Strategic use of available agents through multiple lines of therapy for advanced ER/PR-negative disease: A discussion of 9 Things to Know About Metastatic Breast Cancer Beyond 1 st Line Chemotherapy Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA

1. Most women are candidates for multiple lines of therapy

Approximately how many total lines of chemotherapy were received by the last 5 patients you treated who died of metastatic breast cancer (average of the 5 patients)? N Love, Research to Practice, 2008

Line of Therapy Average Weeks on Treatment st2nd3rd4th5th6th7th Overall ER+ HER2+ TN Duration of Chemotherapy for Advanced Breast Cancer Burstein, Litsas 2010 Unpublished data

Line of Therapy Average Weeks on Treatment st2nd3rd4th5th6th7th Overall ER+ HER2+ TN Duration of Chemotherapy for Advanced Breast Cancer Burstein, Litsas 2010 Unpublished data Median # of regimens: 4

2. Tumor biology / tumor subset governs outcomes – Triple negative tumors stand out as having a different trajectory

Line of Therapy Average Weeks on Treatment st2nd3rd4th5th6th7th Overall ER+ HER2+ TN Duration of Chemotherapy for Advanced Breast Cancer Burstein, Litsas 2010 Unpublished data Median # of regimens: 4

Line of Therapy Average Weeks on Treatment st2nd3rd4th5th6th7th Overall ER+ HER2+ TN Duration of Chemotherapy for Advanced Breast Cancer Burstein, Litsas 2010 Unpublished data

Chemotherapy Outcomes in Non-TN vs TN Metastatic Breast Cancer RESPONSE RATES StudyAgentsNon-TNTN CALGB 9342Paclitaxel23%26% E2100Paclitaxel23%22% Pac + Bev54%43% BMSIxabepilone19%17% BMSCapecitabine16%9% Cape + Ixa37%27% TIME TO PROGRESSION CALGB 9342Paclitaxel4.5 m2.8 m E2100Paclitaxel9 m5 m Pac + Bev13 m9 m BMSIxabepilone3.6 m2.7 m BMSCapecitabine5.0 m2.1 m Cape + Ixa7.1 m4.1 m RIBBON2Chemo6.0 m2.8 m Chemo + Bev7.4 m6.5 m

3. Where are we with PARP inhibitors?

Gem/Carbo +/- BSI-201 in Triple Negative Metastatic Breast Cancer MBC Triple Negative Prior Chemo N=120 Gemcitabine 1000 mg/m 2 d 1,8 Carbo AUC 2 d 1,8 Gemcitabine 1000 mg/m2 d 1,8 Carbo AUC 2 d 1,8 BSI mg/kg d 1,4,8, 11 CYCLES EVERY 21 DAYS RESTAGE EVERY 2 CYCLES O’Shaugnessy et al, ASC0 2009

Chemotherapy+/- iniparib for triple-negative breast cancer: phase II O'Shaughnessy J et al. N Engl J Med 2011;364:

Iniparib Data Oral Presentation vs Publication Results EndpointVenueGC aloneGC + BSI201 Response rateASCO ’0916%48% NEJM ‘1132%52% PFSASCO ’093.3 m6.9 m NEJM ‘113.6 m5.9 m OSASCO ’095.7 m9.2 m NEJM ’117.7 m12.3 m

Gem/Carbo (GC) (N= 258) Gemcitabine 1000 mg/m 2 IV d 1, 8 Carboplatin AUC2 IV d 1, 8 21-day cycles Gem/Carbo + Iniparib (GCI) (N= 261) Gemcitabine mg/m2 IV d 1, 8 Carboplatin - AUC2 IV d 1, 8 Iniparib mg/kg IV d 1,4,8,11 21-day cycles R Study Population: Stage IV TNBC ECOG PS 0–1 Stable CNS metastases allowed 0-2 prior chemotherapies for mTNBC Randomization stratified by prior chemo in the metastatic setting: 1 st - line (no prior therapy) 2 nd /3 rd -line (1-2 prior therapies) Study Design: Multi-center, randomized open-label Phase III Trial Schema Crossover allowed to GCI following Disease Progression* (central review) N = 519 * Prospective central radiology review of progression required prior to crossover 96% (n=152) of progressing patients crossed over to GCI at time of primary analysis NCT

Months Since Study Entry Probability of Progression Free Survival No. at risk GC GCI No. at risk GC GCI Efficacy Endpoints – ITT population Probability of Survival Months Pre-specified alpha = 0.04 PFS GC (N=258) GCI (N=261) Median PFS, mos (95% CI) 4.1 (3.1, 4.6) 5.1 (4.2, 5.8) HR (95% CI)0.79 (0.65, 0.98) p-value0.027 Pre-specified alpha = 0.01 OS GC (N=258) GCI (N=261) Median OS, mos (95% CI) 11.1 (9.2, 12.1) 11.8 (10.6, 12.9) HR (95% CI)0.88 (0.69, 1.12) p-value0.28

Overall Response Rate* – ITT Population Response, n (%) GC N = 258 GCI N = 261 Complete response 4 (1.6)5 (1.9) Partial response74(29)83 (32) Stable disease89 (35)99 (38) Progressive disease62 (24) Inevaluable29 (11)12 (4.6) SD > 6 months14 (5.4)19 (7.3) ORR, n (%) (95% CI) 78 (30) (25 ‒ 36%) 88 (34) (28 ‒ 40%) Clinical Benefit Rate, n (%) [CR +PR +SD(> 6 mos)] 92 (36)107 (41) 17 * Independent central review, RECIST confirmation of response

What’s going on? Not all exploratory studies stand up to validation in larger experience Iniparib probably is NOT a PARP inhibitor

What’s going on? Not all exploratory studies stand up to validation in larger experience Iniparib probably is NOT a PARP inhibitor That is to say, inadequate preliminary science

4. What are the real goals of treatment for refractory disease?

Goals of Chemotherapy for Advanced Breast Cancer Relieve symptoms associated with advanced cancer, such as pain, fatigue, or dyspnea Prevent symptomatic progression of tumor Prolong survival Enhance quality of life To make advanced breast cancer a “chronic” condition

Does Chemotherapy Palliate Refractory Breast Cancer?  3rd line chemotherapy:  30% had improvement in emotional status  34% had major improvement in HRQL scores  6% had objective clinical response  Tumor response correlated with more energy, diminished distress, and functional improvement  Not all “benefit” was seen in responders, and not all “responders” benefit McLachlan SA, Pintilie M, Tannock IF. Breast Cancer Res Treatment 1999;54:213

Cumulative Incidence of Adverse Symptom Events over Time as Reported by Patients versus Clinicians at Successive Office Visits. Basch E. N Engl J Med 2010;362: Clinical teams under-report symptoms relative to patients Survey of consecutive office visits among 467 cancer patients at MSKCC

Trade-offs Cancer-related symptoms Benefits of chemotherapy Side effects of chemotherapy, especially chronic side effects (fatigue, neuropathy, GI discomfort) The tyranny of the infusion room The hope that comes with doing something

5. There are a lot of choices once you get beyond 1 st or 2 nd line, but there really aren’t much data

AuthorAgentPrior TherapyRRTTP ATC Blum JCO 1999 Capecitabine ✓✓ 20%3m Miller JCO 2005 Capecitabine ✓✓ 19%4m Thomas JCO 2007 Capecitabine ± Ixabepilone ✓✓ 14% 35% 4.2m 5.8m Geyer NEJM 2006 Capecitabine ± Lapatinib ✓✓ 14% 22% 4.3m 5.9 m Perez JCO 2007 Ixabepilone ✓✓✓ 11%3m O’Shaughnessy CBC 2005 Pemetrexed ✓✓✓ 8%2.9m Krop SABCS 09 T-DM1 *HER2+ only ✓✓✓ 32%7.3m Chemotherapy Outcomes in Refractory Breast Cancer

Typical Clinical Outcomes with Single-agent Chemotherapy for Advanced Breast Cancer Response rateTime to Progression 1 st line25 to 45%5 to 8 m 2 nd line15 to 30%2 to 5 m 3 rd line0 to 20%1 to 4 m 4 th lineFew data 5 th lineFewer data 6 th line etcNo data

6. Newer options: ixabepilone

Overview: Mechanism of action of microtubule-targeting drugs DestabilizersStabilizers  Polymerization  Polymerization Vinca alkaloids / eribulin Taxanes / epothilones

Ixabepilone: Epothilone B Analog Furthest developed agent in a new class of antineoplastics, the epothilones Epothilones bind to microtubules resulting in polymerization and apoptosis Novel microtubule-stabilizing agent with tubulin- binding mode distinct from other agents S.cellulosumEpothilone BIxabepilone Lee JJ, Swain SM. Semin Oncol. 2005;32(suppl 7):S22-S26; Kamath K et al. J Biol Chem. 2005;280: ; Mozzetti S et al. Clin Cancer Res. 2005;11:

Ixabepilone in MBC: Summary of Single-Agent Phase II Trials 1. Roche H et al. J Clin Oncol. 2007;23: Low et al. J Clin Oncol 2005;23:2726– Denduluri N et al. J Clin Oncol. 2007;23: Thomas E et al. J Clin Oncol. 2007;23: After Adjuvant Anthracycline 1 (40 mg/m 2 q3w) Taxane Naïve MBC 2 (6 mg/m 2 daily X 5) Taxane Pretreated MBC 3 (6 mg/m 2 daily X 5) Taxane Resistant MBC 4 (40 mg/m 2 q3w) Percentage (%) SD RR N=65N=23N=37N=49

. Thomas E S et al. JCO 2007;25: ©2007 by American Society of Clinical Oncology Capecitabine +/- ixabepilone after anthracyclines and taxanes

Time to resolution of neuropathy Thomas E S et al. JCO 2007;25: ©2007 by American Society of Clinical Oncology

. Perez E A et al. JCO 2007;25: ©2007 by American Society of Clinical Oncology Ixabepilone After Anthracyclines, Taxanes and Capecitabine

Perez E A et al. JCO 2007;25: ©2007 by American Society of Clinical Oncology

Capecitabine ± Ixabepilone in Triple Negative MBC Rugo H, et al. SABCS Abstract Pooled triple negative subgroup (n = 443) EfficacyIxa + Cape (n = 191) Cape (n = 208) ORR31%15% CR3%1% PR28%14% Median PFS4.2 mo1.7 mo HR0.63 P value< Median OS10.3 mos (n = 213) 9.0 mos (n = 230) HR0.87 P value0.18 Selected Grade 3/4 AEs Ixa + Cape (n = 209) Cape (n = 226) Neutropenia70%8% Febrile neutropenia 4%< 1% Leukopenia63%5% Peripheral neuropathy 23%< 1% Hand-foot syndrome 14%16% Fatigue11%3% 37

7. New options: eribulin

Eribulin mesylate (E7389) Synthetic analogue of halichondrin B Binds to unique site on tubulin –Suppresses microtubule polymerization –Sequesters tubulin into nonfunctional aggregates –Creates irreversible mitotic block Inhibition of breast cancer cell line growth in vitro Jordan M A et al. Mol Cancer Ther 2005;4: MCF7

Vahdat, L. T. et al. J Clin Oncol; 27: Eribulin: Phase II Results in A- and T-Treated MBC Dosing 1.4 mg/m 2 days 1, 8, 15 q28d or days 1,8 q21 days Response rate (n=103) Overall 11% ER+ 15% TN 7% HER2+ 8% Grade 3 or 4 side effects neutropenia 64% febrile neutropenia4% fatigue 5% neuropathy5%

Locally recurrent or MBC 2-5 prior chemotherapies Progression ≤6 months of last chemotherapy Neuropathy ≤grade 2 ECOG ≤2 Eribulin mesylate 1.4 mg/m 2, 2-5 min IV Day 1, 8 q21 days Treatment of Physician’s Choice (TPC) Any monotherapy (chemotherapy, hormonal, biological)* or supportive care only † Randomization 2:1 PFS ORR Safety Overall survival Primary endpoint Secondary endpoints EMBRACE study design Stratification: –Geographical region, prior capecitabine, HER2/neu status Global, randomized, open-label Phase III trial (Study 305) Patients (N=762) −≥2 for advanced disease −Prior anthracycline and taxane * Approved for treatment of cancer †Or palliative treatment or radiotherapy administered according to local practice, if applicable ECOG, Eastern Cooperative Oncology Group; IV, intravenous; PFS, progression-free survival; HER2/neu, human epidermal growth factor receptor 2

EMBRACE Trial OSPFS RR: Eribulin 12%, TPC 5% Cortest, et al. 2011:377;

7. Angiogenesis inhibition in TN BC

Progression-free Survival Overall Survival Miller K et al. N Engl J Med 2007;357: Response Rates Paclitaxel Paclitaxel + Bevacizumab P Value All patients14.2%28.2%< Measurable disease 9.1%10.97%<0.0001

E2100: Bevacizumab and Triple Negative Breast Cancer TumorNo.PFS (median; months) Response Rate (%) PacPac + Bev HRPacPac + Bev ER- PR %43% ER+ PR %54% ER+ PR KD Miller, et al. NEJM 2007

RIBBON-2 trial design Taxane (paclitaxel 90 mg/m 2 d1, 8, 15 q4w or paclitaxel 175 mg/m 2, nab-paclitaxel 260 mg/m 2, or docetaxel 75–100 mg/m 2 q3w) Gemcitabine (1250 mg/m 2 d1, 8 q3w) Capecitabine (1000 mg/m 2 bid d1–14 q3w) Vinorelbine (30 mg/m 2 d1, 8, 15 q3w) BEV or PLA (15 mg/kg q3w or 10 mg/kg q2w, depending on CT regimen) Stratification factors: CT regimen; interval from LR/MBC diagnosis to 1st progression; ER and PgR status Investigator’s choice of chemotherapy Taxane or gemcitabine or capecitabine or vinorelbine Treat to disease progression; crossover after progression permitted BEV + CT PLA + CT HER2-negative LR/mBC, one prior line of CT, no prior anti-VEGF therapy (n=684) R 2:1 ER = estrogen receptor; PgR = progesterone receptor; PLA = placebo; R = randomization

Summary of efficacy in RIBBON-2 (all patients) Brufsky et al. SABCS 2009 EndpointBEV + CT (n=459) PLA + CT (n=225) Median PFS, months PFS hazard ratio (95% CI) a Log-rank test 0.78 (0.64–0.93) p= Median overall survival (OS), months OS hazard ratio (95% CI), preliminary analysis a 0.90 (0.71–1.14) Log-rank test a p= year OS rate, % ORR, %4030 Mantel–Haenszel test a,b p= a Stratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression, ER/PgR receptor status) b Not significant at prespecified α=0.01

Baseline characteristics Characteristic TNBC populationAll patients BEV + CT (n=112) PLA + CT (n=47) BEV + CT (n=459) PLA + CT (n=225) Median age, years (range)55 (28–86)49 (33–79)55 (25–86)55 (23–90) Age <40 years, %91399 Measurable disease, % Metastatic sites, % ≥ Visceral Interval from LR/MBC diagnosis to 1st progression <6 months, % CT partner, % Taxane Gemcitabine Capecitabine1621 Vinorelbine

No. at risk: BEV + CT Placebo + CT TNBC population: PFS PFS BEV + CT (n=112) PLA + CT (n=47) Events, n (%)94 (84)42 (89) Median, months HR a (95% CI) Log-rank test (0.33–0.74) p= Time (months) a Stratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression) Estimated probability

No. at risk: BEV + CT Placebo + CT TNBC population: Interim OS OS BEV + CT (n=112) PLA + CT (n=47) Events, n (%)52 (46)29 (62) Median, months HR a (95% CI) Log-rank test (0.39–1.007) p= Estimated probability a Stratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression) Time (months)

TNBC population: ORR a Patients (%) BEV + CT (n=112) PLA + CT (n=47) 41 (95% CI 31–51) 18 (95% CI 8–34) Difference: 23% (95% CI 7–39%) p= a Stratified analysis (CT regimen, interval from LR/MBC diagnosis to 1st progression)

8. Other targets for TN BC

Triple-Negative Breast Cancers: Potential Therapeutic Targets Cell Cycle Transcriptional Control MAP Kinase PathwayAkt Pathway EGFR Tyrosine Kinase C-KIT tyrosine kinase Cell Death After Cleator S et al. Lancet Oncol. 2006:8: DNA Repair pathways Anti- Angiogenesis Cetuximab Dasatinib Sunitinib PARP inhibitors; Trabectedin Bevacizumab MAPK inhibitors; NOTCH inhibitors

EGFR Inhibitors in Breast Cancer In unselected metastatic breast cancer, single agent EGFR inhibitors have not shown great activity: Phase II ZD1839 (Robertson) 2/27 PR 6/27 SD Phase II ZD1839 (Baselga) 0/31 PR 12/31 SD Phase II OSI-774 (Dickler, Winer) 1/69 PR 3/69 SD Phase II ZD1839 (Albain) 1/63 PR 7/63 SD Summary RR: 2%

Cetuximab in Triple Negative MBC: Clinical Efficacy Carey. SABCS (abstr 307). Best Response Cetuximab Alone (n=31) CR0 PR2 (6%) SD5 (16%) Clinical Benefit3 (105)

Cisplatin For Advanced Breast Cancer AuthorSledge, et al. JCO 1988;6:1811 Kolaric, et al. Can Chem Pharm 1983;11:108 Martino, et al. J Can Res Clin Onc 1984;108:354 Forastriere, et al. Am J Clin Onc 1982:5:243 No. Patients Line of therapy1st refractory Dose / schedule and Responses 30 mg/m2 d mg/m2 d of mg/m2 q3 0 of 18 47%54% ER+ 1 of 7 ER - 5 of mg/m2 2 of mg/m2 q3 4 of 19

Platinum & EGFR Inhibition in Triple-negative Breast Cancer TBCRC01: Carey LA, et al. ASCO 2008 BALI-1: Baselga et al. SABCS 2010

9. Caring for patients with refractory MBC is where you practice the art of medicine