Herceptin Pivotal Studies

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1 Herceptin Pivotal Studies Nuhad K Ibrahim, MD, FACP Associate Professor of Medicine Breast Medical Oncology Department MD Anderson Cancer Center Houston, TX, USA nibrahim@mdanderson.org

2 Herceptin (trastuzumab): History and Introduction Murine HER2/neu gene cloned Association of HER2 with poor clinical outcome Phase I IND for rhumab HER2 Phase II Phase III Human HER2 gene cloned mumab 4D5 trastuzumab FDA approval 9/25/98

3 Herceptin : Humanized Anti-HER2 Antibody HER2 epitopes recognized by hypervariable murine antibody fragment Targets HER2 protein High affinity (K d = 0.1 nm) and specificity Human IgG-1 95% human, 5% murine Decreases potential for immunogenicity Increases potential for recruiting immune effector mechanisms Baselga. Satellite Symposium, 23rd Annual San Antonio Breast Cancer Symposium 2000.

4 Potential Mechanisms of Action of Trastuzumab: Preclinical Studies Cytostatic Inhibits tumor cell proliferation by downregulating HER2 expression and blocking heterodimerization with other HER members Induces G1 arrest and p27 cell cycle inhibitor Blocks HER2 cleavage/constitutive activation Cytotoxic Initiates Fc-receptor mediated antibody-dependent cellular cytotoxicity and complement-mediated cytolysis Potentiates chemotherapy (promotes apoptosis) Baselga and Albanell. Ann Oncol. 2001;12(suppl 1):S35.

5 Herceptin Combination Pivotal Trial in First-Line MBC: Schema N = 469 MBC HER2 positive No prior CT for MBC Measurable disease KPS 60% STRATIFY No prior adjuvant AC RANDOMIZE Prior adjuvant AC RANDOMIZE Herceptin + AC (n = 143) AC (n = 138) Herceptin + Taxol (n = 92) Taxol (n = 96) AC = doxorubicin (60 mg/m 2 ) [or epirubicin (75 mg/m 2 )] + cyclophosphamide (600 mg/m 2 ) q3w for 6 cycles; Taxol (175 mg/m 2 x 3 h) q3w for 6 cycles; Herceptin (4 mg/kg) loading dose, 2 mg/kg qw until progression. Slamon et al. N Engl J Med. 2001;344:783.

6 Herceptin Combination Pivotal Trial: Efficacy Summary Subgroup Overall Herceptin Herceptin Herceptin + AC AC + Taxol Taxol + CT CT Parameter (n = 143) (n = 138) (n = 92) (n = 96) (n = 235) (n = 234) ORR (%) p value < 0.02 < < Median DR (mo) p value < 0.01 < Median TTP (mo) p value < < < Median survival (mo) p value Herceptin Package Insert Slamon et al. N Engl J Med. 2001;344:783.

7 Herceptin Combination Pivotal Trial: Results (Age 60 vs 60 y) 60 Years 60 Years Herceptin Herceptin + CT CT + CT CT Parameter (n = 180) (n = 180) (n = 55) (n = 54) Response rate (%) 94 (52) 59 (33) 24 (44) 15 (28) p value < < 0.01 Median survival (mo) Risk reduction % CI Compared with CT alone, Herceptin + CT significantly improved response rate, regardless of age; median survival was improved in both age groups, with the greatest improvement in patients > 60 years old Update of Fyfe et al. Proc Am Soc Clin Oncol. 2001;20:48a. Abstract 189.

8 Herceptin Combination Pivotal Trial: Effect of ER Status ER+ ER Herceptin Herceptin + CT CT + CT CT Parameter (n = 97) (n = 87) (n = 98) (n = 106) Response rate (%) 51 (53) 29 (33) 53 (54) 35 (33) p value NS NS Median TTP (mo) p value NS NS Risk reduction, survival (range) ( ) ( ) Similar Herceptin benefit was seen in both ER+ and ER patients Update of Bolton et al. Proc Am Soc Clin Oncol. 2001;20:44a. Abstract 172.

9 % of patients improved Herceptin Combination Pivotal Trial: QOL Improvements (QLQ-C30) 60 Herceptin + CT CT 50 p = p = 0.03 p = NS p = NS 40 p = p = Global Physical Role Fatigue Social Emotional QOL Update of Osoba et al. Proc Am Soc Clin Oncol. 2000;19:436a. Abstract 1710.

10 Probability of survival Herceptin Combination Pivotal Trial: Overall Survival FISH+ FISH 1.0 Herceptin + CT (n = 176) CT (n = 169) 1.0 Herceptin + CT (n = 50) CT (n = 56) 0.8 RR = 0.71 p = RR = 1.11 p = NS mo 26.2 mo mo 24.0 mo Months Months Update of Mass et al. Proc Am Soc Clin Oncol. 2001;20:22a. Abstract 85.

11 Herceptin after adjuvant chemotherapy significantly improves disease-free survival in HER2-positive early breast cancer HERA trial Michael Untch Ludwig-Maximilians-Universität München, Germany on behalf of the HERA Study Team

12 HER2 and Herceptin HER2-positive breast cancer is associated with early progression and poor overall prognosis 20-25% of women with breast cancer have HER2-positive disease Targeting HER2 with Herceptin is associated with significant survival benefits in women with metastatic breast cancer Early and accurate determination of HER2 status has prognostic and therapeutic importance

13 Importance of HER2 testing Patient tumour sample IHC FISH or CISH FISH or CISH Herceptin therapy Herceptin therapy + Herceptin therapy IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation; CISH, chromogenic in situ hybridisation Bilous et al 2003

14 HERA trial design Women with HER2-positive invasive early breast cancer (IHC 3+ or FISH+ centrally confirmed) Surgery + (neo)adjuvant CT ± RT Stratification Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, region Randomisation 2 years Herceptin 8 mg/kg 6 mg/kg 3 weekly schedule 1 year Herceptin 8 mg/kg 6 mg/kg 3 weekly schedule Observation HERA, HERceptin Adjuvant; CT, chemotherapy; RT, radiotherapy

15 Key inclusion criteria Centrally confirmed HER2 overexpression (IHC 3+) or amplification (FISH+) Node-positive or (sentinel) node-negative with >T1c Completed >4 cycles of approved adjuvant or neoadjuvant CT Baseline LVEF >55% (Echo or MUGA scan) after completion of (neo)adjuvant CT and RT Known hormone receptor status (ER / PgR or ER alone) LVEF, left ventricular ejection fraction; ER, oestrogen receptor; PgR, progesterone receptor

16 Disease-free survival Patients (%) Observation 1 year Herceptin 40 2-year Events DFS HR 95% CI p value No. at risk , 0.67 < Months from randomisation Median follow-up: 1 year HR, hazard ratio; CI, confidence interval

17 Cardiac safety No. patients (%) Observation 1 year Herceptin p value Decrease by >10 EF points and LVEF <50% a,b 34 (2.21) 113 (7.08) <0.001 Symptomatic CHF, including severe CHF c 1 (0.06) 29 (1.73) <0.001 Severe CHF c 0 9 (0.54) Cardiac death c 1 (0.06) a Many were single observations not confirmed at subsequent time points b Observation, n=1540; Herceptin, n=1595 c Observation, n=1710; Herceptin, n=1677 CHF, congestive heart failure

18 Conclusions Herceptin following adjuvant CT significantly prolongs DFS in women with HER2- positive breast cancer Herceptin significantly reduces the risk of distant metastases Herceptin was associated with a low incidence of severe CHF (0.5%) Long-term follow-up will provide clarification of the survival gain further safety data information on optimum Herceptin treatment duration (1 vs 2 years)

19 NSABP-B31 / NCCTG N9831: interim combined analysis Edith Perez Mayo Clinic, Jacksonville, FL, USA

20 Rationale for combined analysis National Cancer Institute sponsored 2 trials of adjuvant Herceptin NSABP-B31 NCCTG N9831 Control and concurrent treatment groups similar compared standard chemotherapy (AC) followed by paclitaxel with or without concurrent Herceptin therapy Joint analysis plan was agreed with the FDA

21 NSABP-B31 and NCCTG N9831 trial designs NSABP-B31 Arm 1 Arm 2 NCCTG N9831 Arm A Arm B Arm C = doxorubicin / cyclophosphamide (AC) 60 / 600 mg/m 2 q3w x 4 = paclitaxel (P) 175 mg/m 2 q3w x 4 = P 80 mg/m 2 qw x 12 = Herceptin (H) 4 mg/kg loading dose 2 mg/kg qw x 51

22 Combined analysis Control Arm 1 (B31) Arm A (N9831) Herceptin Arm 2 (B31) Arm C (N9831) = doxorubicin / cyclophosphamide (AC) 60 / 600 mg/m 2 q3w x 4 = paclitaxel (P) 175 mg/m 2 q3w x 4 = P 80 mg/m 2 qw x 12 = Herceptin (H) 4 mg/kg loading dose 2 mg/kg qw x 51 n=3351 Median follow-up: 2 years

23 Combined analysis: DFS Patients (%) % 85% year median follow-up ACPH ACP n HR=0.48; p< Events % 67% Years from randomisation Romond et al 2005

24 Subgroup analyses: DFS All data Age, years > <39 Hormone receptor Positive Negative Tumour size, cm > <2.0 No. positive nodes Protocol N9831 B HR Romond et al 2005

25 Time to 1st distant recurrence Patients (%) % 90% ACPH ACP n HR=0.47; p< Events % 74% Years from randomisation Romond et al 2005

26 Hazard of distant recurrence Rate per 1000 women/ year ACP ACPH Years from randomisation Romond et al 2005

27 Overall survival Patients (%) % 91% 90 92% 87% ACPH ACP HR=0.67; p=0.015 n Deaths Years from randomisation Romond et al 2005

28 N9831: DFS Patients (%) % 86% 80 78% ACPH ACP n HR=0.55; 2p= Events % Years from randomisation Romond et al 2005

29 Combined analysis: summary of efficacy end points No. events H vs obs HR (95% CI) DFS 133 vs ( ) Time to distant recurrence 96 vs ( ) Overall survival 62 vs ( ) HR Median follow-up: 2 years Romond et al 2005

30 LVEF evaluation schedule 0 months 3 months 6 months 9 months 18 months (post-ac) (post-p or -PH) MUGA (B31 and N9831) or echo scan (N9831) Post-AC LVEF >LLN or decrease <16 points from baseline to initiate Herceptin MUGA, multiple-gated acquisition; LLN, lower limit of normal

31 N9831: 3-year cumulative incidence of cardiac events 39 cardiac events were reported in 3 treatment arms over 3 years 2 cardiac deaths, 37 CHFs Cumulative incidence, % Time since registration, years Arm A ACP (n=670) Arm B ACPH (n=718) Arm C ACPH (n=579) Perez et al 2005

32 N9831: radiotherapy does not increase the incidence of cardiac events Cumulative incidence, % Arm B ACPH Arm C ACPH Radiotherapy n 1 year 2 years n 1 year 2 years Yes No Perez et al 2005

33 Summary Herceptin given concurrently with paclitaxel following AC significantly reduces the risk of DFS events by 52% significantly reduces the risk of distant recurrence by 53% significantly improves overall survival, with a 33% reduced risk of mortality The risk of cardiac events was low <4% incidence, Herceptin vs non-herceptin in both trials risk of cardiac events may increase with age

34 Conclusions Adjuvant Herceptin is recommended for patients with HER2- positive early breast cancer unless a specific contraindication exists can be administered concomitantly with radiotherapy Careful monitoring of cardiac function is essential with adjuvant Herceptin therapy

35 BCIRG 006 John Crown St Vincent s Hospital, Dublin, Ireland

36 Trial design 4 x AC 4 x D HER2 positive (FISH positive) Node positive or high-risk node negative n=3222 Stratified by nodes and hormonal receptor status ACD ACDH DCarboH 4 x AC 4 x D 6 x D and Carbo 1 year Herceptin 1 year Herceptin AC, doxorubicin + cyclophosphamide; D, docetaxel; Carbo, carboplatin

37 DFS Patients (%) % 91% 86% 86% 80% 84% 80% 77% 73% HR=0.49 HR= n Events ACDH DCarboH ACD Years Slamon et al 2005

38 Patients 80 (%) Grade 3/4 haematological toxicity ACD (n=1050) ACDH (n=1068) DCarboH (n=1056) Slamon et al 2005

39 Patients 30 (%) ACD (n=1050) 25 ACDH (n=1068) DCarboH (n=1056) Grade 3/4 non-haematological toxicity Slamon et al 2005

40 Cardiovascular risk factors ACD (n=1073) ACDH (n=1074) DCarboH (n=1075) Age, years median range Risk factors, no. patients diabetes hypercholesterolaemia hyperlipidaemia obesity hypertension Radiotherapy, no. patients after chemotherapy to left chest Slamon et al 2005

41 Clinically significant cardiac events statistical analysis ACD (n=1050) ACDH (n=1068) DCarboH (n=1056) Patients % % CI p=0.016 p=0.11 p=0.54 Slamon et al 2005

42 Clinically significant cardiac events as per independent review panel ACD (n=1050) ACDH (n=1068) DCarboH (n=1056) Cardiac death, n Grade 3/4 cardiac ischaemia / infarction, n Grade 3/4 arrhythmia, n 7* 4* 9* Grade 3/4 CHF, n *5 / 20 arrhythmias not yet adjudicated by independent review panel (2 in ACD, 1 in ACDH, 2 in DCarboH) Slamon et al 2005

43 LVEF Mean LVEF: all observations DCarboH ACD ACDH (n=1029) (n=1012) (n=1040) 189 pts 290 pts pts Days Slamon et al 2005

44 HER2 and topo II in BCIRG 006: 2120 / 3222 patients analysed 17 q q q 21.2 n=2120 Topo II non-coamplified Co-amplified 1285 pts (60%) 91 pts (4%) 744 pts (35%) HER2 core region Topo II region Normal Amplified Deletion Topo II, topoisomerase II

45 Patients (%) 100 DFS topo II co-amplified vs non-co-amplified: all patients Patients Events Topo II Co-amplified Non-co-amplified p< Years Slamon et al 2005

46 Patients (%) DFS co-amplified topo II Patients Events ACDH ACD DCarboH p= Months Slamon et al 2005

47 Patients (%) DFS non-co-amplified topo II Patients Events ACDH DCarboH ACD p< Months Slamon et al 2005

48 Conclusions BCIRG 006 has confirmed the benefit of Herceptin in early breast cancer With a favourable overall safety profile, the risk : benefit ratio warrants the use of Herceptin in early breast cancer Preliminary data on topo IIα status suggest that not all patients benefit equally from anthracyclines Cardiac safety improves with DCarboH Further follow-up is required to determine whether efficacy differs between ACDH and DCarboH

49 Neoadjuvant therapy with paclitaxel followed by FEC chemotherapy with trastuzumab in HER-2 positive operable breast cancer PI. Aman Buzdar, MD

50 C um ul ati ve proporti on survi vi ng di sease-free Who benefits from a particular adjuvant chemotherapy? P = Mo n t h s p C R < p C R Those who have a complete eradication of their breast cancer (pcr) by preoperative chemotherapy benefit! Kuerer H et al. J Clin Oncol 1999

51 Phase II Trials of Trastuzumab Neoadjuvant Therapy for Breast Cancer *42% of patients had <5 mm residual tumors. Percent Study (N) Regimen ORR ccr pcr Mohsin 2005 T qw 3, T + D qw 12 Gennari 2004 (11) T qw Burstein 2003 (40) T qw 12 + P qw Bines 2003 (33) T qw 12 + D q3w Harris 2003 (42) T qw 12 + V qw Limentani 2003 (45) T qw 12 + DV q2w * Mohsin et al. J Clin Oncol. 2005;23:epub ahead of print; Gennari et al. Clin Cancer Res. 2004;10:5650; Burstein et al. J Clin Oncol. 2003;21:46; Bines et al. Breast Cancer Res Treat. 2003:82:S56. Abstract 243; Harris et al. Proc Am Soc Clin Oncol. 2003;22:22. Abstract 86; Limentani et al. Breast Cancer Res Treat. 2003;83:S58. Abstract 251.

52 Phase III Trial of Neoadjuvant Trastuzumab + Chemotherapy for Operable Breast Cancer HER2+ (IHC 3+/FISH+) N=42* R ARM 1 Paclitaxel 4 + T 12 ARM 2 Paclitaxel 4 FEC 4 + T 12 N=19 FEC 4 N=23 Additional 22 patients Local and adjuvant therapy *Paclitaxel 225 mg/m 2 q3w. FEC = 5-fluorouracil 500 mg/m 2 d1, 4 + epirubicin 75 mg/m 2 d1 + cyclophosphamide 500 mg/m 2 d1, all q3w. T = trastuzumab 4 mg/kg d1, then 2 mg/kg qwx24 weeks Buzdar et al. J Clin Oncol. 2005;23:

53 Score Current Clinical Practices for Herceptin Patient Selection In current clinical practice, either IHC or FISH is used for primary testing IHC /1+ HER2 results inconsistent with clinical profile FISH Amplified Nonamplified Treat with Herceptin Possible benefit High overexpressors Other therapies Significant false-positive with HercepTest suggests in some cases retesting with FISH may be warranted

54 Guidelines on HER2 Testing NCCN Clinical Practice Guideline (2004): Recommends HER2 testing for all invasive breast cancer cases, using IHC and/or FISH FISH retesting of IHC 2+ recommended ASCO Practice Guideline for Tumor Markers (2000): HER2 overexpression should be evaluated on every primary breast cancer either at the time of diagnosis or at the time of recurrence. Measures of HER2 amplification may also be of value.

55 Guidelines on HER2 Testing (cont.) College of American Pathologists consensus statement (2003): Laboratories should calculate their FISH/IHC concordance rates If FISH-neg/IHC 0 and FISH-pos/IHC 3+ concordance is >95%: OK to use IHC as screening test All IHC 1+ and 2+ should be retested by FISH If FISH-neg/IHC 1+ concordance is also >95%, OK to not retest IHC 1+ with FISH, but should document in a path report comment If do not wish to check concordance, Zarbo & or Hammond, concordance Arch Pathol Lab Med, 2003 <95%, consider performing both IHC and FISH on all

56 Thank You