1. Management of CNS Metastases From Breast Cancer Nancy U. Lin, MD Dana-Farber Cancer Institute ABC1 Advanced Breast Cancer First Consensus Conference Lisbon, Portugal November 4, 2011

3. Barnholtz-Sloan et al, JCO 2004 Risk of Brain Metastasis (Breast Cancer) by Stage at Diagnosis Distant (Stage IV): 13.5% Regional: 7.6% Localized: 2.5%

4. High Risk of Brain Metastases in Patients with HER2+ MBC Study Incidence Bendell et al, Cancer 2003 34% Clayton et al, Br J Cancer 2004 39% Stemmler et al, Breast 2006 31% Kennecke et al, J Clin Oncol 2010 29% (ER-) 15% (ER+) Brufsky et al, Clin Cancer Res 2011 44% (ER-) 31% (ER+)

5. High Risk of Brain Metastases in Patients with Triple-Negative MBC Study Incidence Lin et al, Cancer 2008 46% Kennecke et al, J Clin Oncol 2010 25% % Site Parenchymal only Leptomeningeal only Parenchymal + LM 75 15 9 Status of systemic dz at time of CNS diagnosis Stable/responsive Progressive 17 83

6. When does seeding occur? Initial diagnosis First recurrence Progression #1 Progression #2 ……… ..…....Sanctuary effect…. . . . . . . . . . . . . . . . . . . . . . Continuous seeding. . . . Implications for predictive models, screening and/or prevention studies, tumor resistance, trials in established brain mets

7. CNS Recurrence in the Adjuvant Setting Romond et al, N Engl J Med 2005 Patients Trial B-31 Trial N9831 Control Trastuzumab Control Trastuzumab All pts with f/u 872 864 807 808 Any 1 st event 171 83 90 50 Distant recurrence 111 60 63 30 CNS as 1 st event 11 21 4 12 Any CNS 35 28 NR NR

8. Burstein et al, Ann Oncol 2005 Timing of CNS Progression in MBC PD: CNS PD: non-CNS

11. Is Prevention a Feasible Goal? Gril, B. et al. J. Natl. Cancer Inst. 2008

12. Prevention Trials: Possible Schema HER2+ MBC 1-4 brain mets Stable extracranial disease SRS and/or surgery R Trastuzumab ??? HER2+ MBC No brain mets R Trastuzumab-based chemotherapy ???

14. Prognostic Factors Vary by Primary Tumor: Diagnosis-Specific GPA NSCLC / SCLC KPS Age Extracranial Mets # Brain Mets Breast KPS Tumor Subtype Age Sperduto et al, IJROBP 2010; IJROBP 2011; and in press Melanoma KPS # Brain Mets Renal Cell Ca KPS # Brain Mets GI Malignancies KPS GPA

15. Survival After CNS Diagnosis by Breast Cancer Subtype *among pts receiving trastuzumab Study HER2+* TN Bendell et al, 2003 13 mo Gori et al, 2007 23 mo Eichler et al, 2008 17.1 mo 4.0 mo Nam et al, 2008 3.4 mo Park et al, 2009 14.9 mo Dawood et al, 2008 11.6 mo Lin et al, 2008 4.9 mo Melisko et al, 2008 23.1 mo Niwinska et al, ASCO 2009 13 mo 3-4 mo Anders et al, Cancer 2010 14-15 mo 2.9 mo Brufsky et al, CCR 2011 17.5 mo*

22. Mechanisms of Drug Resistance Quentin Smith Paul Lockman Texas Tech University 1.5 nCi/g Normal Brain 23-26 nCi/g Tumor

23. Mechanisms of Drug Resistance Study Patient population ORR Burstein et al, Ann Oncol 2008 Refractory 1.4% by IRR Blackwell et al, Ann Oncol 2010 Refractory 5.1% Blackwell et al, J Clin Oncol 2010 Refractory 6.9% Gomez et al, J Clin Oncol 2008 First-line 24%

24. Mechanisms of Drug Resistance CNS ORR in phase 2 lapatinib trials = 2.6% and 6% Study Patient population ORR Burstein et al, Ann Oncol 2008 Refractory 1.4% by IRR Blackwell et al, Ann Oncol 2010 Refractory 5.1% Blackwell et al, J Clin Oncol 2010 Refractory 6.9% Gomez et al, J Clin Oncol 2008 First-line 24%

27. Ongoing/Planned Trials of Cytotoxic Agents Intervention Tumor Type(s) PI Lead site Trial identifier Irinotecan + TMZ Breast Melisko UCSF NCT00617539 TPI 287 Breast Ibrahim MDACC NCT01332630 2B3-101 Solid Tumors Gladines to-BBB NCT01386580 GRN 1005 Breast Lin Geron Anticipate study activation 4Q 2011

29. Responses observed in breast, NSCLC, ovarian ca, SCLC Sarantopoulos et al, ASCO 2010 Phase I ANG 005 (Solid Tumors) Dose (mg/m 2 ) 30-300 mg/m 2 420-700 mg/m 2 MTD 650 mg/m 2 Prior Taxane Failures* Sample Size (n=33) n=12 n=21 n=12 n=12 CR PR 5 5 4 MR 6 2 5 SD 5 4 1 1 PD 7 6 4 2 RR 0% 24% 42% 33%

31. L: lapatinib C: capecitabine T: trastuzumab Studies of L+C for HER2+ Breast Cancer Brain Metastases *Prospective trial Study N Prior chemo Prior RT Response criteria CNS ORR TTP/PFS OS Lin et al CCR 2009* 50 81% with > 2 T+chemo; PD on lapatinib monotherapy 100% 50% vol NSS, steroids, lack of non-CNS PD 20% 3.6 mo NR Boccardo et al, ASCO 2008 (LEAP) 138 Prior T required NR Investigator-assessed on survey 18% Median time on study 2.8 mo NR Sutherland et al, Br J Ca 2010 (LEAP) 34 82% with > 2 chemo for MBC; prior T required 94% RECIST 21% 5.1 mo NR Metro et al, Ann Oncol 2011 22 Median of 2 prior T-based tx for MBC 86% WHO 32% 5.1 mo 27.9 mo Lin et al, J Neuro-Oncol 2011* 13 Prior T required 100% 50% vol, NSS, steroids, lack of non-CNS PD 38% NR NR Bachelot et al, ASCO 2011* 45 22% with > 2 T+chemo (31%: no prior T for MBC) 0% 50% vol, NSS, steroids, lack of non-CNS PD 67% 5.5 mo 91% alive at 6 mo

32. Burstein et al, J Clin Oncol 2010 Neratinib in HER2+ MBC

33. Targeting the PI3K Pathway Meric-Bernstam and Gonzalez-Angulo, JCO, 2009

34. BKM120 Can Prevent Brain Metastases in a Preclinical Model of HER2 Breast Cancer (Lollini et al, personal communication) Slide courtesy Cristian Masaceni, Novartis Green fluorescent tumor cells (metastases derived from intravenous injection of tumor cells) are no longer detectable in the brain of mice treated with BKM120 The incidence of brain metastases after intramammary tumor growth decreases by half following treatment with BKM120

35. Ongoing/Planned Trials for HER2+ BM Intervention Tumor Type PI Lead site Trial identifier Neratinib (HKI-272) HER2+ Breast Freedman Dana-Farber/ TBCRC Anticipate study activation Jan 2012 Afatinib (BIBW 2992) HER2+ Breast Joensuu Boehringer Ingelheim EudraCT 2010-021415-16 Everolimus + trastuzumab HER2+ Breast Anders UNC Chapel Hill Anticipate study activation 4Q2011 BKM120 + trastuzumab HER2+ Breast -- Novartis In development

36. Ongoing/Planned Trials: Other Targets Intervention Tumor Type PI Lead site Trial identifier Carboplatin + Bevacizumab + trastuzumab Breast Lin Dana-Farber NCT01004172 Cisplatin + etopsoide + Bevacizumab Breast Lu National Taiwan University Hospital NCT01281696 WBRT + Bevacizumab Solid tumors Levy Centre Francois Baclesse NCT01332929 ABT-888 + WBRT Solid tumors Giranda Abbott NCT00649207 BSI-201 + irinotecan Breast (triple neg) Anders UNC NCT01173497

38. Acknowledgements AVON Partners for Progress Award ASCO Foundation (YIA, CDA) Breast Cancer Research Foundation Berry Junior Faculty Award Hurricane Voices Karen Webster and David Evans Research Fund NCI SPORE in Breast Cancer Women’s Cancer Program Executive Council Award