Chemotherapy for Recurrent Or Metastatic Breast Cancer

Selección de QT en cáncer de mama avanzado ¿Hay una secuencia óptima?

E. Ciruelos Servicio Oncología Médica Hospital Universitario 12 de Octubre, Madrid Systemic Therapy for Metastatic Breast Cancer

• Metastatic breast cancer is incurable and remains an important medical problem • Treatment is palliative • Endocrine treatment: best effect in ER/PgR positive • Chemotherapy in HR-negative or HR-positive and resistant or fast progressive disease (liver/lung mets) • Median OS once chemotherapy is improving • HER2 positive: different options Systemic Treatment Approach for HER2-Negative, Metastatic Breast Cancer

Metastatic Breast Cancer

• Asymptomatic disease • Symptomatic disease •Limited metastases (bone & soft tissue) •Extensive metastases or visceral crisis • Positive hormone receptors • Negative hormone receptors • Hormone responsive • No response to hormones • Disease-free interval 2 years

Hormonal Therapy Chemotherapy

Response No response No progression Progression of disease

If disease progresses, second-line hormonal therapy Second-line chemotherapy Chemotherapy for Recurrent or Metastatic Breast Cancer: NCCN Guidelines Single Agents Combinations • Anthracyclines • CAF/FAC – Doxorubicin – Epirubicin • FEC – Pegylated liposomal doxorubicin • AC • Taxanes • EC – Paclitaxel – Docetaxel • AT – Albumin-bound paclitaxel • CMF • Antimetabolites • Docetaxel/capecitabine – Capecitabine, Gemcitabine • GT • Other microtubule inhibitors • Paclitaxel/bevacizumab – Vinorelbine, Eribulin • Other single agents – Cyclophosphamide, Mitoxantrone – Cisplatine, Etoposide, Vinblastine, Fluorouracil NCCN Clinical Practice Guidelines in Oncology: Breast Cancer . – Ixabepilone

Chemotherapy for MBC

Sequential single agents preferred for most patients Supported by clinical trial data Variety of options—no single ‘gold standard’ Limits toxicity However, combinations may be preferred for rapidly progressive symptomatic disease Reduction in symptoms outweighs potential toxicity May not be candidate for subsequent therapy if continued progression MBC: Systemic Treatment Approach

• Anthracyclines and taxanes: the standard of care – Increasing use in the adjuvant setting – 15-40% relapse rate after anthracycline-taxane therapy – No treatment has resulted in an improvement in OS after anthracyclines/taxanes

E1193 Phase III Trial Dox vs Pac vs Dox + Pac Combination in MBC

Results: Efficacy and Tolerability

Outcome Dox Pac Dox + Pac P Value

0.007* Response rate (%) 36 34 47 0.004†

Median survival (mon) 18.9 22.2 22.0 NS

0.0022* TTP (mo) 6.0 6.3 8.2 0.0567†

Gr III/IV leukopenia (%) 47 60 55 —

Gr III/IV infection (%) 4.1 8.3 12.7 —

Gr III/IV neurologic 1.6 3.7 10.7 — complications (%)

† *Dox vs Dox + Pac; Pac vs Dox + Pac. *Sledge GW et al. J Clin Oncol. 2003;21(4):588-592.

CABLG 9840: Efficacy in MBC

Weekly paclitaxel is more effective than administration every 3 weeks for MBC

RR: 42% vs 29% Unadjusted Odds Ratio [OR]: 1.75; P = .0004

Median TTP: 9 vs 5 months Adjusted HR: 1.43; P < .0001

Median OS: 24 vs 12 months Adjusted HR: 1.23; P =.0092

Seiderman AD, et al. J Clin Oncolo. 2008; 26: 1642-1649.

Phase III: Docetaxel Dose-response Study in Advanced BC

ITT Analysis Dose-response relationship observed for tumor response (P = 0.026) but not for TPP (P = .067) No significant dose-response for OS (P = .17)

No dose-related increase in hematologic or non-hematologic toxicity

TAX 311 Phase III Study: Docetaxel vs Paclitaxel

Efficacy (ITT population) Median OS: docetaxel 15.4 vs paclitaxel 12.7 months (HR, 1.41; 95% CI: 1.15-1.73, P = .03) Median TTP: docetaxel 5.7 vs paclitaxel 3.6 months (HR, 1.64; 95% CI: 1.33-2.02, P < .0001) ORR: docetaxel 32% vs paclitaxel 25% (P = .10)

More treatment-related hematologic and non-hematologic AEs with docetaxel vs paclitaxel

Jones SE, et al. J Clin Oncol. 2005;23:5542-5551. Single-agent vs Combination Trials

Overall Grade IV Median TTP Clinical Trial* Survival Neutropenia (mon) (mon) (%) Albain et al (N=529) Pac 2.9 15.8 7 Pac + Gem 5.2 18.5 17 O’Shaughnessy et al (N=511) Docetaxel (Doc) 4.2 11.5 11 Doc + Cap 6.1 14.5 12

Albain KS et al. J Clin Oncol. 2004;22(14) Abstract 810. O'Shaughnessy J et al. J Clin Oncol. 2002;20(12):2812-2823. Alternative Microtubule Targeting Agents • New formulations of taxanes - Nab-paclitaxel • Epothilones – Ixabepilone, KOS 862 (EPO D), ZK-EPO, patupilone • Halichondrin B analogue – Eribulin (E7389) • Vinca alkaloids – Vinorelbine, vinflunine • Antibody linked to a antimicrotubular agent – TDM1 Alternative Microtubule Targeting Agents • New formulations of taxanes - Nab-paclitaxel • Epothilones – Ixabepilone, KOS 862 (EPO D), ZK-EPO, patupilone • Halichondrin B analogue – Eribulin (E7389) • Vinca alkaloids – Vinorelbine, vinflunine • Antibody linked to a antimicrotubular agent – CDX-011 (CRO 11vc MMAE) ABRAXANE®

Abraxane particle Dissociation into individual Albumin-bound paclitaxel drug-bound albumin molecules

Albumin

Mean size 130 nm Paclitaxel

• Paclitaxel and albumin are associated through hydrophobic interactions, with paclitaxel particles in a non-crystalline, amorphous, readily bio-available state1 • Once in circulation, paclitaxel nanoparticles dissolve into smaller albumin- paclitaxel complexes virtually identical in size to endogenous albumin1

1. Desai N Drug Delivery Report. 2007/2008;16:37–41. Albumin-mediated transport into tumour

Intratumoural concentration of nab-drugs may be increased by:

• Transport across tumour blood vessels via caveolar transcytosis pathway

• Potential binding to SPARC in the tumour extracellular matrix

Fig from Hassan R., Optimizing Care in Advanced Lung Cancer. ASCO 2010, Oral Abstract Discussion Improved Survival of nab®-Paclitaxel vs Cremophor® EL Paclitaxel in MBC in ≥ Second-Line 1.00 nab-Paclitaxel (n = 131) CrEL Paclitaxel (n = 136)

P = .024 0.75 HR = 0.73 Median = 56.4 weeks

0.50

Median = 46.7 weeks

Probability of survival Probability 0.25

0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 Weeks Among patients who had received prior therapy, the OS was significantly longer in the nab-paclitaxel group than the CrEL paclitaxel group Cremophor® is a registered trademark of BASF. nab® is a registered trademark of Celgene Corporation. HR, hazard ratio; MBC, metastatic breast cancer; OS, overall survival. Gradishar W, J Clin Oncol 2005; 23: 7794 Phase II in first-line HER2- MBC: Investigator-Assessed PFS

nab-Paclitaxel Docetaxel 300 mg/m2 100 mg/m2 150 mg/m2 100 mg/m2 q3w qw 3/4 qw 3/4 q3w PFS, months Arm A Arm B Arm C Arm D Overall (n = 76) (n = 76) (n = 74) (n = 74) P valuea

N Median N Median N Median N Median All patients 76 10.9 76 7.5 74 14.6 74 7.8 .008 < 65 years 67 10.9 62 7.5 64 14.1 55 7.6 .012 ≥ 65 years 9 13.8 14 9.2 10 18.9 19 8.5 .564 DM Visceral 64 10.9 61 7.5 59 13.1 67 7.8 .022 Nonvisceral 12 16.4 15 7.7 15 > 19.2 7 11.0 .575 Lesion sites < 5 39 10.2 37 8.7 38 13.1 41 7.6 .417 ≥ 5 25 12.1 24 6.9 21 14.1 26 7.8 .009 Premenopausal 26 11.0 14 7.5 21 12.9 12 5.6 .137 Postmenopausal 49 10.9 62 7.5 53 14.6 60 8.4 .022 a Based on log-rank test. Gradishar et al. J Clin Oncol 2009;27:3611–3619 Gradishar et al. ASCO Breast 2011; Clin Br Ca 2012 Phase II in first-line HER2- MBC: OS

nab-Paclitaxel Docetaxel 300 mg/m2 100 mg/m2 150 mg/m2 100 mg/m2 q3w qw 3/4 qw 3/4 q3w (n = 76) (n = 76) (n = 74) (n = 74) A B C D P value HR Overall: .047b — Median OSa 27.7 22.2 33.8 26.6 C vs B: .008 0.575 (months)1 C vs D: NS 0.686 Alternative Microtubule Targeting Agents • New formulations of taxanes - Nab-paclitaxel • Epothilones – Ixabepilone, KOS 862 (EPO D), ZK-EPO, patupilone • Halichondrin B analogue – Eribulin (E7389) • Vinca alkaloids – Vinorelbine, vinflunine • Antibody linked to a antimicrotubular agent – CDX-011 (CRO 11vc MMAE)

Ixabepilone Ixabepilone Ixabepilone Alternative Microtubule Targeting Agents • New formulations of taxanes - Nab-paclitaxel • Epothilones – Ixabepilone, KOS 862 (EPO D), ZK-EPO, patupilone • Halichondrin B analogue – Eribulin (E7389) • Vinca alkaloids – Vinorelbine, vinflunine • Antibody linked to a antimicrotubular agent – CDX-011 (CRO 11vc MMAE) Eribulin’s novel mechanism of inhibiting microtubule dynamics (Jordan et al., 2005)

Eribulin 1 Eribulin inhibits microtubule growth

Microtubule Microtubule Dynamics Polymerization Eribulin causes globular tubulin 3 Growing aggregates microtubule

Eribulin

MTOC

Microtubule Shortening Depolymerization Globular microtubule tubulin aggregates Eribulin has no effect on microtubule 2 shortening

MT drawing created by M. Asada, TRL, Eisai; later adapted by B. Littlefield, ERI Eribulin Phase 2 &3 Breast Cancer Studies

Study 201 (proof of concept)

Single-arm

Primary endpoint ORR1

Study 211: Phase II Trials II Phase Single-arm Primary endpoint ORR2

Late-stage Second-line

Study 305: Study 301: Eribulin vs TPC Eribulin vs Capecitabine

Primary endpoint OS3 Primary endpoint OS/PFS4 Phase III III Phase Trials TPC, Treatment of Physician’s Choice.

1Vahdat LT, et al. J Clin Oncol. 2009;27:2954-2961. 2 Cortes J, et al. J Clin Oncol. 2010:28(25):3922-8. 3Twelves C, et al. J Clin Oncol. 2010;28:18s, 2010 (suppl; abstr CRA1004^). 4www.clinicaltrials.gov. NCT00337103; Accessed 28 August 2010.

Phase II studies confirmed activity of eribulin in patients with pre-treated MBC

• ORR: 11.5% • Median DOR: 5.6 months 1 201 Study • Median PFS: 2.6 months (N=103): • 6-month PFS 25.9% (95% CI, 15.5, 36.3) Prior taxane & Primary endpoint: • Median OS: 9.0 months (range 0.5–27.2 months) anthracycline* • ORR with independent • 6-month survival 67.8% (95% CI, 58.0, 77.6) • 1-year survival 45.7% (95% CI, 35.2, 56.2) review

211 Study2 Secondary endpoints: (N=299): • DOR, PFS, OS, AEs • ORR: 9.3% • Median DOR: 4.1 months Prior taxane, • Median PFS: 2.6 months anthracycline, • 6-month PFS 15.6% (95% CI, 10.7, 20.5) & capecitabine* • Median OS: 10.4 months • 6-month survival 72.3% (95% CI, 66.9, 77.6)

*MBC patients with progression of disease ≤6 months of last chemotherapy and, if present, pre-existing neuropathy ≤grade 2

AEs = adverse events; CI = confidence interval; DOR = duration of response; MBC = metastatic breast cancer; ORR = overall response rate; OS = overall survival; PFS = progression-free survival 1. Vahdat L, Pruitt B et al. J Clin Oncol. 2009;27:2954–2961; 2. Cortes J, Vahdat L et al. J Clin Oncol. 2010;28:3922–3928

EMBRACE compared eribulin with treatment choices

Global, open-label, randomised, Phase III study

Eribulin (n=508) 2 Patients (N=762) 1.23mg/m * IV over 2–5 minutes on • Locally recurrent or MBC Days 1 and 8 of every 21-day cycle Primary endpoint: − 2–5 prior chemotherapies • OS − ≥2 for advanced disease RANDOMISATION 2:1† • Prior anthracycline and taxane Secondary endpoints: • Progression ≤6 months of last TPC (n=254): • PFS chemotherapy • Any monotherapy (cytotoxic, • ORR • Neuropathy ≤grade 2 hormonal, biological); or • Safety • ECOG PS ≤2 • Palliative treatment; or • Radiotherapy

*Equivalent to 1.4mg/m2 eribulin mesylate †Patients were stratified by geographical region, prior capecitabine treatment, and HER-2 status before randomisation

ECOG PS = Eastern Cooperative Oncology Group performance status; EMBRACE = Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus Eribulin; HER-2 = human epidermal growth factor receptor-2; MBC = metastatic breast cancer; ORR = objective response rate; OS = overall survival; PFS = progression-free survival Cortes J, O’Shaughnessy J et al. Lancet. 2011;377:914–923 Updated OS analysis

Median OS, months Eribulin (n=508) 13.2 TPC (n=254) 10.5 HR 0.81 95% CI 0.67, 0.96 P value* 0.014

Analysis occurred at 589 events (deaths), representing 77% of the ITT population *Nominal P value from stratified log-rank test

CI = confidence interval; HR = hazard ratio; ITT = intent-to-treat; OS = overall survival; TPC = treatment of physician’s choice Cortes J, O’Shaughnessy J et al. Lancet. 2011;377:914–923; Twelves C, Loesch D et al. San Antonio Breast Cancer Symposium. 2010;Poster P6-14-18

PFS analysis

PFS (ITT population) was longer with eribulin vs TPC in both the independent (3.7 vs 2.2 months) and investigator (3.6 vs 2.2 months) review Statistically significant by investigator (but not independent) review

ITT = intent-to-treat (all randomised patients); PFS = progression-free survival; PP = per protocol (patients who met key inclusion criteria and no major protocol violation); TPC = treatment of physician’s choice Cortes J, O’Shaughnessy J et al. Lancet. 2011;377:914–923

Randomized, open-label Phase III trial (Study 301)

Patients (N=1102) Co-primary endpoint Locally advanced or MBC Eribulin mesylate • OS and PFS 2† • ≤3 prior chemotherapy 1.4 mg/m 2- to 5-min IV regimens (≤2 for Day 1 & 8 q21 days Secondary endpoints advanced disease) • Prior anthracycline and • Quality of life taxane in (neo)adjuvant Randomization 1:1 • ORR • setting or for locally Duration of response advanced or MBC • 1-, 2- and 3-year survival • Tumor-related symptom Capecitabine assessments 2 1250 mg/m BID orally • Safety parameters Days 1-14, q21 days • Population PK (eribulin arm Stratification: only)

Geographical region, HER2 status

†Equivalent to 1.23 mg/m2 eribulin 301: Overall Survival

Median OS 1.0 (months) Eribulin (n=554) 15.9

0.8 Capecitabine (n=548) 14.5

HR† 0.879 (95% CI 0.770, 1.003) 0.6 p value‡=0.056

0.4 Survival Survival probability 0.2

0.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 Time (months)

ITT population; †HR Cox model including geographic region and HER2 status as strata ‡p value from stratified log-rank test based on clinical database This presentation is the intellectual property of the author. Progression-free Survival Independent Review Investigator Review Median Median (months) (months)

1.0 Eribulin (n=554) 4.1 1.0 Eribulin (n=554) 4.2 Capecitabine (n=548) 4.2 Capecitabine (n=548) 4.1 0.8 0.8

HR† 1.079 (95% CI 0.932, 1.250) HR† 0.977 (95% CI 0.857, 1.114) 0.6 0.6 p value‡=0.305 p value‡=0.736

0.4 0.4

Survival probability Survival Survival probability Survival 0.2 0.2

0.0 0.0 0 4 8 12 16 20 24 28 32 36 40 44 0 4 8 12 16 20 24 28 32 36 40 44 Time (months) Time (months)

ITT population; †HR Cox model including geographic region and HER2 status as strata ‡p value from stratified log-rank test based on clinical database Overall Survival By Receptor Status Subgroup HR (95% CI) Eribulin Capecitabine Median (months) Overall 0.879 (0.770, 1.003) 15.9 14.5 HER2 status

Positive 0.965 (0.688, 1.355) 14.3 17.1

Negative n=755 0.838 (0.715, 0.983) 15.9 13.5

ER status

Positive 0.897 (0.737, 1.093) 18.2 16.8

Negative n=449 0.779 (0.635, 0.955) 14.4 10.5

Triple negative

Yes n=284 0.702 (0.545, 0.906) 14.4 9.4

No 0.927 (0.795, 1.081) 17.5 16.6

0.2 0.5 1.0 2 5

ITT population Favors eribulin Favors capecitabine Alternative Microtubule Targeting Agents • New formulations of taxanes - Nab-paclitaxel • Epothilones – Ixabepilone, KOS 862 (EPO D), ZK-EPO, patupilone • Halichondrin B analogue – Eribulin (E7389) • Vinca alkaloids – Vinorelbine, vinflunine • Antibody linked to a antimicrotubular agent – CDX-011 (CRO 11vc MMAE) Vinflunine: PHASE II STUDIES - Single agent activity (ITT analysis)  Vinflunine IV 320 mg/m² every 3 weeks

Study Code Clinical setting Nb of RR Disease Median Median (Publication) pts (%) control PFS overall rate (%) (months) survival (months) IN 206 Second-line 60 30 65 3.7 14.3 (Campone M. Post- 32 resistant 34 59 Br J. Cancer, 2006) anthracyclines to taxane and post-taxanes IN 207 Third-line 56 12.5 43 2.6 11.4 (Fumoleau P. Post Am. J. Oncology, 2009) anthracyclines and post-taxanes

Promising activity of vinflunine as a single agent in metastatic breast cancer Development program of vinflunine in breast cancer METASTATIC BREAST CANCER

Third to sixth line First to third line First line post-anthra, post-taxane post-anthra and post-anthra post-vinca and post-taxane post-capecitabine

Study 303 Study 305 Study 308 VFL + Gemcitabine VFL + Capecitabine VFL single agent versus versus versus Gemcitabine + Taxol Capecitabine Alkylating agent

Primary : PFS Primary : PFS Primary : OS endpoint endpoint endpoint

n = 994 pts n = 764 pts n = 586 pts Alternative Microtubule Targeting Agents • New formulations of taxanes - Nab-paclitaxel • Epothilones – Ixabepilone, KOS 862 (EPO D), ZK-EPO, patupilone • Halichondrin B analogue – Eribulin (E7389) • Vinca alkaloids – Vinorelbine, vinflunine • Antibody linked to a antimicrotubular agent – TDM1 T-DM1: Mechanism of Action

HER2 T-DM1

Emtansine release

P Inhibition of P microtubule P polymerization Lysosome

Internalization

Nucleus

Adapted from LoRusso PM, et al. Clin Cancer Res 2011. 42 MBC: Systemic Treatment Approach

• Few proven options for patients failing anthracyclines/taxanes – Capecitabine is the “preferred” agent for anthracycline and/or taxane failures – Response Rates of 10-20% in phase II/III studies – Limited efficacy of other agents (e.g. gemcitabine, liposomal doxorubicin, vinorelbine, …) No clear standard of care for late-line MBC Therapies depend upon prior treatment, available options, and preferences of individual patients and their oncologists Currently, few treatment options have demonstrated overall survival benefit as a single agent in late-line MBC

Antiangiogénicos Agents Targeting the Vascular Endothelial Growth Factor Pathway

Anti-VEGF antibodies VEGF Soluble (Bevacizumab) VEGF receptors (Aflibercept)

Anti-VEGFR antibodies Endothelial cell (ramucirumab) P P P P P P P P VEGFR-1 VEGFR-2

Survival Proliferation Migration Small-molecule inhibitors ANGIOGENESIS (Sunitinib, sorafenib, axitinib, pazopanib) Modified from: Ferrara. The Oncologist. 2004;9(suppl 1):2-10. Bevacizumab in 1st-line MBC: Significantly Improved PFS and ORR

RIBBON-14 E21001,2a AVADO3b Capecitabine Tax/anthra Bev Placebo Bevc Placebo Bev Placebo Bev Pacl + pacl + doce + doce + cape + cape + t/a + t/a Median PFS, months 5.8 11.3 8.1 10.0 5.7 8.6 8.0 9.2 HR for PFS 0.48 0.67 0.69 0.64 p<0.0001 p=0.0002d p=0.0002 p<0.0001

ORR, % 22 50 46 64 24 35 38 51 p<0.0001 p=0.0003d p=0.0097 p=0.0054

1-year OS rate, %d 74 81 76 64 74 81 83 81 p<0.0001 p=0.02 p=0.076 p=0.44

Median OS, months 24.8 26.5 31.9 30.2 21.2 29.0 23.8 25.2

HR for OS 0.87 1.03 0.85 1.03 p=0.14 p=0.85 p=0.27 p=0.83

1Klencke et al. ASCO 2008; 2Gray et al. JCO 2009 3Miles et al. JCO 2010; 4Robert et al JCO 2011 ROSE/TRIO-12: First-line docetaxel  ramucirumab for HER2-negative mBC

Docetaxel 75 mg/m2 HER2-negative + placebo q3w mBC, no prior cytotoxic therapy Treat to for advanced R PD or disease toxicity 1:2 Docetaxel 75 mg/m2 N=1144 + ramucirumab 10 mg/kg q3w

Stratification factors: Primary endpoint: Investigator-assessed PFS • Previous taxane Events in 796/1113 patients, 86% power to detect a • Visceral metastasis HR of 0.75 (median 68 months) • Hormone receptor status Enrolment: Aug 2008 to Dec 2011 • Geographic region Mackey JR, et al. SABCS 2013 ROSE/TRIO-12: Summary of efficacy DOC–PLA DOC–RAM (N=385) (N=759) Investigator-assessed PFS HR (95% CI) 0.88 (0.75–1.01) p=0.077 Median, months 8.2 9.5 IRC-assessed PFS HR (95% CI) 0.79 (0.67–0.94) p=0.008 Median, months 8.5 11.1 OS HR (95% CI) 1.01 (0.83–1.23) Median, months 27.2 27.3 Objective RR, % 38 45 p=0.027 Time to progression HR (95% CI) 0.78 (0.65–0.93) p=0.034 Median, months 8.2 9.7 •Antiangiogenics: Manteinance therapy? ESMO 2014: - with Bevacizumab after PD (TANIA trial) - with Bevacizumab + chemo before PD (IMELDA trial)

•Despite treatment, most advanced tumors become resistant and progress2 •Chemoresistance is the major cause of treatment failure3

1. Adapted from National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer V.2.2007. http://www.nccn.org. Accessed April 30, 2007; 2. Bernard-Marty C et al. Oncologist. 2004;9(6):617-632; 3. Longley DB, Johnson PG. J Pathol. 2005;205(2):275-292. •Antiangiogenics: Manteinance therapy? ESMO 2014: - with Bevacizumab after PD (TANIA trial) - with Bevacizumab + chemo before PD (IMELDA trial)

•Despite treatment, most advanced tumors become resistant and progress2 •Chemoresistance is the major cause of treatment failure3

Adjuvant Metastatic1

Anthracyclines (A) 1st Line 2nd Line 3rd Line

Taxanes (after A) Cap (after A + T) VNR, Gem, Taxanes (T) platinum, nab- paclitaxel, lipo anthrac., eribulin (after A + T +Cap)

Cap (after A + T) VNR, Gem, platinum, nab-paclitaxel, lipo anthrac., eribulin (after A + T +Cap)

Algoritmo?

Adjuvant Metastatic1

Anthracyclines (A) 1st Line 2nd Line 3rd Line

Taxanes (after A) Cap (after A + T) VNR, Gem, Taxanes (T) platinum, nab- paclitaxel, lipo anthrac., eribulin (after A + T +Cap)

Cap (after A + T) VNR, Gem, platinum, nab-paclitaxel, lipo anthrac., eribulin (after A + T +Cap)

Combinations Cap+taxane (after A) Gem + taxane (after A) Cap + Ixa/VFL (after A + T) Bevacizumab + Paclitaxel/Cape

Algoritmo?

Adjuvant Metastatic1

Anthracyclines (A) 1st Line 2nd Line 3rd Line

Taxanes (after A) Cap (after A + T) VNR, Gem, Taxanes (T) platinum, nab- paclitaxel, lipo anthrac., eribulin (after A + T +Cap)

Cap (after A + T) CLINICALVNR, Gem, platinum, nab-paclitaxel, lipo anthrac., eribulin TRIALS(after A + T +Cap)

Combinations Cap+taxane (after A) Gem + taxane (after A) Cap + Ixa/VFL (after A + T) Bevacizumab + Paclitaxel/Cape

New Targets

• Is adequate (and relevant) material available? o primary vs secondary disease, tumour heterogeneity o circulating tumour cells o plasma/serum markers • Target identification: can the target be measured reliably? o ER cut point vs benefit o HER2, IHC vs FISH, degree of amplification and polysomy • Target validation: can changes in the target be measured? o do changes correlate with outcome? • The pathways and mechanisms targeted are often complex o combinations may be required o potential added toxicities • Is the current model of drug development appropriate? o “basket trials” • Many agents will only benefit a minority of patients o target identification and validation o risk of false-negative studies o Is the study powered to test effects in unselected patients or in the targeted subset? • Will Next Generation Sequencing reliably identify relevant groups? o Sequencing platforms

Plataformas de secuenciación

Barreras accionables

Incluir un número de centros Pacientes metastásicas que llegan a consulta adecuado en 100% programa piloto

Diseminación de importancia del Pacientes que aceptan someterse a cribado y para programa para las las que hay disponible muestra de calidad aceptable 70%? pacientes. Rol del oncólogo. Pacientes con perfil molecular cuya enfermedad progresa (y que no se hayan perdido al seguimiento) 65%?

Candidatas con mutación(es) accionable(s) 30%? ENDPOINT Colaboraciones con farma y Candidatas para otros grupos académicos. quienes haya un Cual sería el Diversificar el pipeline de ensayo abierto que número mínimo ensayos con terapias dirigidas 20%? se adecúe a perfil para que la plataforma de Pacientes que cribado valga la aceptan entrar 15%? pena? en estudio Medical Achievements in Oncology: Targeted Breast Cancer Treatments Targeted Agents Indication 1o Endpoint (months) Hazard Ratio (95% CI)

*Bevacizumab + Paclitaxel vs Paclitaxel HER2– aBC PFS: 11.3 vs. 5.8 0.48 (0.39, 0.61); P<.0001 (Gray, J Clin Oncol, 2009) Pertuzumab + TRAS + Docetaxel (Baselga, HER+ aBC PFS: 18.5 vs 12.4 0.62 (0.51, 0.75); P<.001 NEJM, 2012) Trastuzumab + Chemotherapy + (Slamon, NEJM, 2001) HER aBC TTP: 7.4 vs 4.6 0.51 (0.41, 0.63); P<.001

†T-DM1 vs LAP + CAP HER+ aBC PFS: 9.6 vs 6.4 0.65 (0.55, 0.77); P<.001 (Verma, NEJM, 2012) Fulvestrant vs Anastrozole PMW HR+ aBC TTP: 23.4 vs 13.1 0.66 (0.47, 0.92); P<.01 (Robertson, Breast Cancer Res Treat, 2012) Everolimus + EXE vs PBO + EXE PMW HR+ aBC PFS: 6.9 vs 2.8 0.43 (0.35, 0.54); P<.001 (Baselga, NEJM, 2012)

*FDA approval for bevacizumab (Avastin) was revoked for breast cancer on November 18, 2011, due to safety concerns and lack of efficacy. †Not FDA approved. Abbreviations: aBC, advanced breast cancer; BC, breast cancer; CAP, capecitabine; CI, confidence interval; EXE, exemestane; HR, hormone receptor; LAP, lapatinib; NR, not reported; OS, overall survival; PBO, placebo; PFS, progression-free survival; PMW, postmenopausal women; TRAS, trastuzumab; TTP, time to progression. 59