1. William J. Gradishar MD, FACP Betsy Bramsen Professor of Breast Oncology Director, Maggie Daley Center For Women's Cancer Care Robert H. Lurie Comprehensive Cancer Center Northwestern University Feinberg School of Medicine Chicago, IL Future therapeutics for HER2 positive metastatic breast cancer

2. ‘Irreversible’ tyrosine kinase inhibitors  Irreversible TKIs form covalent bonds with tyrosine kinase Irreversible bond  TK remains inhibited until new receptor/TK complex can be synthesized  Afatinib and neratinib are HER1[EGFR]/HER2 TKIs in development Awada et al, Cancer Treat Rev. 2012;38:494-501.

3. Afatinib in trastuzumab refractory MBC  Patients with pretreated MBC (n=41) Median prior lines of chemotherapy: 3 >1 year trastuzumab therapy: 68% Response to trastuzumab: ► CR: 2 ► PR: 13 ► SD: 13  Response to afatinib: PR: 4 (10%) SD: 15 (37%) (6 patients were not evaluable) Median PFS: 15 weeks Median OS: 61 weeks.  Adverse events: Grade 3 or 4 diarrhea Rash Lin et al, Breast Cancer Res Treat. 2012;133:1057-65.

4. Ongoing LUX-breast clinical trials with afatinib in breast cancer 1. Harbeck et al, J Clin Oncol. 2012;30 (suppl); abstr TPS649. 2. Hickish et al, J Clin Oncol. 2012;30 (suppl); abstr TPS651. 3. Joensuu & Kaci, J Clin Oncol. 2012;30 (suppl); abstr TPS647. LUX-breast 1 1 LUX-breast 2 2 LUX-breast 3 3 Study design Randomized Phase IIIOpen-label Phase IIRandomized Phase II Patients Target 780 HER2 + MBC Progression on or after 1 prior trastuzumab regimen Target 120 HER2 + MBC Progression after adjuvant / neoadjuvant trastuzumab and / or lapatinib Target 120 HER2 + MBC Progressive / recurrent brain metastases during / after prior trastuzumab or lapatinib Treatment arms Afatinib (40 mg) + vinorelbine vs Trastuzumab + vinorelbine Afatinib 40 mg followed by afatinib + paclitaxel or Vinorelbine after progression Afatinib (40 mg) vs Afatinib (40 mg) + vinorelbine vs Investigator’s choice Primary endpoint PFSObjective response ratePatient benefit (progression or absence of CNS disease)

5. Neratinib in patients with advanced HER2 positive breast cancer  Open label study in patients with stage IIIB/C and IV breast cancer  n=136 patients Prior trastuzumab (n=66; 63 evaluable) No prior trastuzumab (n=70; 64 evaluable)  Main adverse events; Diarrhea (including grade 3/4 in 29 patients), nausea, vomiting, and fatigue Burstein et al, J Clin Oncol. 2010;28:1301-7. Prior T (n=63) No prior T (n=64) 16 week PFS (%)5978 Median PFS (weeks) 22.339.6 Objective response rate (%) 2456 Clinical benefit (PR, SD) rate (%) 3369

6. Summary  The options available for metastatic/ advanced HER2 positive breast cancer have changed with the availability of pertuzumab and, likely in 2013 trastuzumab emtansine  In addition to antibody based technology, another promising approach are the ‘irreversible’ tyrosine kinase inhibitors These form covalent, irreversible bonds and thus demonstrate a prolonged inhibition of the HER2 TK  Clinical trials are ongoing to confirm the initial Phase IIa results