妇科肿瘤免疫检查点抑制剂临床应用指南Guidelines for clinical application of immune checkpoint inh i bitor in gynecological tumor
孔北华;刘继红;周云;高庆蕾;宋坤;王登凤;陈丽莉;蒋芳;张国楠;向阳;谢幸;马丁;
摘要(Abstract):
<正>肿瘤免疫治疗是继手术治疗、化学治疗(化疗)和放射治疗(放疗)后的第4种肿瘤治疗模式。肿瘤免疫机制复杂,长期以来对其认识不足,肿瘤免疫治疗疗效不佳。自2011年伊匹木单抗在美国获批上市以来,免疫检查点抑制剂(immune checkpoint inhi bitor,ICI)在肿瘤免疫治疗方面取得了突破性进展,特别是在霍奇金淋巴瘤、黑色素瘤等肿瘤的治疗中取得了显著临床疗效。在妇科肿瘤领域,临床研究表明ICI应用于晚期/复发患者具有一定的疗效,国际上已有ICI获批用于妇科肿瘤的临床治疗。
关键词(KeyWords):
基金项目(Foundation):
作者(Authors): 孔北华;刘继红;周云;高庆蕾;宋坤;王登凤;陈丽莉;蒋芳;张国楠;向阳;谢幸;马丁;
参考文献(References):
- [1]BRUNET J F,DENIZOT F,LUCIANI M F,et al.A new member of the immunoglobulin superfamily-CTLA-4[J].Nature,1987,328(6127):267-270.
- [2]KRUMMEL M F,ALLISON J P.CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation[J].JExp Med,1995,182(2):459-465.
- [3]EGEN J G,KUHNS M S,ALLISON J P.CTLA-4:new insights into its biological function and use in tumor immunotherapy[J].Nat Immunol,2002,3(7):611-618.
- [4]ISHIDA Y,AGATA Y,SHIBAHARA K,et al.Induced expression of PD-1,a novel member of the immunoglobulin gene super family,upon programmed cell death[J].EMBO J,1992,11(11):3887-3895.
- [5]NISHIMURA H,NOSE M,HIAI H,et al.Development of lupus-like autoimmune diseases by disruption of the PD-1gene encoding an ITIM motif-carrying immunoreceptor[J].Immunity,1999,11(2):141-151.
- [6]KORMAN A J,PEGGS K S,ALLISON J P.Checkpoint blockade in cancer immunotherapy[J].Adv Immunol,2006,90:297-339.
- [7]WEI S C,LEVINE J H,COGDILL A P,et al.Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade[J].Cell,2017,170(6):1120-1133.
- [8]ANDERSON A C,JOLLER N,KUCHROO V K.Lag-3,Tim-3,and TIGIT:Co-inhibitory Receptors with Specialized Functions in Immune Regulation[J].Immunity,2016,44(5):989-1004.
- [9]DUAN J,CUI L,ZHAO X,et al.Use of Immunotherapy With Programmed Cell Death 1 vs Programmed Cell Death Ligand1 Inhibitors in Patients With Cancer:A Systematic Review and Meta-analysis[J].JAMA Oncol,2020,6(3):375-384.
- [10]SCHUMACHER T N,SCHREIBER R D.Neoantigens in cancer immunotherapy[J].Science,2015,348(6230):69-74.
- [11]GUBIN M M,ZHANG X,SCHUSTER H,et al.Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens[J].Nature,2014,515(7528):577-581.
- [12]KIM J Y,KRONBICHLER A,EISENHUT M,et al.Tumor Mutational Burden and Efficacy of Immune Checkpoint Inhibitors:A Systematic Review and Meta-Analysis[J].Cancers(Basel),2019,11(11):1798.
- [13]BHANGOO M S,BOASBERG P,MEHTA P,et al.Tumor Mutational Burden Guides Therapy in a Treatment Refractory POLE-Mutant Uterine Carcinosarcoma[J].Oncologist,2018,23(5):518-523.
- [14]ASAOKA Y,LJICHI H,KOIKE K.PD-1 Blockade in Tumors with Mismatch-Repair Deficiency[J].N Engl J Med,2015,373(20):1979.
- [15]CHEN P L,ROH W,REUBEN A,et al.Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade[J].Cancer Discov,2016,6(8):827-837.
- [16]WOLCHOK J D,HOOS A,O'DAY S,et al.Guidelines for the evaluation of immune therapy activity in solid tumors:immune-related response criteria[J].Clin Cancer Res,2009,15(23):7412-7420.
- [17]SEYMOUR L,BOGAERTS J,PERRONE A,et al.iRECIST:guidelines for response criteria for use in trials testing immunotherapeutics[J].Lancet Oncol,2017,18(3):e143-e152.
- [18]HODI F S,BALLINGER M,LYONS B,et al.ImmuneModified Response Evaluation Criteria In Solid Tumors(imRECIST):Refining Guidelines to Assess the Clinical Benefit of Cancer Immunotherapy[J].J Clin Oncol,2018,36(9):850-858.
- [19]NISHINO M,GARGANO M,SUDA M,et al.Optimizing immune-related tumor response assessment:does reducing the number of lesions impact response assessment in melanoma patients treated with ipilimumab?[J].J Immunother Cancer,2014,2:17.
- [20]CHIOU V L,BUROTTO M.Pseudoprogression and ImmuneRelated Response in Solid Tumors[J].J Clin Oncol,2015,33(31):3541-3543.
- [21]CHAMPIAT S,DERCLE L,AMMARI S,et al.Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by Anti-PD-1/PD-L1[J].Clin Cancer Res,2017,23(8):1920-1928.
- [22]BILLAN S,KAIDAR-PERSON O,GIL Z.Treatment after progression in the era of immunotherapy[J].Lancet Oncol,2020,21(10):e463-e476.
- [23]HERZOG T J,ARGUELLO D,REDDY S K,et al.PD-1,PD-L1 expression in 1599 gynecological cancers:Implications for immun otherapy[J].Gynecol Oncol,2015,137:204-205.
- [24]BONNEVILLE R,KROOK M A,KAUTTO E A,et al.Landscape of Microsatellite Instability Across 39 Cancer Types[J].JCO Precis Oncol,2017,2017:PO.17.00073.
- [25]SHAO C,LI G,HUANG L,et al.Prevalence of High Tumor Mutational Burden and Association With Survival in Patients With Less Common Solid Tumors[J].JAMA Netw Open,2020,3(10):e2025109.
- [26]LE D T,DURHAM J N,SMITH K N,et al.Mismatch repair deficiency predicts response of solid tumors to PD-1blockade[J].Science,2017,357(6349):409-413.
- [27]MARABELLE A,LE D T,ASCIERTO P A,et al.Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer:Results From the PhaseⅡKEYNOTE-158 Study[J].J Clin Oncol,2020,38(1):1-10.
- [28]MARABELLE A,FAKIH M,LOPEZ J,et al.Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab:prospective biomarker analysis of the multicohort,openlabel,phase 2 KEYNOTE-158 study[J].Lancet Oncol,2020,21(10):1353-1365.
- [29]OTT P A,BANG Y J,BERTON-RIGAUD D,et al.Safety and Antitumor Activity of Pembrolizumab in Advanced Programmed Death Ligand 1-Positive Endometrial Cancer:Results From the KEYNOTE-028 Study[J].J Clin Oncol,2017,35(22):2535-2541.
- [30]AZAD N S,GRAY R J,OVERMAN M J,et al.Nivolumab Is Effective in Mismatch Repair-Deficient Noncolorectal Cancers:Results From Arm Z1D-A Subprotocol of the NCI-MATCH(EAY131) Study[J].J Clin Oncol,2020,38(3):214-222.
- [31]OAKNIN A,GILBERT L,TINKER A,et al.Interim analysis of the immune-related endpoints of the mismatch repair deficient(dMMR) and proficient (MMRp) endometrial cancer cohorts from the GARNET study[C/OL].Society of Gynecological Oncology 2021 Virtual Annual Meeting on Women's Cancer,2021.(2021-03-19)[2021-08-23].https://www.gynecologiconcology-online.net/article/S0090-8258(21)00672-7/fulltext.
- [32]ANTILL Y C,KOK P S,ROBLEDO K P,et al.Activity of durvalumab in advanced endometrial cancer (AEC) according to mismatch repair (MMR) status:The phaseⅡPHAEDRA trial(ANZGOG1601)[J].J Clin Oncol,2019,37(15_suppl):5501.
- [33]KONSTANTINOPOULOS P A,LUO W,LIU J F,et al.PhaseⅡStudy of Avelumab in Patients With Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer[J].J Clin Oncol,2019,37(30):2786-2794.
- [34]TAMURA K,HASEGAWA K,KATSUMATA N,et al.Efficacy and safety of nivolumab in Japanese patients with uterine cervical cancer,uterine corpus cancer,or soft tissue sarcoma:Multicenter,open-label phase 2 trial[J].Cancer Sci,2019,110(9):2894-2904.
- [35]FLEMING G F,EMENS L A,EDER J,et al.Clinical activity,safety and biomarker results from a phaseⅠa study of atezolizumab (atezo) in advanced/recurrent endometrial cancer (rEC)[J].J Clin Oncol,2017,35(15_suppl):5585.
- [36]HUANG Y,KIM B Y S,CHAN C K,et al.Improving immunevascular crosstalk for cancer immunotherapy[J].Nat Rev Immunol,2018,18(3):195-203.
- [37]MAKKER V,TAYLOR M H,AGHAJANIAN C,et al.Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer[J].J Clin Oncol,2020,38(26):2981-2992.
- [38]MAKKER V,COLOMBO N,HERRáEZ A C,et al.A multicenter,open-label,randomized,phaseⅢstudy to compare the efficacy and safety of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer[C/OL].Society of Gynecological Oncology 2021 Virtual Annual Meeting on Women's Cancer,2021.(2021-03-19)[2021-08-23].https://www.gynecolo giconcology-online.net/article/S0090-8258(21)00657-0/fulltext.
- [39]ZITVOGEL L,KEPP O,KROEMER G.Immune parameters affecting the efficacy of chemotherapeutic regimens[J].Nat Rev Clin Oncol,2011,8(3):151-160.
- [40]SAMANTA D,PARK Y,NI X,et al.Chemotherapy induces enrichment of CD47+/CD73+/PDL1+immune evasive triplenegative breast cancer cells[J].Proc Natl Acad Sci U S A,2018,115(6):E1239-E1248.
- [41]WANG W,KRYCZEK I,DOSTáL L,et al.Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer[J].Cell,2016,165(5):1092-1105.
- [42]PINEDA M J,SCHILDER J,HILL E K,et al.A Big Ten Cancer Research Consortium phaseⅡtrial of pembrolizumab with carboplatin and paclitaxel for advanced or recurrent endometrial cancer[J].J Clin Oncol,2020,38(15_suppl):6022.
- [43]LIU Y,WU L,TONG R,et al.PD-1/PD-L1 Inhibitors in Cervical Cancer[J].Front Pharmacol,2019,10:65.
- [44]FRENEL J S,LE TOURNEAU C,O'NEIL B,et al.Safety and Efficacy of Pembrolizumab in Advanced,Programmed Death Ligand 1-Positive Cervical Cancer:Results From the PhaseⅠb KEYNOTE-028 Trial[J].J Clin Oncol,2017,35(36):4035-4041.
- [45]CHUNG H C,ROS W,DELORD J P,et al.Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer:Results From the PhaseⅡKEYNOTE-158 Study[J].JClin Oncol,2019,37(17):1470-1478.
- [46]NAUMANN R W,HOLLEBECQUE A,MEYER T,et al.Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical,Vaginal,or Vulvar Carcinoma:Results From the PhaseⅠ/ⅡCheck Mate 358 Trial[J].J Clin Oncol,2019,37(31):2825-2834.
- [47]SANTIN A D,DENG W,FRUMOVITZ M,et al.PhaseⅡevaluation of nivolumab in the treatment of persistent or recurrent cervical cancer (NCT02257528/NRG-GY002)[J].Gynecol Oncol,2020,157(1):161-166.
- [48]WU X,XIA L,ZHOU Q,et al.Gls-010,a novel anti-PD-1mAb in Chinese patients with recurrent or metastatic cervical cancer:Results from a multicenter,open-label and single-arm phase II trial[J].J Clin Oncol,2020,38(15_suppl):6032.
- [49]TEWARI K S,MONK B J,VERGOTE I,et al.VP4-2021:EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9:Interim analysis of phaseⅢtrial of cemiplimab vs.investigator's choice(IC) chemotherapy (chemo) in recurrent/metastatic (R/M)cervical carcinoma[J].Ann Oncol,2021,32(7):940-941.
- [50]COLOMBO N,DUBOT C,LORUSSO D,et al.Pembro lizumab for Persistent,Recurrent,or Metastatic Cervical Cancer[J].Engl J Med,2021.Epub ahead of print.
- [51]O'MALLEY D M,OAKNIN A,MONK B J,et al.LBA34Single-agent anti-PD-1 balstilimab or in combination with anti-CTLA-4 zalifrelimab for recurrent/metastatic (R/M)cervical cancer (CC):Preliminary results of two independent phaseⅡtrials-ScienceDirect[J].Ann Oncol,2020,31(Suppl4):S1164-S1165.
- [52]NAUMANN R W,OAKNIN A,MEYER T,et al.Efficacy and safety of nivolumab (Nivo)+ipilimumab (Ipi) in patients (pts)with recurrent/metastatic (R/M) cervical cancer:Results from CheckMate 358[J].Ann Oncol,2019,30(Suppl 5):v898-v899.
- [53]LAN C,SHEN J,WANG Y,et al.Camrelizumab Plus Apatinib in Patients With Advanced Cervical Cancer (CLAP):AMulticenter,Open-Label,Single-Arm,PhaseⅡTrial[J].J Clin Oncol,2020,38(34):4095-4106.
- [54]XIA L,ZHOU Q,ZHANG Y,et al.840P Famitinib malate plus camrelizumab for recurrent platinum-resistant ovarian/fallopian tube/primary peritoneal cancer and advanced cervical cancer:An open-label,multicenter phaseⅡstudy[J].Ann Oncol,2020,31(Suppl 4):S630.
- [55]XU Q,CHEN C B,SUN Y,et al.Anlotinib plus sintilimab in patients with recurrent advanced cervical cancer:A prospective,multicenter,single-arm,phaseⅡclinical trial[C].Chicago:ASCO,2021:abs 5524.
- [56]FRIEDMAN C F,SNYDER CHAREN A,ZHOU Q,et al.PhaseⅡstudy of atezolizumab in combination with bevaci zumab in patients with advanced cervical cancer[J].J Imm unother Cancer,2020,8(2):e001126.
- [57]WANG M,FAN W,YE M,et al.Molecular profiles and tumor mutational burden analysis in Chinese patients with gynecologic cancers[J].Sci Rep,2018,8(1):8990.
- [58]CHIN C D,FARES C M,CAMPOS M,et al.Association of PD-L1 expression by immunohistochemistry and gene microarray with molecular subtypes of ovarian tumors[J].Mod Pathol,2020,33(10):2001-2010.
- [59]BRAHMER J R,TYKODI S S,CHOW L Q,et al.Safety and activity of anti-PD-L1 antibody in patients with advanced cancer[J].N Engl J Med,2012,366(26):2455-2465.
- [60]HAMANISHI J,MANDAI M,IKEDA T,et al.Safety and Antitumor Activity of Anti-PD-1 Antibody,Nivolumab,in Patients With Platinum-Resistant Ovarian Cancer[J].J Clin Oncol,2015,33(34):4015-4022.
- [61]HAMANISHI J,TAKESHIMA N,KATSUMATA N,et al.Nivolumab Versus Gemcitabine or Pegylated Liposomal Doxorubicin for Patients With Platinum-Resistant Ovarian Cancer:Open-Label,Randomized Trial in Japan (NINJA)[J].J Clin Oncol,2021:JCO2100334.
- [62]VARGA A,PIHA-PAUL S,OTT P A,et al.Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer:Analysis of KEYNOTE-028[J].Gynecol Oncol,2019,152(2):243-250.
- [63]MATULONIS U A,SHAPIRA R,SANTIN A,et al.Final results from the KEYNOTE-100 trial of pembrolizumab in patients with advanced recurrent ovarian cancer[J].J Clin Oncol,2020,38(15_suppl):6005.
- [64]LIU J F,GORDON M,VENERIS J,et al.Safety,clinical activity and biomarker assessments of atezolizumab from a Phase I study in advanced/recurrent ovarian and uterine cancers[J].Gynecol Oncol,2019,154(2):314-322.
- [65]DISIS M L,TAYLOR M H,KELLY K,et al.Efficacy and Safety of Avelumab for Patients With Recurrent or Refractory Ovarian Cancer:Phase 1b Results From the JAVELIN Solid Tumor Trial[J].JAMA Oncol,2019,5(3):393-401.
- [66]PUJADE-LAURAINE E,FUJIWARA K,LEDERMANN J A,et al.Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinumrefractory ovarian cancer (JAVELIN Ovarian 200):an openlabel,three-arm,randomised,phase 3 study[J].Lancet Oncol,2021,22(7):1034-1046.
- [67]MONK B J,COLOMBO N,OZA A M,et al.Chemotherapy with or without avelumab followed by avelumab maintenance versus chemotherapy alone in patients with previously untreated epithelial ovarian cancer (JAVELIN Ovarian 100):an open-label,randomised,phase 3 trial[J].Lancet Oncol,2021:S1470-2045(21)00342-9.
- [68]O'CEARBHAILL R E,HOMICSKO K,WOLFER A,et al.AphaseⅠ/Ⅱstudy of chemo-immunotherapy with durvalumab(durva) and pegylated liposomal doxorubicin (PLD) in platinum-resistant recurrent ovarian cancer (PROC):Genomic sequencing and updated efficacy results[J].Gynecol Oncol,2020,159(Suppl_1):41.
- [69]LEE E K,XIONG N,CHENG S C,et al.Combined pembrolizumab and pegylated liposomal doxorubicin in platinum resistant ovarian cancer:A phase 2 clinical trial[J].Gynecol Oncol,2020,159(1):72-78.
- [70]WALSH C S,KAMRAVA M,ROGATKO A,et al.PhaseⅡtrial of cisplatin,gemcitabine and pembrolizumab for platinumresistant ovarian cancer[J].PLoS One,2021,16(6):e0252665.
- [71]ZAMARIN D,BURGER R A,SILL M W,et al.Randomized PhaseⅡTrial of Nivolumab Versus Nivolumab and Ipilimumab for Recurrent or Persistent Ovarian Cancer:An NRG Oncology Study[J].J Clin Oncol,2020,38(16):1814-1823.
- [72]MORONEY J W,POWDERLY J,LIEU C H,et al.Safety and Clinical Activity of Atezolizumab Plus Bevacizumab in Patients with Ovarian Cancer:A PhaseⅠb Study[J].Clin Cancer Res,2020,26(21):5631-5637.
- [73]LIU J F,HEROLD C,GRAY K P,et al.Assessment of Combined Nivolumab and Bevacizumab in Relapsed Ovarian Cancer:A Phase 2 Clinical Trial[J].JAMA Oncol,2019,5(12):1731-1738.
- [74]GONZáLEZ-MARTíN A,CHUNG H,SAADA-BOUZID E,et al.Efficacy and safety of lenvatinib plus pembrolizumab in patients with previously treated ovarian cancer in the multicohort phase 2 LEAP-005 study[J].Int J Gynecol Cancer,2020,30(Suppl 3):A1-A2.
- [75]DREW Y,KAUFMAN B,BANERJEE S,et al.PhaseⅡstudy of olaparib+durvalumab (MEDIOLA):Updated results in germline BRCA-mutated platinum-sensitive relapsed (PSR)ovarian cancer (OC)[J].Ann Oncol,2019,30:v485-v486.
- [76]KONSTANTINOPOULOS P A,WAGGONER S,VIDAL G A,et al.Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma[J].JAMA Oncol,2019,5(8):1141-1149.
- [77]ZSIROS E,LYNAM S,ATTWOOD K M,et al.Efficacy and Safety of Pembrolizumab in Combination With Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Ovarian Cancer:A Phase 2 Nonrandomized Clinical Trial[J].JAMA Oncol,2021,7(1):78-85.
- [78]DREW Y,PENSON R T,O'MALLEY D M,et al.814MOPhaseⅡstudy of olaparib (O) plus durvalumab (D) and bevacizumab (B)(MEDIOLA):Initial results in patients (pts) with nongermline BRCA-mutated (non-gBRCAm) platinum sensitive relapsed (PSR) ovarian cancer (OC)[J].Ann Oncol,2020,31:S615-S616.
- [79]MOORE K N,BOOKMAN M,SEHOULI J,et al.Atezolizumab,Bevacizumab,and Chemotherapy for Newly Diagnosed StageⅢorⅣOvarian Cancer:Placebo-Controlled Rand omized PhaseⅢTrial (IMagyn050/GOG 3015/ENGOT-OV39)[J].J Clin Oncol,2021,39(17):1842-1855.
- [80]GHORANI E,KAUR B,FISHER R A,et al.Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia[J].Lancet,2017,390(10110):2343-2345.
- [81]HUANG M,PINTO A,CASTILLO R P,et al.Complete Serologic Response to Pembrolizumab in a Woman With Chemoresistant Metastatic Choriocarcinoma[J].J Clin Oncol,2017,35(27):3172-3174.
- [82]CHOI M C,OH J,LEE C.Effective anti-programmed cell death 1 treatment for chemoresistant gestational trophoblastic neoplasia[J].Eur J Cancer,2019,121:94-97.
- [83]程红燕,杨隽钧,赵峻,等.PD-1抑制剂治疗耐药复发妊娠滋养细胞肿瘤的初步探讨[J].中华妇产科杂志,2020,55(6):390-394.
- [84]YOU B,BOLZE P A,LOTZ J P,et al.Avelumab in Patients With Gestational Trophoblastic Tumors With Resistance to Single-Agent Chemotherapy:Cohort A of the TROPHIMMUNPhaseⅡTrial[J].J Clin Oncol,2020,38(27):3129-3137.
- [85]CHENG H,YANG J,ZHAO J,et al.177 Camrelizumab combined with apatinib for refractory gestational trophoblastic neoplasia:A phase 2,single-arm,prospective Study[J].Int JGynecol Cancer,2020,30(Suppl 3):A76-A77.
- [86]CURTI B D,FARIES M B.Recent Advances in the Treatment of Melanoma[J].N Engl J Med,2021,384(23):2229-2240.
- [87]INDINI A,DI GUARDO L,CIMMINIELLO C,et al.Investigating the role of immunotherapy in advanced/recurrent female genital tract melanoma:a preliminary experience[J].JGynecol Oncol,2019,30(6):e94.
- [88]FROMMER R S,MILESHKIN L,MANZYUK L,et al.Pembrolizumab for Vulvar Squamous Cell Carcinoma:Results From the Phase 2 KEYNOTE-158 Study[C/OL].Society of Gynecol ogical Oncology 2021 Virtual Annual Meeting on Women's Cancer;2021.(2021-03-19)[2021-08-23].https://www.gynecologiconcology-online.net/article/S0090-8258(21)00728-9/fulltext.
- [89]HAANEN J B A G,CARBONNEL F,ROBERT C,et al.Management of toxicities from immunotherapy:ESMO Clinical Practice Guidelines for diagnosis,treatment and follow-up[J].Ann Oncol,2017,28(suppl_4):iv119-iv142.
- [90]PUZANOV I,DIAB A,ABDALLAH K,et al.Managing toxicities associated with immune checkpoint inhibitors:consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group[J].J Immunother Cancer,2017,5(1):95.
- [91]National Comprehensive Cancer Network.NCCN Clinical Practice Guidelines in Oncology:Management of ImmunotherapyRelated Toxicities (Version 3.2021)[OL].[2021-08-13].https://www.nccn.org/professionals/physician_gls/pdf/immuno therapy.pdf.
- [92]TEUFEL A,ZHAN T,H?RTEL N,et al.Management of immune related adverse events induced by immune checkpoint inhibition[J].Cancer Lett,2019,456:80-87.
- [93]BERTRAND A,KOSTINE M,BARNETCHE T,et al.Immune related adverse events associated with anti-CTLA-4 antibodies:systematic review and meta-analysis[J].BMC Med,2015,13:211.
- [94]WANG P F,CHEN Y,SONG S Y,et al.Immune-Related Adverse Events Associated with Anti-PD-1/PD-L1 Treatment for Malignancies:A Meta-Analysis[J].Front Pharmacol,2017,8:730.
- [95]WANG D Y,SALEM J E,COHEN J V,et al.Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors:ASystematic Review and Meta-analysis[J].JAMA Oncol,2018,4(12):1721-1728.
- [96]DISIS M L,TAYLOR M H,KELLY K,et al.Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer:phase 1b results from the JAVELIN solid tumor trial[J].JAMA Oncol,2019,5(3):393-401.
- [97]YUEN C,FLEMING G,MEYERS M,et al.Myasthenia gravis induced by avelumab[J].Immunotherapy,2019,11(14):1181-1185.
- [98]MINION L E,TEWARI K S.Cervical cancer-State of the science:From angiogenesis blockade to checkpoint inhibition[J].Gynecol Oncol,2018,148(3):609-621.
- [99]NAIDOO J,WANG X,WOO K M,et al.Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy[J].J Clin Oncol,2017,35(7):709-717.
- [100]NAIDOO J,PAGE D B,LI B T,et al.Toxicities of the antiPD-1 and anti-PD-L1 immune checkpoint antibodies[J].Ann Oncol,2015,26(12):2375-2391.
- [101]KHUNGER M,RAKSHIT S,PASUPULETI V,et al.Incidence of Pneumonitis With Use of Programmed Death 1