Sustained benefits for women with HER2-positive early breast cancer JORGE MADRID BIG GOCCHI PROTOCOLO HERA

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1 Sustained benefits for women with HER2-positive early breast cancer JORGE MADRID BIG GOCCHI PROTOCOLO HERA

2 The fascinating history of Herceptin Murine HER2 / neu gene cloned Human HER2 gene cloned mumab 4D5 Phase I IND for rhumab HER2 Paclitaxel + H and H mono US approval Paclitaxel + H and H mono EU approval Adjuvant H approval 1st IA of HERA HERA 2-year follow-up HERA 4-year follow-up and 1-year H vs 2-year H IA Association of HER2 with poor clinical outcome HERA recruitment opens HERA final analysis 1-year H vs 2-year H HER2, human epidermal growth factor receptor 2; H, Herceptin; IA, interim analysis

3 HERA study design HER2-positive early breast cancer (IHC 3+ and / or FISH+) n=5102 Surgery + (neo)adjuvant chemotherapy + radiotherapy Observation Herceptin q3w x 1 year Herceptin q3w x 2 years Option to cross over to Herceptin (after IA 2005) IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation

4 End points of the HERA trial Primary end point DFS 1-year Herceptin vs observation 2-year Herceptin vs observation Secondary end points OS, RFS, distant DFS, safety 1-year Herceptin vs observation 2-year Herceptin vs observation compare DFS, OS, RFS, distant DFS and safety 1-year Herceptin vs 2-year Herceptin DFS, disease-free survival; OS, overall survival; RFS, relapse-free survival

5 HERA 2008 interim analysis: 2-year vs 1-year Herceptin Statistical assumptions HR <0.80 DFS 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 2008 interim analysis 500 events reached June 2008 October 2008 IDMC advises Executive Committee Interim analysis positive Data release at SABCS HR, hazard ratio; IDMC, Independent Data Monitoring Committee Database cleaning Trial continues as planned No data release Final analysis triggered by 725 events (~2011)

6 HERA: IDMC recommendations October 2008 Do not release information on the 2-year Herceptin arm Continue the 1-year Herceptin vs 2-year Herceptin comparison Release 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

7 HERA study design HER2-positive early breast cancer (IHC 3+ and / or FISH+) n=5102 Surgery + (neo)adjuvant chemotherapy + radiotherapy Observation Herceptin q3w x 1 year Herceptin q3w x 2 years Option to cross over to Herceptin (after IA 2005)

8 HERA: DFS and OS over time 1 and 2 years follow-up Median follow-up (% follow-up time after selective crossover) DFS benefit No. of DFS events H 1 year vs observation Median follow-up (% follow-up time after selective crossover) OS benefit No. of deaths H 1 year vs observation year (0%) 127 vs 220 p< year (0%) 29 vs 37 p= years (4.3%) 218 vs 321 p< years (4.1%) 59 vs 90 p= Favours 1 Favours no 2 Herceptin HR Herceptin 0 Favours 1 Favours no 2 Herceptin HR Herceptin 1 Piccart-Gebhart et al 2005; 2 Smith et al 2007

9 DFS (ITT): 4-year median follow-up Patients (%) year Herceptin Observation 6.4% Events year DFS HR % CI 0.66, Months from randomisation p value < No. at risk

10 OS (ITT): 4-year median follow-up Patients (%) Observation 1-year Herceptin 1.6% Events year DFS HR % CI 0.70, Months from randomisation p value No. at risk

11 HERA: DFS and OS over time Median follow-up (% follow-up time after selective crossover) DFS benefit No. of DFS events H 1 year vs observation Median follow-up (% follow-up time after selective crossover) OS benefit No. of deaths H 1 year vs observation year (0%) 127 vs 220 p< year (0%) 29 vs 37 p= years (4.3%) 218 vs 321 p< years (4.1%) 59 vs 90 p= years (33.8%) 369 vs 458 p< years (30.9%) 182 vs 213 p= Favours 1 Favours no 2 Herceptin HR Herceptin 0 Favours 1 Favours no 2 Herceptin HR Herceptin 1 Piccart-Gebhart et al 2005; 2 Smith et al 2007

12 Specific question 1 Crossover to Herceptin of 52% of the patients originally allocated to observation disrupted the randomised comparison between 1-year Herceptin and observation Question: To what extent might crossover have biased the ITT analysis?

13 Flow chart of observation patients: by status on 16 May patients originally randomised to observation 344 patients 1354 patients 16 May DFS event or lost to follow-up 2005 alive and disease-free 198 alive post DFS event 469 patients remained on observation 344 patients ineligible for crossover

14 Time to selective crossover by calendar date (n=885) Proportion 0.6 Switched to Herceptin No. at risk Observation May Aug Nov Mar Jun Sep Dec Randomisation to 1st dose Diagnosis to 1st dose Follow-up from 1st dose Median time (range), months 22.8 (<1-52.7) 30.9 ( ) 29.1 ( )

15 Baseline characteristics of observation patients alive and disease free on 16 May 2005 Compared to patients who did not selectively cross over to Herceptin, those who did were more likely to: be younger have received anthracyclines and anthracyclines plus taxanes be diagnosed with node-positive disease have hormone receptor-positive tumours

16 Specific question of 1354 patients (65%) in the observation group who were alive and disease free on May crossed over and received Herceptin Questions: What was the course of disease in the subgroups of observation patients who did or did not cross over to active therapy? Is there any effect of the late introduction of Herceptin?

17 Landmark of 16 May 2005 The landmark analysis considers only patients who were alive and disease free on 16 May 2005

18 DFS (landmark analysis): Herceptin vs observation Patients alive and disease free (%) Observation: Alive and disease free on 16 May 2005 Herceptin: Alive and disease free on 16 May 2005 No. at risk Months from randomisation

19 DFS (landmark analysis): observation (alive, no DFS event), selective crossover and no crossover Patients alive and disease free (%) No. at risk 20 Observation: Alive and disease free on 16 May 2005 Selective crossover 0 No crossover Months from randomisation

20 OS (landmark analysis): Herceptin vs observation Patients alive and disease free (%) No. at risk Observation: Alive and disease free on 16 May 2005 Herceptin: Alive and disease free on 16 May Months from randomisation

21 OS (landmark analysis): crossover vs no-crossover Patients alive (%) No. at risk Observation: Alive and disease free on 16 May 2005 Selective crossover No crossover Months from randomisation

22 Cardiac safety: safety analysis population a No. patients (%) Cardiac death Severe CHF (NYHA III and IV) Symptomatic CHF (II, III and IV) Confirmed significant LVEF drop Herceptin discontinued due to cardiac problems Observation a n= (0.1) 0 (0.0) 3 (0.2) 13 (0.8) 1-year Herceptin n= (0.0) 13 (0.8) 33 (2.0) 62 (3.7) 87 (5.2) a Patients 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

23 Cardiac safety: observation group Cardiac death Severe CHF (NYHA III and IV) Symptomatic CHF (II, III and IV) Confirmed significant LVEF drop Herceptin discontinued due to cardiac problems No crossover after 16 May 05 n=469 0 (0.0) 0 (0.0) 1 (0.2) 5 a (1.1) Crossover n=885 0 (0.0) 0 (0.0) 9 (1.0) 26 (2.9) 43 (4.9) a For 3 of the patients, the LVEF drop occurred between 16 May 05 and the date of the patient decision and may have influenced the patient decision

24 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 IDMC Extensive selective crossover of observation patients to active therapy biased the ITT comparison Landmark analysis of observation patients who were disease free on 16 May 2005 explored the effects of later introduction of Herceptin Lack of randomisation limits the interpretation of the landmark analysis different outcome due to drug effect or patient characteristics?

25 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 longer statistically significant Patients crossing over at a later date appear to benefit from 1 year of Herceptin

26 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 time Prolonged 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

27 Additional studies demonstrate consistent DFS benefit for Herceptin HERA CTx H 1 year B-31 / N9831 AC PH BCIRG 006 AC TH TCarboH DFS benefit Median follow-up, years NOAH CTx / H H 1 year 3 FinHer a VH / TH CEF b PACS-04 a CTx H 1 year n=231 n= Favours 1 Favours no 2 Herceptin HR Herceptin a Based on small subgroups of patients with HER2-positive breast cancer; Gianni et al 2008; b DDFS; CTx, chemotherapy; AC, doxorubicin, cyclophosphamide; Gianni et al 2009; Joensuu et al 2009; P, paclitaxel; T, docetaxel; Carbo, carboplatin; V, vinorelbine; Slamon et al 2006; Perez et al 2007; CEF, cyclophosphamide, epirubicin, 5-fluorouracil Smith et al 2007; Spielmann et al 2007

28 1-year Herceptin treatment consistently reduces the risk of death by one-third OS benefit Median follow-up, years HERA CTx H 1 year 4 B-31 / N9831 AC PH 3 BCIRG 006 AC TH 3 TCarboH 3 FinHer VH / TH CEF n= Favours 1 Favours no 2 Herceptin HR Herceptin Gianni et al 2009; Joensuu et al 2009; Slamon et al 2006; Perez et al 2007; Smith et al 2007

29 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 + lapatinib) BETH (Herceptin + Avastin)

30 ALTTO: Phase III randomised open-label trial comparing adjuvant lapatinib +/ Herceptin HER2-positive early breast cancer (n=8000) Surgery and completion of (neo)adjuvant anthracycline-based chemotherapy No taxane Concurrent taxanes e for 12 weeks H a q3w for 52 weeks L b qd for 52 weeks H c qw for 12 weeks L d qd + H c q3w for 52 weeks H a q3w for 52 weeks L b qd for 52 weeks H c qw for 12 weeks L d qd + H c q3w for 52 weeks 6-week washout 6-week washout L b qd for 34 weeks L b qd for 34 weeks a Herceptin 8 mg/kg iv loading dose followed by 6 mg/kg q3w; b Lapatinib 1500 mg; c Herceptin 4 mg/kg iv loading dose followed by 2 mg/kg qw; d Lapatinib 1000 mg; e Paclitaxel 80 mg/m 2 qw or docetaxel q3w

31 BETH: Phase III randomised trial comparing Herceptin-containing adjuvant regimens +/ Avastin Resected node-positive or high-risk node-negative HER2-positive early breast cancer n~3600 (maximum) a CTx b + Herceptin CTx b + Herceptin + Avastin Herceptin continued q3w until 1 year total Herceptin + Avastin continued q3w until 1 year total Primary endpoint: DFS Secondary endpoints: OS; RFS; distant recurrence-free interval; safety; biomarker analysis a Actual recruitment to date ~300; b Docetaxel 75 mg/m 2 q3w + carboplatin AUC 6 q3w or docetaxel 100 mg/m 2 FEC; CTx, chemotherapy; q3w, three weekly

32 Conclusions 1 year of Herceptin remains the most appropriate and evidence-based approach for patients with HER2-positive early breast cancer Studies are ongoing to address optimal treatment duration Development of new anti-her2 treatment regimens will lead to greater patient benefits