Metastatic Breast Cancer and Emerging Research Kathryn J

Metastatic Breast Cancer and Emerging Research Kathryn J. Ruddy, MD MPH Assistant Professor of Oncology Mayo Clinic

Overview • What is metastatic disease? • Breast cancer subtypes – Treatment of Her 2+ disease – Treatment of ER-/Her 2 - disease • Exciting new research directions

Metastatic breast cancer • Stage IV disease – Has spread from the breast and axillary lymph nodes to other organs • Accounts for 5 -10% of all breast cancer at the time of diagnosis • Stage IV breast cancer is usually incurable, but can often be controlled for years utilizing sequential drug therapy

Treatment for metastatic disease • Treated primarily with systemic therapy, but sometimes with palliative radiation also; surgery is rarely utilized • After the disease develops resistance to one drug, a patient is switched to a new drug • Aims of therapy are to: – Prolong time to progression – Prolong survival – Palliate • Reduce tumor burden • Minimize treatment toxicity • Disease subtype is critical to treatment decision-making

Breast cancer subtypes • There are three main subtypes of breast cancer • Oncologists use breast cancer subtype to guide treatment decisions • Clinical trials often focus on specific subtypes

Subtypes TALK to your doctor if you are not sure what type of breast cancer you have Slide courtesy of Nancy Lin

Treatment Hormone receptor positive Triple-negative HER 2 -Positive Herceptin + perjeta + chemotherapy Hormonal therapy Chemotherapy TDM 1 Hormonal therapy Chemotherapy Herceptin + chemotherapy Chemotherapy Lapatinib +Herceptin + chemotherapy *Note, these are just examples. Each patient is different and treatment is tailored accordingly. Slide courtesy of Nancy Lin

HER 2+ disease: a paradigm for advances in targeted therapy

HER 2+ disease: major advances Three Large Adjuvant Trials Reported Trastuzumab Approved 2002 1998 First Preoperative Trials Reported Paving The Way For Use in Early Stage Disease 2005 Lapatinib Approved 2005 20072008 Initial Trials of T-DM 1, Neratinib 2010 Pertuzumab Approved Preoperative Trials of Dual Blockade 2012 2013 T-DM 1 Approved • HER 2 is an important target; anti-HER 2 drugs can be effective with chemo, with endocrine therapy, or alone • Meaningful progress has been made with novel therapies that are well tolerated • Resistance is a major challenge but new technologies are allowing this to be overcome Slide courtesy of Ian Krop

Trastuzumab in HER 2+ metastatic breast cancer Protein Receptor HER 2 Gene Normal Cell HER 2+ Cell Can combine with many different chemotherapies (e. g. , paclitaxel, docetaxel, vinorelbine, capecitabine) and targeted agents (e. g. , lapatinib) Graphic adapted from image at http: //www. gene. com/gene/research/focusareas/oncology/herpathwayexpertise. jsp Slamon et al, NEJM 2001

Lapatinib • Oral dual tyrosine kinase inhibitor of HER 2 and EGFR • FDA approved in combination with capecitabine for trastuzumabresistant disease • May have CNS penetration • Well tolerated; common toxicities include rash and diarrhea Geyer et al, NEJM 2006

Pertuzumab with trastuzumab HER 2 receptor Pertuzumab Trastuzumab Dimerisation domain of HER 2 • • Inhibitor of HER dimerization: binds HER 2 and prevents formation of homo- or heterodimers Suppresses activation of several intracellular signaling cascades driving cancer cell growth Synergistic with trastuzumab Approved for first-line treatment of metastatic Her 2+ breast cancer in combination with trastuzumab and taxane chemotherapy Slide courtesy of Ian Krop

CLEOPATRA: phase 3 study of pertuzumab in untreated metastatic disease Docetaxel + trastuzumab + placebo HER 2 -positive MBC 1: 1 N=808 Docetaxel + trastuzumab + pertuzumab Pertuzumab prolongs time until progression by six months (from 12. 5 to 18. 5 months) Baselga et al, SABCS 2011 and NEJM, 2011

Toxicities Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Diarrhea 184 (46. 3) 272 (66. 8) Alopecia 240 (60. 5) 248 (60. 9) Neutropenia 197 (49. 6) 215 (52. 8) Nausea 165 (41. 6) 172 (42. 3) Fatigue 146 (36. 8) 153 (37. 6) Rash 96 (24. 2) 137 (33. 7) Decreased appetite 105 (26. 4) 119 (29. 2) Mucosal inflammation 79 (19. 9) 113 (27. 8) Asthenia 120 (30. 2) 106 (26. 0) Peripheral edema 119 (30. 0) 94 (23. 1) Constipation 99 (24. 9) 61 (15. 0) Febrile neutropenia* 30 (7. 6) 56 (13. 8) Dry skin 17 (4. 3) 43 (10. 6) Adverse event, n (%) *Febrile neutropenia rate 12% vs 26% in Asia, 10% or less in all other regions --No difference in cardiac toxicity rate (2% v 1%) Baselga et al, SABCS 2011 and NEJM, 2011

Trastuzumab Emtansine (T-DM 1) • T-DM 1 is an antibody drug -conjugate • Trastuzumab linked to a potent chemotherapy (DM 1) • Average of 3. 5 DM 1 per antibody Slide courtesy of Ian Krop

T-DM 1 selectively delivers DM 1 to HER 2+ cells HER 2 Receptor-T-DM 1 complex is internalized into HER 2 -positive cancer cell T-DM 1 binds to the HER 2 protein on cancer cells Potent antimicrotubule agent is released once inside the HER 2 -positive tumor cell Slide courtesy of Ian Krop

EMILIA: randomized trial comparing TDM 1 to capecitabine and lapatinib in previously treated patients HER 2+ MBC (N=980) T-DM 1 PD 3. 6 mg/kg q 3 w IV 1: 1 • Prior taxane and trastuzumab Capecitabine 1000 mg/m 2 orally bid, days 1– 14, q 3 w + Lapatinib PD 1250 mg/day orally qd T-DM 1 prolongs time until progression by three months (from 6. 4 to 9. 6 months) Blackwell et al, ASCO 2012

Th 3 RESA: randomized trial comparing T-DM 1 to physician’s choice HER 2 positive T-DM 1 q 3 w Metastatic breast cancer Prior trastuzumab, lapatinib and chemotherapy N = 795 2: 1 randomization 2 1 Treatment of physician’s choice Study treatment continues until disease progression or unmanageable toxicity T-DM 1 prolongs time until progression by three months (from 3. 3 to 6. 2 months) Wildiers et al, ECC-ESMO 2013

T-DM 1 is well-tolerated • Common side effects: – Decreased platelet count – Elevated liver tests • Does not cause typical chemotherapy side effects • No hair loss • Significant nausea or diarrhea are not common • Does not cause immune suppression or significant neuropathy

Novel HER 2 -directed agents in clinical development Class Example(s) HER 2 -targeted TKI Neratinib, afatinib, ARRY-380 HER 2 -targeted liposome MM-302 Trifunctional antibody Ertumaxomab HER 2 vaccine AE 37

ER+ disease: improving on already very effective treatments

Endocrine therapy for metastatic disease • Premenopausal – Tamoxifen – Ovarian suppression/ablation – Ovarian suppression + aromatase inhibition – Megace • Postmenopausal – Tamoxifen – Aromatase Inhibitor +/everolimus – Fulvestrant – Megace

Targeting the PI 3 Kinase pathway Polyak and Filho, Cancer Cell, 2012

Everolimus is an MTOR inhibitor

New drug approval: everolimus Exemestane + everolimus • 3. 2 months* • 7. 8 months* *Median time from study entry until worsening of cancer Approved by the FDA in 2012 for patients with metastatic, hormone-receptor positive, HER 2 -negative breast cancer Slide courtesy of Nancy Lin

What’s next for everolimus? • Multiple studies underway – In HER 2+ cancers – In triple negative cancers – Studying this drug in combination with otherapies

Testing the addition of an HSP 90 inhibitor to hormonal therapy Slide courtesy of Nancy Lin

Tumor volume (mm 3) Testing the addition of an HSP 90 inhibitor to hormonal therapy Ganetespib induces regression in tumors progressing on fulvestrant Days of treatment ER+ and HER 2 negative breast cancer Fulvestrant + ganestespib Fulvestrant + ganetespib Slide courtesy of Nancy Lin

Other agents of interest in ER+ disease • • • Endoxifen CDK 4/6 inhibitors PI 3 Kinase inhibitors Anti-IGF-1 R Ab SRC/Abl tyrosine kinase inhibitors Combination therapy with targeted agents that may overcome endocrine resistance

Triple negative breast cancer: still searching for a target

Triple negative recurrences happen early Rates of distant recurrence following surgery in triple-negative vs other breast ca Dent et al, Clin Cancer Res 2007

There are many chemotherapies that are active against metastatic disease • Mitotic inhibitors – vinorelbine – paclitaxel – docetaxel • Antifolates – methotrexate • Topoisomerase inhibitors – doxorubicin

Platinums • Sledge (JCO 1988) reported 47% response rate in first line metastatic disease • Abandoned for many years because of concerns about toxicity—largely replaced by taxanes • Recent interest in patients with triple negative breast cancer – DNA crosslinking mechanism of action • New data from a series of neoadjuvant studies supports activity in TNBC Sledge et al, JCO 2008; Silver et al JCO 2010; Gronwold et al, ASCO 2009; Sikov SABCS 2013

New chemotherapy: eribulin • Metastatic breast cancer • At least 2 prior chemotherapies Approved by the FDA in 2011 Halichondria okadai

PARP inhibitors • PARP 1 is a protein that is important for repairing single-strand DNA breaks • PARP inhibitors prevent DNA repair, leading to cell death • Fast-dividing tumors and tumors containing BRCA mutations, which also impair DNA repair, may be most sensitive to PARP inhibitors • Ongoing trials are investigating the efficacy of PARP inhibitors in breast cancer, particularly triple negative breast cancer and BRCA-associated breast cancer

Targeting the androgen receptor in triple negative breast cancer T T Inhibit binding to receptor (AR) AR Cell cytoplasm Inhibit nuclear translocation of AR Cell nucleus AR Tumor Death Inhibit AR-mediated DNA binding

Other agents of interest in triple negative disease • • PI 3 Kinase inhibitors SRC/Abl tyrosine kinase inhibitors HSP 90 inhibitors More to come…

What does all this complexity mean? “half empty” • There is likely not going to be a single “cure for cancer” • Different cancers may have different strengths & weaknesses • Figuring this out won’t be easy! Slide courtesy of Erica Mayer

What does all this complexity mean? “half full” • There is likely not going to be a single “cure for cancer” • The opportunity to individualize therapy—one size doesn’t fit all • Different cancers may have • We may be able take advantage different strengths & weaknesses of specific weaknesses of cancers and knock out specific strengths • Figuring this out won’t be easy! • But should be possible! Slide courtesy of Erica Mayer

Outstanding research questions 1. How many subtypes of breast cancer are there, and by understanding this, can we find new targets and new treatments? Can we better “tailor” treatments? 2. What causes resistance to hormonal therapy? To chemotherapy? Can it be prevented or overcome? 3. What lifestyle factors (e. g. , exercise? ) might be important for patients with metastatic disease? 4. How can we minimize toxicities of treatment?

Summary • Not all breast cancers are alike • We have many clues to guide therapy • But we need clinical trials and continued basic and translational research to make new breakthroughs that make a difference for patients

Thank you!