New Agents as Options in the Treatment of Breast Cancer in Realities and Possibilities

Transcription

1 New Agents as Options in the Treatment of Breast Cancer in Realities and Possibilities Peter M. Ravdin, MD, PhD UT Health Science Center San Antonio San Antonio, TX

2 New Options for the Treatment of BC Strategic Overview Multiplicity of Agents, Targeting FDA Launches a Radical Change Approval Process Accelerated Approvals Based on NeoAdjuvant Trials A New Mechanism, A New Agent Everolimus Her2 Family Work Trastuzumab SQ, Pertuzumab, T DM1 (2/22/13), Vaccines

3 New Options for the Treatment of BC The Goals Better efficacy Less toxicity Better targeting New classes of targets Setting the stage for adjuvant use

4 Cytotoxic Chemotherapy Agents For MBC: NCCN Listed Single Agents Anthracyclines Doxorubicin Epirubicin Peg Lipo Doxorubicin Taxanes Paclitaxel Docetaxel nab Paclitaxel Microtubule Agents Eribulin Ixepebilone Vinorelbine Anti metabolites Capecitabine Gemcitabine Not much happened in 2012 Without Targeting Biomarkers Only Modest Progress Is Probable

5 CALGB 40502/NCCTGN063H 1 st Line Evaluation of 3 Microtubular Agents Paclitaxel 90 mg/kg QW * 3 of 4 W N= 799 1:1:1 Randomization No prior systemic chemo for MBC. No adjuvant therapy within last 12 months nab Paclitaxel 150 mg/kg QW * 3 of 4 W Ixabepilone 16 mg/kg QW * 3 of 4 W J Clin Oncol 30, 2012 (suppl; abstr CRA1002)

6 Biomarkers Slide 2 from talk on genomic tests and biomarkers at the SABCS 2012 Educational Session on the topic. We all know that it will work, we are not there yet. Lajos Pusztai at the 2012 SABCS

7 Phase Randomized II Trial of Letrozole +PD N= 165 1:1 Randomization ER+, Her2 **MBC or LABC 1 st Line Therapy PD / Letrozole ( 125 / 2.5 mg P0 QD )) Letrozole ( 2.5 mg P0 QD ) ** All patients were ER+, Her2, but in the second phase of the study (n= 99) an additional restriction was that the patients had to have amplified CCND1 amp and/or loss of p16. SABCS Abstract S1 6; 2012

8 PD Letrozole Progression Free Survival Progression Free Survival Probability LET: 7.5 months HR = 0.37 (CI ) p< PD + LET: 26.1 months Time (Month) SABCS Abstract S1 6; 2012

9 PD Letrozole Grade 3 / 4 Toxicity PD LET (n = 83) LET (n = 77) Neutropenia 51 1 Leukopenia 14 0 Fatigue 2 1 Anemia 4 1 Nausea 2 1 Hot flush 0 0 Alopecia 0 0 Arthralgia 0 1 Diarrhea 4 0 SABCS Abstract S1 6; 2012

10 Phase II Randomized Neoadjuvant Trial of Paclitaxel + LCL161 In Triple Negative BC N= 200 1:1 Randomization Operable Candidate Triple Negative T2, N0 2 Paclitaxel IV QW *12 Paclitaxel IV QW *12 with LCL161 PO QW *12 All patients will have baseline and biological analysis to test prospectively a signature.

11 FDA Approval For A New Drug In The Curative Scenario (Adjuvant Therapy) Requires Greater Than 10 Years: A Long Time Start In Metastatic BC Step 1: Phase I and II Trials Step 2: Phase III Then in Early BC Step 3: Adjuvant Therapy Phase III Trial 11

12 Neoadjuvant Phase III Trials For Early Breast Cancer For Accelerated Development Treatment Prior to Surgery Endpoint 1 (pcr at Surgery) in Weeks Endpoint 2 (DFS and OS) in 5-10 Years 12

13 Guidance for Industry Pathologic Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval This draft guidance, when finalized, will represent the Food and Drug Administration s (FDA s) current thinking on this topic. May

14 FDA s Exploration of the use of NeoAdjuvant therapy trials for drug approval. Propose a uniform definition of pcr for regulatory purposes. Pathologic complete response (pcr) is defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypt0 ypn0 in the current AJCC staging system). the presence of residual DCIS or LCIS at the time of surgery should not be used to judge the effectiveness of neoadjuvant systemic therapy 14

15 FDA s Exploration of the use of neoadjuvant therapy trials for drug approval. Briefly summarize what is currently known about the relationship between pcr and prognosis. A Cochrane meta-analysis of 14 trials of preoperative versus postoperative chemotherapy enrolling 5,500 patients with a median follow-up of 18 to 124 months has been done. It reported that the risk of death in patients who attained pcr was reduced by almost half compared with patients who had residual tumor present at the time of surgery (HR 0.48; 95 percent CI 0.33, 0.69) (van der Hage et al. 2007). 15

16 Intrinsic Molecular Classification of Breast Cancer Intrinsic Subtypes Luminal A Luminal B HER2+ Basal-like (TN) IHC markers Mostly ER+ Mostly ER+ HER2 over expressed Mostly triplenegative (not always!) Proliferation & Grade Low Ki67, low grade Often high Ki67, high grade High Ki67 High Ki67, high grade Perou et al, Nature 2000;406:747-52

17 Intrinsic Molecular Classification of Breast Cancer Intrinsic Subtypes IHC markers Proliferation & Grade Rx Implications In Adj. and NeoAdj. Luminal A Mostly ER+ Low Ki67, low grade Indolent, responsive to endocrine Rx Luminal B Mostly ER+ Often high Ki67, high grade Less/unresponsive to endocrine Rx, more responsive to chemo HER2+ HER2 over expressed High Ki67 Worse natural history, quite sensitive to anti- HER2 Rx Basal-like (TN) Mostly triplenegative (not always!) High Ki67, high grade Worse natural history, quite responsive to chemo (eg, preop chemo & pcr)

18 New Options for the Treatment of BC FDA Approvals Everolimus Pertuzumab T DM1 (Feb. 22, 2013) NCCN lists as an option Everolimus Pertuzumab

19 Everolimus

20 Blocking mtor By Everolimus Has Multiple Effects Inhibition of mtor by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose update in in vitro and/or in vivo studies Growth Factor Pathway Everolimus Nutrient Pathway Growth & Proliferation Cellular Metabolism Angiogenesis 20

21 Critical Phase III s For Everolimus In Breast The 3 Bolero Trials Bolero 1 Trastuzumab and paclitaxel with or without everolimus as first line chemotherapy for patients with Her2 positive MBC Bolero 2 Exemestane with or without Everolimus for postmenopausal women with ER+ Locally Advanced or Metastatic Breast Cancer Who Are Refractory to Letrozole or Anastrozole Bolero 3 Trastuzumab and vinorelbine with or without everolimus as first line chemotherapy for patients with Her2 positive MBC

22 Everolimus FDA Approval For MBC (August 29 th, 2012) US Package Insert Postmenopausal women with advanced hormone receptorpositive, HER2 negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole. NCCN added text in 2012 MBC recommendations Consider the addition of everolimus to exemestane in women who fulfill the eligibility criteria for Bolero 2.

23 Phase III Trial Evaluating Whether Everolimus Adds To Exemestane (Bolero 2) N= 724 2:1 Randomization ER and or PgR positive Her2 non amplified MBC, 0 1 prior chemo Recurrence or progression on a non steroidal AI Exemestane Exemestane + Everolimus Exemestane: 25 mg P0 QD; Everolimus 10 mg PO QD Baselga, et al. N Engl J Med 2012;366:520 9.

24 18 Month Median PFS Update at For Bolero at 2012 SABCS Probability (%) of Event EVE 10 mg + EXE (n/n = 188/485) PBO + EXE (n/n = 132/239) HR = 0.38 (95% CI: ) Log-rank P value: <.0001 Kaplan-Meier medians EVE 10 mg + EXE: months PBO + EXE: 4.14 months Time (week) N Engl J Med 2012;366: Update at 18 months SABCS 2012: P

25 Phase III Trial Evaluating Whether Adds To Exemestane (Bolero 2) No Report On Overall Survival Effects Yet Deaths at 18 months 25.4 % in combined therapy group. 32.2% in the exemestane placebo group Why not OS? No, Small number of events. OS hazard rate differences often are slower to emerge than PFS differences. N Engl J Med 2012;366: Update at 18 months SABCS 2012; P

26 Everolimus: Toxicity In Bolero 2 ( % Grade 3 / 4 ) Toxicity Ever. + Exe Exe. Stomatitis 8.0* 0.8 Diarrhea Nausea Fatigue Infections 5.0* 2 Hyperglycemia Cough Dyspnea Epistaxis 0 0 Pneumonitis 3.0* 0 * Package insert specifically warns about these toxicities.

27 Everolimus: Critique Positive Elements 6 month improvement in PFS (more than doubling) Everolimus + Exemestane is an all oral regimen Modest toxicity Negative / Cautionary Elements The everolimus adds toxicity Is the control arm too weak? Awaiting the results for OS. No predictive test for the addition of everolimus yet. Everolimus is very costly ($134,852 for 1 year)

28 TAMRAD: Randomized Phase II Trial Testing Everolimus + Tamoxifen vs Tamoxifen N= 111 1:1 Randomization ER and or PgR positive Her2 non amplified MBC Experiencing progression. Must have had prior AI Prior adjuvant Tam allowed Tamoxifen Tamoxifen + Everolimus Tamoxifen: 20 mg P0 QD; Everolimus 10 mg PO QD Bachelot et al. JCO August 1, 2012 vol. 30 no

29 TAMRAD: Randomized Phase II Trial Testing Everolimus + Tamoxifen vs Tamoxifen (TTP) 8.6 months HR = 0.54 (CI ) p = months ORR 14% and 13% in the Everolimus + Tam. therapy and Tam, (P<0.001),

30 TAMRAD: Randomized Phase II Trial Testing Everolimus + Tamoxifen vs Tamoxifen (Overall Survival) > 32 months 32 months HR = 0.45 (CI ) p= 0.01 Bachelot et al. JCO August 1, 2012 vol. 30 no

31 Randomized Phase II Trial Testing Everolimus + Tamoxifen vs Tamoxifen Outcomes strongly favored the combination Median PFS For combination was 8.6 months vs 4.5 months for tamoxifen PFS HR = 0.54 (CI ) Median OS For combination was >40 months vs 33 months for tamoxifen OS HR = 0.45 (CI ) JCO August 1, 2012 vol. 30 no

32 Everolimus: Toxicity In TAMRAD ( % Grade 3 / 4 ) Toxicity Tam+Ever. Tam Any Stomatitis 11* 0 Diarrhea 2 0 Nausea 4 0 Fatigue 11 6 Infections 7* 5 Neutropenia 2 5 Pneumonitis 2* 4 * Package insert specifically warns about these toxicities. JCO August 1, 2012 vol. 30 no

33 Gateway To Adjuvant Therapy (North American Centers ) EBC, ER+, Her2 Chemotherapy completed But 2 5 years of standard adjuvant hormone therapy must be planned. Start date Sept 2012 Target n = 3500 Planned Hormonal Tx + Placebo Planned Hormonal Tx + Everolimus Everolimus 10 mg PO QD treatment duration 1 year ClinicalTrials.gov NCT

34 Gateway To Combination with Chemotherapy For MBC Bolero 1 MBC or LABC Her2+ Prior Chm and Trastuzumab allowed but must be completed > 12 months ago. Target n = 719 Paclitaxel QW*3 and Trastuzumab QW*4 And Placebo QW Paclitaxel QW*3 and Trastuzumab QW*4 And Everolimus Cycle Length 4 Weeks Start Sept Data collection finished in Oct Expected reporting date. December 2013 NCT

35 Her2 Targeting Agents

36 Four Her2 Targeting Agents Are Available Trastuzumab, Pertuzumab, TDM1, and Lapatinib Trastuzumab Subcutaneous??, Vaccine? 1 st Line: Pertuzumab/Docetaxel/Trastuzumab 2 nd Line: T DM1 Questions still being working on. 1) How to best use them in combination and sequenced with each other or with other agents?

37 Subcutaneous Trastuzumab If Denosumab (An Antibody) Can Be Given (120 mg in 1.7 ml) SQ, Why Can t Trastuzumab? It Can!

38 Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2 positive, clinical stage I III breast cancer (HannaH study): a phase 3, open label, multicentre, randomised trial Gustavo Ismael, Roberto Hegg, Susanne Muehlbauer, Dominik Heinzmann, Bert Lum, Sung Bae Kim, Tadeusz Pienkowski, Mikhail Lichinitser, Vladimir Semiglazov, Bohuslav Melichar, Christian Jackisch Lancet Oncology August 9, 2012 vol. 13 ;

39 HannaH: Randomized NeoAdjuvant Phase III Trial Evaluating SubQ vs IV Trastuzumab N= 596 1:1 Randomization Operable LABC or IBC Her2 positive D * 4, then FEC * 4 with Trastuzumab IV 8/6 mg/kg IV Median weight 66 kg D * 4, then FEC * 4 with Trastuzumab SQ 600 mg SQ Q3W Docetaxel 75 mg/m2 IV Q3W * 4 Then FEC (500/75/500) Q3W * 4 +/ Trastuzumab during treatment To be followed to complete a year of trastuzumab for 1 year Ismael, G. et al. Lancet Oncology August 9, 2012 vol. 13 ;

40 HannaH: Randomized NeoAdjuvant Phase III Trial Evaluating SubQ vs IV Trastuzumab Ismael, G. et al. Lancet Oncology August 9, 2012 vol. 13 ;

41 HannaH: Evaluating IV vs SQ Trastuzumab Formulation Intravenous trastuzumab was given every 3 weeks as per the manufacturer s label (8 mg/kg loading dose, 6 mg/kg maintenance dose). Subcutaneous trastuzumab was given at a fixed dose of 600 mg in a volume of 5 ml (including U rhuph 20) and was injected into the thigh with a hand held syringe at a steady rate over about 5 min by the nursing team at alternating sites every 3 weeks. No loading dose was required for subcutaneous trastuzumab administration. [[ rhuph 20 is recombinant human hyaluronidase ]]

42 HannaH: Evaluating IV vs SQ Trastuzumab Pharmacokinetic ( Ctrough was higher in the SQ Patients ) Ismael, G. et al. Lancet Oncology August 9, 2012 vol. 13 ;

43 HannaH: Evaluating IV vs SQ Trastuzumab Efficacy (Equally Effective) Ismael, G. et al. Lancet Oncology August 9, 2012 vol. 13 ;

44 HannaH: Evaluating IV vs SQ Trastuzumab Pharmacokinetic ( Ctrough was higher in the SQ Patients ) Ismael, G. et al. Lancet Oncology August 9, 2012 vol. 13 ;

45 HannaH: Evaluating IV vs SQ Trastuzumab Cardiac Safety ( Uncommon in both groups) No cases of symptomatic congestive heart failure NYHA class III or IV were reported. Two patients in the subcutaneous group had NYHA class II congestive heart failure compared with none in the intravenous group. Six (2 1%) of 298 patients in the intravenous group and seven (2 4%) of 297 in the subcutaneous group had a significant LVEF drop (decrease 10 percentage points from baseline to <50%).

46 HannaH: Evaluating IV vs SQ Trastuzumab Authors Conclusion Subcutaneous trastuzumab, administered over about 5 min, has a pharmacokinetic profile and efficacy non inferior to standard intravenous administration, with a similar safety profile to intravenous trastuzumab, and therefore offers a valid treatment alternative.

47 HannaH: Evaluating IV vs SQ Trastuzumab My Comment For a 66 kg woman IV will require 400 mg of trastuzumab SQ will require 600 mg of trastuzmab in a special formulation (with recombinant human hyaluronidase This is likely to double the cost for drug The savings will be the cost of a 5 minute injection vs a 30 minute infusion. I think this strategy will not be economically viable.

48 Pertuzumab

49 The Her System HER2 HER1,3,or 4 HER2 HER1/3/4 Target For Herceptin Subdomain IV Trastuzumab: Inhibits ligand independent HER2 signaling Activates ADCC Pertuzumab: Inhibits ligand dependent HER2 dimerization and signaling Activates ADCC ADCC, antibody dependent cell mediated cytotoxicity; ECD, extracellular domain

50 An Active Dimer of Her2 and Her3 HER2 HER2 HER3 HER1/3/4 Subdomain IV Trastuzumab: Inhibits ligand independent HER2 signaling Activates ADCC Pertuzumab: Inhibits ligand dependent HER2 dimerization and signaling Activates ADCC ADCC, antibody dependent cell mediated cytotoxicity; ECD, extracellular domain

51 Pertuzumab Blocks The Formation of Her Receptor Dimers HER2 HER2 Pertuzumab HER3 HER1/3/4 Target For Herceptin Subdomain IV Trastuzumab: Inhibits ligand independent HER2 signaling Activates ADCC Pertuzumab: Inhibits ligand dependent HER2 dimerization and signaling Activates ADCC Prevents HER2 ECD shedding ADCC, antibody dependent cell mediated cytotoxicity; ECD, extracellular domain

52 Pertuzumab (Perjeta) FDA Approval For MBC (June 8 th, 2012) US Package Insert PERJETA is a HER2/neu receptor antagonist indicated in combination with trastuzumab and docetaxel for the treatment of patients with HER2 positive metastatic breast cancer who have not received prior anti HER2 therapy or chemotherapy for metastatic disease. NCCN added text in 2012 MBC recommendations pertuzumab + trastuzumab + docetaxel (category 1) or pertuzumab + trastuzumab + paclitaxel as options under preferred first line options for Her2 positive disease.

53 Cleopatra: Phase III Trial of Pertuzumab In Combination of Trastuzumab/Docetaxel N= 808 1:1 Randomization MBC, Her2 + No prior chemotherapy or biological therapy for MBC Pertuzumab + Trastuzumab/Docetaxel Placebo + Trastuzumab/Docetaxel Trastuzumab (8 mg /kg LD then 6 mg/ kg Q3W and Docetaxel 75 mg/m2 Q3W Pertuzumab 840 mg LD then 420 mg Q3W Baselga; N Engl J Med 2012;366:

54 PFS in Phase III Trial of Pertuzumab in Combination with Trastuzumab/Docetaxel + Pertuzumab (median 18.5 mns) + Placebo (median 12.4 mns) HR = 0.62 (CI ) p< N Engl J Med 2012;366:

55 OS in Phase III Trial of Pertuzumab in Combination with Trastuzumab/Docetaxel HR = 0.66 (CI ) p< Pertuzumab (68 events) + Placebo (96 events) At 30 months median follow up SABCS 2012 P N Engl J Med 2012;366:

56 Cleopatra: Pertuzumab or Placebo Pertuzumab Improved Efficacy With Little or No Additional Toxicity Median PFS For pertuzumab was 18.5 months vs 12.4 months for placebo PFS HR = 0.62 (CI ) ORR (CR + PR) Pertuzumab 80.2 % p < Placebo 69.4 % Median OS To early for median estimates. OS HR = 0.64 (CI ) JCO August 1, 2012 vol. 30 no

57 Cleopatra ( % Grade 3 / 4 ) Toxicity Placebo Pertuzumab Neutropenia Febrile Neutro Leukopenia Diarrhea Peripheral Anemia Asthenia Fatigue Low ANC LVEF Dyspnea 2 1 N Engl J Med 2012;366:

58 Gateway To Adjuvant Therapy (A multicenter International trial) Planned N= 3806 Recruiting now. 1:1 Randomization EBC, Her2 + Normal LVEF Pertuzumab (1 yr) + Trastuzumab/CTX Placebo (1 yr) + Trastuzumab/CTX Trastuzumab (8 mg /kg LD then 6 mg/ kg Q3W and 6 8 Cycles of chemotherapy) Pertuzumab 840 mg LD then 420 mg N Engl J Med 2012;366:

59 Pertuzumab + Trastuzumab as Adjuvant Therapy for 1 Year For a 70 kg Woman Trastuzumab (8 mg /kg LD then 6 mg/ kg Q3W) 560 mg Loading ( 6 * 70) = 420 mg * 12 cycles = 5040 mg Cost of trastuzumab = $199 / 10 mg $ 111,440 Pertuzumab 840 mg LD then 420 mg Q3W 840 mg Loading 420 mg * 12 cycles = 5040 Cost of Pertuzumab = $ 306 / 10 mg $ 179,928 Cost of Pertuzumab + Trastuzumab $ 291,368

60 T DM1

61 Mertansine Trastuzumab Emtansine (T DM 1)

62 EMILIA Trial (Evaluating T DM1) N= 991 1:1 Randomization MBC or LABC Her2 + Prior Tras. and Taxane LEVF > 50% T DM1 (3.6 mg/kg D1 Q3W Capecitabine / Lapatinib (1000mg/m2 BID 1 14 Q3W / 1250 mg QD Trastuzumab Emtansine for HER2 Positive Advanced Breast Cancer. Verma et al N Engl J Med 2012; 367: November 8, 2012 DOI: /NEJMoa

63 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 4 8, 2012 Trastuzumab emtansine (T DM1) FDA Review Decision For MBC (February 26 th, 2013) Review Anticipated To Cover Emilia The major review will be of the EMILIA Trial comparing the efficacy of capecitabine/lapatinib (a regimen FDA reviewed and previously approved) with single agent as T DM1. No comments as of yet NCCN added text in 2012 Trastuzumab Emtansine for HER2 Positive Advanced Breast Cancer. Verma et al N Engl J Med 2012; 367: November 8, 2012 DOI: /NEJMoa

64 Trastuzumab emtansine (T DM1) FDA Review Decision For MBC (February 26 th, 2013) Review Anticipated To Cover Emilia Eligible patients had documented progression of unresectable, locally advanced or metastatic HER2 positive breast cancer previously treated with a taxane and trastuzumab. Inclusion criteria were progression during or after the most recent treatment for locally advanced or metastatic disease or within 6 months after treatment for early stage disease,. Single Agent for 2 nd Line For Metastatic Disease. Trastuzumab Emtansine for HER2 Positive Advanced Breast Cancer. Verma et al N Engl J Med 2012; 367: November 8, 2012 DOI: /NEJMoa

65 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 4 8, 2012 Trastuzumab emtansine (T DM1) FDA Decision For MBC ( of February 22 nd, 2013) KADCYLA is a HER2 targeted antibody and microtubule inhibitor conjugate indicated, as a single agent, for the treatment of patients with HER2 positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: Received prior therapy for metastatic disease, or Developed disease recurrence during or within six months of completing adjuvant therapy

66 EMILIA Trial (Progression Free Survival) HR = 0.65 (p = 0.001) Objective Response Rate: Cape/Lap: 31%; T DM1 44%, p < Trastuzumab Emtansine for HER2 Positive Advanced Breast Cancer. Verma et al N Engl J Med 2012; 367: November 8, 2012 DOI: /NEJMoa

67 EMILIA Trial (Overall Survival) HR = 0.68 (p = 0.001) Trastuzumab Emtansine for HER2 Positive Advanced Breast Cancer. Verma et al N Engl J Med 2012; 367: November 8, 2012 DOI: /NEJMoa

68 EMILIA: T DM1 or Lap/Cape. T DM1 Improved Efficacy With Some Toxicity Advantages Median PFS For T DM1 has an advantage (9.6 months vs 6.4 months) PFS HR = 0.65 (CI ; p < ) ORR (CR + PR) T DM % ( ) Lap/Cape 30.8 % (CR = ) p < Median OS For T DM1 has an advantage (30.9 months vs 25.1 months) OS HR = 0.68 (CI ; p = ) NEJM Oct.18,2012

69 EMILIA Trial (Grade 3 or 4 Toxicity) Capecitabine + Lapatinib T DM1 Any Event 57 % 41% Diarrhea 20 % 2 % Hand / Foot Syn 16 % 0% Fatigue 4 % 2% Mucositis 2 % 0 % Elevated AST 1 % 4 % Low Platelets 0 % 13 % In both treatment groups 2% of the patients developed a LVEF or a decrease of > 15% from baseline.

70 Gateway To Adjuvant Therapy (A multicenter International single arm Phase II trial) Goal: Safety and Feasibility Planned N= 153 Recruiting complete. EBC, Her2 + Normal LVEF Anthracycline Based (Neo) Adjuvant Chemotherapy Program T DM1 Every 3 Weeks For a Year T DM1 ( 3.6 mg ) IV Every 3 Weeks ClinicalTrials.gov NCT

71 The ADAPT Trial Phase II Neoadjuvant Assessment of T DM1 T DM1 3.6 mg/kg Q3W * 4 N= 380 1:1:1 Randomization Clinically N0, Operable T1 T4 (not IBC) Her2 +, HR + T DM1 3.6 mg/kg Q3W * 4 + an AI Trastuzumab 8 then 6 mg/kg Q3W + an AI ClinicalTrials.gov NCT

72 Four Her2 Targeting Agents Are Available Trastuzumab, Pertuzumab, TDM1, and Lapatinib For Her2+ Aggressive MBC (?) 1 st Line: Pertuzumab/Docetaxel/Trastuzumab 2 nd Line: T DM1 Questions still being working on. 1) How to best use them in combination and sequenced with each other or with other agents?

73 Her2 Targeting Vaccines For Breast Cancer??? 73

74 Vaccines For Breast Cancer??? Recent approval in Prostate CA reignite an interest E75 peptide (KIFGSLAFL, HER2: ) Non Randomized Trial Cancer 2012;118: Clinical Trial Results of the HER 2/neu (E75) Vaccine to Prevent Breast Cancer Recurrence in High Risk Patients. Mittendorf EA., Peoples GE [[BAMC]]. ( ) Followed by a Ongoing Randomized Trial

75 HER2/neu Peptide Vaccines Trans Membrane Extra Cellular Domain (aa 1-652) Domain (aa ) Intra Cellular Domain (aa ) ECD TMD ICD I I S A V V G I L GP2-peptide vaccine (aa ) MHC Class I : HLA-A2 Stimulate CD8 T cells K I F G S L A F L E75-peptide vaccine (aa ) MHC Class I : HLA-A2 & HLA-A3 Stimulate CD8 T cells G V G S P Y V S R L L G I C L AE37-peptide vaccine (aa ) MHC Class II : multi-allele Stimulate CD4 T cells

76 Adjuvant Phase II Study of an E75 Vaccine N= 182 No blinding No randomization T1 4, N 0 3 Her ER any E75 peptide + GM CSF Must have either HLA A2 or A3 N = 106 Observation Must have neither HLA A2 or A3 N = 76 Primary Endpoint DFS at 24 Months ClinicalTrials.gov NCT

77 US Military Cancer Institute Clinical Trials Group Study I 01 and I 02 Cancer 2012;118:

78 Adjuvant Phase III Study of an E75 Vaccine N= 700 1:1 Randomization T1 3, NP Her2 1+, 2+ HLA A2 or HLA A3 Completed Adj Chemo No autoimmune disease E75 peptide + GM CSF Q month * 6 then Q 6 mns Placebo peptide + GM CSF Q month * 6 then Q 6 mns Primary Endpoint DFS Started 11/2011, Completion date 2022 ( ) ClinicalTrials.gov NCT

79 New Agents In Breast Cancer: Summary 1) Work with new biomarkers to allow selection of the most appropriate agents has not yet reached validated practical application, but is an area of intense effort. 2) There is a new regulatory interest in the use of neoadjuvant trials for breast cancer drug approval. 3) New agents have become available in : Everolimus, Pertuzumab, T DM1. 4) New classes of therapeutic agents are in development: e.g. CDK inhibitors, a number of which look very promising.