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Kathy D. Miller, MD Associate Professor and Sheila D. Ward Scholar Indiana University Melvin and Bren Simon Cancer Cente

Kathy D. Miller, MD Associate Professor and Sheila D. Ward Scholar Indiana University Melvin and Bren Simon Cancer Center Indianapolis, IN. Clinical Updates. Advances in Targeted Therapies for Breast Cancer A Report From SABCS 2009. Discussion Topics. HER2 positive disease

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Kathy D. Miller, MD Associate Professor and Sheila D. Ward Scholar Indiana University Melvin and Bren Simon Cancer Cente

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  1. Kathy D. Miller, MD Associate Professor and Sheila D. Ward Scholar Indiana University Melvin and Bren Simon Cancer Center Indianapolis, IN Clinical Updates Advances in Targeted Therapies for Breast Cancer A Report From SABCS 2009

  2. Discussion Topics • HER2 positive disease • Growing number of options • Angiogenesis • Bevacizumab questions answered and rephrased • Small molecule success and disappointment

  3. HER2: What We Knew Before SABCS • Trastuzumab • Active as single agent and adds to chemo/HRT • Effective with chemo beyond PD • Adds to lapatinib monotherapy (ORR, PFS) • Lapatinib • Active as single agent and adds to chemo/HRT • Effective with chemo after PD on trastuzumab • MULTIPLE new agents in development

  4. Case 1 • 54 year old woman with newly diagnosed stage II breast cancer s/p lumpectomy and axillary dissection • Primary tumor 1.9 cm • Involves 1 of 14 LN (1/2 SN, 0/12 additional LN) • Grade III • ER+ 15%, PR- • HER2 2+ by IHC (intense staining in 20% of cells) • FISH equivocal with ratio 2.15 • Do you recommend adjuvant trastuzumab?

  5. Background • In 2007, ASCO/CAP recommended new guidelines to define HER2 positivity by both IHC 3+* and FISH+** • 3+ IHC: Uniform intense membrane staining of > 30% of invasive tumor cells • FISH+: HER2/CEP17 ratio > 2.2 • Original HER2 eligibility criteria in the pivotal N9831 Phase III Adjuvant HER2 Trial • 3+ IHC: Uniform intense membrane staining of > 10% of invasive tumor cells • FISH+: HER2/CEP 17 ratio ≥ 2.0 HerceptTest DAKO, Carpenteria, CA; FISH: PathVysion, Abbott Molecular; Masood S et al. Ann Clin Lab Sci 1998;28(4):215-223; Perez EA et al. SABCS 2009 #701

  6. N9831 DFS Based on Original Criteria: HER2 Non-positive* vs. HER2+** * HER2 Non-positive (IHC ≤ 10 and FISH Ratio < 2.0) ** HER2+ (IHC > 10 or FISH Ratio ≥ 2.0) Perez EA et al. SABCS 2009 #701

  7. N9831 DFS Based on 2007 ASCO/CAP: HER2 Non-positive* vs. HER2+** * HER2 Non-positive (IHC ≤ 30 and FISH Ratio ≤ 2.2) ** HER2+ (IHC >30 or FISH Ratio > 2.2) Perez EA et al. SABCS 2009 #701

  8. Conclusions • A small percentage (by IHC:3.7%, FISH 1.4%, both:1.7%) of N9831 pts did not meet ASCO/CAP 2007 HER2 positivity guidelines when applied retrospectively • Trastuzumab effect appeared similar for HER2+ pts regardless of ASCO/CAP or originally used FDA-approved guidelines • Data support determining eligibility for trastuzumab based on the original definition of HER2 positivity (IHC 3+, >10% staining; FISH ratio>2.0). Perez EA et al. SABCS 2009 #701

  9. Case 1 • 54 year old woman with newly diagnosed stage II breast cancer s/p lumpectomy and axillary dissection • Primary tumor 1.9 cm • Involves 1 of 14 LN (1/2 SN, 0/12 additional LN) • Grade III • ER+ 15%, PR- • HER2 2+ by IHC (intense staining in 20% of cells) • FISH equivocal with ratio 2.15 • Do you recommend adjuvant trastuzumab? • YES

  10. BCIRG 006 NCCTG N9831 IHC orFISH FISH NSABP B-31 HERA Observation IHC orFISH IHC orFISH AC P D DCarbo Standard Trastuzumab 1 year Adjuvant Trastuzumab 1 v 2 years IHC, immunohistochemistry;FISH, fluorescence in situ hybridisation

  11. BCIRG 006 DFS Events First / Second / Third Planned Efficacy Analyses (cutoff dates: 30June2005 / 01Nov2006 / 16Oct2009) • Median follow-up time = 23/36/65 months • 322/462/656 DFS events (42% additional events) • Breast cancer relapse • Second primary malignancy • Death • 84/185/348 deaths (88% additional deaths)

  12. Current BCIRG 006Disease-Free Survival – 3rd Planned Analysis

  13. Current BCIRG 006Overall Survival – 3rd Planned Analysis

  14. Cardiac Deaths and CHF as per Independent Review Panel

  15. Therapeutic Index – Most Recent Data

  16. Efficacy Analysis *Patients eligible for crossover censored Data frozen on 11/3/2009 Control (A)* vs Sequential (B)* AC → T → H AC → T Perez EA et al, SABCS 2009

  17. Alive anddisease free (%) 100 AC → T → H (164 events) 90 85.2% 80.1% 80 79.7% 70 71.9% AC → T (222 events) Log rank P=0.0005 60 50 735 675 624 586 513 1097 No. at risk 728 643 581 529 1087 447 40 0 1 2 3 4 5 Years from randomization Control vs Sequential Perez EA et al, SABCS 2009

  18. Efficacy Analysis *Censoring based on temp closure of C,and eligibility for crossover Data frozen on 11/3/2009 Sequential (B)* vs Concurrent (C) AC → T+H → H AC → T → H N9831 Perez EA et al, SABCS 2009

  19. Sequential vs Concurrent 1st Interim Analysis • At 50% of planned number of events (312 events) • 1,903 pts, median follow-up: 5.3 yr • 75% of pts followed for 5 yr • DFS may differ with respect to the timing of trastuzumab’s addition to AC → T • Log rank P=0.019 (HR 0.77; 95% CI 0.61-0.96) • Not crossing the boundary for statistical significance, pre-set at 0.00116 Perez EA et al, SABCS 2009

  20. Alive anddisease free (%) Sequentialvs Concurrent AC →T+ H → H (138 events) 100 89.1% 90 84.2% 85.7% 80 79.8% AC → T → H (174 events) 70 Logrank p=0.0190 60 50 949 837 788 740 676 456 No. at risk 830 766 705 954 641 418 40 0 1 2 3 4 5 Years from randomization Perez EA et al, SABCS 2009

  21. Conclusions • DFS is significantly improved with the additionof 52 wks of trastuzumab to AC  T • There is a statistically significant 33% reduction in the risk of an event with the sequential addition of trastuzumab following AC  T • 5 yr DFS: 72% vs. 80% • There is a strong trend for a 25% reductionin the risk of an event with starting trastuzumab concurrently with taxane relative to sequentially • 5 yr DFS: 80% vs. 84% Perez EA et al, SABCS 2009

  22. Median follow-up HERA 1 year Combined analysis 2 years 2 years BCIRG 006 AC DH 2 years BCIRG 006 DCarboH 3 years FinHER VH / DH CEF FavorsTrastuzumab Favors noTrastuzumab 0 1 2 HR Trastuzumab DFS Piccart-Gebhart et al 2005; Romond et al 2005;Slamon et al 2005; Joensuu et al 2005

  23. Adjuvant Trastuzumab • Test everyone for HER2, inquire about testing quality and look carefully at ‘equivocal’ results • Most important message -> Give Trastuzumab! • Either TCH or AC>TH supported by data • Differences between regimens modest • Slightly more recurrence with TCH balanced by increased cardiac and long-term marrow toxicity with AC>TH • Give concurrently with chemo unless there is a compelling reason not to

  24. Case 2 • 74 year old presents with 5 cm primary breast mass with associated axillary adenopathy. • ER-, PR-, HER2 3+ by IHC (FISH ratio 8.9) • Staging finds several liver lesions, largest 2.2 cm • Biopsy of liver lesion confirms MBC, HER2+ • LFTs normal • LVEF 62% • She refuses chemotherapy but will consider other options, family supports her wishes • What would you recommend?

  25. Lapatinib Trastuzumab Pathway ActivationHER Ligands

  26. Lapatinib + Trastuzumab Lapatinib 1500 mg PO QD (n = 148) EGF104900 Primary endpoint: PFS Secondary endpoints: OS ORR CBR Optional crossover to trastuzumab arm if PD after 4 wks (n = 77) Heavily pretreated patients with HER2-positive MBC and progression on trastuzumab (N = 296) Lapatinib 1000 mg PO QD + Trastuzumab 4 mg/kg loading dose, then 2 mg/kg IV wkly (n = 148) Stratified by visceral disease and hormone receptor status PO, orally; QD, once daily. Blackwell K, et al. SABCS 2009 # 61.

  27. Lapatinib + Trastuzumab 52% of patients crossed over from single-agent lapatinib to combination therapy on progression. Blackwell K, et al. SABCS 2009 # 61.

  28. Lapatinib + Trastuzumab Safety Update • Most AEs reported in ≥ 10% of patients were grade 1/2 • Diarrhea was the only grade 3/4 AE reported in ≥ 5% of patients • 8% of patients receiving lapatinib plus trastuzumab vs 7% receiving lapatinib alone • 1 fatal cardiac event in combination arm * Defined as grade ≥ 3 LV dysfunction, LVEF decrease ≥ 20% from baseline and below lower limit of normal defined by institution. Blackwell K, et al. SABCS 2009 # 61.

  29. Lapatinib + Trastuzumab • Lapatinib + trastuzumab associated with 26% improvement in OS vs lapatinib alone • Significant survival benefit despite 52% crossover • Supports combination arm of ALTTO • Lapatinib plus trastuzumab well tolerated • AEs comparable to lapatinib alone • Offers possible options for heavily pretreated patients who progress on trastuzumab Blackwell K, et al. SABCS 2009 # 61.

  30. T-DM1 • T-DM1, an antibody-drug conjugate, combines biologic effect of trastuzumab against HER2-expressing cells with highly potent antimicrotubule agent DM1 • MOA likely involves receptor-mediated internalization of T-DM1 after binding to HER2, resulting in intracellular release of DM1 Austin CD et al. Mol Biol Cell. 2004;15:5268-5282.

  31. T-DM1 Monotherapy • Multicenter, single arm (N=110) • Primary endpoint – ORR by IRF at 24 weeks • Eligibility • Prior anthracycline, taxane, capecitabine, trastuzumab, lapatinib • Active disease progression on last therapy • LVEF 50% or better Krop I, et al. SABCS 2009.#5090.

  32. T-DM1 Monotherapy • ORR (by independent review) 32.7% • Clinical benefit rate (by independent review) 44.5% • Median PFS 7.3 months • T-DM1 well tolerated • Thrombocytopenia • Offers a very real option for additional therapy for HER2+ patients Krop I, et al. SABCS 2009 #5090.

  33. P<0.0001 Response Rates for Novel HER2-Targeting Agents After Progression on Trastuzumab Modi et al, ASCO 2008; Gelmon et al, ASCO 2008; Swaby et al, ASCO 2009; Burris et al, ESMO 2009.

  34. Topics • HER2 positive disease • Growing number of options • Angiogenesis • Bevacizumab questions answered and rephrased • Small molecule success and disappointment

  35. Angiogenesis • Angiogenesis is important for tumor growth • Highly regulated, multiple redundant pathways • VEGF among the most potent and frequently overexpressed • Bevacizumab • Modest activity as monotherapy • Disappointing results in initial randomized trial • E2100, then AVADO and RIBBON-1 • Now RIBBON-2

  36. RANDOMI ZE Paclitaxel + Bevacizumab • 28-day cycle: • Paclitaxel 90 mg/m2 D1, 8 and 15 • Bevacizumab 10 mg/kg D1 and 15 Paclitaxel • Stratify: • DFI < 24 mos. vs. > 24 mos. • < 3 vs. > 3 metastatic sites • Adjuvant chemotherapy: yes vs. no • ER+ vs. ER- vs. ER unknown E2100 Miller K, et al. N Engl J Med. 2007;357:2666-2676

  37. Primary endpoint: progression-free survival Secondary endpoints: overall response rate, duration of response, time to treatment failure, overall survival, safety, quality of life *Docetaxel was administered for a maximum of nine cycles, but earlier discontinuation was permitted Treat withplacebo/bevacizumabto diseaseprogression All patientsgiven optionto receive bevacizumabwith 2nd-linechemotherapy Docetaxel* 100mg/m2+ placebo q3w • 1st-line locally recurrent • or mBC (n=705) • Stratification factors: • region • prior taxane/time to relapse since adjuvant chemo • measurable disease • hormone receptor status Docetaxel* + bevacizumab 7.5mg/kg q3w Docetaxel* + bevacizumab 15mg/kg q3w AVADO Miles D, et al. J Clin Oncol. 2008;26(18S). LBA 1011.

  38. Previously untreated MBC • (n=1,237) • Stratification Factors: • Disease-free interval • Previous adjuvant chemotherapy • Number of metastatic sites • Cape, T or Anthra CHOICE OF CHEMO BY INVESTIGATOR Chemo +bevacizumabq3w Treat until PD Optional2nd-line Chemo+ bevacizumab RANDOMIZE 2:1 Chemo +placeboq3w RIBBON-1 Capecitabine or TaxaneorAnthracycline • Capecitabine (1000 mg/m2 BID x 14d) • Taxane (docetaxel or protein-bound paclitaxel) • Anthracycline-based chemotherapy (AC, EC, FAC, FEC) • Placebo or bevacizumab (15 mg/kg) Robert et al, ASCO 2009 #1005

  39. Study Design 1Miller K, et al. N Engl J Med. 2007;357:2666-2676; 2Miles D, et al. J Clin Oncol. 2008;26(18S). LBA 1011. 39

  40. Patient Population 1Miller K, et al. N Engl J Med. 2007;357:2666-2676; 2Miles D, et al. J Clin Oncol. 2008;26(18S). LBA 1011.

  41. Efficacy Relative increase in RR 20-50%

  42. Case 3 • 63 year old with metastatic breast cancer consults you for advice on additional therapy • Initial diagnosis 6 years ago, adjuvant AC x 4 cycles followed by AI for stage I disease (T2.1 cm, LN-, G2, ER+, PR-, HER2-) • Metastatic disease identified with bone invovlement and mediastinal and SC adneopathy ~28 months ago • Initially treated with fulvestrant > PR lasting 12 months • Tamoxifen > SD lasting 6 months • Exemestane > PD after 2 months • Capecitabine > PR lasting 8 months, now with PD

  43. Case 3 • Currently has minimally symptomatic bone involvement (does not require narcotics) with asymptomatic mediastinal nodes and new pulmonary nodules (largest 1.6 cm) • PS = 1 • Local oncologist has recommended taxane based therapy • Would you add bevacizumab?

  44. Second-line Chemotherapy of choice† HER (-) Bevacizumab 10 mg/kg q2w (Bevacizumab 15 mg/kg q3w) Randomize 2:1 Chemotherapy of choice† Placebo †Docetaxel, paclitaxel (qw or q3w), nab-paclitaxel, gemcitabine, vinorelbine, or capecitabine. Ribbon 2 National Cancer Institute. Clinical Trials (PDQ). Available at: http://www.cancer.gov/search/clinical_trials/.

  45. Key Eligibility Criteria • One prior cytotoxic treatment for MBC • ECOG performance status (PS) 0 or 1 • HER2-negative or HER2 status unknown • No prior therapy with bevacizumab or other VEGF pathway- target therapy

  46. Primary Endpoint of PFS(ITT Population) Brufsky et al, SABCS 2009 #42

  47. Cohort-Specific Analyses of PFS(ITT Population) Brufsky et al, SABCS 2009 #42

  48. What We’ve Learned • Bevacizumab is an important component of initial chemotherapy for metastatic HER2- breast cancer • Increases RR • Prolongs PFS • Adds to second-line chemo in patients who didn’t get bevacizumab with initial chemo • Toxicity differs among reported regimens • Bevacizumab associated toxicity consistent

  49. Remaining Questions • Combine with anti-HER2 and hormonal therapies • Optimal duration of therapy • Why have we failed to demonstrate a difference in OS?

  50. In Search of OS • There is no difference • Subsequent therapy obscures benefit of 1st line therapy • Reported trials individually underpowered • Amenable to meta-analysis (see ASCO 2010) • Resistance to bevacizumab = more aggressive disease • Rapid regrowth of vasculature after stopping bevacizumab

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