PMID- 36041429
OWN - NLM
STAT- MEDLINE
DCOM- 20221018
LR  - 20221207
IS  - 2666-6340 (Electronic)
IS  - 2666-6340 (Linking)
VI  - 3
IP  - 10
DP  - 2022 Oct 14
TI  - Gemcitabine combined with apatinib and toripalimab in recurrent or metastatic 
      nasopharyngeal carcinoma.
PG  - 664-681.e6
LID - S2666-6340(22)00319-1 [pii]
LID - 10.1016/j.medj.2022.07.009 [doi]
AB  - BACKGROUND: The role of a triple combination of gemcitabine (chemotherapy) plus 
      apatinib (anti-vascular endothelial growth factor [VEGFR]) and toripalimab 
      (anti-PD-1) (GAT) in recurrent/metastatic nasopharyngeal carcinoma (RM-NPC) is 
      unclear. METHODS: Between August 2019 and April 2020, 41 patients with RM-NPC 
      were enrolled and received GAT for up to 6 cycles followed by apatinib and 
      toripalimab. The primary endpoint was the safety. The secondary endpoints 
      included the objective response rate (ORR) and progression-free survival (PFS). 
      Integrated genomic and transcriptional analyses were conducted to identify the 
      patients who benefited in response to this novel combination therapy. FINDINGS: 
      As of April 1, 2022, treatment-related grade 3 or 4 adverse events (AEs) occurred 
      in 23 of 41 patients (56.1%, 95% confidence interval [CI] 41%-70.1%). G3-4 
      nasopharyngeal necrosis was observed in 9 (9/41, 21.9%) patients. High-risk 
      factors for necrosis included repeated radiotherapy and an interval of less than 
      12 months from the last radiotherapy. The ORR was 90.2% (95% CI: 76.9%-97.2%). 
      The median PFS was 25.8 months (95% CI: not reached (NR)-NR), and the 24-month 
      PFS rate was 50.7% (95% CI: 34.0%-67.4%). MAS-related GPR family member F 
      (MRGPRF) high expression in tumors correlated with poor PFS from the GAT therapy, 
      characterized by high epithelial mesenchymal transition signatures. Serial 
      circulating tumor DNA (ctDNA) sequencing could predict PFS outcomes to 
      combination therapy. CONCLUSIONS: GAT therapy exhibits a promising antitumor 
      activity and manageable toxicities in patients with RM-NPC. Patients with 
      repeated radiotherapy and an interval of less than 12 months from the last 
      radiotherapy should be carefully selected for antiangiogenic therapies. MRGPRF 
      expression and serial ctDNA monitoring could identify patients that derive 
      benefits from the combination therapy. TRIAL REGISTRATION: ClinicalTrials.gov: 
      NCT04073784. FUNDING: This research was funded by the National Natural Science 
      Foundation of China (nos. 81772895 and 82002857), the Key-Area Research and 
      Development of Guangdong Province (2020B1111190001), the Special Support Program 
      for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou 
      Science and Technology Plan Project (202103010001), and the National "Ten 
      Thousand Talents Program" Science and Technology Innovation Leading Talents 
      (84000-41180005).
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - You, Rui
AU  - You R
AD  - Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 
      Dongfeng East Road, Guangzhou 510060, P.R. China; Sun Yat-sen University Cancer 
      Center, State Key Laboratory of Oncology in South China, Collaborative Innovation 
      Center for Cancer Medicine, Guangzhou 510060, P.R. China; Guangdong Key 
      Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, 
      P.R. China.
FAU - Zou, Xiong
AU  - Zou X
AD  - Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 
      Dongfeng East Road, Guangzhou 510060, P.R. China; Sun Yat-sen University Cancer 
      Center, State Key Laboratory of Oncology in South China, Collaborative Innovation 
      Center for Cancer Medicine, Guangzhou 510060, P.R. China; Guangdong Key 
      Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, 
      P.R. China.
FAU - Ding, Xi
AU  - Ding X
AD  - Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 
      Dongfeng East Road, Guangzhou 510060, P.R. China; Sun Yat-sen University Cancer 
      Center, State Key Laboratory of Oncology in South China, Collaborative Innovation 
      Center for Cancer Medicine, Guangzhou 510060, P.R. China; Guangdong Key 
      Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, 
      P.R. China.
FAU - Zhang, Wei-Jing
AU  - Zhang WJ
AD  - Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South 
      China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, 
      P.R. China; Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and 
      Therapy, Guangzhou 510060, P.R. China; Department of Medical Imaging, Sun Yat-sen 
      University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, P.R. China.
FAU - Zhang, Meng-Xia
AU  - Zhang MX
AD  - Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 
      Dongfeng East Road, Guangzhou 510060, P.R. China; Sun Yat-sen University Cancer 
      Center, State Key Laboratory of Oncology in South China, Collaborative Innovation 
      Center for Cancer Medicine, Guangzhou 510060, P.R. China; Guangdong Key 
      Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, 
      P.R. China.
FAU - Wang, Xiao
AU  - Wang X
AD  - Novogene Co, Ltd, Beijing 100000, P.R. China.
FAU - Xu, Han-Shi
AU  - Xu HS
AD  - Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 
      Dongfeng East Road, Guangzhou 510060, P.R. China; Sun Yat-sen University Cancer 
      Center, State Key Laboratory of Oncology in South China, Collaborative Innovation 
      Center for Cancer Medicine, Guangzhou 510060, P.R. China; Guangdong Key 
      Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, 
      P.R. China.
FAU - Liu, Yong-Long
AU  - Liu YL
AD  - Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 
      Dongfeng East Road, Guangzhou 510060, P.R. China; Sun Yat-sen University Cancer 
      Center, State Key Laboratory of Oncology in South China, Collaborative Innovation 
      Center for Cancer Medicine, Guangzhou 510060, P.R. China; Guangdong Key 
      Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, 
      P.R. China.
FAU - Ouyang, Yan-Feng
AU  - Ouyang YF
AD  - Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 
      Dongfeng East Road, Guangzhou 510060, P.R. China; Sun Yat-sen University Cancer 
      Center, State Key Laboratory of Oncology in South China, Collaborative Innovation 
      Center for Cancer Medicine, Guangzhou 510060, P.R. China; Guangdong Key 
      Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, 
      P.R. China.
FAU - Duan, Chong-Yang
AU  - Duan CY
AD  - Department of Biostatistics, School of Public Health, Southern Medical 
      University, Guangzhou 510515, P.R. China.
FAU - Gu, Chen-Mei
AU  - Gu CM
AD  - Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 
      Dongfeng East Road, Guangzhou 510060, P.R. China; Sun Yat-sen University Cancer 
      Center, State Key Laboratory of Oncology in South China, Collaborative Innovation 
      Center for Cancer Medicine, Guangzhou 510060, P.R. China; Guangdong Key 
      Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, 
      P.R. China.
FAU - Wang, Zhi-Qiang
AU  - Wang ZQ
AD  - Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 
      Dongfeng East Road, Guangzhou 510060, P.R. China; Sun Yat-sen University Cancer 
      Center, State Key Laboratory of Oncology in South China, Collaborative Innovation 
      Center for Cancer Medicine, Guangzhou 510060, P.R. China; Guangdong Key 
      Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, 
      P.R. China.
FAU - Liu, You-Ping
AU  - Liu YP
AD  - Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 
      Dongfeng East Road, Guangzhou 510060, P.R. China; Sun Yat-sen University Cancer 
      Center, State Key Laboratory of Oncology in South China, Collaborative Innovation 
      Center for Cancer Medicine, Guangzhou 510060, P.R. China; Guangdong Key 
      Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, 
      P.R. China.
FAU - Hua, Yi-Jun
AU  - Hua YJ
AD  - Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 
      Dongfeng East Road, Guangzhou 510060, P.R. China; Sun Yat-sen University Cancer 
      Center, State Key Laboratory of Oncology in South China, Collaborative Innovation 
      Center for Cancer Medicine, Guangzhou 510060, P.R. China; Guangdong Key 
      Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, 
      P.R. China.
FAU - Huang, Pei Yu
AU  - Huang PY
AD  - Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 
      Dongfeng East Road, Guangzhou 510060, P.R. China; Sun Yat-sen University Cancer 
      Center, State Key Laboratory of Oncology in South China, Collaborative Innovation 
      Center for Cancer Medicine, Guangzhou 510060, P.R. China; Guangdong Key 
      Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, 
      P.R. China.
FAU - Chen, Ming-Yuan
AU  - Chen MY
AD  - Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 
      Dongfeng East Road, Guangzhou 510060, P.R. China; Sun Yat-sen University Cancer 
      Center, State Key Laboratory of Oncology in South China, Collaborative Innovation 
      Center for Cancer Medicine, Guangzhou 510060, P.R. China; Guangdong Key 
      Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou 510060, 
      P.R. China. Electronic address: chmingy@mail.sysu.edu.cn.
LA  - eng
SI  - ClinicalTrials.gov/NCT04073784
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220829
PL  - United States
TA  - Med
JT  - Med (New York, N.Y.)
JID - 101769215
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Circulating Tumor DNA)
RN  - 0 (Endothelial Growth Factors)
RN  - 0 (Pyridines)
RN  - 0W860991D6 (Deoxycytidine)
RN  - 5S371K6132 (apatinib)
RN  - 8JXN261VVA (toripalimab)
RN  - 0 (Gemcitabine)
SB  - IM
MH  - Antibodies, Monoclonal, Humanized
MH  - Circulating Tumor DNA
MH  - Clinical Trials as Topic
MH  - Deoxycytidine/analogs & derivatives
MH  - Endothelial Growth Factors/therapeutic use
MH  - Humans
MH  - *Nasopharyngeal Carcinoma/drug therapy
MH  - *Nasopharyngeal Neoplasms/drug therapy
MH  - Necrosis
MH  - Neoplasm Recurrence, Local/drug therapy
MH  - Pyridines
MH  - Gemcitabine
OTO - NOTNLM
OT  - MRGPRF
OT  - Translation to patients
OT  - apatinib
OT  - ct-DNA sequencing
OT  - gemcitabine
OT  - genomic
OT  - nasopharyngeal carcinoma
OT  - recurrent/metastatic
OT  - toripalimab
OT  - transcriptional analyses
COIS- Declaration of interests All authors declare no conflicts of interest.
EDAT- 2022/08/31 06:00
MHDA- 2022/10/19 06:00
CRDT- 2022/08/30 18:42
PHST- 2022/03/08 00:00 [received]
PHST- 2022/06/07 00:00 [revised]
PHST- 2022/07/27 00:00 [accepted]
PHST- 2022/08/31 06:00 [pubmed]
PHST- 2022/10/19 06:00 [medline]
PHST- 2022/08/30 18:42 [entrez]
AID - S2666-6340(22)00319-1 [pii]
AID - 10.1016/j.medj.2022.07.009 [doi]
PST - ppublish
SO  - Med. 2022 Oct 14;3(10):664-681.e6. doi: 10.1016/j.medj.2022.07.009. Epub 2022 Aug 
      29.