西妥昔单抗联合化疗ppt课件

1、西妥昔单抗结合化疗西妥昔单抗结合化疗胃癌一线治疗的新契机胃癌一线治疗的新契机chances of cetuximab in the first line treatment of AGC张张 小小 田田北京大学临床肿瘤学院消化内科北京大学临床肿瘤学院消化内科Dr. Xiaotian ZhangGI Department, Peking University, School of Oncology (PUSC)Can target therapy break the bottleneck of chemotherapy in gastric cancer?Current status of AG

2、C chemotherapyORR: 4050%Overall survival less than 1 yearPoor Tolerance西妥昔单抗可否成为晚期胃癌治疗的西妥昔单抗可否成为晚期胃癌治疗的新契机？新契机？契机契机哲学：德文哲学：德文moment的意译的意译英文：英文：Chance， moment ，turning point中文：通常指事物开展过程中的关键、枢纽或决议中文：通常指事物开展过程中的关键、枢纽或决议 性的环节性的环节CetuximabPanitumumab Trastuzumab GefitnibErlotinib Imatinib TKRISIS2503FT1b

3、evacizumab VatalanibSU5416p53PLCP13KG3Bcl-2Caspasep70S6KPKCRafMekAktRacPKCCa2 IP3DAG ERK/MAPK血管通透性改动转录/增殖P27 P21细胞凋亡sorafenibEGFVEGFAKTRasP53P13KPLCVEGFRVEGF-RTK细胞膜mTORCyclinD1BAD RasFakRAD001MMPMarimastatFlavopiridolToGA 实验设计实验设计HER2-positiveadvanced GC (n=584)5-FU or capecitabinea + cisplatin(n=29

4、0)R5-FU or capecitabinea + cisplatin+ trastuzumab(n=294)Phase III, randomized, open-label, international, multicenter study1Bang et al; Abstract 4556, ASCO 2021 3807 patients screened1 810 HER2-positive (22.1%)HER2 receptortrastuzumabPrimary end point: OSTime (months)29429027726624622320918517314314

5、71171139090647147563243243016211413712665401000No. at risk1.00246810 12 14 16 18 20 22 24 26 28 30 32 34 36EventFC + TFCEvents167182HR0.7495% CI0.60, 0.91p value0.0046MedianOS13.811.1T, trastuzumabGlobal AVAGASTDomestic AVATAR NCT00887822贝伐单抗贝伐单抗/卡培他滨卡培他滨/顺铂一线治疗

6、晚期胃癌的多中顺铂一线治疗晚期胃癌的多中心心III期随机对照临床研讨期随机对照临床研讨cisplatin 80mg/m2 infused over 120minutes on day 1capecitabine 1000mg/m2 orally twice a day on days 1-14bevacizumab Q3W, 7.5mg/kg XP+bevacizumabCetuximab in AGC 新契机新契机 循证医学根据循证医学根据EXTRA研讨：研讨： 多中心、单组、前瞻性的多中心、单组、前瞻性的II期临期临床研讨床研讨 个体化治疗时代：个体化治疗时代： from evidence

7、-based to information-based medicine疗效预测因子的初步讨论疗效预测因子的初步讨论Case 1 分享胜利分享胜利Case 2 谨慎察看谨慎察看西妥昔单抗在中国胃癌患者西妥昔单抗在中国胃癌患者中的运用实例分享中的运用实例分享EXTRA study Investigator initiated trial, partially founded by Merck EMR62202-769 A phase II study of cetuximab (Erbitux) with cisplatin and capecitabine (Xeloda) as 1st li

8、ne treatment in the advanced gastric cancer 西妥昔单抗结合顺铂西妥昔单抗结合顺铂/卡培他滨一线治疗进卡培他滨一线治疗进展期胃癌的展期胃癌的II期临床研讨期临床研讨Principal investigatorDr. Lin Shen, Peking University School of Oncology, Cancer Hospital, , China EXTRA study Investigator initiated trial, partially founded by MerckSitesRegistration in NIHNo.: N

9、CT00477711.website: /ct/show/NCT004777117 sites in china：北京大学肿瘤医院、解放军北京大学肿瘤医院、解放军307医院、医科院肿瘤医院、医院、医科院肿瘤医院、青岛大学附属医院、浙江大学附属第一医院、青岛大学附属医院、浙江大学附属第一医院、黑龙江省肿瘤医院、上海长征医院黑龙江省肿瘤医院、上海长征医院Planned study period Enrolment start date (FPI): Mar 2019Enrolment finish date (LPI): Feb 2019Treatment pe

10、riod end date (LP off treatment): Aug 2019Planned number of patients Total number: 41 calculated using Simons 2-stage design. 1st stage: at least 5 or more PR or CR out of 17 pts. 2nd stage: additional 24 assessable patients. Study designA prospective single arm, open, multicenter phase II studyEXTR

11、A study Investigator initiated trial, partially founded by MerckChemotherapy administration cisplatin 80mg/m2 infused over 120minutes on day 1capecitabine 1000mg/m2 orally twice a day on days 1-14Cetuximab Weekly, 400mg/m2 loading dose over 2 hours on day 1, 250mg/m2 subsequent dose over 60min.EXTRA

12、 study Investigator initiated trial, partially founded by MerckPrimary endpoint:Tumor response rate ORRSecondary endpoints: Time to progressionTTPDisease control rate DCROverall survival OSSafety predictive markers：K-ras, b-raf, p53 genes mutations, EGFR gene copy number，EXTRA study Investigator ini

13、tiated trial, partially founded by MerckIRB: consisting of 2 radiologists and 1 medical oncologistSupervision： The Clinical Research Associating Center of Peking University, School of OncologyScreenTreatmentDDPXelodacetuximabd1d15d8Sample collection6cycs XelodaPDStatistical AnalysisPeripheral blood：

14、TS,TP,DPD，血清细胞因子，基因遗传多态性，血清细胞因子，基因遗传多态性Tumor tissue：expression of EGFR detected by IHCTumor tissue embedded in parrafin：DNA extractionSequence analysis ：k-ras ，b-rafCISH: EGFR gene copy numberprotocol designHistologically confirmed gastric or EGJ adenocarcinomaUnresectable recurrent or metastatic di

15、seaseAge 18 years oldsigned informed consentMeasurable disease according to the RECIST criteriaPrevious neo-adjuvant or adjuvant treatment for gastric cancer, more than 6 month No prior radiotherapy except at non-target lesion of the study more than 4 weeksLife expectancy of 2 monthKarnofsky perform

16、ance status 60ALT and AST2.5 times ULN (5 times ULN in patients with liver metastases) Serum albumin level 3.0g/dL, Serum AKP 2.5 times ULN, Bilirubin level 1.5mg/dLSerum creatinine 4109/L , absolute neutrophil count 4109/L, platelet100109/L, Hb9g/dl Criteria for inclusion Criteria for exclusionBrai

17、n metastasis (known or suspected)Previous systemic therapy for metastatic gastric cancerInability to take oral medicationPrevious EGFR pathway-targeting therapySurgery (excluding diagnostic biopsy) within 4 weeks prior to study entryHeart failure, coronary artery disease, myocardial infarction withi

18、n the last 6mKnown allergy to any study treatmentPregnancy or lactation periodAny investigational agent within the past 28 daysOther previous malignancy within 5 year, except non-melanoma skin cancerPrevious adjuvant therapy with capecitabine+platinum, less than 6 monthsPre-existing neuropathygrade

19、1Legal incapacity 2019.2.12 获得伦理经过，获得伦理经过，2019.4.30 第一例第一例 接受治疗接受治疗2019.10.20 完成完成17例疗效评价，例疗效评价，8例例PR， 完成第一阶段完成第一阶段2019.5.2 完成全部病例入组完成全部病例入组54例入组例入组2例例 挑选失败，挑选失败，3例退出研讨例退出研讨49例例 接受接受1周期以上治疗周期以上治疗47例例 可评价疗效可评价疗效末次随访为末次随访为2019.4，仍有，仍有2例患者生存例患者生存Study progressionSite No.No. of enrolled patients.No of E

20、valuated patients01(北肿北肿)242102(307)151303(医肿医肿)5404(青医青医)3305(浙医浙医)2206(黑龙江黑龙江)2207(长征长征)22Total N5447 Status of EnrollmentSafetyDrug exposure and relative dose intensity (N=52)cetuximabcisplatincapecitabineAdministration cycles*Total672222259Median 1244Range1-181-60.5-12Relative dose intensityMedi

21、an1.01.01.0Range1.00.625-1.00.63-1.0Cetuximab未因不良反响减量或停药未因不良反响减量或停药15例患者例患者28.8%因化疗药物相关不良反响减量，因化疗药物相关不良反响减量，10例患者例患者19.2%因化疗药物相关不良反响延期治疗因化疗药物相关不良反响延期治疗13例患者例患者25.0%进入卡培他滨维持治疗，中位维持周期进入卡培他滨维持治疗，中位维持周期3.5 (range 116).Result of EXTRA studyZhang X, Shen L et al. Control/Tracking Number: 09-AB-10721- ASCO

22、GI2019.4-2019.554 pts enrolled (Response was evaluable in 47 pts)Regimens:Cetuximab 500mg/m2 initial and 250mg/m2 subsequently Cape 1000mg/m2 Bid d1-14，q3WDDP 80mg/m2 iv d1 q3W RECIST criteria and CTC v3.0Response CR 1 (2.1%)PR 24 (51.1%)SD 15 (31.9%)PD 7 (14.9%)ORR: 53.2%mTTP: 5.3m, DCR 85.1%，OS: 1

23、1.5mWaterfall plot of single centerToxicityGrade2343/4n%n%n%n%HematologicNeutropenia1732.71223.111.91325.0Thrombocytopenia35.823.811.935.8anemia611.511.911.923.8Febrile neutropenia23.823.8NonhematologicNausea/vomiting1630.8611.5611.5Allergy611.5Rash1223.159.659.6Desquamotion59.6paronychia23.823.8fat

24、igue917.323.823.8Electrolyte imbalance(Ca, Mg, K)59.647.747.7Hand-foot syndrome 1121.247.747.7Abdominal pain47.711.911.9Infection35.835.8Toxicity Grade 2 to 4 ，ocurred in at Least 5% of Patients (N=52) Cetuximab in AGC 新契机新契机 循证医学根据循证医学根据 EXTRA研讨：研讨： 平安，有效平安，有效 个体化治疗时代个体化治疗时代from evidence-based to i

25、nformation-based 疗效预测因子的初步讨论疗效预测因子的初步讨论nComplete/partial responseP value for trendn%Total cutaneous toxicities0.008Grade 0/125936.0Grade 2/3221777.3Acne-like rash0.032Grade 0/1301240.0Grade2171376.5Single factor analysis of predictive markers-RashInfluence of skin reaction and rash on response rates

26、 (N=47) EGFR expressionn2/3 rashComplete/partial responsennNegative/11300758.3a2/3311548.41551.7bP value0.0010.251a: Response was evaluable in 12 case of EGFR expression negative/1+ group.b: Response was evaluable in 29 case of EGFR expression 2+/3+ group. Relation of EGFR expression with rash and r

27、esponse (n=44)Relationship of Rash and OSN=49 monthmonth30.0025.0020.0015.0010.005.000.00PercentagePercentage1.00.20.0 皮疹皮疹2/3级级17.57月月皮疹皮疹0/1级级 7.77月月p0.05monthmonth30.0025.0020.0015.0010.005.000.00percentagepercentage1.00.20.0 TGF-high 12.867月月TGF-low 7.767月月 Relationship of TGF-

28、 and OSN=44p0.05monthmonth30.0025.0020.0015.0010.005.000.00percentagepercentage1.00.20.0EGFA61G GG 13.300月月EGFA61G GA 8.933月月Relationship of EGFA61G polymorphism and OSN=44p25ng/L296.0334.676-7.3842912.8677.065-18.668EGFA61G polymorphismG/A122.6670.000-5.3830.052138.933m5.253-12.6130.059G/G

29、265.3332.752-7.9152613.3008.601-17.999EGF300ng/L 162.8672.344-3.3890.357167.7674.500-11.0330.029300ng/L295.3674.136-6.5973011.1007.013-15.187EGFR expression Grade 0/1105.0002.446-7.5540.552138.7673.952-13.5810.238Grade 2/3306.0303.271-8.7893111.1007.516-16.284TS5-UTR polymorphismNon 3RG233.6302.112-

30、5.1480.475249.1007.624-10.5760.2043RG225.2301.829-8.6312213.3004.958-21.642TGF300+GGof EGFA61Gone or none 252.8702.323-3.4110.008268.9336.186-11.6810.047both176.2004.676-7.7241716.60010.688-22.512Single factor analysis of Efficacy predictive markers Hazard ratio95%CIP valuerash0.3870.163-0.9220.032TGF1.0400.457-2.3680.925EGF0.6040.277-1.3160.204EGFA61G polymorphism0.4250.202-0.8