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Future therapeutics for HER2 positive metastatic breast cancer

Future therapeutics for HER2 positive metastatic breast cancer. 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

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Future therapeutics for HER2 positive metastatic breast cancer

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  1. Future therapeutics for HER2 positive metastatic breast cancer • William J. GradisharMD, 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

  2. ‘Irreversible’ tyrosine kinase inhibitors • IrreversibleTKIs 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 ClinOncol. 2012;30 (suppl); abstrTPS649. 2. Hickish et al, J ClinOncol. 2012;30 (suppl); abstrTPS651. 3. Joensuu & Kaci, J ClinOncol. 2012;30 (suppl); abstrTPS647.

  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 ClinOncol. 2010;28:1301-7.

  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

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