.0) 20 (100.0)
  Serious AEs 41 (41.0) 8 (40.0)
    Leading to treatment discontinuation 16 (16.0) 0
    Leading to any dose modification/interruptionb 12 (12.0) 2 (10.0)
    Treatment-related 18 (18.0) 7 (35.0)
  AEs leading to treatment discontinuation 17 (17.0) 0
  AEs leading to any dose modification/interruptionb 28 (28.0) 4 (20.0)
  Treatment-related AEs 84 (84.0) 20 (100.0)
    Leading to treatment discontinuation 7 (7.0) 0
    Leading to any dose modification/interruptionb 17 (17.0) 2 (10.0)
  Grade 3/4 AEs 51 (51.0) 17 (85.0)
    Treatment-related 31 (31.0) 17 (85.0)
  Grade 5 AEs 11 (11.0) 1 (5.0)
    Treatment-related 1 (1.0)d 0
  AESIs 64 (64.0) 12 (60.0)
AEs, n 913 399
Deathsc, n(%) 71 (71.0) 3 (15.0)
Withdrawal from study due to an AE, n(%) 0 0

表6

阿替利珠单抗单药组的不良事件"

Items Atezolizumaba(n=100) Items Atezolizumaba(n=100)
AEs (≥10%), n(%) 98 (98.0) AEs leading to treatment discontinuation, n(%) 17 (17.0)
  Aspartate aminotransferase increased 30 (30.0)   Hepatic function abnormal 3 (3.0)
  Anemia 29 (29.0)   Death 2 (2.0)
  Pyrexia 28 (28.0)   Dyspnea 2 (2.0)
  Alanine aminotransferase increased 26 (26.0)   Aspartate aminotransferase increased 1 (1.0)
  Decreased appetite 24 (24.0)   Blood creatinine phosphokinase increased 1 (1.0)
  Fatigue 24 (24.0)   Esophagobronchial fistula 1 (1.0)
  Blood bilirubin increased 24 (24.0)   Fistula 1 (1.0)
  White blood cell count decreased 22 (22.0)   Hyponatremia 1 (1.0)
  Neutrophil count decreased 16 (16.0)   Neoplasm progression 1 (1.0)
  Bilirubin conjugated increased 15 (15.0)   Pneumonia fungal 1 (1.0)
  Hyponatremia 13 (13.0)   Polymyositis 1 (1.0)
  Weight decreased 13 (13.0)   Sudden death 1 (1.0)
  Proteinuria 13 (13.0)   Transaminases increased 1 (1.0)
  Upper respiratory tract infection 13 (13.0)
  Nausea 11 (11.0)
  Hypoalbuminemia 10 (10.0)

表7

阿替利珠单抗联合吉西他滨和顺铂组的不良事件(≥10%)"

Items Atezolizumab+ gemcitabine+ cisplatina (n=20)
Anemia 15 (75.0)
Decreased appetite 13 (65.0)
White blood cell count decreased 13 (65.0)
Nausea 11 (55.0)
Platelet count decreased 11 (55.0)
Neutrophil count decreased 10 (50.0)
Neutropenia 8 (40.0)
Vomiting 8 (40.0)
Alanine aminotransferase increased 7 (35.0)
Hypoalbuminemia 6 (30.0)
Leukopenia 6 (30.0)
Thrombocytopenia 6 (30.0)
Fatigue 5 (25.0)
Pyrexia 5 (25.0)
Rash 5 (25.0)
Aspartate aminotransferase increased 4 (20.0)
Asthenia 4 (20.0)
Hyponatremia 4 (20.0)
Lymphocyte count decreased 4 (20.0)
Productive cough 4 (20.0)
Blood lactate dehydrogenase increased 3 (15.0)
Bone marrow failure 3 (15.0)
Chest pain 3 (15.0)
Constipation 3 (15.0)
Gamma-glutamyltransferase increased 3 (15.0)
Hemoptysis 3 (15.0)
Hypoproteinemia 3 (15.0)
Weight decreased 3 (15.0)
Abdominal discomfort 2 (10.0)
Amylase increased 2 (10.0)
Bilirubin conjugated increased 2 (10.0)
Blood bilirubin increased 2 (10.0)
Blood creatinine increased 2 (10.0)
Hypochloremia 2 (10.0)
Hypokalemia 2 (10.0)
Hypothyroidism 2 (10.0)
1 International Agency for Research on Cancer. China (Globocan 2020)[EB/OL]. (2021-03)[2021-05-15] https://gco.iarc.fr/today/data/factsheets/populations/160-china-fact-sheets.pdf.
2 Arnold M , Soerjomataram I , Ferlay J , et al. Global incidence of oesophageal cancer by histological subtype in 2012[J]. Gut, 2015, 64 (3): 381- 387.
doi: 10.1136/gutjnl-2014-308124
3 Salehiniya H , Mohammadian M , Mohammadian-Hafshejani A , et al. Nasopharyngeal cancer in the world: Epidemiology, incidence, mortality and risk factors[J]. World Cancer Res J, 2018, 5 (1): e1046.
4 Merck. Highlights of prescribing information. Keytruda® (Pembrolizumab)[EB/OL]. (2014)[2022-05-12]. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf.
5 Fuchs CS , Doi T , Jang RW , et al. Safety and efficacy of pembro-lizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial[J]. JAMA Oncol, 2018, 4 (5): e180013.
doi: 10.1001/jamaoncol.2018.0013
6 Bristol Myers Squibb Company. Highlights of prescribing information. Opdivo (Nivolumab)[EB/OL]. (2014)[2022-05-03]. https://packageinserts.bms.com/pi/pi_opdivo.pdf.
7 Ma BBY , Lim WT , Goh BC , et al. Antitumor activity of ni-volumab in recurrent and metastatic nasopharyngeal carcinoma: An international, multicenter study of the Mayo clinic phase 2 consortium (NCI-9742)[J]. J Clin Oncol, 2018, 36 (14): 1412- 1418.
doi: 10.1200/JCO.2017.77.0388
8 NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer. Version 3.2022[EB/OL]. (2022-03-16)[2022-05]. http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
9 Herbst RS , Soria JC , Kowanetz M , et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients[J]. Nature, 2014, 515 (7528): 563- 567.
doi: 10.1038/nature14011
10 Weinstock C , Khozin S , Suzman D , et al. U.S. Food and Drug Administration approval summary: Atezolizumab for metastatic non-small cell lung cance[J]. Clin Cancer Res, 2017, 23 (16): 4534- 4539.
doi: 10.1158/1078-0432.CCR-17-0540
11 Genentech. FDA approves Genentech's Tecentriq plus chemothe-rapy (abraxane and carboplatin) for the initial treatment of metastatic non-squamous non-small cell lung cancer[N/OL]. (2019-12-03)[2021-05-03] https://www.gene.com/media/press-releases/14827/2019-12-03/fda-approves-genentechs-tecentriq-plus-c.
12 F. Hoffmann-La Roche Ltd. European Commission approves Roche's new Tecentriq-based combination therapy as an initial treatment for most common form of advanced lung cancer[N/OL]. (2019-09-06)[2021-05-11] https://www.roche.com/media/releases/med-cor-2019-09-06.htm.
13 F. Hoffmann-La Roche Ltd. FDA approves Roche's Tecentriq in combination with Avastin for people with the most common form of liver cancer[N/OL]. (2020-06-02)[2021-05-15] https://www.roche.com/media/releases/med-cor-2020-06-02.htm.
14 Finn RS , Qin S , Ikeda M , et al. Atezolizumab plus Bevacizumab in unresectable hepatocellular carcinoma[J]. N Engl J Med, 2020, 382 (20): 1894- 1905.
doi: 10.1056/NEJMoa1915745
15 Xu ZY , Brown L , Pan GW , et al. Lifestyle, environmental pollution and lung cancer in cities of Liaoning in northeastern China[J]. Lung Cancer, 1996, 14 (Suppl 1): S149- S160.
16 Grenade C , Phelps MA , Villalona-Calero MA . Race and ethnicity in cancer therapy: What have we learned?[J]. Clin Pharmacol Ther, 2014, 95 (4): 403- 412.
doi: 10.1038/clpt.2014.5
17 Genentech. Highlights of prescribing information. Tecentriq®(atezolizumab)[EB/OL]. (2016)[2022-05-15]. https://www.gene.com/download/pdf/tecentriq_prescribing.pdf.
18 West H , McCleod M , Hussein M , et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): A multicentre, randomised, open-label, phase 3 trial[J]. Lancet Oncol, 2019, 20 (7): 924- 937.
doi: 10.1016/S1470-2045(19)30167-6
19 Lee MS , Ryoo BY , Hsu CH , et al. Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): An open-label, multicentre, phase 1b study[J]. Lancet Oncol, 2020, 21 (6): 808- 820.
doi: 10.1016/S1470-2045(20)30156-X
20 Zhang T , Xie J , Arai S , et al. The efficacy and safety of anti-PD-1/PD-L1 antibodies for treatment of advanced or refractory can-cers: A meta-analysis[J]. Oncotarget, 2016, 7 (45): 73068- 73079.
doi: 10.18632/oncotarget.12230
21 Le DT , Kavan P , Kim TW , et al. KEYNOTE-164: Pembrolizu-mab for patients with advanced microsatellite instability high (MSI-H) colorectal cancer[J]. J Clin Oncol, 2018, 36 (Suppl 15): 3514.
doi: 10.1200/jco.2018.36.15_suppl.3514
22 Colevas AD , Bahleda R , Braiteh F , et al. Safety and clinical activity of atezolizumab in head and neck cancer: Results from a phase Ⅰ trial[J]. Ann Oncol, 2018, 29 (11): 2247- 2253.
doi: 10.1093/annonc/mdy411
23 Schiller JH , Harrington D , Belani CP , et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer[J]. N Engl J Med, 2002, 346 (2): 92- 98.
doi: 10.1056/NEJMoa011954
24 International Agency for Research on Cancer. All cancers (Globocan 2020)[EB/OL]. (2020-12)[2022-05-12] https://gco.iarc.fr/today/data/factsheets/cancers/39-All-cancers-fact-sheet.pdf.
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