Beyond Second-Line Treatment for Metastatic Breast Cancer

Transcription

1 Expert Review in Metastatic Breast Cancer: Beyond Second-Line Treatment for Metastatic Breast Cancer Reference Slide Deck

2 Natural History of Advanced Breast Cancer

3 Breast Cancer Statistics Approximately 235,000 new cases diagnosed in ,000 deaths attributed to breast cancer Leading New Cancer Cases and Deaths Male Prostate 238,590 (28%) Lung 118,080 (14%) Colon & rectum 73,680 (9%) Urinary bladder 54,610 (6%) Melanoma of the skin 45,060 (5%) Non-Hodgkin lymphoma 37,600 (4%) Oral cavity & pharynx 29,880 (3%) Leukemia 27,880 (3%) Pancreas 22,740 (3%) All sites 854,790 (100%) Estimated New Cases* Female Breast 232,340 (29%) Lung & bronchus 110,110 (14%) Colon & rectum 69,140 (9%) Uterine corpus 49,310 (6%) Thyroid 45,560 (6%) Non-Hodgkin lymphoma 32,140 (4%) Melanoma of the skin 31,630 (4%) Kidney & renal pelvis 24,720 (3%) Pancreas 22,480 (3%) Ovary 22,240 (3%) All sites 805,500 (100%) Estimated Deaths Male Female Lung & bronchus Lung & bronchus 87,260 (28%) 72,220 (26%) Prostate Breast 29,720 (10%) 39,620 (14%) Colon & rectum Colon & rectum 26,300 (9%) 24,530 (9%) Pancreas Pancreas 19,480 (6%) 18,980 (6%) Liver & intrahepatic bile duct Ovary 14,890 (5%) 14,030 (6%) Leukemia Leukemia 13,660 (4%) 10,060 (4%) Esophagus Non-Hodgkin lymphoma 12,220 (4%) 8,430 (4%) Urinary bladder Uterine corpus 10,820 (34%) 8,190 (3%) Non-Hodgkin lymphoma Liver & intrahepatic bile duct 10,590 (3%) 6,780 (3%) Kidney & renal pelvis Brain & other nervous system 8,780 (3%) 6,150 (3%) All sites All sites 306,920 (100%) 273,430 (100%) *Excludes basal and squamous cell skin cancers and in situ carcinoma except urinary bladder. American Cancer Society. Cancer Facts & Figures Atlanta: American Cancer Society; 2015.

4 Overall Survival From Time of Breast Cancer Recurrence Advanced Breast Cancer: Are Outcomes Improving? Time, months There have been gains in the survival of patients with metastatic breast cancer (MBC) over the past several decades, but it remains an incurable disease Giordano S, et al. Cancer. 2004;100(1):44-52.

5 Goals of Treatment of Advanced Breast Cancer (ABC) RESPONSE / SURVIVAL QUALITY OF LIFE Live longer Prolong survival EQUILIBRIUM Live better Symptom palliation or delay Favorable tradeoff profile Toxicity Convenience Cost

6 Goals of Therapy Patient Goals Extend survival Minimize toxicity Hair loss Fatigue Maximize QOL IV access Frequency of visits Clinical Trial Endpoints / Outcomes Response rate (RR) Response duration TTP / TTF / PFS OS QOL Safety IV, intravenous; OS, overall survival; PFS, progression-free survival; QOL, quality of life; TTF, time to treatment failure; TTP, time to progression

7 Stan Teich. The Art of Medicine Chemotherapy for MBC: Oncology Pathways

8 The Complexity of a Tailored Treatment Choice in ABC Disease Characteristics Disease burden (visceral vs nonvisceral) Prior therapies and response Aggressiveness of disease ER/PgR, HER2 receptor status Disease-free interval HETEROGENEOUS Guidelines Vague Choice of Treatment Available Options Numerous Patient Characteristics Patient preference (eg, oral vs IV treatment) Performance status Age, comorbidities Menopausal status ER, estrogen receptor; PgR, progesterone receptor

9 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ): Breast Cancer. Version Available at: Accessed February 17, NCCN Recommended Single Agents for Advanced Breast Cancer Preferred Single Agents Anthracyclines Taxanes Antimetabolites Doxorubicin Pegylated liposomal doxorubicin Other Single Agents Cyclophosphamide Carboplatin Cisplatin Ixabepilone Paclitaxel Docetaxel Albumin-bound paclitaxel Epirubicin Etoposide (PO) 5-Fluorouracil Mitoxantrone Capecitabine Gemcitabine Other Microtubule Inhibitors Vinorelbine Eribulin

10 NCCN Recommended Combination Therapy for Advanced Breast Cancer Preferred Chemotherapy Combinations CAF/FAC (cyclophosphamide doxorubicin/fluorouracil) FEC AC (fluorouracil/epirubicin/ cyclophosphamide) (doxorubicin/ cyclophosphamide) AT (doxorubicin/docetaxel; doxorubicin/paclitaxel) CMF (cyclophosphamide/ methotrexate/fluorouracil) Docetaxel/capecitabine GT (gemcitabine/paclitaxel) EC (epirubicin/ cyclophosphamide) Other Combinations Ixabepilone + capecitabine National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ): Breast Cancer. Version Available at: Accessed NCCN Clinical February Practice 17, Guidelines in Oncology. Breast Cancer. V ;BINV-O:1.

11 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ): Breast Cancer. Version Available at: Accessed February 17, 2016.

12 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ): Breast Cancer. Version Available at: Accessed February 17, 2016.

13 International Consensus Guidelines for ABC Sequential monotherapy is the preferred choice in advanced disease in absence of: Rapid clinical progression Life-threatening visceral metastases Need for rapid symptom and/or disease control Usually each regimen should be given until progression of disease or unacceptable toxicity (unacceptable should be defined together with the patient) Cardoso F, et al. Ann Oncol. 2014;25(10): Cardoso F, et al. Breast. 2014;23(5):

14 DeVita VT Jr, et al, eds. Cancer, Principles & Practice of Oncology, 9th ed. Philadelphia: Lippincott- Raven Publishers; 1997, p Likelihood of Response by Extent of Prior Treatment Probability of Response by Line of Therapy 70% 60% 50% 40% 30% 20% 10% 0% Number of Prior Regimens Probability of Response patients who benefit from chemotherapy (in the metastatic setting) may be treated successfully with other regimens at the time of progression. However, the chance of response decreases by about half with each subsequent treatment.

15 Agent Choice of Chemotherapy by Line of Therapy 1 st Line N = nd Line N = rd Line N = th Line N = 1059 Paclitaxel 26% 28% 22% 18% Capecitabine 22% 18% 16% 16% Trastuzumab 20% 19% 19% 19% Docetaxel 17% 13% 8% 6% Doxorubicin 11% 6% 7% 9% Bevacizumab 10% 14% 18% 18% Gemcitabine 10% 16% 19% 19% Carboplatin 9% 8% 8% 7% Vinorelbine 7% 12% 14% 14% Lapatinib NR NR 6% 8% *End date of follow-up period = March 31, 2010 or disenrollment from eligible health plan Ray S, et al. 2013;2(2):

16 Typical Clinical Outcomes With Single-Agent Chemotherapy for ABC Response Rate Time to Progression 1 st line 25% to 45% 5 months to 8 months 2 nd line 15% to 30% 2 months to 5 months 3 rd line 0% to 20% 1 months to 4 months 4 th line Few data 5 th line Fewer data 6 th line etc No data

17 Chemotherapy for ABC: Duration of Chemotherapy Treatment by Tumor Subtype and Line of Therapy Single center experience at Dana-Farber Cancer Institute Seah DS, et al. J Natl Compr Canc Netw. 2014;12(1):71-80.

18 Treatment Options in Anthracycline and Taxane Pretreated Patients With HER2-Negative ABC

19 Treatment After Taxanes: Resistance, Refractoriness, and Toxicity Limits Refractory Resistant Treated = progression on agent = progression or recurrence shortly (<12 months) after exposure = received in past Treatment limiting toxicity issues: Neuropathy Hypersensitivity

20 Capecitabine Following Anthracycline-Based and Taxane-Based Chemotherapy and 1-2 Lines Prior Chemo for MBC Response rates: 9% to 19% Miller KD, et al. J Clin Oncol. 2005;23(4):

21 Eribulin Monotherapy Versus Treatment of Physician's Choice (EMBRACE) Median prior chemo: 3 to 4 regimens Prior A 100% Prior T 100% Prior C 73% Endpoint Eribulin TPC OS 13.1 months 10.6 months PFS 3.7 months 2.2 months RR 13% 5% Cortes J, et al. Lancet. 2011;377(9769):

22 Eribulin Mesylate Versus Capecitabine in Patients Previously Treated With an Anthracycline and a Taxane Response rates: E = 11%, C = 11.5% Kaufman PA, et al. J Clin Oncol. 2015;33(6):

23 Chemotherapy After Anthracyclines and Taxanes for ABC Results in older trials affected by heterogeneity in treatment and tumor subsets Outcomes for refractory, HER2 negative/er positive or triplenegative breast cancer (TNBC) remain poor TTP tends to be shorter in TNBC than refractory, ER-positive disease, reflecting the arc of natural history of these tumors Multiple agents available and utilized Single-agent therapy is the clinical standard In routine practice, cumulative fatigue and neuropathy remain the treatment-limiting toxicities True clinical benefit beyond third-line or fourth-line chemotherapy is not well characterized Central nervous system (CNS) metastases are a more common problem now that patients are generally living longer

24 Ixabepilone in ABC: Who? What? When?

25 Overview: Mechanisms of Action of Vinca Alkaloids and Taxanes Vinca alkaloids Taxanes/epothilones Destabilizers Stabilizers Polymerization Mitotic spindle formation blocked Polymerization MT bundling multipolar spindles

26 Epothilones: New Antitubulins Structurally unrelated to the taxanes Binding site on B tubulin differs from taxanes Epothilones appear to possess several advantages over paclitaxel Avoid development of resistance Have greater polymerizing activity than paclitaxel Ixabepilone active against various taxane-sensitive and taxane-resistant cell lines Produced by Sorangium cellulosum More potent polymerizing agents compared to taxanes Giannakakou P, et al. Proc Natl Acad Sci U S A. 2000;97(6): Computer model of beta-tubulin mutations Taxane Epothilone

27 1. Thomas E, et al. J Clin Oncol. 2007;25(23): Low JA, et al. J Clin Oncol. 2005;23(12): Perez EA, et al. J Clin Oncol. 2007;25(23): Thomas ES, et al. J Clin Oncol. 2007;25(33): Roché H, et al. Proc Am Soc Clin Oncol. 2002;21:Abstract Denduluri N, et al. J Clin Oncol. 2007;25(23): Roché H, et al. J Clin Oncol. 2007;25(23): Moulder et al. Breast Cancer Res Treat. 2007;106(Suppl 1): Abstract Ixabepilone Studies in Taxane-Naïve or Pretreated MBC: Response Rate 75 ORR, % TTP 5.7 mo Thomas 1 Multi Low 2 T Perez 3 Triple Res Thomas 4 A/T Roché 5 A Denduluri 6 Roché 7 Moulder 8 Roché 5 Taxane Pretreated Taxane-Naïve Ixabepilone Ixabepilone + Capecitabine

28 Capecitabine ± Ixabepilone in Anthracyclineand Taxane-Resistant, Locally-Advanced (LA) or MBC: Study Design Median 5 treatment cycles MBC / LA Anthracycline pre-treated / resistant + taxaneresistant (n=752) Resistance: Progression/recurrence: (Neo)adjuvant: <6 months anthracycline, <12 months taxane Metastatic: <3 months anthracycline, <4 months taxane Capecitabine 2500 mg/m 2 d1-14, q3w Capecitabine 2000 mg/m 2 d1-14, q3w + ixabepilone 40 mg/m 2 d1, q3w Primary Endpoint: PFS Secondary Endpoints: Tumor response rate, time to response, duration of overall response, OS, safety, patient symptoms Thomas ES, et al. J Clin Oncol. 2007;25(33):

29 Capecitabine ± Ixabepilone in Anthracyclineand Taxane-Resistant, Locally-Advanced (LA) or MBC: PFS Kaplan-Meier PFS Curve Proportion Not Progressed p= months vs 4.2 months P =.0003 HR 0.75 ( ) Time, months Capecitabine + ixabepilone (310 events/375 patients; median TTP, 5.8 months) Capecitabine (329 events/377 patients; median TTP, 4.2 months) Efficacy maintained despite dose reduction, in elderly, and in early relapse Thomas ES, et al. J Clin Oncol. 2007;25(33):

30 Capecitabine +/- Ixabepilone: Response and Toxicity Response rates 14.3% vs 34.7% (p<0.0001) Time to response 12 weeks Duration of response 5.6 months vs 6.4 months No difference in OS Toxicity (grade 3/4) Peripheral neuropathy: 0/0 vs 22/0.8 Hand foot syndrome: 17/0 vs 18/0 Neutropenia: 9/2 vs 32/36 Hepatic metabolism Thomas ES, et al. J Clin Oncol. 2007;25(33):

31 Capecitabine ± Ixabepilone in Anthracyclineand Taxane-Resistant, Locally-Advanced or MBC: PFS by Subgroup 12 Capecitabine Capecitabine + ixabepilone Median PFS, months HR = 0.75 HR = 0.68 HR = 0.74 HR = 0.69 HR = 0.65 HR = n= 377 / / / / / / 202 All TN NTN HER2(+) ER(+) ER(-) TN, triple-negative; NTN, not TN Rugo H, et al. Breast Cancer Res Treat. 2007;106(Suppl 1): Abstract Pivot X, et al. J Clin Oncol. 2007;25(18S): Abstract 221.

32 Capecitabine ± Ixabepilone in TN MBC Pooled TN subgroup (n = 443) Efficacy Ixa + Cape (n = 191) Cape (n = 208) ORR 31% 15% CR 3% 1% PR 28% 14% Median PFS 4.2 months 1.7 months HR 0.63 P value <.0001 Median OS 10.3 months (n = 213) HR 0.87 P value months (n = 230) Selected Grade 3/4 AEs Ixa + Cape (n = 209) Cape (n = 226) Neutropenia 70% 8% Febrile neutropenia 4% <1% Leukopenia 63% 5% Peripheral neuropathy Hand-foot syndrome 23% <1% 14% 16% Fatigue 11% 3% AE, adverse event Rugo H, et al. Cancer Res. 2009;69(Suppl 2): Abstract 3057.

33 Smith JW 2 nd, et al. Breast Cancer Res Treat. 2013;142(2): Fountzilas G, et al. PLoS One. 2013;8(7):e Tolaney SM, et al. Ann Oncol. 2013;24(7): Roché H, et al. Clin Breast Cancer. 2012;12(3): Additional Studies in MBC Weekly versus every 3 weeks 171 patients; 16 mg/m 2 vs 40 mg/m 2 6-month PFS: 28.6% vs 42.7% (P =.03) Median PFS: 2.9 months vs 5.3 months (P =.05) More grade 3/4 neutropenia (6.1% v 38.2%) and withdrawal due to AE in the q3 week arm Higher-dose weekly therapy (20 mg/m 2 ) Associated with 27% (vs 12%) grade 3/4 sensory neuropathy With epirubicin (MTD 30 plus 75 mg/m 2 q3 wks) With trastuzumab in HER2+ 39 patients ORR 44%; grade 2 neuropathy 56%

34 Yardley D, et al. J Clin Oncol. 2015;33(suppl): Abstract Clavarezza M, et al. Oncologist. 2013;18(8): Gonzalez Angulo AM, et al. Clin Breast Cancer. 2015;15(5): Yardley DA, et al. Breast Cancer Res Treat. 2015;154(2): Saura C, et al. Oncologist. 2013;18(7): Studies in Early-Stage Disease Titan: Adjuvant AC followed by ixabepilone vs weekly paclitaxel in TNBC 614 patients randomized No difference in disease-free survival (DFS) or OS Neoadjuvant dose-dense FEC followed by dose dense ixabepilone pcr in 38% (16/42) 47.8% (11/23) in HR Not feasible: One toxic death, significant toxicity Residual disease after neoadjuvant therapy 43 patients, trial stopped early due to toxicity No efficacy signal Neoadjuvant ixabepilone plus cyclophosphamide x 6 pcr 27/161 (17%); 26% in TNBC βiii tubulin+ predicted response to both ixabepilone and paclitaxel

35 Novel Ixabepilone Combinations Combination chemotherapy partners Approved in combination with capecitabine Has been evaluated with bevacizumab, cetuximab (30% vs 35.9%), trastuzumab (RR 44%), sorafenib Chemotherapy combinations are challenging Overlapping toxicities and identifying meaningful endpoints Sequential chemotherapy strategies Target breast cancer subgroups Explorations in TNBC Immunotherapy checkpoint inhibitor combinations Combinations with androgen receptor agents, FGFR, PI3K, HDAC, PARP, CDK 4/6 Tredan O, et al. Clin Breast Cancer. 2015;15(1):8-15. Tolaney SM, et al. Ann Oncol. 2013;24(7):

36 Ixabepilone Efficacy by Disease Stage and Degree of Resistance ORR, % A/T Multi T T-Naïve Median Response Duration, months 12 Ixabepilone + Capecitabine A/T Multi T T-Naïve Ixabepilone A/T, anthracycline- / taxane-resistant; Multi, multi-resistant, T, taxane-resistant, T-naïve, taxane-naïve Fumoleau P, et al. Eur J Cancer Suppl. 2007;5(4): Abstract 2119.

37 Principal dose-limiting toxicities Neutropenia (grade 3/4 50%), febrile 5% Anemia, thrombocytopenia (grade 3/4 8%) Peripheral neuropathy (grade 3/4 14% to 25%) Fatigue (grade 3/4 15%) Ixabepilone Adverse Event Profile Managed by dose reductions, schedule modifications, pharmacologically (growth factor support, tricyclics, methylphenidate) Safety prolife similar to other microtubule agents Eribulin (grade 3/4 neutropenia 57%, neuropathy 8%) Ixabepilone [prescribing information]. Princeton, NJ: R-Pharm US, LLC; Eribulin mesylate [prescribing information]. Woodcliff Lake, NJ: Eisai Inc; 2016.

38 Chemotherapy-Induced Neuropathy Peripheral neuropathy this can be significant and dose limiting General population prevalence is 2% to 3%, 50% to 60% in diabetics Affects about 38% of patients getting specific neurotoxic drugs and combinations Combinations with taxanes and platinums have highest risk Vinca alkaloids, bortezomib Sensory, motor, or autonomic Interferes with ability to perform Limits ability to deliver therapy Comorbid conditions, prior therapies Predictive testing, recovery, prognostic significance Hershman DL, et al. J Clin Oncol. 2014;32(18):

39 Chemotherapy-Induced Peripheral Neuropathy Chemotherapy-induced peripheral neuropathy (CIPN) is distinguished by symmetric, distal, length dependent glove and stocking distribution Longest nerves/axons are first affected Predominately sensory rather than motor Sensory axonal damage with reduced amplitude of sensory nerve action potentials Motor function remains unchanged in most cases Fibers are differentially sensitive to neurotoxic effects of chemotherapy Hershman DL, et al. J Clin Oncol. 2014;32(18):

40 Mechanisms Oxidative stress Demyelination Cytokine mediated inflammation Sodium ion channel dysfunction Damage to dorsal root ganglion?genetics factors genetic polymorphisms Diagnosing and grading of CIPN is not uniform

41 No Real Prevention Agents Prevention Glutathione Amifostine Org 2766 N-acetylcysteine Calcium/magnesium infusions B vitamins and vitamin E Treatment Duloxetine Alpha-lipoic acid, acetyl-l-carnitine, nimodipine Capsaicin topical Hershman DL, et al. J Clin Oncol. 2014;32(18):

42 1. Vahdat L, et al. Breast Cancer Res Treat. 2013;140(2): Sparano J, et al. J Clin Oncol. 2010;28(20): Rugo H, et al. J Clin Oncol. 2015;33(21): Fountzilas G, et al. PLoS One. 2013;8(7):e Peripheral Neuropathy Comparisons Trials All Grades PN Grade 3 Grade 4 Eribulin vs ixabepilone % vs 44.0% 9.8% vs 20.0% 0% Ixabepilone/capecitabine vs capecitabine 2 66% vs 21% 24% vs 1.2% 0.7% vs 0% Paclitaxel vs nab-paclitaxel vs ixabepilone 3 18% vs 27% vs 25% Ixabepilone qwk vs q3wk 4 12% vs 27%

43 Ixabepilone Monotherapy in MBC: AEs by Schedule Ixabepilone Grade 3/4 treatmentrelated Aes (TRAEs) 16 mg/m 2 D1, 8, 15 q28 40 mg/m 2 q3week 22% 57% Serious AEs 28% 36% Grade 3/4 neutropenia 5% 33% Fatigue 5% 16% Neuropathy 5% 14% Dehydration 1% 10% Smith JW, et al. Cancer Res. 2009;69(24 Suppl): Absract 6099.

44 1. Yardley DA, et al. J Clin Oncol. 2015;33(suppl): Abstract Horak CE, et al. Clin Cancer Res. 2013;19(6): Ixabepilone CIPN in Neo/adjuvant Neuropathy Adj AC-Pac 1 Adj AC-Ixa 1 Neo AC-Pac 2 Neo AC-Ixa 2 All grades 62.5% 50.5% 50% 43% Grade 1/2 56.2% % 39.3% Grade 3 6.3% 8.2% 3.5% 4.1% All taxane-naïve patients

45 Time Course of Neuropathy With Ixabepilone Phase II trial comparing incidence and severity of peripheral neuropathy associated with eribulin versus ixabepilone Time to onset: Ixabepilone 11 weeks Eribulin 36 weeks Time to resolution: Ixabepilone 10 weeks Eribulin 48 weeks Vahdat L, et al. Breast Cancer Res Treat. 2013;140(2):

46 CIPN Prognostic Significance Phase II first-line ixabepilone MBC trial (n = 50): Longitudinal follow-up (anthra pretreated) Aim: Evaluate mechanism-based neurotoxicity with ixabepilone efficacy Severe neuropathy (38%) correlated with: Higher ORR (79% vs 48%; P =.042) Longer TTP (11.4 months vs 6.8 months; P =.023) Longer OS (36.6 months vs 19.9 months; P =.05) Patients received a median of 4 cycles afterwards 62% received taxanes: Neither neurotoxicity or response was affected by prior ixabepilone Ixabepilone neurotoxicity is a predictor of treatment outcomes Favorable prognostic factor highlighting risk-to-benefit ratio Durando X, et al. Oncology. 2015;88(3):

47 Approved Combination Ixabepilone + capecitabine Preclinical studies demonstrate synergism Phase III trial ORR for 42% vs 23% PFS 5.3 months vs 3.8 months Q-TWiST 3.8 week improvement in Vahdat L, et al. J Geriatr Oncol. 2013;4(4):

48 Conclusions: Who, What, When? Improved efficacy in more proliferative disease Similar to other microtubule inhibitors Every-3-week therapy is superior to weekly therapy Higher-dose weekly therapy is not feasible Lower-dose every-3-week therapy may be preferable and more feasible Treatment in earlier line settings is likely to be more tolerable with less neuropathy and neutropenia

49 Treatment Options for Antracycline-Pretreated and Taxane-Pretreated Patients: Novel Strategies in Development for Patients With Taxane-Resistant Disease

50 Novel Pharmacology of Etirinotecan Pegol (EP) Compared to irinotecan, EP prolongs elimination half-life of SN38 from 2 days to 50 days in patients 1 Given its size, EP escapes from leaky tumor vasculature, concentrating the active metabolite in tumor 2 In a murine model of brain metastases, EP results in 100-fold greater concentration of SN38 in brain lesions compared to irinotecan, prolonging survival 3 Irinotecan Ester-based Releasable Linker 20 kda, 4-arm PEG BEACON Phase III trial : Etirinotecan vs TPC in ER+ or TN MBC post- A- T- Cape-pretreatment Hydrolysis Hydrolysis SN38, Active 1. Jameson GS, et al. Clin Cancer Res. 2013;19(1): Hoch U, et al. Cancer Chemother Pharmacol. 2014;74(6): Nounou MI, et al. Cancer Res. 2014;74(19 Suppl): Abstract 35.

51 BEACON Phase III Study Design Single-Agent Etirinotecan Pegol Locally recurrent or MBC (n = 852) Previously treated with an anthracycline, a taxane, and capecitabine; ECOG prior chemotherapies for advanced disease Progression 6 months of last chemotherapy Stable brain metastasis allowed R 145 mg/m 2 every 3 weeks (n = 429) Single-Agent Treatment of Physician s Choice (TPC) (n = 423) eribulin, paclitaxel, docetaxel, ixabepilone, vinorelbine, gemcitabine, or nab-paclitaxel Primary Endpoint OS Secondary Endpoints PFS, ORR, CBR, DoR, HRQoL Exploratory Endpoints PD Markers in CTC, others CBR, clinical benefit rate; CTC, circulating tumor cellsdor, duration of response; HRQoL, health-related quality of life; PD, pharmacodynamic Perez EA, et al. J Clin Oncol. 2015;33(suppl): Abstract 1001.

52 BEACON: Outcomes Primary Analysis of Overall Survival (at 647 events) 1.0 Survival Probability EP TPC OS 12.4 months 10.3 months PFS 2.4 months 2.8 months RR 16% 17% 0.2 HR (95% CI): ( ) Log-rank P value = Number at Risk: Months From Randomization Perez EA, et al. J Clin Oncol. 2015;33(suppl): Abstract 1001.

53 OS: Patients With History of Brain Metastases (n = 67) Events OS, Months 95%CI EP (n = 36) Survival Probability TPC (n = 31) HR (95% CI): ( ) Log-rank P value = Number at Risk: Months From Randomization Perez EA, et al. J Clin Oncol. 2015;33(suppl): Abstract

54 Phase III Vinflunine vs Alkylating Agent for Pretreated MBC 594 patients previously treated with an anthracycline (A), taxane (T), antimetabolite (AM), and vinca alkaloid (VA); median 4 prior regimens for MBC Vinflunine 280 mg/m 2 vs TPC (CTX or Cb or Cp) Primary endpoint median OS 9.1 months (VFL) vs 9.3 months (AA) Median PFS 2.4 months (VFL) vs 1.9 months (AA) ORR 6% (VFL) vs 4% (AA) Grade 3/4 toxicities VFL ANC 19%; asthenia 11% Consider VFL evaluation 320 mg/m 2 Cortes J, et al. J Clin Oncol. 2015;33(suppl): Abstract 1031.

55 IMMU-132: Impressive Efficacy in Patients With Heavily Pretreated Metastatic TNBC IMMU-132: Time to Progression for TNBC Grade 3 Grade 4 Neutropenia 17 (16%) 6 (6%) Anemia 6 (6%) 0 (0%) Fatigue 6 (6%) 0 (0%) Diarrhea 4 (4%) 0 (0%) Febrile neutropenia 3 (3%) 2 (2%) Note: Grade 2 alopecia n = 20 (18%) Grade 3 lymphopenia and vomiting 2 patients Grade 3 asthenia, dizziness, urinary tract infection, leucopenia, decreased white blood cell count 1 patient each Bardia A, et al. Cancer Res. 2016;76(4 Suppl): Abstract PD3-06.

56 Panaik A, et al. Cancer Res. 2014;74(19 Suppl): Abstract CT-232. Tolaney SM, et al. J Clin Oncol. 2015;33(suppl): Abstract 522. Phase Ib Abemaciclib +/- Endocrine Therapy Single-agent abemaciclib: 36 HR+ MBC patients 7 prior regimens ORR 25% and CBR 61% Median PFS 9 months

57 Improving Chemotherapy Outcomes for MBC Use the best available therapies today Understand mechanisms of resistance and develop strategies to overcome them Develop biomarkers to predict treatment benefit Sequential monochemotherapy presently serves the needs of the majority of scenarios Select combinations based on evidence, but individualized for the unique patient The Art of Medicine intersecting with the Science of Medicine