RTP TV: An 8-Part Live CME Webcast Series

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Joyce O'Shaughnessy, MD Co-Director, Breast Cancer Research ProgramBaylor-Charles A Sammons Cancer CenterTexas Oncology, PAUS OncologyDallas, Texas. Eric P Winer, MDThompson Investigator in Breast Cancer ResearchChief, Division of Women's Cancers Dana-Farber Cancer InstituteProfessor of MedicineHarvard Medical SchoolBoston, Massachusetts.

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RTP TV: An 8-Part Live CME Webcast Series

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1. RTP TV: An 8-Part Live CME Webcast Series

3. Disclosures for Moderator Neil Love, MD

4. Disclosures for Joyce O’Shaughnessy, MD

5. Disclosures for Eric P Winer, MD

6. RTP TV: An 8-Part Live CME Webcast Series

7. Survey of 100 Practicing Oncologists 95% – fraction who see patients with TNBC 10 – median number of patients with metastatic TNBC currently in their practices

8. Survey of 100 Practicing Oncologists Fraction with a patient who has received… Iniparib – 23% Olaparib – 16% Veliparib – 7%

9. Survey of 100 Practicing Oncologists If you were to attend a CME conference on breast cancer, to what extent would you be interested in learning about the following topics? Response scale 0 – 10 0 = no interest 10 = very interested

10. TNBC: New Agents and Regimens

11. TNBC: PARP Inhibitors

12. Survey of 100 Practicing Oncologists What question(s) would you like to pose to a clinical investigator with expertise in the management of TNBC? 97 questions/cases received

13. When will newer agents be integrated into earlier lines of treatment?

14. When is BRCA testing indicated in a patient with TNBC?

15. Under what conditions should metastatic sites be biopsied?

16. Are there other new noncytotoxic, targeted agents in TNBC in addition to PARP inhibitors? — Naples, FL

18. Case 1 (Dr O’Shaughnessy) 50 yo woman with basal-like TNBC Preoperative AC ? paclitaxel: pCR • Tumor “melts away” after 1 cycle of AC Locoregional RT 2 years later, very rapidly growing ipsilateral internal mammary node protruding from her chest and invading sternum and mediastinal LNs Patient enrolls on a trial of gem/carbo ± iniparib* Major response for 8 cycles (6 months) Tissue harvested for total genome sequencing Paclitaxel/bevacizumab Response for 6 months but progressing

19. Progression with Regrowth of Ipsilateral Mammary Mass and Mediastinal Nodes

20. Phase II Study of Iniparib plus Gemcitabine/Carboplatin in mTNBC

21. A Randomized Phase III Study of Iniparib (BSI-201) in Combination with Gemcitabine and Carboplatin in Metastatic Triple-Negative Breast Cancer (mTNBC) O’Shaughnessy J et al. Proc ASCO 2011;Abstract 1007.

22. Phase II Study of Iniparib plus Gemcitabine/Carboplatin in mTNBC

23. Metastatic Triple-Negative Breast Cancer (mTNBC) 15% of breast cancers; clinically defined as ER-negative, PR-negative and HER2-non-overexpressing Heterogeneous disease with generally virulent natural history Shares gene expression profiles with basal-like, claudin-low and other molecular subtypes No clinical implications of molecular subtypes at present

24. Iniparib (BSI-201) A novel, investigational, anticancer agent In triple-negative breast cancer cell lines: Induces cell cycle arrest in the G2/M phase Induces double strand DNA damage ?H2AX foci but does not inhibit PARP1 and 2 at physiologic drug concentrations Potentiates cell-cycle arrest induced by DNA damaging agents, including platinum and gemcitabine Physiologic targets of iniparib and its metabolites are under investigation

25. Preclinical Pharmacodynamic and Pathway Analysis of 3 Presumed PARP Inhibitors: ABT-888, AZD2281, BSI-201 ABT-888 and AZD2281 are mediated by PARP1 or PARP2. Iniparib (BSI-201) suppressed genes in the telomere pathway, suggesting PARP5/6 as potential targets.

26. Schema

27. Study Objectives Primary: Coprimary endpoints: Overall survival (OS) Progression-free survival (PFS) Study considered positive if either endpoint met Secondary: Objective response rate (ORR) Safety, tolerability and pharmacokinetics of GCI

28. Treatment-Emergent Adverse Events Safety Population (Prior to crossover, >5% Grade 3/4 in GCI arm)

36. Deconstructing the molecular portraits of breast cancer

41. Case 2 (Dr Winer) 48 yo premenopausal, BRCA1/2-negative woman presents 6 years ago with weakly ER+, PR- T2N1 breast cancer Neoadjuvant AC ? paclitaxel Excision/re-excision plus RT Tamoxifen Ipsilateral breast recurrence 1 year later Mastectomy Waxing and waning supraclavicular adenopathy over next 18 months until diagnosed with local recurrence Needle biopsy reveals metastatic TNBC, with small pulmonary nodule Enrolled on TBCRC009: Phase II study of cisplatin or carboplatin for metastatic TNBC* Clinical CR after 7 cycles of cisplatin Treatment discontinued due to toxicity (fatigue, neuropathy) No further therapy for past 2 years, 4 months

43. TBCRC009: A Multicenter Phase II Study of Cisplatin or Carboplatin for Metastatic Triple-Negative Breast Cancer and Evaluation of p63/p73 as a Biomarker of Response

44. Phase II Study of Cisplatin or Carboplatin for mTNBC 86 patients enrolled to physician's choice of either cisplatin or carboplatin Overall RR: 30.2%, including 4 CR (4.7%) and 22 PR (25.6%) RR by treatment (exploratory): 37% cisplatin 23% carboplatin p63/p73 analysis is ongoing

45. Submitted Case Dr Frances de la Serna, Philippines 40 yo woman with axillary lymphadenopathy in 1/2010 Excisional biospy: Ductal carcinoma consistent with breast primary in 4 nodes Ultrasound: 2 solid masses in breast (15.1 and 20.9 mm) Neoadjuvant anthracycline/taxane-based therapy x 2 cycles ? surgery No residual tumor or LVI in the breast 7/9 nodes positive ER/PR-, HER2 1-2+ (FISH positive) Receives chemotherapy/trastuzumab

46. Submitted Case (Continued) 12/2010: Neck mass FNB: Metastatic carcinoma Multiple enlarged lymph nodes in supraclavicular and jugular chains Excisional biopsy: ER/PR/HER2-negative adenocarcinoma Patient receives cisplatin/gemcitabine Resolution of enlarged nodes 5/2011: Neck mass Biopsy: Metastatic carcinoma Multiple nodules on the skin flap Plan: Continue cisplatin

47. Local versus Central Laboratory Discrepancies in TNBC Status (CIBOMA/2004-01/GEICAM/2003-11) N = 1,441 patient samples sent for central laboratory confirmation In 130 cases (9%) tumors were found to not be TNBC by central determination 71% of discrepant results involved ER or PR status 22% of discrepant results involved HER2 status

51. TBCRC 018: Phase II Study of Iniparib plus Chemotherapy to Treat Triple-Negative Breast Cancer (TNBC) Brain Metastases (BM) Anders CK et al. Proc ASCO 2011;Abstract TPS127: Trials in Progress.

54. Case 3 (Dr O’Shaughnessy) A woman in her mid-50s with locally advanced and metastatic TNBC Enrolled in a study of total genome sequencing Determined to have a high level BRAF amplicon Enrolled on a Phase I trial of MEK plus AKT inhibitors* Significant response in a very large, fungating breast

58. A Phase I Dose-Escalation Study of Oral MK-2206 (Allosteric AKT Inhibitor) with Oral Selumetinib (MEK Inhibitor) in Patients with Advanced or Metastatic Solid Tumors

61. Schedule of Events

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