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

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 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. Adjuvant Trastuzumab 1 v 2 years IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation ACPDDCarboStandard HERA IHC or FISH Observation Trastuzumab 1 year NCCTG N9831 BCIRG 006 FISH NSABP B-31 IHC or FISH

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 006 Disease-Free Survival – 3 rd Planned Analysis

13. Current BCIRG 006 Overall Survival – 3 rd 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 AC → T AC → T → H vsControl (A)*Sequential (B)* Perez EA et al, SABCS 2009

17. Alive and disease free (%) Years from randomization No. at risk 735 728 675 643 624 581 586 529 513 447 85.2% 79.7% 80.1% 71.9% 40 50 60 70 80 90 100 012345 AC → T (222 events) AC → T → H (164 events) Log rank P=0.0005 1097 1087 Control vs Sequential

18. Efficacy Analysis *Censoring based on temp closure of C, and eligibility for crossover Data frozen on 11/3/2009 AC → T+H → H AC → T → H vsConcurrent (C)Sequential (B)* 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 and disease free (%) 837 830 788 766 740 705 676 641 456 418 No. at risk 89.1% 85.7% 84.2% 79.8% 40 50 60 70 80 90 100 012345 Years from randomization AC → T → H (174 events) AC →T+ H → H (138 events) Logrank p=0.0190 949 954 Perez EA et al, SABCS 2009 Sequential vs Concurrent

21. Perez EA et al, SABCS 2009 Conclusions DFS is significantly improved with the addition of 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% reduction in the risk of an event with starting trastuzumab concurrently with taxane relative to sequentially –5 yr DFS: 80% vs. 84%

22. Piccart-Gebhart et al 2005; Romond et al 2005;Slamon et al 2005; Joensuu et al 2005 012 HERA1 year Combined analysis2 years Median follow-up Favors Trastuzumab Favors no Trastuzumab HR BCIRG 006 DCarboH 2 years BCIRG 006 AC DH FinHER VH / DH CEF 3 years Trastuzumab DFS

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. TrastuzumabLapatinib Pathway Activation HER Ligands

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

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

28. Cardiac AEs N Lapatinib + Trastuzumab (n = 149) Lapatinib (n = 146) Any, N113 Grade 3/4 31 Serious events*103 Treatment-related events102 * Defined as grade ≥ 3 LV dysfunction, LVEF decrease ≥ 20% from baseline and below lower limit of normal defined by institution. 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 Blackwell K, et al. SABCS 2009 # 61.

29. 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 Lapatinib + Trastuzumab

30. Austin CD et al. Mol Biol Cell. 2004;15:5268-5282. 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

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. Krop I, et al. SABCS 2009 #5090. 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 T-DM 1 Monotherapy

33. 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. P<0.0001

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. Stratify: DFI 24 mos. 3 metastatic sites Adjuvant chemotherapy: yes vs. no ER+ vs. ER- vs. ER unknown RANDOMIZERANDOMIZE Paclitaxel + Bevacizumab 28-day cycle: Paclitaxel 90 mg/m 2 D1, 8 and 15 Bevacizumab 10 mg/kg D1 and 15 Paclitaxel Miller K, et al. N Engl J Med. 2007;357:2666-2676 E2100

37. AVADO 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 Docetaxel* 100mg/m 2 + placebo q3w Docetaxel* + bevacizumab 7.5mg/kg q3w Docetaxel* + bevacizumab 15mg/kg q3w All patients given option to receive bevacizumab with 2 nd -line chemotherapy 1 st -line locally recurrent or mBC (n=705) Stratification factors: region prior taxane/time to relapse since adjuvant chemo measurable disease hormone receptor status Treat with placebo/ bevacizumab to disease progression Miles D, et al. J Clin Oncol. 2008;26(18S). LBA 1011.

38. Capecitabine (1000 mg/m 2 BID x 14d) Taxane (docetaxel or protein-bound paclitaxel) Anthracycline-based chemotherapy (AC, EC, FAC, FEC) Placebo or bevacizumab (15 mg/kg) CHOICE OF CHEMO BY INVESTIGATOR Capecitabine or Taxane or Anthracycline Previously untreated MBC (n=1,237) Stratification Factors: Disease-free interval Previous adjuvant chemotherapy Number of metastatic sites Cape, T or Anthra Chemo + bevacizumab q3w Chemo + placebo q3w Treat until PD RANDOMIZE 2:1 Optional 2nd-line Chemo + bevacizumab Robert et al, ASCO 2009 #1005 RIBBON-1

39. 1 Miller K, et al. N Engl J Med. 2007;357:2666-2676; 2 Miles D, et al. J Clin Oncol. 2008;26(18S). LBA 1011. E2100 1 AVADO 2 RIBBON-1: Cape RIBBON-1: A/T Placebo Controlled NoYes Chemotherapy Weekly paclitaxel q3w docetaxelCapecitabine q3w doce/nabP AC/FAC/EC/FEC Dose of Bevacizumab 10 mg/kg q2wk 7.5 or 15 mg/kg q3wk 15 mg/kg q3wk Primary Endpoint PFSPFS (IRF)PFS (Inv) IRF reviewRetrospectiveYes 39 Study Design

40. E2100 1 AVADO 2 RIBBON-1: Cape RIBBON-1: A/T N673736615622 ER-/PR -35%22%23%24% > 3 sites45%46%44%45% Measureable disease 73%83%80%84% Adjuvant Chemo/Taxane 65%/16%66%/15%72%/40%45%/15% Patient Population 1 Miller K, et al. N Engl J Med. 2007;357:2666-2676; 2 Miles D, et al. J Clin Oncol. 2008;26(18S). LBA 1011.

41. E2100AVADORIBBON-1: Cape RIBBON-1: A/T PP+BD+PlD+BC+PlC+BA/T + PlA/T+B ORR25%49% 55%/63%24%35%38%51% PFS (months) 5.911.88.08.7/8.85.78.68.09.2 HR0.60 P <0.0001 0.79 (7.5 mg) P = 0.0318 0.72 (15 mg) P = 0.0099 0.69 P = 0.0002 0.64 P <0.0001 OS (months) 25.226.7NR 21.22923.825.2 HR0.88 P = 0.16 0.92 (7.5 mg) 0.86 (15 mg) 0.85 P = 0.27 1.03 P = 0.83 Relative increase in RR 20-50% Efficacy

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

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

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

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

51. Remaining Questions Combine with anti-HER2 and hormonal therapies Optimal duration of therapy Why have we failed to demonstrate a difference in OS? Does the choice of chemotherapy matter?

52. Does the Choice of Chemo Matter? HR broadly similar but absolute improvements in PFS gain differ widely –Ability to continue combined therapy –Interval censoring May depend on mechanism(s) of action? –Inherent anti-angiogenic effect of chemotherapy –Chemotherapy induced release of bone marrow progenitors –Role of VEGF on tumor cells

53. TKI Alternatives: Sorafenib Targets Both Tumor-Cell Proliferation and Angiogenesis Wilhelm et al, SABCS 2009 #42

54. TIES Program Trials to Investigate the Efficacy of Sorafenib in Breast Cancer

55. Baselga et al, SABCS 2009 #45 A Multinational Double-Blind, Randomized Phase 2b Study Evaluating the Efficacy and Safety of Sorafenib Compared to Placebo when Administered in Combination with Capecitabine in Patients with Locally Advanced Metastatic Breast Cancer

56. Gradishar et al, SABCS 2009 #44 A Double-Blind, Randomized Phase 2b Study Evaluating the Efficacy and Safety of Sorafenib Compared to Placebo when Administered in Combination with Paclitaxel in Patients with Locally Advanced Metastatic Breast Cancer http://www.clinicaltrials.gov/ct/show/NCT00499525

57. Top Line Efficacy and Safety (SOLTI-0701 & NU 07B1) Baselga et al. (Capecitabine+/- Sorafenib) Gradishar et al. Paclitaxel +/- Sorafenib Median PFS, * mos 4.1 vs. 6.4 HR=0.576; P=0.0006** 5.6 vs. 6.9 HR=0.788; P=0.09** TTP, * mos 4.2 vs. 6.8 (P=0.0005**) HR=0.562 (0.394, 0.799) 5.6 vs. 8.1 (P=0.0171**) 0.674 (0.465, 0.975) Overall response rate, * % 31 vs 38 P=0.1229** 54 vs 67 P=0.0234** On-study deaths, * n (%)5 (4.5) vs 5 (4.5)4 (3) vs 16 (14) Subjects with AE leading to discontinuation of study treatment, * n (%) 9 (8) vs 14 (13.4)12 (10) vs 35 (30) * Chemotherapy + placebo vs chemotherapy + sorafenib ** One-sided

58. Adverse Event Rates (Safety Population) Overall incidence ≥ 10% and Grade 3/4 ≥ 3% in either teratment arm Baselga et al.Gradishar et al. S+C N=112 Pl+C N=112 S+P N=115 Pl+P N=118 All (%) Grade 3 (%) All (%) Grade 3 (%) All (%) Grade 3 (%) All (%) Grade 3 (%) HFSR89456313553073 Diarrhea535305373253 Asthenia240272297213 Fatigue142131143202 Dyspnea125 3131143 Neutropenia114422410194 P=Paclitaxel, S=Sorafenib, C=Capecitabine, Pl=Placebo

59. SABCS 2009 #45 PFS: ITT Population

60. SOLTI-0701: Capecitabine +/- Sorafenib 42% reduction in risk of disease progression or death –PFS benefit observed in subgroup analyses –PFS benefit noted in both first-line and second-line therapy Increased incidence of hand-foot syndrome –Attention to dose modification critical Phase III registration trial planned for sorafenib/capecitabine in advanced breast cancer

61. Motesanib Blocks More Than One Mechanism Involved in Tumorigenesis

62. Mackey et al, SABCS 2009 #47 Study Design Mackey et al, SABCS 2009 #47

63. Objective Response Rate (ITT Population) Mackey et al, SABCS 2009 #47

64. Progression-Free Survival (ITT Population) Mackey et al, SABCS 2009 #47

65. Progression-Free Survival (ITT Population)

66. Favors Capecitabine Phase III Sunitinib vs. Capecitabine HER2 negative, prior anthracycline and taxane required N=483 ORR 11.3 % vs. 16.4% PFS 2.8 months vs. 4.2 months Barrios et al, SABCS 2009 #46

67. Conclusions Bevacizumab is an important component of initial chemotherapy for patients with HER2- disease –Some benefit in second line if not given prior All bevacizumab containing regimens are not equal –Toxicity differences clear –Efficacy? –Differences in chemotherapy affects may be important Small molecule VEGF TKIs have some activity as well but toxicity troublesome

68. I don’t know if heavier than air flight is possible, but I’m committed to living my life dedicated to its possibility. - Wilbur Wright The Future Is Possible