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1、HER2阳性EBC的应对策略,HER2阳性EBC的应对策略,Adjuvant CMF,Risk of recurrence,Bonadonna et al. BMJ 2019; 330: 217,1976,The CMF programme,CMF vs observation,C, cyclophosphamide;M, methotrexate;F, 5-fluorouracil,First publication: Bonadonna et al. N Engl J Med 1976; 294: 405-410,Latest data,Risk of death,1976,Adjuvan
2、t CMF21%Risk of recurre,Adjuvant tamoxifen,36%,Risk of recurrence,Risk of death,First publication: Lancet 1983; 1: 257-261,Br J Cancer 1988; 57: 608-611,Latest data,1983,NATO trial,Tamoxifen vs observation,Adjuvant tamoxifen36%29%Risk o,Adjuvant anthracyclines,Risk of recurrence,First publication: L
3、evine et al. J Clin Oncol 2019; 16: 2651-2658,Latest data,Levine et al. J Clin Oncol 2019; 23: 5166-5170,2019,NCIC MA.5,CEF vs CMF,C, cyclophosphamide; E, epirubicin;F, fluorouracil; M, methotrexate,Adjuvant anthracyclinesRisk of,Adjuvant taxanes,Risk of recurrence,Risk of death,2019,First publicati
4、on: Henderson et al. Proc Am Soc Clin Oncol 2019; 17: 101a, abs 390A,CALGB 9344,ACP vs AC,17%,A, doxorubicin;C, cyclophosphamide;P, paclitaxel,Latest data,Henderson et al. J Clin Oncol 2019; 21: 976-983,Adjuvant taxanes18%Risk of rec,Adjuvant aromatase inhibitors,Risk of recurrence,First publication
5、: Baum et al. Breast Cancer Res Treat 2019; 69: 210, abs 8,2019,ATAC,Anastrozole vs tamoxifen,Howell et al. Lancet 2019; 365: 60-62,Latest data,Adjuvant aromatase inhibitors1,Adjuvant Herceptin,36%,34%,Risk of recurrence,Risk of death,First presentation: Piccart-Gebhart et al. ASCO 2019,Smith et al.
6、 Lancet 2019; 369: 29-36,Latest data,3 further large studies have also demonstrated similar significant reductions in risk of relapse and risk of death,Romond et al. N Engl J Med 2019; 353: 1673-1684; Slamon et al. SABCS 2019; abs 52,2019,HERA,1-year Herceptin vs observation after chemotherapy,Adjuv
7、ant Herceptin36%34%Risk o,HER2: role in breast cancer,Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein and part of the HER family of 4 growth factor receptors (HER1 to HER4)1Overexpression of HER2 and / or amplification of the HER2 gene occurs in up to 30% of breast cancers
8、1-3HER2 positivity is associated with2-4aggressive diseasea high risk of relapsepoor survivalHER2 is the only member of the HER family acknowledged in guidelines for its prognostic and predictive value in breast cancer5HER2 is an important therapeutic target,Slamon DJ, et al. Science 1989; 244: 7077
9、12Slamon DJ, et al. Science 1987; 235: 177182Penault-Llorca F, et al. J Clin Oncol (Meeting Abstracts) 2019; 23: 69s, abs 764 Press MF, et al. J Clin Oncol 2019; 15: 28942904 Goldhirsch A, et al. Ann Oncol 2019; 17: 17221776,HER2: role in breast cancerHum,Inhibition of HER2-mediated signalling,Activ
10、ation of antibody-dependent cellular cytotoxicity (ADCC),Herceptin is effective across all stages of disease by activating the immune system and suppressing HER2,Additional mechanismsPrevents formation of truncated HER2 (p95)Inhibition of HER2-regulated angiogenesis,Slamon DJ, et al. N Engl J Med 20
11、19; 344: 783-792 Marty M, et al. J Clin Oncol 2019; 23: 4265-4274Baselga J. Oncology 2019; 61 (Suppl 2): 14-21 Piccart-Gebhart MJ, et al. N Engl J Med 2019; 353: 16591672Romond EH, et al. N Engl J Med 2019; 353: 16731684Slamon D, et al. Breast Cancer Res Treat 2019; 94 (Suppl 1): S5, abs 1Slamon D,
12、et al. Abstract 52 presented at the 29th SABCS, San Antonio, Texas, USA, 14-17 December 2019Smith I, et al. Lancet 2019; 369: 29-36,Inhibition of HER2-mediated s,The fascinating history of Herceptin,Phase I IND for rhuMAb HER2,Murine HER2 / neu gene cloned,Human HER2 gene cloned,muMAb 4D5,Associatio
13、n of HER2 with poor clinical outcome,Paclitaxel + H and H mono US approval,Paclitaxel + H and H mono EU approval,1st IA of HERA,1992,1985,1990,1981,1987,2000,2019,2019,2019,HERA recruitment opens,HERA 2-year follow-up,Adjuvant H approval,2019,HERA 4-year follow-up and 1-year H vs 2-year H IA,2019,HE
14、RA final analysis 1-year H vs 2-year H,HER2, human epidermal growth factor receptor 2; H, Herceptin; IA, interim analysis,The fascinating history of Her,Adjuvant Chemotherapy,Adjuvant Chemotherapy,HERA study design,Herceptin q3w x 1 year,Observation,HER2-positive early breast cancer(IHC 3+ and / or
15、FISH+)n=5102,Herceptin q3w x 2 years,Option to cross over to Herceptin(after IA 2019),Surgery + (neo)adjuvant chemotherapy + radiotherapy,IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation,HERA study designHerceptin Obs,End points of the HERA trial,Primary end pointDFS1-year Hercept
16、in vs observation2-year Herceptin vs observationSecondary end pointsOS, RFS, distant DFS, safety 1-year Herceptin vs observation2-year Herceptin vs observationcompare DFS, OS, RFS, distant DFS and safety 1-year Herceptin vs 2-year Herceptin,DFS, disease-free survival; OS, overall survival; RFS, rela
17、pse-free survival,End points of the HERA trialPr,HERA 2019 interim analysis: 2-year vs 1-year Herceptin,Statistical assumptionsHR 0.80DFS absolute reduction 4.9%5-year DFS 1-year arm: 70%5-year DFS 2-year arm: 74.9%p value 0.014 for early release of results,Final analysis triggered by 725 events (20
18、19),Trial continues as planned,No data release,HR, hazard ratio; IDMC, Independent Data Monitoring Committee,HERA 2019 interim analysis: 2,HERA: IDMC recommendations October 2019,Do not release information on the 2-year Herceptin armContinue the 1-year Herceptin vs 2-year Herceptin comparisonRelease
19、 updated information on 1-year Herceptin vs observation,No conclusions can be drawn regarding the efficacy of Herceptin therapy for 2 years vs 1 year,HERA: IDMC recommendations Oc,HERA study design,HER2-positive early breast cancer(IHC 3+ and / or FISH+)n=5102,Surgery + (neo)adjuvant chemotherapy +
20、radiotherapy,Herceptin q3w x 1 year,Observation,Option to cross over to Hercep,HERA: DFS and OS over time 1 and 2 years follow-up,No. of deathsH 1 year vs observation,0,1,2,FavoursHerceptin,Favours noHerceptin,HR,OS benefit,29 vs 37p=0.26,201911 year(0%),59 vs 90p=0.0115,Median follow-up (% follow-u
21、p time after selective crossover),201922 years(4.1%),201911 year (0%),Median follow-up (% follow-up time after selective crossover),201922 years (4.3%),No. of DFS eventsH 1 year vs observation,127 vs 220p0.0001,218 vs 321p0.0001,0,1,2,FavoursHerceptin,Favours noHerceptin,HR,DFS benefit,1Piccart-Gebh
22、art et al 2019; 2Smith et al 2019,HERA: DFS and OS over time 1,DFS : 4-year median follow-up,100,80,60,40,20,0,0,6,12,18,24,30,48,36,42,Months from randomisation,16981703,15641619,14401552,13631485,12971414,12401352,712854,11801280,9921020,No. at risk,Events458369,4-yearDFS72.278.6,HR0.76,95% CI0.66
23、, 0.87,p value0.0001,1-year Herceptin,Observation,6.4%,Patients (%),DFS : 4-year median follow-up1,OS : 4-year median follow-up,0,6,12,18,24,30,48,36,42,Months from randomisation,16981703,16421660,16011640,15561615,15191577,14711524,828953,13981447,11751149,Events213182,4-yearDFS87.789.3,HR0.85,95%
24、CI0.70, 1.04,p value0.1087,1.6%,1-year Herceptin,Observation,100,80,60,40,20,0,Patients (%),No. at risk,OS : 4-year median follow-up06,HERA: DFS and OS over time,No. of deathsH 1 year vs observation,0,1,2,FavoursHerceptin,Favours noHerceptin,HR,OS benefit,29 vs 37p=0.26,201911 year(0%),59 vs 90p=0.0
25、115,182 vs 213p=0.1087,Median follow-up (% follow-up time after selective crossover),201922 years(4.1%),20194 years(30.9%),201911 year (0%),Median follow-up (% follow-up time after selective crossover),201922 years (4.3%),20194 years (33.8%),No. of DFS eventsH 1 year vs observation,127 vs 220p0.0001
26、,218 vs 321p0.0001,369 vs 458p0.0001,0,1,2,FavoursHerceptin,Favours noHerceptin,HR,DFS benefit,1Piccart-Gebhart et al 2019; 2Smith et al 2019,4 year DFS： 78.6% vs. 72.2%,4年OS：89.3% vs.87.7%,HERA: DFS and OS over timeNo.,Crossover to Herceptin of 65% of the patients originally allocated to observatio
27、n disrupted the randomised comparison between 1-year Herceptin and observationQuestion: To what extent might crossover have biased the ITT analysis?,Specific question 1,Crossover to Herceptin of 65%,Flow chart of observation patients:by status on 16 May 2019,1698 patients originally randomised to ob
28、servation,1354 patients alive and disease-free,16 May,2019,344 patients DFS event or lost to follow-up198 alive post DFS event,Flow chart of observation pati,Time to selective crossover by calendar date (n=885),0.6,0.5,0.4,0.3,0.2,0.0,16 May 2019,22 Aug 2019,28 Nov 2019,6 Mar 2019,12 Jun 2019,18 Sep
29、 2019,25 Dec 2019,1354,1193,596,209,116,71,30,0.1,Switched to Herceptin,No. at riskObservation,Proportion,Randomisation to 1st doseDiagnosis to 1st doseFollow-up from 1st dose,Median time (range), months22.8 (1-52.7)30.9 (9.1-58.3)29.1 (0.8-34.5),Time to selective crossover by,Baseline characteristi
30、cs of observation patients alive and disease free on 16 May 2019,Compared to patients who did not selectively cross over to Herceptin, those who did were more likely to:be youngerhave received anthracyclines and anthracyclines plus taxanesbe diagnosed with node-positive diseasehave hormone receptor-
31、positive tumours,Baseline characteristics of ob,885 of 1354 patients (65%) in the observation group who were alive and disease free on May 16 2019 crossed over and received HerceptinQuestions:What was the course of disease in the subgroups of observation patients who did or did not cross over to act
32、ive therapy? Is there any effect of the late introduction of Herceptin?,Specific question 2,885 of 1354 patients (65%) in,Landmark of 16 May 2019,The landmark analysis considers only patients who were alive and disease free on 16 May 2019,Landmark of 16 May 2019,0,Herceptin: Alive and disease free o
33、n 16 May 2019,6,12,18,24,30,36,42,48,1481,1480,1473,1447,1399,1351,1280,1020,854,100,80,60,40,20,0,No. at risk,Patients alive and disease free (%),DFS (landmark analysis): Herceptin vs observation,Observation: Alive and disease free on 16 May 2019,Months from randomisation,1354,1353,1339,1316,1278,1
34、239,1180,992,712,0Herceptin: Alive and disease,DFS (landmark analysis): observation (alive, no DFS event), selective crossover and no crossover,100,80,60,40,20,0,0,Patients alive and disease free (%),6,12,18,24,30,36,42,48,No. at risk,DFS (landmark analysis): obser,0,Months from randomisation,6,12,1
35、8,24,30,36,42,48,13541481,13541481,13501481,13441474,13321461,13161438,12701378,10651094,759910,100,80,60,40,20,0,OS (landmark analysis): Herceptin vs observation,No. at risk,Patients alive and disease free (%),Herceptin: Alive and disease free on 16 May 2019,Observation: Alive and disease free on 1
36、6 May 2019,0Months from randomisation6121,Observation: Alive and disease free on 16 May 2019,0,Months from randomisation,6,12,18,24,30,36,42,48,100,80,60,40,20,0,No. at risk,Patients alive (%),OS (landmark analysis): crossover vs no-crossover,1354,1354,1350,1344,1332,1316,1270,1065,759,Observation:
37、Alive and disease,Cardiac safety,Cardiac deathSevere CHF (NYHA III and IV)Symptomatic CHF (II, III and IV)Confirmed significant LVEF drop,1 (0.1)0 (0.0)3 (0.2)13 (0.8),0 (0.0)13 (0.8)33 (2.0)62 (3.7)87 (5.2),No. patients (%),Observationa n=1719,1-year Herceptinn=1682,Herceptin discontinued due to ca
38、rdiac problems,aPatients who crossed over are censored from the date of starting Herceptin treatment,CHF, congestive heart failure; NYHA, New York Heart Association; LVEF, left ventricular ejection fraction,Cardiac safetyCardiac death1 (,Cardiac safety: observation group,Cardiac deathSevere CHF (NYH
39、A III and IV)Symptomatic CHF (II, III and IV)Confirmed significant LVEF drop,0 (0.0)0 (0.0)1 (0.2)5a (1.1),0 (0.0)0 (0.0)9 (1.0)26 (2.9) 43 (4.9),Crossover n=885,Herceptin discontinued due to cardiac problems,aFor 3 of the patients, the LVEF drop occurred between 16 May 05 and the date of the patien
40、t decision and may have influenced the patient decision,No crossover after 16 May 05 n=469,Cardiac safety: observation gr,HERA 4-year follow-up data: summary (1),The updated analysis at 4 years was limited to 1-year Herceptin vs observation as recommended by IDMCExtensive selective crossover of obse
41、rvation patients to active therapy biased the ITT comparisonLandmark analysis of observation patients who were disease free on 16 May 2019 explored the effects of later introduction of HerceptinLack of randomisation limits the interpretation of the landmark analysisdifferent outcome due to drug effe
42、ct or patient characteristics?,HERA 4-year follow-up data: su,HERA 4-year follow-up data: summary (2),In HERA, the DFS benefit associated with Herceptin is maintained at 4-year median follow-up 50% of patients in the observation arm crossed over to Herceptin treatment, therefore the OS benefit is no
43、 longer statistically significantPatients crossing over at a later date appear to benefit from 1 year of Herceptin,HERA 4-year follow-up data: su,HERA: conclusions and next steps,4-year follow-up data support the hypothesis that the risk of relapse in HER2-positive early breast cancer persists over
44、timeProlonged exposure to the Herceptin antibody may improve efficacy This is being tested in the comparison of the 1-year and 2-year groups in the HERA study,HERA: conclusions and next ste,aBased on small subgroups of patients with HER2-positive breast cancer; bDDFS; CTx, chemotherapy; AC, doxorubi
45、cin, cyclophosphamide; P, paclitaxel; T, docetaxel; Carbo, carboplatin; V, vinorelbine; CEF, cyclophosphamide, epirubicin, 5-fluorouracil,Additional studies demonstrate consistent DFS benefit for Herceptin,3,4,5,4,Gianni et al 2019; Gianni et al 2009; Joensuu et al 2009; Slamon et al 2019; Perez et
46、al 2019;Smith et al 2019; Spielmann et al 2019,3,3,Median follow-up, years,DFS benefit,B-31 / N9831 ACPH,HERA CTxH 1 year,FinHera VH / THCEFb,PACS-04a CTxH 1 year,BCIRG 006 ACTH,TCarboH,n=231,n=528,NOAH CTx / HH 1 year,3,0,1,2,Favours Herceptin,Favours no Herceptin,HR,aBased on small subgroups of p,
47、1-year Herceptin treatment consistently reduces the risk of death by one-third,0,1,2,B-31 / N9831 ACPH,3,HERA CTxH 1 year,4,OS benefit,BCIRG 006 ACTH,3,TCarboH,3,Favours Herceptin,Favours no Herceptin,HR,5,FinHer VH / THCEF,n=231,Median follow-up, years,Gianni et al 2009; Joensuu et al 2009; Slamon
48、et al 2019; Perez et al 2019; Smith et al 2019,1-year Herceptin treatment con,HER2-positive breast cancer: outstanding questions,Concurrent or sequential Herceptin therapy?Herceptin efficacy in lower-risk patients?Optimal treatment duration?Translational research?New combinations?ALTTO (Herceptin +
49、lapatinib)BETH (Herceptin + Avastin),HER2-positive breast cancer:,Ld qd + Hc q3w for 52 weeks,Lb qd for 52 weeks,ALTTO: Phase III randomised open-label trial comparing adjuvant lapatinib +/ Herceptin,Surgery and completion of (neo)adjuvant anthracycline-based chemotherapy,Concurrent taxanese for 12
50、weeks,aHerceptin 8 mg/kg iv loading dose followed by 6 mg/kg q3w; bLapatinib 1500 mg; cHerceptin 4 mg/kg iv loading dose followed by 2 mg/kg qw; dLapatinib 1000 mg; ePaclitaxel 80 mg/m2 qw or docetaxel q3w,No taxane,Hc qw for 12 weeks,Ha q3w for 52 weeks,6-week washout,Lb qd for 34 weeks,HER2-positi
