1. Novel Her-2- neu Targeted Agents Jame Abraham, M.D, FACP Bonnie Wells Wilson Distinguished Professor Chief, Section of Hematology-Oncology West Virginia University Morgantown, WV

2. 55 year old woman was diagnosed with IIB breast cancer in 2001 ER/PR positive and her-2 neu positive Developed metastatic disease involving bone, lung and lymph nodes about 6 years back Brain mets for the past 3 years

3. Treated with variety of trastuzumab and lapatinib containing regimens Taxanes, Ixabepilone, navelbine, capecitabine, gemcitabine, carboplatin, liposomal doxorubicin, faslodex, letrozole, tamoxifen, bevacizumab etc.

4. Potential Mechanisms of Trastuzumab Resistance Altered receptor-antibody interactions Increased signaling through other HER family receptors (EGFR, HER3) Increased signaling due to PI3K/Akt pathway changes Increased signaling through alternate growth regulatory pathways (IGF-1R, VEGF)

5. What is next? T-DM1 (Antibody drug conjugate) Pertuzumab ( HER2 dimerisation inhibitor) Neratinib ( pan-ErbB receptor tyrosine kinase inhibitor of ErbB-1,-2,-4)

6. Three drugs Phase II/III T-DM1 Pertuzumab Neratinib

7. Trastuzumab-MCC-DM1 – Binds to HER2 with affinity similar to trastuzumab – Provides intracellular delivery of mertansine Derivative of maytansine, a natural-product microtubule polymerization inhibitor 20-100 more potent than vincristine Higa et al. Expert Anti Can 2010

8. Phase II Study of Trastuzumab-DM1 (T-DM1), a Novel HER2 Antibody–Drug Conjugate, in Patients with HER2+ Metastatic Breast Cancer Previously Treated with an Anthracycline, a Taxane, Capecitabine, Lapatinib, and Trastuzumab Krop I, LoRusso P, Miller KD, Modi S, Yardley D, Rodriguez G, Agresta S, Zheng M, Amler L, Rugo H Presented at the 32nd Annual San Antonio Breast Cancer Symposium. December 9-13, 2009. Abstract 5090.

9. TDM4374g: Study Design T-DM1 3.6 mg/kg IV q 3 weeks HER2-positive patients with metastatic breast cancer n=110 Primary endpoint: ORR by IRF Secondary endpoints: ORR by INV; PFS, DoR, CBR by INV and IRF Primary efficacy analysis data cut at 24 weeks post-LPI Follow-up: 30 days post-last dose unless SAE (90 days) ORR=objective response rate; IRF=independent review facility; INV=investigator assessment; DoR=duration of response; CBR=clinical benefit rate; LPI=last patient in; SAE=serious adverse event. 9 Krop I, et al. Presented at the 32nd Annual San Antonio Breast Cancer Symposium. December 9-13, 2009. Abstract 5090. Multi-institutional, Open-label, Single-arm Phase II Trial

10. Median number of agents for metastatic disease (range)* 7.0 (1–15) Median number of agents in all therapy setting (range)*8.0 (1–19) Number of patients with 5 prior agents, n (%)**109 (99.1) Prior trastuzumab Median duration of prior trastuzumab in metastatic setting, months (range) 19.4 (2–116) Prior lapatinib Median duration of prior lapatinib in metastatic setting, months (range) 6.9 (0–23) *Includes all agents intended for the treatment of breast cancer except hormonal therapy. * * One patient did not receive a taxane. TDM4374: Prior Chemotherapy and Anti-HER2 Therapy 10 Krop I, et al. Presented at the 32nd Annual San Antonio Breast Cancer Symposium. December 9-13, 2009. Abstract 5090.

11. TDM4374: Efficacy Conclusions Single agent T-DM1 demonstrated robust anti-tumor activity in a predefined population that had a median time from metastatic diagnosis of over 3 years and received over 2 years of prior HER2-directed therapy – ORR: 32.7% (as per independent review); 30% (as per investigator) – CBR: 44.5% (as per independent review); 40% (as per investigator) Substantial clinical benefit was seen in this prespecified patient population that has not been previously studied – Pre-defined treatment with an anthracycline, a taxane, capecitabine, trastuzumab, and lapatinib – Received two HER2-directed regimens in the metastatic setting – Progressive disease on last regimen received 11 Krop I, et al. Presented at the 32nd Annual San Antonio Breast Cancer Symposium. December 9-13, 2009. Abstract 5090.

12. TDM4374: Safety Conclusions T-DM1 is well-tolerated by patients at the dose and schedule tested with no dose- limiting cardiotoxicity or new safety signals – One patient died from hepatic dysfunction Toxicities observed are acceptable and manageable in this patient population 12 Krop I, et al. Presented at the 32nd Annual San Antonio Breast Cancer Symposium. December 9-13, 2009. Abstract 5090.

13. Randomized, phase II, international, open-label study HER2-positive, measurable disease required Stratification factors – World region, prior adjuvant trastuzumab therapy, disease-free interval Primary endpoints: PFS by INV, safety Key Secondary endpoints: ORR, clinical benefit, OS, QOL, symptom control Phase III Study Design 1:1 HER2-positive, recurrent locally advanced BC or MBC (n=137) T-DM1 3.6 mg/kg Q3W until PD Trastuzumab 8 mg/kg dose; 6 mg/kg Q3W + Docetaxel 75 or 100 mg/m 2 Q3W Crossover T-DM1 PD Perez EA, et al. Abstr LBA3. ESMO 2010

14. Study Status Study fully enrolled with N=137, Sept 2008- Dec 2009 Clinical data cutoff date for analysis is April 2 nd, 2010 – Median duration of follow-up – 5.9 months in the trastuzumab + docetaxel arm – 6.1 months in the T-DM1 arm Only clinical data prior to T-DM1 cross-over were included in efficacy and safety analyses Perez EA, et al. Abstr LBA3. ESMO 2010

15. Objective Response by Investigator (ITT) Randomized Patients T-DM1 (n=67) Trastuzumab + Docetaxel (n=70) Patients with an Objective Response,* n (%)32 (47.8)29 (41.4) 95% CI(35.4, 60.3)(30.2, 53.8) Patients with Clinical Benefit, † n (%)37 (55.2)40 (57.1) 95% CI(43.1, 67.2)(44.8, 68.9) Perez EA, et al. Abstr LBA3. ESMO 2010

16. HER2-positive, locally advanced or metastatic BC; previously received trastuzumab-based therapy Lapatinib (1250 mg/day) (Days 1–21) + Capecitabine (1000 mg/m 2 ) (Days 1–14 q3w) T-DM1 (3.6 mg/kg) q3w Study TDM4370g: T-DM1 vs. Capecitabine + Lapatinib in HER2-positive MBC (EMILIA) Randomized, Phase III multicenter (n=260 sites), open-label study Enrollment began February 2009 Planned total enrollment: 580 patients Primary end point: PFS Secondary end points: OS, quality of life 16 Source: http://www.clinicaltrials.gov

17. Three drugs Phase II/III T-DM1 Pertuzumab Neratinib

18. Pertuzumab HER2 Dimerisation Inhibitor By blocking HER2 dimerisation, pertuzumab inhibits key HER signalling pathways that mediate cancer cell proliferation and survival 1–4 Pertuzumab prevents the formation of HER2:HER3 receptor pairs 1,5 HER2 Dimerisation domain 1. Agus et al. Cancer Cell 2002;2:127–137; 2. Baselga. Cancer Cell 2002;2:93–95; 3. Citri et al. Exp Cell Res 2003;284:54–65. 4. Franklin et al. Cancer Cell 2004;5:317–328; 5. Hughes et al. Mol Cancer Ther 2009;8:1885–1892 Pertuzumab HER3

19. Neoadjuvant pertuzumab (P) and Trastuzumab (H): Antitumor and Safety Analysis of a Randomized Phase II study (‘NeoSphere’) L Gianni, T Pienkowski, Y-H Im, L Roman, L-M Tseng, M-C Liu, A Lluch-Hernandez, V Semiglazov, T Szado, G. Ross on behalf of the ‘NeoSphere’ Investigators San Antonio Breast Cancer Symposium, Dec 10, 2010

20. NeoSphere: Study Design THP (n=107) Docetaxel + Herceptin + Pertuzumab HP (n=107) Herceptin + Pertuzumab TP (n=96) Docetaxel + Pertuzumab SURGERYSURGERY Docetaxel q3w x 4→FEC q3w x 3 Herceptin q3w cycles 5–17 FEC q3w x 3 Herceptin q3w cycles 5–17 FEC q3w x 3 Herceptin q3w cycles 5–17 FEC q3w x 3 Herceptin q3w cycles 5–21 Study dosing: q3w x 4 TH (n=107) Docetaxel + Herceptin Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve & primary tumours >2cm (N=417 ) BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide *Locally advanced=T2–3, N2–3, M0 or T4a–c, any N, M0; operable=T2–3, N0–1, M0; inflammatory = T4d, any N, M0 3

21. NeoSphere: Study Design and Objectives THP (n=107) Docetaxel (75  100 mg/m 2 ) Herceptin (8  6 mg/kg) Pertuzumab (840  420 mg) HP (n=107) Herceptin (8  6 mg/kg) Pertuzumab (840  420 mg) TP (n=96) Docetaxel (75  100 mg/m 2 ) Pertuzumab (840  420 mg) Study dosing: q3w x 4 TH (n=107) Docetaxel (75  100 mg/m 2 ) Herceptin (8  6 mg/kg) SURGERYSURGERY Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve & primary tumours >2cm (N=417 ) BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide *Locally advanced=T2–3, N2–3, M0 or T4a–c, any N, M0; operable=T2–3, N0–1, M0; inflammatory = T4d, any N, M0 4 Phase II design Primary End Point: comparison of pCR rates TH v. THP TH v. HP THP v. TP Secondary End Points: Clinical response DFS Breast Conservation rate Biomarker evaluation

22. NeoSphere pCR rates: ITT population summary p = 0.0141 50 40 30 20 10 0 THTHPHP TP pCR, %  95% CI p = 0.0198 p = 0.003 Treatment 29.0% 45.8% 16.8% 24.0% 6

23. NeoSphere: pCR and Hormone Receptors Status 7 20 26 17 37 27 30 6 63  95% CI

24. Summary Significantly higher pCR rate with Herceptin + pertuzumab when combined with docetaxel (THP) Substantial antitumor activity and a very favourable therapeutic ratio for the Herceptin + pertuzumab doublet without chemotherapy Consistently higher pCR rates in ER and PR negative tumors than in ER and/or PR positive tumors, including those treated with HP without chemotherapy Excellent tolerability and lack of any meaningful increase in cardiac risk with the addition of pertuzumab over a short course of 4 cycles of neoadjuvant therapy 14

25. CLEOPATRA Phase III Study of Trastuzumab + Pertuzumab in HER2+ MBC 1:1 randomization HER2+ MBC N = 800 Docetaxel + Herceptin + placebo Docetaxel + Herceptin + pertuzumab An international Phase III randomized, double-blind, placebo- controlled study (approximately 250 sites worldwide) Endpoints: Progression-free survival Overall survival Biomarker analysis

26. Three drugs Phase II/III T-DM1 Pertuzumab Neratinib

27. Neratinib : Irreversible TKI of ErbB family Potent, low molecular weight, orally administered, irreversible pan-ErbB receptor tyrosine kinase inhibitor of ErbB-1,-2,-4.

28. P EGFR P ErbB3 P P P P P P gefitinib (or erlotinib) trastuzumab IGF-1R P X HER2 HKI-272 P Neratinib: pan-inhibitor of ErbB receptor kinase family reversible irreversible (Lapatinib reversible)

29. Comparison of Lapatinib and Neratinib across Phase II studies Lapatinib ORR% Neratinib ORR% HER2-positive, Trastuzumab refractory 5.1%26% HER2-positive, Trastuzumab naive 35%56%

30. Clinical outcomes of patients with prior trastuzumab (T) or no prior T treatment: Burstein H J et al. JCO 2010;28:1301-1307 ©2010 by American Society of Clinical Oncology Objective response rates were 24% in patients who had trastuzumab 56% in trastuzumab naïve patients

31. Efficacy of Neratinib/Paclitaxel in HER2+ Metastatic Breast Cancer 102 patients w. MBC, 1 st to 4 th -line Neratinib 240mg qd in combination with Paclitaxel 80mg/m2 days 1,8,15 of 28-d cycle Gupta et al. SABCS abstract 5081, 2009

32. Response data Prior RxOverall Response Rate All evaluable patients 61 of 97(67%) Prior Taxane43 of 60 (72%) Prior Herceptin55 of 97 (57%) Prior Lapatinib9 of 13 (69%) Gupta et al. SABCS abstract 5081, 2009

33. FB-7: A Phase II Randomized Clinical Trial Evaluating Neoadjuvant Therapy Regimens with Weekly Paclitaxel and Neratinib or Trastuzumab Followed by Doxorubicin and Cyclophosphamide with Postoperative Trastuzumab in Women with Locally Advanced HER2-Positive Breast cancer

34. STUDY SCHEMA Randomization to a Preoperative Regimen Surgery (lumpectomy or mastectomy; evaluation of axilla) Clinical Stage IIIA, IIIB, or IIIC HER2-Positive Invasive Breast Cancer Diagnosed by Core Needle Biopsy or Limited Incisional Biopsy with Palpable Mass in Breast or Axilla ≥ 2.0 cm or Inflammatory Breast Cancer Group 1 Cycles 1-4: Paclitaxel 80 mg/m 2 IV on Days 1, 8, and 15 q 28 days + Trastuzumab IV weekly: 4 mg/kg loading dose, then 2 mg/kg weekly for 15 doses (for a total of 16 doses) ↓ Cycles 5-8: AC* q 21 days Group 2 Cycles 1-4: Paclitaxel 80 mg/m 2 IV on Days 1, 8, and 15 q 28 days + Neratinib 240 mg PO daily until 7 days after last dose of paclitaxel ↓ Cycles 5-8: AC* q 21 days

35. Her-2 positive Stage II-IIIC patients Completed Trastuzumab Within 1 year Neratinib daily P.O Placebo daily P.O 1 year 3144A2-3004-WW: A Randomized Double-Blind Placebo-Controlled Trial of Neratinib (HKI-272) After Trastuzumab in Women with Early-Stage HER- 2/neu Overexpressed/Amplified Breast Cancer (ExNET study)

36. NSABP B-47 Adjuvant Trastuzumab in HER2 Low EBC Primary Breast Cancer IHC 1+ or 2+ for HER2 and FISH Negative Docetaxel 75mg/m 2 + CTX 600mg/m 2 Q3wk x 6 or ACx4  Paclitaxel Qwk x 12 Std or DD AC Randomization Docetaxel 75mg/m 2 + CTX 600mg/m 2 Q3wk x 6 or ACx4  Paclitaxel Qwk x 12 Std or DD AC + Trastuzumab x 1 yr beginning with TC or WP

37. Thank you for your attention T-DM1 (Antibody drug conjugate) Pertuzumab ( HER2 dimerisation inhibitor) Neratinib (pan-ErbB receptor tyrosine kinase inhibitor of ErbB-1,-2,-4)