New Treatment Options for Metastatic Breast Cancer A Focus on HER2+ & Triple Negative Disease

New Treatment Options for Metastatic Breast Cancer A Focus on HER2+ & Triple Negative Disease Maureen Trudeau, MD, FRCP(C) October 29 th, 2010 Sunnybrook Odette Cancer Center Toronto, Canada

Objectives 1. Discuss the treatment options for HER2+ metastatic breast cancer 2. Discuss the treatment options for triple negative (TN) metastatic breast cancer 3. Discuss recent clinical trial results in HER2+ and TN metastatic breast cancer

Case 1: AK 45 year old woman treated for Hodgkin s disease at age 17 with chemo and upper mantle radiation In 2003 developed right infiltrating duct breast cancer ER, PR, HER2+ disease, 6 nodes +, treated with AC T after bilateral mastectomies In 2006 relapsed in bone. Treated with Taxol plus Herceptin then Herceptin alone for 1 year At progression in skin enrolled in a phase II study of Pertuzumab +/ Trastuzumab in July 2008

Case #2: MB 35 year old female at diagnosis (2006), 2.2cm, grade 3 IDC, LVI, node, triple negative Treated with adjuvant FEC100 at outside hospital and adjuvant radiation Winter 2008, recurrent chest colds, persistent cough (6 months after completing adjuvant tx) CT scan Chest April 2008 multiple lung mets (no other mets) Seen in consultation at SB Significant shortness of breath and cough Treated on ATHENA trial with wkly taxol + AVASTIN (switched to Abraxane b/c of hypersensitivty reaction to taxol)

Where to start? The London Underground A human cancer cell, pathways visualized by Gene Network Sciences

The oncology roadmap: A mechanism driven (rather than indication driven) approach to cancer I. Bombing the Tumor Targeting antibody-drug conjugates to tumor antigens Signal transduction II. Choking the Tumor Targeting pathways for growth, life, and death Cell cycle IV. Undermining the Tumor Halting the regrowth and spread of cancer cells Proteolysis Metabolism DNA repair III. Starving the Tumor Targeting angiogenesis V. Rejecting the Tumor Cancer immunotherapy

ER+ 65-75% All Breast Cancer HER2+ 15-20% Basaloid 15%

Gene Expression Patterns of Breast Carcinomas Predict Survival ER Gene expression ER Gene expression O.S. A B C D E Basal-like HER2 Subgroup Subgroup = E = D Normal breast like Luminal Subtype C Luminal Subtype B Luminal Subtype A months Adapted from Sorlie et al. PNAS, 2001

Herceptin appears to change the course of HER2+ Breast Cancer (NEJM 2006) Effect of HER2/neu Amplification and Trastuzumab on the Kaplan Meier Estimates of Survival Free of a First Distant Recurrence of Breast Cancer. CI denotes confidence interval. Joensuu et al. 354 (8): 809, Figure 3 NEJM, February 23, 2006

In MBC, Trastuzumab increases survival, but does not provide cure Patients, n 20,000 18,000 16,000 14,000 12,000 10,000 8000 6000 4000 2000 Trastuzumab introduced (adjuvant) No. of patients prevented from developing metastases Incidence of HER2+ MBC following without Trastuzumab introduction of Trastuzumab 27,737 50-60% 1 st line objective response Most eventually progress on therapy 0 2000 2005 2010 2015 Year MBC, metastatic breast cancer Weisgerber-Kriegl et al 2008

MOA of Trastuzumab Anti-signaling - Inhibition of HER2 shedding. - Inactivation of AKT signaling. Engagement of Fc Receptor Binding - Immune Effector Function: ADCC. -Fc R binding and ADCC are not the same. - Hypercross-linking of Cell Surface Receptors. Not necessarily mutually exclusive

Trastuzumab Mechanism of Action There are four distinct mechanisms of action: 1. Activation of antibody-dependent cellular cytotoxicity (ADCC) Trastuzumab HER2 NK cell Release substances Tumor Cell Death 2. Prevention of formation of p95 HER2, a truncated and very active form of HER2 HER2 p95 HER2 Cleaved Metalloproteinase Trastuzumab HER2 3. Inhibition of cell proliferation by preventing HER2-activated intracellular signalling Signalling cell proliferation HER2 No signalling Trastuzumab 4. Inhibition of HER2-regulate angiogenesis tumor tumor Angiogenesis tumor Decreased blood supply Nahta et al. Breast Cancer Res 2006; Clynes et al. Nat Med 2000; Gennari et al. Clin Cancer Res 2004; Arnould et al. Br J Cancer 2006; Molina et al. Cancer Res 2001; Fry et al. Breast Cancer Res 2001; Gershtein et al. Clin Chim Acta 1999; Yakes et al. Cancer Res 2002;Longva et al. Int J Cancer 2005; Izumi et al. Nature 2002; Nahta et al. Breast Cancer Res 2006; Wen et al. Oncogene 2006

Trastuzumab and Pertuzumab: Distinct Epitopes on HER2 Extracellular Domain I I III II Trastuzumab III II Pertuzumab IV IV Potent inhibitor of HER2-mediated signaling pathways Activates antibody-dependent cellular cytotoxicity Prevents receptor dimerization Potent inhibitor of HER-mediated signaling pathways Inhibits shedding and, thus, formation of p95

Pertuzumab: Phase II Results Novel HER2 targeted monoclonal antibody Phase II study of pertuzumab/trastuzumab HER2+ MBC; progression on prior trastuzumab ORR = 24% No significant cardiac events observed Pertuzumab +/ trastuzumab after progression on prior HER2 targeted therapy Combination active in pts with progression on prior trastuzumab and pertuzumab Efficacy Endpoint Pertuzumab (n = 29) Pertuzumab/ Trastuzumab (n = 14) ORR 1 (3%) 3 (21%) CBR 3 (10%) 6 (43%) Baselga et al., J Clin Oncol 2010; 28: 1138 44. Baselga et al. SABCS 2009; abstract 5114.

Phase III Cleopatra Trial Ongoing Eligibility criteria: HER2+ Locally recurrent or MBC No prior chemotherapy or targeted therapy for metastatic disease = 1 prior hormonal therapy for metastatic disease =12 month diseasefree interval since completion of systemic therapy R a n d o m i z e Accrual goal = 800 Trastuzumab 8mg/kg loading, then 6mg/kg q3w + Docetaxel 75 mg/m 2 q3w + Placebo Trastuzumab 8mg/kg loading, then 6mg/kg q3w + Docetaxel 75 mg/m 2 q3w + Pertuzumab 840mg (cycle1), then 420mg q3w 1 endpoint: PFS by independent review

Case again Response in skin nodule on Pertuzumab Developed brain mets in March 2009 and Trastuzumab added back plus brain radiation After 6 months presented with confusion, slowed motor and mental functions. CT changes called central pontine myelinolysis (CMP). Treatment stopped At progression in liver in June 2010 enrolled in clinical trial of TDM 1 vs. Capecitabine + Lapatinib

Phase III Randomized Trial of Capecitabine/Lapatinib vs. Trastuzumab MCC DM1 in HER2 Postive MBC Previously Treated with Trastuzumab T-DM1 3.6mg/kg IV Day 1 Randomize Capecitabine 1000mg/m 2 PO bid, Days 1-14 Lapatinib 1250mg PO daily Both regimens repeated q 21 days

Novel Cytotoxics: Antibody Drug Conjugates Trastuzumab MCC DM1 (T DM1) Binds to HER2 with affinity similar to trastuzumab Provides intracellular delivery of mertansine Derivative of maytansine, a natural-product microtubule polymerization inhibitor 20-100 more potent than vincristine

T-DM1 Selectively Delivers a Highly Toxic Payload to HER2-Positive Tumor Cells UNIQUE DUAL MoAb Trastuzumab-like activity by binding to HER2 Targeted intracellular delivery T-DM1 binds of to a the potent HER2 protein on cancer cells antimicrotubule agent, DM1 Receptor-T-DM1 complex is internalized into HER2- positive cancer cell Potent antimicrotubule agent is released once inside the HER2-positive tumor cell Baselga J, et al. Nat Rev Cancer. 2009;9:463-475.

Phase II Study: TDM4374g Single-agent T-DM1, a novel HER2 directed ADC, demonstrated robust antitumor activity in a predefined population that had a median time from metastatic diagnosis of >3 years and received >2 years of prior HER2-directed therapy: ORR: 32.7% IRF, 30% INV CBR: 44.5% IRF, 40% INV This robust level of activity was seen in an advanced patient population not previously studied: Required prior treatment included an anthracycline, a taxane, capecitabine, trastuzumab, and lapatinib Received 2 HER2-directed regimens in the metastatic setting Progressive disease on last regimen received

T DM1 Clinical Trials for HER2+ MBC Patients Phase I N=52, with 2 schedules of single agent T-DM1 Ph II (pivotal) T-DM1 in patients who progressed on HER2 therapy Randomized Ph II study in the front-line setting* N=120, T-DM1 vs trastuzumab + docetaxel Randomized Phase III N=580, T-DM1 vs lapatinib + capecitabine Exploratory combination trials T-DM1 + pertuzumab, T-DM1 + taxanes Stuart Lutzker, Scott Holden, Barb Klencke

Case again Response in liver, skin, nodes on TDM 1 on study Response ongoing Hemorrhage into eyes secondary to diabetic retinopathy treated with intraocular Bevacizumab

Phase III Trials of Continued HER2 Targeted Therapy in MBC Previously Treated with Trastuzumab TBPTrial a EGF100151 Trial Capecitabine/ Capecitabine/ Capecitabine Capecitabine Trastuzumab Lapatinib (n = 68) (n = 201) (n = 75) (n = 198) 37 (48%) 20 (27%) 24% 14% Overall Response Rate OR 2.50; P =.0115 OR 1.9; P =.017 58 (75%) 40 (54%) 29% 17% Clinical Benefit Rate b OR 2.59; P =.0068 OR 2.0; P =.008 Median Time to Progression Median Overall Survival 8.2 months 5.6 months 6.2 months 4.3 months HR 0.69; P =.0338 HR 0.57; P <.001 25.5 months 20.4 months 15.6 months 15.3 months HR 0.76; P =.2570 HR 0.78; P =.177 a German Breast Group 26/Breast International Group 03-05 trial b CR + PR + SD > 24 weeks for TBP trial; CR + PR + SD 6 months for EGF100151 trial. von Minckwitz et al. J Clin Oncol 2009; 27:1999 2006. Cameron et al. Oncologist Aug 2010 (epub ahead of print).

Lapatinib + Capecitabine vs. Capecitabine Cameron, Casey, Olivia, et al., The Oncologist 2010

Lapatinib + Capecitabine vs. Capecitabine Cameron, Casey, Olivia, et al., The Oncologist 2010

Lapatinib Studies in Patients with CNS Metastases Phase III trial of lapatinib/capecitabine (n = 198) vs. capecitabine alone (n = 201) in MBC: Exploratory analysis of the brain as site of first progression: 2% vs. 6%; P =.045 Small phase II trial of recurrent CNS metastases (n = 39): 2.6% PR; 18% progression free at 16 weeks Phase II trial of recurrent CNS metastases: Geyer et al. J Clin Oncol 2007 26(suppl):40s (abstract 1035). Lin et al. J Clin Oncol 2008; 26:1993 9. Lin et al. Cancer Therapy Res 2009; 15:1452 9.

Clinical Trials of Neratinib in Patients Previously Treated with HER2 Targeted Agents a Intent-to-treat population b ORR for patients who have received prior lapatinib or trastuzumab Burstein et al. J Clin Oncol; February 8, 2010 [e pub ahead of print]. Swaby et al. J Clin Oncol 2009; 27(suppl):42s (abstract 1004). Chow et al. Cancer Res 2009; 69(suppl):792s (abstract 5081).

Trastuzumab disrupts ligand independent HER2 HER3 PI3K complex The oncogenic unit in HER2+ve breast cancer is a complex between HER2-HER3 Junttila et al. Cancer Cell, 2009.

PI3 Kinase Inhibitor: GDC 0941 Inhibition of PI3K by GDC-0941 O S O N N S O N N N N NH Enzyme IC 50 Class 1A: p110 alpha 3 nm p110 alpha E545K 3 nm p110 alpha H1047R 3 nm p110 beta 33 nm p110 delta 3 nm Class 1B: p110 gamma 75 nm Class 1A PI3K Pan inhibitor PIK Family, (>200 fold selectivity) Class II: CIIbeta 0.670 um Class III: VPS34 >10 um Class IV: DNA-PK 1.230 um Class IV: mtor (Ki) 0.580 um Protein Kinase panel >300 fold selectivity against 228 kinase panel Folkes et al. 2008 J Med Chem.

GDC 0941 Overcomes Trastuzumab Resistance Junttila et al. Cancer Cell, 2009.

The Triple Negative Breast Cancer Estrogen Receptor (ER) negative Progesterone receptor (PR) negative Her2neu (HER2) negative ER/PR/HER2 - Basal-Like

Triple Negative Breast Cancers Comprise approximately 15% of all invasive cancers More common in: Younger patients African Americans (up to 60% premenopausal women in Africa) BRCA1 mutation carriers ( up to 80%) Unique Morphologic Attributes Pushing border high grade central scarring/acellular zone Stromal/peritumoral lymphocytic infiltrate

Triple-Negative Tumors are Heterogeneous IDC NOS, high grade ILC high grade, pleomorphic Metaplastic, high grade Myoepithelial carcinoma High grade (oat-cell) neuroendocrine Poor prognosis Apocrine Medullary Adenoid-cystic Metaplastic, low grade low grade adenosquamous fibromatosis-like Good prognosis

Hazard Rate of Distant Recurrence Other (290 of 1421) Triple-negative (61 of 180) Hazard Rate 0.35 0.30 0.25 0.20 0.15 Median Time to Distant Recurrence TN Breast Ca = 2.6 yrs Other Breast Ca = 5 yrs p < 0.0001 0.10 0.05 0.00 0 1 2 3 4 5 6 7 8 9 10 Years after first surgery Dent R, Trudeau M, Pritchard K, Hana W, Narod S. et al. Clinical Cancer Res 2007

Median Time from Distant Relapse to Death Triple Negative Breast CA 9 months Other Breast CA 22 months 0 5 10 15 20 25 Dent R, Trudeau M, Pritchard K, Hana W, Narod S. et al. Clinical Cancer Res 2007

Poor Outcome of Metastatic TNBC (N = 112) Initial therapy Median D.F.I. First distant relapse First Line CT 12 weeks Second Line CT 9 weeks Third Line CT 4 wks F. Kassam, #1121 F. Heitz, #1010 Is RECIST adequate? Higher risk for developing brain mets OR : 4.16 (95% CI 2.26 7.64) Median O.S. = 3.0 months

Patterns of Metastatic Spread Non-productive dry cough But...Bone Marrow infiltration

What is Standard Therapy for Triple Negative Breast Cancer? No specific systemic regimen guidelines exist Little data in which to base decisions Few historical controls making it challenging to design clinical trials for this subgroup

Chemosensitive early TNBC has a favourable Outcome

Taxanes for Metastatic TNBC? Trial Phase N Setting Taxane Outcome in TNBC Harris et al. CALGB 9342 III 44 1 st / 2 nd line Metastatic Paclitaxel Weekly and q3wk ORR = 26% TTF= 2.8 months OS = 8.6 months ECOG 2100 III 10 9 1 st line Metastatic Paclitaxel Weekly ORR = 11.7% PFS = 5.3 months AVADO III 52 1 st line Metastatic Docetaxel q3wk ORR = 23.1% PFS = 8.2 months

Angiogenic Switch and VEGF dependency Small tumour (1 2mm) Avascular Dormant Larger tumour Vascular Metastatic potential Angiogenic switch Over-expression of pro-angiogenic signals, such as VEGF Adapted from Bergers G, et al. Nature 2002;3:401 10

Bevacizumab for TNBC Trial / Arm E2100 Median PFS (mo) in TNBC Subset Paclitaxel (n=110) 5.3 Paclitaxel + bevacizumab (n=122) 10.6 AVADO Docetaxel + placebo (n=52) 5.4 Docetaxel + bevacizumab 15 mg/kg (n=58) 8.2 RIBBON-1 Taxane/anthracycline + placebo (n=46) 6.2 Taxane/anthracycline + bevacizumab (n=96) 6.5 Capecitabine + placebo (n=50) 4.2 Capecitabine + bevacizumab (n=87) 6.1 ATHENA Taxane-based regimen + bevacizumab (n=577) 7.2* *Median PFS vs non-tnbc subgroup. No survival data in TNBC

Bevacizumab Delivers a Consistent PFS Benefit in Patients With Triple Negative Disease RIBBON-1 2 E2100 1 AVADO 2 Capecitabine Taxane/anthracycline Median, months Median, months Median, months Median, months Pac Bev + pac Pla + doc Bev + doc Pla + cap Bev + cap Pla + t/a Overall* n=722 n=488 n=615 n=622 Bev + t/a 5.8 11.3 8.1 10.0 5.7 8.6 8.0 9.2 HR=0.48 HR=0.67 HR=0.69 HR=0.64 Triple- n=232 n=111 n=137 n=142 negative 5.3 10.6 6.1 8.1 4.2 6.1 6.2 6.5 HR=0.49 HR=0.68 HR=0.72 HR=0.78 *Stratified analyses Unstratified analyses 1. O Shaughnessy, et al. SABCS 2009; 2. Glaspy, et al. EBCC 2010

Case #2: MB Treated from April 2008 to September 2008 with excellent clinical and radiological response October 2008 presented with new headaches, MRI shows diffuse brain and leptomeningeal disease Treated with WBR with good response Treated with Cisplatin and Gemcitabine x 8 months with good clinical and radiologic response

TNBC Shares Clinical and Pathologic Features with BRCA 1 Related Breast Cancers Characteristics Hereditary BRCA1 Triple Negative/Basal-Like 1,2,3 ER/PR/HER2 status Negative Negative TP53 status Mutant Mutant BRCA1 status Mutational inactivation* Diminished expression* Gene-expression pattern Basal-like Basal-like Tumor histology Chemosensitivity to DNAdamaging agents Poorly differentiated (high grade) Highly sensitive Poorly differentiated (high grade) Highly sensitive *BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID4 4 1 Perou et al. Nature. 2000; 406:747-752 3 Sorlie et al. Proc Natl Acad Sci U S A 2001;98:10869-74 2 Cleator et al.lancet Oncol 2007;8:235-44 4 Miyoshi et al. Int J Clin Oncol 2008;13:395-400 4

Platinum for Neoadjuvant Therapy in BRCA1 Mutation Carriers in Poland Gronwald et al. ASCO 2009 BRCA1 Mutation Carriers with Tumors >2cm CISPLATIN 75mg/m2 q 3wks IV x 12 wks Clinical and Pathological Response N = 25 median age: 46 28% with clinically positive lymph nodes 22 pts completed 4 cycles of Cisplatin, 3 patients completed 2 cycles. Results Complete PR = 72%

Platinum Agents for TNBC Trial Phase / No. of TNBC pts Setting Regimen Outcome in TNBC Gronwald II (N =25) Neoadjuvant Cisplatin pcr = 72% Sikov (2009) II (n=12) Neoadjuvant Carbo-P vs carbo-p-h pcr=67% Torrisi (2008) II (n=30) Neoadjuvant TNBC E-Cis-F P pcr=40%; ORR=86% Silver (2010) II (n=28) Neoadjuvant TNBC Cis pcr=22% Uhm (2009) II (n=36) Metastatic Carbo-P or Cis-P ORR 37.5%

Reference Regimen n Prior Rx RR TTP OS Nagourney JCO 2000 Burch Am J Oncol 2005 Fuentes Anticancer Drugs 2006 Heinemann Cancer Chemo Pharmacol 2006 Seo Cancer Chemo Pharmacol 2007 Tas Invest New Drugs 2008 Kim Cancer Res Treat 2008 Gem 1 g/m 2 D1,8,15 Cis 30 mg/m2 D1,8,15 Gem 1g/m2 D1,8,15 Cis 25 mg/m2 D1,8,15 Gem 1.2g/m2 D1,8 Cis 75 mg/m2 D1 Gem 750 mg/m2 D1,8, Cis 30 mg/m2 D1,8 Gem 1250 mg/m2 D1, 8 Cis 75 mg/m2 D1 Gem 2 g/m2 D1,8 Cis 50 mg/m2 D1,8 Gem 1 g/m2 D1,8 Cis 60 mg/m2 Chew JCO 2009 Gem 1 g/m2 D2,8 Cis 25 mg/m2 D1 4 Somali Chemotherapy 2009 Gem 1 g/m2 D1, 8 Cis 30 mg/m2 30 ++ 50% 14 weeks 58 Anthra and taxane 29%, then 32%; 31 and 26 weeks 68 and 54 weeks 42 No 81% 15 months 28 months 38 Prior anthra, taxane 40% 6 months 14 months 30 Prior taxane 30% 7 months 15 months 27 Prior anthra, taxane 38 Prior anthra or taxane 26% 7 months 29% 5 months 20 months 136 74 ++ treated 26% 11 and 13 months 31 Prior anthra and taxane 26% 4 months 10 months

PARP inhibitors (PARPi) Single stranded breaks are usually repaired by the base excision repair pathway, of which PARP1 is one of the central components In the absence of this pathway, single stranded breaks degenerate to double stranded breaks, which are not repaired by BRCA null cells In vitro data has shown that inhibition of PARP1 leads to highly selective apoptosis of BRCA1 null cells

Poly(ADP ribose) polymerase (PARP) A key regulator of DNA damage repair processes Involved in DNA base excision repair (BER) Binds directly to DNA damage Produces large branched chains of poly (ADP ribose) Attracts and assists BER repair effectors XRCC1 PNK Polß Lig3

Phase II Trial of Olaparib: Efficacy ITT cohort 400 mg BID N = 27 100 mg BID N = 27 Best percent change from baseline in target lesions by genotype ORR 11 (41%) 6 (22%) CR 1 (4%) 0 PR 10 (37%) 6 (22%) Median PFS 5.7 mo (4.6 7.4) 3.8 mo (1.9 5.6) Tutt A et al. J Clin Oncol 2009; 27(18S):803s (abstr CRA501)

Phase II Trial of Iniparib in TNBC: Study Design Metastatic TNBC N = 120 Multicenter Open label RANDOMIZE 1:1 Gemcitabine (1000 mg/m 2, IV, d 1, 8) Carboplatin (AUC 2, IV, d 1, 8) Iniparib (5.6 mg/kg, IV, d 1, 4, 8, 11) Gemcitabine (1000 mg/m 2, IV, d 1, 8) Carboplatin (AUC 2, IV, d 1, 8) RESTAGING Every 2 Cycles * Patients randomized to gem/carbo alone could crossover to receive gem/carbo + iniparib at disease progression

Phase II Trial of Iniparib: PFS (Data through March 09 Iniparib + Gem/Carbo (n = 57) Median PFS = 6.9 months Gem/Carbo (n = 59) Median PFS = 3.3 months P < 0.0001 HR = 0.342 (95% CI, 0.200-0.584)

Phase II Trial of Iniparib: Overall Survival, ITT (Data through November 2009 Iniparib/Gem/Carbo: median = 12.2 months Gem/Carbo: median = 7.7 months OS, % Months O'Shaughnessy J et al. SABCS 2009. Abstract 3122.

Phase II Study of Olaparib in Advanced Serous Ovarian Cancer and Triple Negative Breast Cancer Efficacy Ovarian Breast (n = 64) (n = 26) ORR in Planned Cohorts BRCA 4/10 (40%) 0/9 (0) Unknown BRCA 14/53 (26%) 0/14 (0) ORR by Actual BRCA Status Mutant BRCA 7/17 (41%) 0/8 (0) Non-BRCA 11/46 (24%) 0/15 (0) Median PFS 219 days 54 days Gelmon et al., J Clin Oncol 2010; 28(suppl):233s (abstract 3002).

Phase I/II Study of Olaparib Plus Paclitaxel for Triple Negative Metastatic Breast Cancer Dose modifications: Cohort 1 (No G-CSF) (n = 9) - Cohort 1: paclitaxel modified in 89%; olaparib modified in 44% - Cohort 2: paclitaxel modified in 60%; olaparib modified in 30% Conclusions: - Olaparib/paclitaxel is active in triple-negative MBC. - Associated neutropenia reduced paclitaxel dose intensity Cohort 2 (G-CSF ) (n = 10) Overall Response Rate 33% 40% Stable Disease = 7 Weeks 33% 40% Median Progression-Free Survival (95% CI) 6.3 (3.5-8.9) months 5.2 (3.5-NC) months Eligibility: = 1 prior cytotoxic regimen Regimen: olaparib 200 mg p.o., b.i.d. paclitaxel 90 mg/m 2 /week 3 of 4 weeks

Phase II Study of Veliparib Plus Temozolomide in Metastatic Breast Cancer: Efficacy Overall Response Rate Total (n = 41) (23 TNBC) BRCA1/2 Mutant (n = 8) BRCA1/2 Normal/Unknown (n = 33) 7% 37.5% 0 Clinical Benefit Rate a 17% 62.5% 6% Median Progression- Free Survival a ORR + stable disease 1.9 months 5.5 months 1.8 months P =.0042 Efficacy appears to be restricted to BRCA1/2 mutation carriers. Further evaluation of this combination is ongoing in BRCA1/2- mutated cancers. Isakoff et al. J Clin Oncol 2010; 28(suppl):118s (abstract 1019).

Development of PARP inhibitors in TNBC Challenges Triple-negative breast cancer Defining triple-negative breast cancers Identifying subset with homologous recombination deficiency What are standards of care for treatment? What should comparators be? Dosing: iv vs po PARP inhibitors Schedule: Intermittent vs continuous Timing: Delivery before, during or after chemotherapy Are they best combined with DNA damaging agent?

Capecitabine for Metastatic TNBC? Trial Phase N Setting Treatment Outcome in TNBC Rugo et al. SABCS 2008 III 208 3 rd line or greater Metastatic Pooled Analysis Capecitabine vs. Cape + Ixabepilone Cape vs. Cape + Ixap ORR = 15 vs. 31% PFS = 1.7 vs. 4.2 mo RIBBON 1 III 50 1 st line Metastatic Capecitabine ORR = 4.2 months

Other Targets for TNBC Target DNA repair pathways Agent/Approach PARP inhibitors (BSI-201, olaparib, AG014699, ABT-888), trabectedin VEGFR-VEGF EGFR Bevacizumab, Sorafenib, IMC113 Erlotinib, Gefinitib, Cetuximab, Panitumumab Angiogenesis Src kinase Checkpoint kinase 1 mtor Androgen receptor TRAIL TGF-beta Endo TAG-1, metronomic chemotherapy Dasatinib UCN-01 RAD001, everolimus, temsirolimus Bicalutamide Lexatumumab GC1008, AP 12009, LY2157299 Androgen receptor Bicalutamide Adapted from Tan and Swain. Cancer Journal. 2008;14.

Treatment Summary for TNBC No standard therapy for metastatic TNBC No evidence that one chemotherapy is superior to another Most active agents currently licensed for use appear to be: Chemotherapy + Bevacizumab Cisplatin based chemotherapy Promising agents likely to be licensed: PARP inhibitors