The Role Of Trastuzumab In Metastatic Her-2 Positive Breast Cancer

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The Role Of Trastuzumab In Metastatic Her-2 Positive Breast Cancer

  1. 1. The Role Of Trastuzumab In Metastatic Her-2 Positive Breast Cancer Elshami M. Elamin, MD Medical Oncologist Central Care Cancer Center www.cccancer.com Wichita, KS –USA
  2. 2. The Enormous Impact of Breast Cancer 192,370 New Cases 40,170 Deaths 4% Melanoma of skin 2% Brain 4% Thyroid 26% Lung & bronchus 27% Breast 15% Breast 15% Lung & bronchus 6% Pancreas 3% Kidney & renal pelvis 9% Colon & rectum 10% Colon & rectum 5% Ovary 3% Ovary 3% Uterus 6% Uterus 4% Non-Hodgkin’s lymphoma 4% Non-Hodgkin’s lymphoma 3% Leukemia 3% Leukemia 2% Liver & intrahepatic bile duct 23% All other sites 25% All other sitesAmerican Cancer Society. Cancer Facts & Figures 2009. Atlanta, GA: American Cancer Society; 2009.
  3. 3. Advanced Breast Cancer MBC remains incurable Goals of therapy include palliation:  delaying disease progression  prolonging survival Treatment is tailored to disease characteristics Challenges remain to:  optimize current therapy  rationally integrate targeted agents into standard regimens  and identify new targets
  4. 4. In the absence of treatment, patients with HER2+ breast cancer have shortened median survival HER2 gene amplification by FISH HER2+ 3 years HER2 normal 6–7 years Unmet need in the HER2+ MBC HER2+ protein overexpression by IHC Combined metastatic and adjuvant patientsSlamon et al. Science 1987;235:177–182. Pauletti et al. J Clin Oncol 2000;18:365–3664 5
  5. 5.  (HER2) overexpression is usually associated with a more aggressive tumor phenotype . Studies have shown that breast cancers that overexpress HER2 have a more aggressive course and higher relapse and mortality rates. HER2 protein overexpression and/or HER2 gene amplification.  Seen in 15%-20% of women with breast cancer
  6. 6. Anti-Her2-neu Therapy
  7. 7. 1. Trastuzumab (Herceptin):  A humanized monoclonal antibody against the extracellular domain of HER2.  Established as the foundation of care for HER2- positive breast cancer  In MBC, is indicated in combination with chemotherapy (taxane) or as monotherapy.2. Lapatinib (Tykerb):  A tyrosine kinase inhibitor that targets HER2 intracellularly by interfering with HER2 signaling  Used in combination with capecitabine, trastuzumab or A.I.
  8. 8. Hercep tin Lapatin ib
  9. 9. Studies in HER2-PositiveMetastatic Breast Cancer
  10. 10. PIVOTAL PHASE III TRIAL ®HERCEPTIN IN COMBINATION WITH CHEMOTHERAPY (H0648G) Slamon DJ, et al. N Engl J Med 2001;344:783–92 Smith IE. Anticancer Drugs 2001;12:S3–10
  11. 11. Pivotal Herceptin combination trial (H0648g) ® design and enrolment  MBC  HER2 overexpression Eligible patients (n=469)  No prior CT for MBC  Measurable disease  KPS 60% No prior anthracyclines Prior anthracyclines Herceptin + AC ® AC Herceptin + paclitaxel ® Paclitaxel (n=143) (n=138) (n=92) (n=96)AC = doxorubicin/epirubicin + cyclophosphamide,CT = chemotherapy, MBC = metastatic breast cancer
  12. 12. Pivotal Herceptin combination therapy trial (H0648g) ® TTP (IHC 3+ patients) 1.0 0.9 Herceptin + CT ® 0.8 CT alone 0.7 P=<0.05Probability of survival 0.6 0.5 0.4 0.3 0.2 0.1 4.6 7.8 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (months)
  13. 13. Pivotal Herceptin combination trial (H0648g) ® TTP (subgroup analysis) AC group (p=0.0003) Paclitaxel group (p=<0.05) 1.0 Herceptin + AC (n=143) ® 1.0 Herceptin + paclitaxel (n=92) ® median = 7.8 months 0.9 median = 6.9 months 0.8 0.8 Paclitaxel (n=96) AC (n=138) median = 2.7 months 0.7Probability median = 6.1 months Probability 0.6 0.6 0.5 0.4 0.4 0.3 0.2 0.2 0.1 0 0 0 5 10 15 20 25 0 2 4 6 8 10 12 14 16 Time (months) Time (months) Cut-off October 1999 ASCO 2000
  14. 14. Pivotal Herceptin combination trial (H0648g) ® overall survival – all patients 1.0 0.9 Herceptin + CT ® 0.8 CT alone 0.7 P=<0.05 Probability of survival 0.6 0.5 0.4 0.3 0.2 0.1 20.3 25.1 0.0 0 5 10 15 20 25 30 35 40 45 50CT patients treated Time (months) ®with Herceptin after 24% 62% 65% 72%disease progression Cut-off October 1999 ASCO 2000
  15. 15. ® Pivotal Herceptin combination trial (H0648g) overall survival – paclitaxel subgroup 1.0 0.9 Herceptin + paclitaxel ® 0.8 Paclitaxel alone 0.7Probability of survival 0.6 0.5 0.4 0.3 0.2 0.1 18 22 0.0 0 5 10 15 20 25 30 35 40 45 50 Time (months)
  16. 16. Pivotal Herceptin combination therapy trial (H0648g) ® overall survival (IHC 3+ patients) 1.0 0.9 Herceptin + CT® 0.8 CT aloneProbability of survival 0.7 p<0.05 0.6 0.5 0.4 0.3 0.2 0.1 0.0 20 29 0 5 10 15 20 25 30 35 40 45 50 Time (months) Mass R et al. Proc ASCO 2000;19:Abstract 291
  17. 17. ® Pivotal Herceptin combination trial (H0648g) TTP – paclitaxel subgroup (IHC 3+ patients) 1.0 0.9 Herceptin + paclitaxel ® 0.8 Paclitaxel alone 0.7Probability 0.6 0.5 0.4 0.3 0.2 0.1 3.0 7.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (months)
  18. 18. ® Pivotal Herceptin combination trial (H0648g) overall survival – paclitaxel subgroup (IHC 3+) 1.0 0.9 Herceptin + paclitaxel ® 0.8 Paclitaxel alone Probability of survival 0.7 0.6 0.5 0.4 0.3 0.2 0.1 18 25 0.0 0 5 10 15 20 25 30 35 40 45 50Paclitaxel patients treated with Time (months)Herceptin after disease progression ® 67% Mass R et al. Proc ASCO 2000;19:Abstract 291
  19. 19. Pivotal Herceptin combination trial (H0648g) ® quality of life (QoL) benefits ® 60 Herceptin + CT CT alone P=< 0.05 p=0.03 50No. of patients improving (%) 40 p=0.08 30 20 10 0 Global Physical Role Social Emotional Fatigue QoL QoL domains Osoba D, et al. Proc Am Soc Clin Oncol 2001;20:28a (Abstract 109)
  20. 20. Pivotal Herceptin combination trial (H0648g) ® conclusions Herceptin in combination with chemotherapy improves TTP and overall survival A survival benefit is seen even though 72% of chemotherapy-alone patients received Herceptin after disease progression Adding Herceptin to paclitaxel  increases median survival from 18.4 to 22.1 months in all patients and from 18 to 25 months in IHC 3+ patients  increases TTP from 3.0 to 6.9 months in all patients and from 3.0 to 7.1 months in IHC 3+ patients
  21. 21. Pivotal Herceptin combination trial (H0648g) conclusions (cont’d) IHC 3+ positivity is highly concordant (89%) with FISH positivity IHC 3+ and FISH-positive patients have a similar outcome (RR, TTP and survival) following Herceptin treatment ® Adding Herceptin to chemotherapy provides ® benefit in both ER-positive and ER-negative patients and in patients aged >60 years
  22. 22. M77001 trialDocetaxel +/- Herceptin Marty M, et al. J Clin Oncol 2004. In press
  23. 23. M77001: trial design HER2-positive MBC (IHC 3+/FISH+) n=188 Two patients did not receive study medication Docetaxel* Docetaxel 100mg/m2 q3w x6 100mg/m2 q3w x6 + Herceptin® 4mg/kg i.v. then 2mg/kg/week until disease progression*Patients progressing on docetaxel alone couldcrossover to receive Herceptin®
  24. 24. M77001: time to disease progression 1.0 Herceptin + docetaxel ® 0.8 Docetaxel alone Estimated probability 0.6 0.4 p=0.0001 0.2 6.1 10.6 0 0 3 6 9 12 15 18 21 24 27 30 MonthsIntent-to-treat population
  25. 25. Significant survival benefit with first-line Herceptin plus docetaxel ® 1.0 Herceptin + docetaxel ® Docetaxel alone 0.8 Estimated probability 0.6 0.4 p=0.0062 0.2 22.1 30.5 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months 8.4 monthsIntent-to-treat population, 12-month cut-offDocumented crossover = 48% Marty M, et al. J Clin Oncol 2004. In press
  26. 26. M77001: conclusions First-line Herceptin® plus docetaxel significantly improves  ORR (61% vs 36%)  TTP (10.6 vs 6.1 months)  estimated median survival (27.7 vs 18.3 months) The data strongly suggest that Herceptin® should be used upfront in combination with docetaxel in HER2-positive metastatic breast cancer
  27. 27. M77001: conclusions (cont’d) M77001 provides unequivocal evidence that Herceptin® plus docetaxel is superior to docetaxel alone in patients with HER2-positive metastatic breast cancer Herceptin adds little to the toxicity profile of docetaxel  low incidence of congestive heart failure (only 2%)  few serious infusion-related reactions  slight increase in haematological toxicity, which is generally manageable  fewer patients in the Herceptin® plus docetaxel arm discontinued treatment due to toxicity than in the docetaxel-alone arm
  28. 28. Herceptin plus a taxane extends survival compared with taxane alone Slamon (H0648g) Marty (M77001) H+P P H+D D IHC 3+ IHC 3+ (n=68) (n=77) (n=92) (n=94)ORR (%) 49 17 61* 36TTP (median, months) 7.1* 3.0 10.6* 6.1OS (median, months) 24.8 17.9 27.7* 18.3H = Herceptin ; P = paclitaxel; D = docetaxel ®*p<0.05 1 Baselga J. Oncology 2001;61(Suppl. 2):14–21 2 Roche, data on file
  29. 29. Extending the benefit of Herceptin ® combination therapy to more patients Alternative effective options required for patients pretreated with a taxane Differing chemotherapy safety profiles allow individualised treatment decisions Several promising Herceptin regimens HER2-positive MBC Non-doxorubicin TripleVinorelbine Gemcitabine Xeloda ® anthracyclines combinations
  30. 30. ®HERCEPTIN PLUS VINORELBINE
  31. 31. Herceptin and vinorelbine: trial overview ®1. Single-centre phase II trial of Herceptin plus ® vinorelbine (n=40)2. Multicentre phase II trial of first-line Herceptin ® plus vinorelbine (n=40)3. European phase II trial of first-line Herceptin plus ® vinorelbine (n=35)4. US phase II trial of first-line Herceptin plus ® vinorelbine (n=54) 1BursteinH, et al. J Clin On 2Jahanzeb M, et al. Oncologist 2002;7:410–417 3Bernardo G, et al. Ann Oncol 2002;13:51 (Abstract 181) 4Bunnel C, et al. Ann Oncol 2002;13:50 (Abstract 180)
  32. 32. Multicentre trial of first-line Herceptin plus vinorelbine ® efficacyPatients evaluable for response n=37 n (% )C o m p le te re s p o n s e 4 (1 1 )P a rtia l re s p o n s e 2 5 (6 8 )S ta b le d is e a s e 4 (1 1 )P ro g re s s iv e d is e a s e 4 (1 1 )O v e ra ll re s p o n s e 2 9 (7 8 )In te n t-to -tre a t re s p o n s e 2 9 (7 2 ) Jahanzeb M, et al. Oncologist 2002;7:410–417
  33. 33. Multicentre trial of first-line Herceptin plus vinorelbine: ® summary Overall response rate in evaluable patients was 78%, with a 72% response rate by ITT analysis Treatment with Herceptin® plus vinorelbine was well tolerated with little grade 3–4 toxicity Response seems to correlate with degree of HER2 positivity by IHC (82% in patients with IHC 3+ disease) Jahanzeb M, et al. Oncologist 2002;7:410–417
  34. 34. US phase II trial of first-line Herceptin plus vinorelbine: ® summary Overall response rate  all patients, 68%  IHC 3+ patients, 68% Majority of side effects mild-to-moderate in severity  most common side effects were fatigue, nausea and constipation Herceptin plus vinorelbine is a well-tolerated ® and effective combination Bunnell C, et al. Ann Oncol 2002;13:50 (Abstract 180)
  35. 35. Herceptin triple combinations ® building on the taxane successA u th o r R e g im e n n O R R (% )Y a rd le y e t a l. 2 0 0 2 C a rb o p la tin / p a c lita x e l 61 66P e re z e t a l. 2 0 0 3 C a rb o p la tin / p a c lita x e l q w 48 71 C a rb o p la tin / p a c lita x e l q 3w 43 65R o b e rt e t a l. 2 0 0 4 C a rb o p la tin / p a c lita x e l 93 52 P a c lita x e l 95 36P e g ra m e t a l. 2 0 0 4 a C is p la tin / d o c e ta x e l 62 79P e g ra m e t a l. 2 0 0 4 b C a rb o p la tin / d o c e ta x e l 59 58V e n tu rin i e t a l. 2 0 0 3 E p iru b ic in / d o c e ta x e l 45 69M ille r e t a l. 2 0 0 2 G e m c ita b in e / p a c lita x e l 45 62Y a rd le y e t a l. 2 0 0 4 V in o re lb in e / d o c e ta x e l 34 70
  36. 36. TRASTUZUMAB + DOCETAXEL WITH ORWITHOUT CAPECITABINE IN PATIENTS WITHHER2-POSITIVE ADVANCED OR METASTATICBREAST CANCER: PRIMARY EFFICACY AND SAFETY RESULTS FROM A RANDOMISED PHASE II STUDY (CHAT) Andrew Wardley Christie Hospital, Manchester, UK On behalf of the CHAT investigators
  37. 37. CHAT study 1st-line therapy for HER2-positive MBC or LABC (majority MBC) H: 8 mg/kg loading dose → 6 mg/kg q3w Until T: 75 mg/m2 q3w PD X: 950 mg/m2 bid Days 1-14 q3w HER2-positive MBC / LABC(FISH+ and / or IHC 3+) R (n=225) H: 8 mg/kg loading dose → 6 mg/kg q3w Until T: 100 mg/m2 q3w PDHER2, human epidermal growth factor receptor 2; LABC, locally advanced breast cancer; MBC,metastatic breast cancer; FISH, fluorescencein situ hybridisation; IHC, immunohistochemistry; R, randomisation; PD, progressive disease; H,trastuzumab; T, docetaxel; X, capecitabine
  38. 38. Progression-free survival Events HR 95% CI p valueProbability 1.0 HTX 59 0.72 0.51, 1.02 0.06 HT 71 0.8 0.6 0.4 0.2 12.8 14.8 0.0 0 5 10 15 20 25 30 35 40 45 50 Months from randomisation HR, hazard ratio; CI, confidence interval
  39. 39. Time to progression Events HR 95% CI p valueProbability 1.0 HTX 55 0.697 0.488, 0.995 0.045 HT 68 0.8 0.6 0.4 0.2 13.8 18.2 0.0 0 5 10 15 20 25 30 35 40 45 50 Months from randomisation HR, hazard ratio; CI, confidence interval
  40. 40. Overall survivalProbability 1.0 0.8 0.6 0.4 Events HR 95% CI p value 0.2 HTX 25 0.82 1.39, 0.48 0.459 HT 30 0.0 0 5 10 15 20 25 30 35 40 45 50 Months from randomisation HR, hazard ratio; CI, confidence interval
  41. 41. Conclusions HTX and HT are effective 1st-line regimens for patients with HER2-positive LABC / MBC High response rates and good tolerability for both regimens HTX showed longer TTP and PFS compared with HT  TTP reached statistical significance (borderline)  PFS did not quite reach statistical significance OS data are immature with only 25% events Follow-up is ongoing
  42. 42. BCIRG 007 First Line Metastatic Breast Cancer 8 TH Docetaxel 100 mg/m2 q3wHER2 + Trastuzumabby FISH 8 TCHN=263 Docetaxel 75 mg/m2 q3w Carboplatin AUC: 6mg/ml/min TrastuzumabStratification: - Prior CT: adjuvant and/or neoadjuvant - Center
  43. 43. BCIRG 007: First-Line Trastuzumab + Docetaxel Carboplatin HER2+ MBC  Median follow-up: 27.6 months 1.0 TH TCH Progression-Free Survival  Time to progression equivalent between arms (P = .57) 0.8  TH: 11.07 months  TCH: 10.35 months 0.6  Similar overall response 0.4  TH: 72.5%  TCH: 72.7% 0.2  Median survival: > 40 months 0 0 1 2 3 4 Years From RandomizationForbes JF, et al. ASCO 2006. Abstract 516.
  44. 44. Overall conclusions Both TH, (T 100) and TCH, (T 75), are effective therapies in this patient population with TTP>10 months and OS>36 months There are no significant differences (TH vs. TCH) in ORR, TTP, or OS; however the study was relatively underpowered to detect smaller differences in clinical outcome (e.g. <50%  in TTP), with a median follow-up duration of 39 months We cannot rule out a contribution of carboplatin in the TCH arm because of the differences in docetaxel dosing
  45. 45. Herceptin® has proven survival benefit in 1st-line MBCH0648g P alone(IHC 3+) PH D aloneM77001 DH DCarboHBCIRG 007 DHUS Oncology PCarboH(IHC 3+) PH 0 10 20 30 40 50 Median survival (months)Carbo, carboplatin; D, docetaxel; H, Herceptin®; Smith et al 2001; Marty et al 2005;IHC, immunohistochemistry; P, paclitaxel Robert et al 2006; Pegram et al 2007
  46. 46. Herceptin breaks through the 12-month progression-free survival barrier Docetaxel 6.5 Median PFS/TTP Chan 1999 Doxorubicin 9 months Chan 1999 5.3 Monotherapy Paclitaxel 6.0 Seidman 2004 Vinorelbine Muhoz 2006 4.1 Doxorubicin + paclitaxel Jassem 2001 8.3 Capecitabine + docetaxel 5.1 O’Shaughnessy 2002 Gemcitabine + paclitaxel 5.2 Combination Albain 2004 chemotherapy Fluorouracil + epirubicin 9.0 Zielinski 2005 Gemcitabine + vinorelbine Muñoz 2006 6.3 Epirubicin + taxane Pacilio 2006 9.0 Anti-Her2 therapy Herceptin + Taxanes 10.6 + chemotherapy Paclitaxel 6.7 0 2 4 6 8 10 12 14PFS = progression-free survival; TTP = time to progression Months
  47. 47. EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer Lapatinib 1250 mg daily + Capecitabine 2000 mg/m2 dailyRefractory, progressive metastatic for Days 1-14, 3-week cyclesor locally advanced HER2+ breast (n = 160) Follow-up: cancer previously treated with until progression anthracycline, or unacceptable taxane, or trastuzumab toxicity (N = 528 planned*) Capecitabine 2500 mg/m2 daily for Days 1-14, 3-week cycles (n = 161) *Study enrollment terminated early by IDMC due to superiority of combination arm in primary endpoint.Geyer CE, et al. ASCO 2006. Clinical Science Symposium.
  48. 48. EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer (cont’d)  Addition of lapatinib to capecitabine Lapatinib + capecitabine in women with treatment-refractory, 100 Capecitabine advanced metastatic breast cancer Progression-Free Survival (%) associated with 80  Longer time to progression  36.9 vs 19.7 wks (P = .00016) 60  Longer progression-free survival 40  36.9 vs 17.9 wks (P = .000045)  Fewer progressions or deaths 20  38% vs 48%  Response (independent review) 0  Overall: 22.5% vs 14.3% (P = .113) 10 20 30 40 50 Time (Wks) ITT populationGeyer CE, et al. ASCO 2006. Clinical Science Symposium.
  49. 49. EGF100151: Lapatinib + Capecitabine in Advanced Breast Cancer (cont’d) 100 Severity Gr 1 Gr 2 Gr 3 Gr 4 80 Rash and/orPatients (%) 60 Diarrhea PPES Skin Reaction 40 26 28 19 20 19 20 12 13 15 11 9 13 12 11 9 6 5 7 1 3 0 0 0 0 0 0 L+C C Alone L+C C Alone L+C C AloneGeyer CE, et al. ASCO 2006. Clinical Science Symposium.
  50. 50. Anti-Her2 Therapy andHormonal Therapy
  51. 51. Phase III trials of hormonal therapy and anti-HER2 therapy in HER2/hormone receptor co-positive patients TAnDEM  Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with HER2-positive, hormone receptor-positive MBC  Kaufman et al. J Clin Oncol 2009EGF30008● Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer● Johnston et al. J Clin Oncol 2009
  52. 52. TAnDEM: a Phase III study of 1st-line trastuzumab and anastrozole in patients with HER2/hormone receptor co-positive MBC Trastuzumab 4 mg/kg loading dose Patient population  2 mg/kg qw • Postmenopausal + anastrozole 1mg/day • Stage IV until disease progression (n=103) • HER2+, ER+ and/or PgR+ R • No prior chemotherapy for MBC • Prior hormonal therapy for MBC Anastrozole 1 mg/day permitteda until disease progression (n=104)*Primary end point● PFSSecondary end points● CBR, ORR, TTP, duration of response, OS, 2-year survival and safety (including cardiac function) *Crossover to receive trastuzumab was allowed (n=73/104)aPrior anastrozole permitted if started ≤ 4 weeks prior to randomisationPFS = time from randomisation to date of progressive disease or death Kaufman et al 2009
  53. 53. TAnDEM: Response Rates ORR + CBR 50 p=0.026 42.7 40 p=0.018 Patients (%) 30 27.9 Anastrozole 20.3 Trastuzumab + 20 anastrozole 10 6.8 0 ORR CBRORR = complete response + partial responseCBR = complete response + partial response + stable disease Kaufman et al 2009
  54. 54. TAnDEM: Progression-free survival 1.0 Events Median PFS 95% CI p value 0.8 A+H 87 4.8 months 3.7, 7.0 0.0016 A 99 2.4 months 2.0, 4.6 HR 0.63 Probability 0.6 95% CI 0.47, 0.84 0.4 0.2 0.0 0 5 10 15 20 25 30 35 40 45 50 55 60 Months No. at risk A+H 103 48 31 17 14 13 11 9 4 1 1 0 0 A 104 36 22 9 5 4 2 1 0 0 0 0 0A, anastrozole; H, trastuzumab; CI, confidence interval; HR, hazard ratio Kaufman et al 2009
  55. 55. TAnDEM: overall survival 1.0 Events Median OS 95% CI p value A + H 58 28.5 months 22.8, 42.4 0.325 0.8 A 64 23.9 months 18.2, 37.4 Probability 0.6 0.4 0.2 0.0 0 5 10 15 20 25 30 35 40 45 50 55 60 No. at risk Months A+H 103 91 83 76 63 49 36 24 12 4 3 0 0 A 104 96 87 73 58 42 34 22 5 2 1 1 0 A trend was observed in favour of trastuzumab despite 70% of patients crossing over73/104 patients (70%) received H later during the course of disease Kaufman et al 2009
  56. 56. EGF30008: a Phase III trial of lapatinib + letrozole in patients with hormone receptor-positive disease Patient population • Postmenopausal Lapatinib 1500 mg/day + Letrozole 2.5 mg/day • Stage IIIb/IIIc/IV (HER2+ n=111) • HER2+, HER2- or unknown R • ER+ and/or PgR+ Letrozole 2.5 mg/day • No prior treatment for MBC + placebo* • Prior adjuvant anti-oestrogen (HER2+ n=108) therapy alloweda HER2+ n=219 (n=1286) Primary end point ● PFS in HER2+ population Secondary end points ● PFS in whole population, OS, ORR, CBR and safety *No crossover was allowedaPatients stratified based on interval since adjuvantanti-oestrogen treatment < 6 months/≥ 6 months or none Johnston et al 2009
  57. 57. EGF30008: Response rates ORR + CBR HER2+ population 60 p=0.003 Letrozole + placebo 50 48% p=0.021 Lapatinib + 40 Letrozole Patients (%) 28% 29% 30 20 15% 10 0 ORR CBRORR = complete response + partial responseCBR = complete response + partial response + stable disease Johnston et al 2009
  58. 58. EGF30008: Progression-free survival HER2+ population 1.0 Events Median PFS p value Let + lap 88 8.2 months 0.019 0.8 Let + p 89 3.0 months HR 0.71 Probability 0.6 95% CI 0.53, 0.96 0.4 0.2 0.0 0 5 10 15 20 25 30 35 40 45 50 No. at risk Months Let + lap 111 69 33 20 12 8 4 1 1 Let + p 108 43 26 18 12 7 5 2 2Let, letrozole; lap, lapatinib; p, placebo Johnston et al 2009
  59. 59. EGF30008: overall survival 1.0 Events Median OS p value Let + lap 50 33.3 months ns 0.8 Let + p 54 32.3 months Probability 0.6 0.4 0.2 0 0 5 10 15 20 25 30 35 40 45 50 No. at risk Months Let + lap 111 104 89 80 64 48 32 19 9 4 Let + p 108 93 76 69 59 38 31 15 8 2 No trend observed in terms of overall survivalns, not significant Johnston et al 2009
  60. 60. Conclusions from TAnDEM and EGF30008 Addition of anti-HER2 therapy to hormonal therapy significantly improved PFS  Reduction of risk of progression 37% in TAnDEM  Reduction of risk of progression 29% in EGF30008 The benefit observed in the control arms was low Why do we observe such low benefit in both control arms?
  61. 61. Does HER2 positivity confer intrinsic resistance to hormonal treatment? HER2+ (n=164) 45 HER2- (n=398) 40 39% 35 32% 30 26%ORR (%) 25 20 17% 15% 15 13% 10 5 0 Letrozole Tamoxifen Letrozole or (n=283) (n=279) tamoxifen (n=562) HER2-positive tumours are less responsive to hormonal treatment in the absence of anti-HER2 therapy Lipton et al 2003
  62. 62. ORRs in HER2/hormone receptor co-positive MBC 100 Combination with HER2/HR 80 chemotherapy co-positive patients ORR (%) HO648g M77001 60 Combination with aromatase inhibitors 40 EGF30008 TAnDEM 20 0 Trastuzumab + Lapatinib + Trastuzumab + Trastuzumab + anastrozole letrozole paclitaxel docetaxel In HER2/hormone receptor co-positive patients the best overall responses are observed when chemotherapy is added to anti-HER2 therapy Kaufmann et al 2009; Johnston et al 2009; Brufsky et al 2004; Extra et al 2004
  63. 63. Conclusions HER2/hormone receptor co-positive breast cancer is an aggressive disease Chemotherapy in combination with trastuzumab for patients with HER2/hormone receptor co- positive disease remains the treatment of choice Anti-HER2 therapy in combination with hormonal therapy should be reserved for patients who are not eligible for chemotherapy
  64. 64. Bevacizumab + Trastuzumab: Phase II Study Design  HER2+ metastatic breast cancer patients (N = 37) received  Bevacizumab 10 mg/kg on Day 7 and then every 2 weeks thereafter  Trastuzumab 4 mg/kg loading dose followed by 2 mg/kg every week  Primary objectives  Assess clinical efficacy of bevacizumab/trastuzumab combination  Assess safety of bevacizumab/trastuzumab combinationPegram M, et al. SABCS 2006. Abstract 301.
  65. 65. Patient Responses to Bevacizumab + Trastuzumab Therapy  More than one half of patients had objective response to treatment Objective Clinical Response, n (%) Patients (N = 37) Overall 20 (54.1)  Complete* 1 (2.7)  Partial* 19 (51.4) Stable disease 11 (29.7) Progressive disease 6 (16.2) *1 complete response and 13 partial responses confirmed by pathology.Pegram M, et al. SABCS 2006. Abstract 301.
  66. 66. Conclusions From Phase II Bevacizumab + Trastuzumab Study  Feasible to combine bevacizumab with trastuzumab in HER2-positive recurrent/metastatic breast cancer patients  Data support the strategy of testing combination therapy directed against both HER2 and VEGF in FISH-amplified HER2 breast cancerPegram M, et al. SABCS 2006. Abstract 301.
  67. 67. TRASTUZUMAB BEYOND PROGRESSION
  68. 68. ADCC is a key mechanism of Herceptin’s antitumour activity in vivo HER2 Tumour + Herceptin cell NK cell ADCC FcgRIII• Once bound to HER2, the Herceptin Fc domain recruits immune cells to target and destroy the tumour ADCC = Antibody-Dependent Cell-Mediated Cytotoxicity
  69. 69.  Herceptin is not subject to classical chemotherapy resistance mechanisms In vitro studies are not predictive of in vivo resistance As activation of the immune system (ADCC) is a key mechanism of action for Herceptin, alternative signalling does not necessarily lead to in vivo resistance Preclinical data suggest that continuation of Herceptin treatment beyond progression in combination with chemotherapy or targeted agents can lead to tumour eradication Clinical data confirm the benefits associated with continuation of Herceptin beyond progression
  70. 70. Background Changing treatment at disease progression is a general principle in oncology However, it is not known if this applies for targeted, non-cytotoxic treatments such as Herceptin Preclinical data indicate  Herceptin is effective against tumour cell proliferation, as long as it is present  Herceptin withdrawal results in rapid tumour cell re-growth  Herceptin inhibits the growth of intrinsically insensitive tumours  Herceptin enhances the activity of other drugs (synergism) Numerous phase II trials and observational studies support the use of Herceptin beyond progression
  71. 71. Trastuzumab re-treatment in patients who relapse following adjuvant trastuzumab therapy Preliminary efficacy data from the (Re-treatment after Herceptin Adjuvant) RHEA trial
  72. 72. Herceptin® is active in retreatment as suggested by preliminary data from RHEA Interim analysis (n=12)  A non-randomised, open-label, 2-cohort (Herceptin® or Herceptin® PD 1 + taxane), Phase II trial (n=80) SD 6  Patients with HER2- PR 5 positive MBC who have relapsed after receiving adjuvant Herceptin®  Final results expected 2010PD, progressive disease; PR, partial response; SD, stable disease Bell et al 2007
  73. 73. Continuing Herceptin and switching chemotherapy provides clear benefits 2nd Herceptin-based regimen Lapatinib + Xeloda Study n ORR, % TTP, months ORR, % TTP, months Hutka et al 2007 12 50 9.0 Tokajuk et al 2006 14 50 5.1 Stemmler et al 2005 23 39 Gelmon et al 2004 65 32 6.0 Bachelot et al 2007 17 29 Morabito et al 2006 7 29 Metro et al 2007 37 29 6.7 Bartsch et al 2006 54 26 6.0 García-Sáenz et al 2005 31 26 3.0 Fountzilas et al 2003 80 24 5.2 Cameron et al 2007 198 24 (32)a 6.2 (5.5)a Bartsch et al 2007 40 20 8.0 Montemurro et al 2006 40 18 6.3 Orlando et al 2006 22 18 6.0 Baselga et al 2007 33 18 Tripathy et al 2004 93 11aData in parentheses by investigator assessment, from US Lapatinib Prescribing Information 2007
  74. 74. Overall survival benefit from continuation of Herceptin®-based therapy after progression Observational studyProbability, 1.0OS Continued Herceptin®: n=112, 46 events 0.8 Discontinued Herceptin®: n=81, 39 events Log-rank test: p=0.0014, 2-sided 0.6 0.4 0.2 13.4 20.1 0.0 0 10 20 30 40 50 60 70 80 Time from 1st progression (months) Jackisch et al 2007
  75. 75. On behalf ofGBG; AGO; CECOG; BOOG; Slovenia; DBG; CR-UK and BIG
  76. 76. GBG-26 is the 1st randomised Phase III study to investigate continuation of Herceptin® Progression under Herceptin®-based first-line therapy + taxane (n=114) monotherapy or non-taxane (n=42) R Xeloda® 2500 mg/m2 bid d1-14 q21d + Xeloda® 2500 mg/m2 bid continuation of d1-14 q21d Herceptin® 6 mg/kg q3w (n=78) (n=78)R, randomisation von Minckwitz et al 2007
  77. 77. Continuation of Herceptin® doublesresponse rate in interim analysis of GBG-26 Herceptin® + Xeloda® (n=78) Patients, 60 Xeloda® (n=78) % 49.1 48.9 50 40 35.1 30 24.6 26.3 20 16.0 10 0 CR + PR SD PDCR, complete response; PD, progressive disease; PR, partial response; SD, stable disease von Minckwitz et al 2007
  78. 78. Continuation of Herceptin® prolongs median PFS in interim analysis of GBG-26 Probability, 1.0 PFS 0.9 Herceptin® + Xeloda® (n=78) 0.8 Xeloda® (n=78) 0.7 0.6 0.5 0.4 0.3 0.2 24.3 36.9 0.1 (5.6)a (8.5)a 0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 Time (weeks)aMedian PFS in months von Minckwitz et al 2007
  79. 79. Conclusions The GBG-26 study demonstrates that continuation of Herceptin extends survival without progression in women with HER2- positive advanced breast cancer who have received a prior Herceptin-based therapy Given the remarkable clinical benefit observed in the GBG-26 study, continuing Herceptin in combination with Xeloda should be considered a new standard of care upon first progression switching to other add-on agents thereafter
  80. 80. EGF104900Lapatinib Plus Trastuzumab Improves PFS and Response Rate vs Lapatinib Alone in Progressive HER2-Positive Metastatic Breast Cancer
  81. 81. Herce ptinSusceptible to Lapati - MDR nibSusceptible to - HER tyrosine kinase- alternative domain mutationssignalling pathways - competition with natural ligand - rapid metabolism by Cyt P450 - alternative signalling pathways
  82. 82. Efficacy results Lapatinib Herceptin + p-value Hazard lapatinib ratioORR (%) 6.9 10.3 0.46CBR (%) 12.4 24.7 0.01PFS (months) 1.9 2.8 0.008 HR 0.73OS (months) 9.0 11.9 0.106 HR 0.75 O’Shaughnessy et al
  83. 83. Continuation of Herceptinprolongs progression freesurvival Probability 1.0 0.8 Herceptin plus lapatinib Lapatinib 0.6 HR = 0.73; p = 0.008 0.4 0.2 8.1 12.0 0.0 0 10 20 30 40 50 60 WeeksPts at riskL 148 53 21 13 5 0LH 148 73 42 27 8 2 O’Shaughnessy et al 2008
  84. 84. Updated Analysis: Phase III Trial of Lapatinib ± Trastuzumab in HER2+ MBC EGF104900 Lapatinib 1500 mg PO QD (n = 148) Heavily pretreated patients Optional crossover to Primary endpoint: with HER2-positive PFS trastuzumab arm if metastatic breast cancer PD after 4 wks (n = 77) and progression on Secondary endpoints: trastuzumab OS Lapatinib 1000 mg PO QD + ORR Trastuzumab 4 mg/kg loading dose, CBR (N = 296) then 2 mg/kg IV wkly (n = 148) Stratified by visceral disease and hormone receptor statusBlackwell K, et al. SABCS 2009. Abstract 61.
  85. 85. Lapatinib ± Trastuzumab in HER2+ MBC Updated OS Analysis  Median OS with lapatinib + trastuzumab 14.0 months vs 9.5 months with lapatinib alone (HR: 0.74; 95% CI, 0.57-0.97; log-rank P = .026)  26% reduction in risk of death with combination vs lapatinib alone  6-month OS: 80% with combination vs 70% with lapatinib alone  12-month OS: 56% with combination vs 41% with lapatinib aloneBlackwell K, et al. SABCS 2009. Abstract 61.
  86. 86. Updated Analysis: Phase III Trial of Lapatinib ± Trastuzumab in HER2+ MBC Lapatinib + trastuzumab associated with 26% improvement in OS vs lapatinib alone  Significant survival benefit despite 52% crossover to combination therapy at disease progression Lapatinib + trastuzumab well tolerated  AEs comparable to lapatinib alone  Higher incidence of serious cardiac AEs with combination vs lapatinib alone Findings support continued use of trastuzumab Offers possible options for heavily pretreated patients who progress on trastuzumab
  87. 87. Conclusions The study showed that the combination of Herceptin plus lapatinib was superior to lapatinib alone In addition to the GBG-26 study, this trial is yet another dataset demonstrating the benefits associated with continuation of Herceptin and switching the combination partner These two phase III studies confirm that continuation of Herceptin throughout the course of disease is the best option for these patients If lapatinib is to be used, it should be given as an add- on to Herceptin in heavily pre-treated patients
  88. 88. Conclusions Combination lapatinib + trastuzumab may be appropriate regimen for patients who wish to defer chemotherapy
  89. 89. Treatments for HER2-positive breast cancer in development
  90. 90. Pertuzumab The first Her2 dimerisation inhibitor  prevents the pairing of HER2 with other HER receptors Pertuzumab + trastuzumab provides a more complete blockade of Her2 signaling pathways 94
  91. 91. Pertuzumab and trastuzumab bind to different regions on HER2 and have synergistic activity HER2 receptor Trastuzumab Pertuzumab Dimerisation domain of HER2 Subdomain IV of HER2● Preferentially inhibits ligand-independent ● Inhibits HER2 forming dimer pairs HER2 signalling ● Suppresses multiple HER signalling pathways,● Prevents shedding of HER2 ECD leading to a more comprehensive blockade of● Flags cells for destruction by the HER signalling immune system ● Flags cells for destruction by the immune system Juntila et al. Cancer Cell 2009
  92. 92. Pertuzumab demonstrated synergistic preclinical efficacy in combination with trastuzumab Pertuzumab + trastuzumab initial combination KPL-4 breast xenograft model 600 Vehicle control Mean tumor volume (mm3) ± SEM Pertuzumab (30a/15 mg/kg/w ip) 500 Trastuzumab (30a/15 mg/kg/w ip) Pertuzumab (30a/15 mg/kg/w ip) 400 + trastuzumab (30a/15 mg/kg/w ip) 300 200 100 0 0 10 20 30 40 50 60 70 80 Treatment period (days) Both pertuzumab and trastuzumab alone showed similar efficacy; combination of the two led to a synergistic effect aloading doseFriess et al. Ann Oncol 2006;17(Suppl. 9): Abstract 96PD 96
  93. 93. PHEREXA: a Phase II trial of trastuzumab + capecitabine with or without pertuzumab Trastuzumab + capecitabine HER2-positive 1:1 MBC (n=450a) Trastuzumab + capecitabine + pertuzumab An international, Phase II, randomised study (~120 sites worldwide) in patients with HER2-positive MBC that has progressed after 1 line of trastuzumab-based therapy in the metastatic setting Enrolment stratified by End points – primary: PFS  CNS metastases – secondary: OS, TTP, TTF,  measurable vs non-measurable disease ORR, CBR, DoR, safety  response to 1st-line trastuzumab therapy and biomarkersaRecruitment has recently begunTTF, time to treatment failure; DoR, duration of response www.clinicaltrials.gov
  94. 94. CLEOPATRA: a Phase III trial of trastuzumab + pertuzumab in the 1st-line setting Docetaxel + trastuzumab + placebo HER2-positive 1:1 MBC (n=800a) Docetaxel + trastuzumab + pertuzumab An international, Phase III, randomised, double-blind, placebo-controlled study (~250 sites worldwide)  End points  PFS and OS  quality of life  biomarker analysisaActual recruitment to date = 662 (at 23 March 2010)PFS, progression-free survival www.clinicaltrials.gov
  95. 95. T-DM1: 1st-in-class HER2 Antibody-Drug Conjugate (ADC) Target expression: HER2 Monoclonal antibody: trastuzumab Cytotoxic agent: DM1 Highly potent chemotherapy (maytansine derivative) T-DM1 Linker Systemically stable Breaks down in target cancer cell
  96. 96. T-DM1 selectively delivers a highly toxic payload to HER2-positive tumour cells T-DM1 binds to the HER2 protein on cancer cells
  97. 97. T-DM1 selectively delivers a highly toxic payload to HER2-positive tumour cellsReceptor-T-DM1 complex isinternalised into HER2-positivecancer cell
  98. 98. T-DM1 selectively delivers a highly toxic payload to HER2-positive tumour cells Potent antimicrotubule agent is released once inside the HER2-positive tumour cell
  99. 99. Conjugation of T-DM1 components markedly increases efficacy in a preclinical model T-DM1 demonstrated rapid and durable reduction in tumour volume in animal breast cancer model, which was specifically engineered to be insensitive to trastuzumab 1500 VehicleMean tumour volume (mm3)  SEM Trastuzumab 15 mg/kg Trastuzumab 15 mg/kg + free DM1 817 µg/m2 1000 Free DM1 817 µg/m2 Free DM1 (near maximum tolerated dose) 1947 µg/m2 T-DM1 15 mg/kg/817 µg/m2 500 0 0 5 10 15 20 25 30 Time (days) Intravenous dosing Parsons et al. AACR 2007
  100. 100. Substantial clinical benefit seen with T-DM1 in a heavily pretreated population Independent Investigator review assessed Tumour response (n=110) (n=110) ORR, % 32.7 30.0 (95% CI) (24.1, 42.1) (22.0, 39.4) CR 0 1.8 PR 32.7 28.2 a SD 46.4 52.7 PD 18.2 13.6 Unevaluable 1.8 0.9 Missing 0.9 2.7 CBR, % 44.5 40.0 (95% CI) (35.1, 54.3) (31.1, 49.3)Median PFS, months (range) 7.3 (0-11.7) n/aaIncluding unconfirmed PRsCI, confidence interval; n/a, not assessed Krop et al. SABCS 2009
  101. 101. T-DM1 is well tolerated with no new safety signals observed Grade 1, Grade 2, Grade 3, Grade 4, All grades, % % % % %Fatigue 30 26 3 - 59Nausea 26 10 1 - 37Thrombocytopenia 11 13 4 2 29AST increased 11 11 3 - 25Pyrexia 13 8 1 - 22Constipation 17 3 1 - 21Dry mouth 17 4 - - 20Headache 17 3 - - 20● Only 6 (5.5%) patients discontinued due to AEsAST, aspartate aminotransferase Krop et al. SABCS 2009
  102. 102. T-DM1: potential future clinical benefit for heavily pretreated patients with HER2-positive MBC T-DM1 has shown robust single-agent activity in heavily pretreated patient groups  substantial clinical benefit observed in patients with PD during prior HER2-targeted therapy T-DM1 is well tolerated with no dose-limiting cardiac events observed Further investigation of T-DM1 is ongoing
  103. 103. TDM4450g: ongoing Phase II study of T-DM1 vs trastuzumab + docetaxel in 1st-line HER2-positive MBCPrimary end point PFS (independent HER2-positive MBC No prior chemotherapy for metastatic disease assessment) (n=120) SafetySecondary end points OS Objective response DoR Trastuzumab + T-DM1 docetaxel CBR Pharmacokinetic ● Study start date July 2008 properties ● Fully recruited ● Results will be presented in 2010 Time to symptom progression www.clinicaltrials.gov
  104. 104. TDM4788g / BO22589: Phase III study of T-DM1 + pertuzumab vs trastuzumab + docetaxel in 1st-line HER2-positive MBCPrimary end point PFS (IRF assessment) HER2-positive MBC Safety No prior chemotherapy for metastatic diseaseSecondary end points (n=1092) ORR as assessed by IRF OS rate 1-year survival Investigator assessed PFS and ORR Investigator / IRF assessed CBR TTF Trastuzumab + T-DM1 + placebo T-DM1 + pertuzumab Duration of objective docetaxel response Safety and tolerability ● Global; study starts summer 2010
  105. 105. EMILIA: ongoing Phase III study of T-DM1 vs capecitabine + lapatinib in the 2nd-line settingPrimary end points HER2-positive incurable locally advanced PFS (independent breast cancer or MBC assessment) Prior trastuzumab and / or taxane (n=580) SafetySecondary end points 1:1 OS PFS (investigator assessment) T-DM1 Capecitabine + 3.6 mg/kg q3w lapatinib ORR CBR n=221 as of 16 March 2010 DoR Quality of life TTF www.clinicaltrials.gov
  106. 106. Her2-targeted therapy ER/PR –ve:  Trastuzumab alone or with Taxol +/- Carbo or Doce or Vinorelbine or Capecitabine ER/PR +ve:  Trastuzumab with endocrine therapy Progression on Trastuzumzab:  Continue Trastuzumab + chemotherapy  Lapatinib +/- Capecitabine  Lapatinib +/- Trastuzumab 1/3/2013 110
  107. 107. Prefererred first-lineNCCN  Trastuzumab with:  Paclitaxel +/- Carboplatin  Docetaxel  Vinorelbine  Capecitabine 1/3/2013 111
  108. 108. Preferred regimens in Trastuzumab-exposed patientsNCCN  Lapatinib + Capecitabine  Trastuzumab + other first-line agents  Trastuzumab + Capecitabine  Trastuzumab + Lapatinib +/- chemo 1/3/2013 112
  109. 109. The optimal duration ofTrastuzumab in patientswith long term control of disease in unknown 1/3/2013 113
  110. 110.  Trastuzumab + chemotherapy or hormonal therapy  1%to 3% incidence of cardiac events Trastuzumab + anthracycline-based combination therapy  27% cardiac dysfunction

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