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Secuencia óptima de tratamiento de quimioterapia en el cáncer de mama metastásico

Javier Cortes, Ramon y Cajal University Hospital, Madrid, Spain Vall d´Hebron Institute of Oncology (VHIO), Medica Scientia Innovation Research (MedSIR) Barcelona, Spain Systemic Treatment Approach for HER2-Negative, Metastatic

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

Response No response No progression Progression of disease

If disease progresses, second-line hormonal therapy Second-line chemotherapy Efficacy with different cytotoxic agents

45% 40% 35% 30% 25% 20% 15% 10% 5% 0% VRL DCT PCT DOX EPI 5-FU CAP

G. Hortobagyi, ASCO 2003 Educational Session MBC: Systemic Treatment Approach

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

• Few proven options for patients failing anthracyclines/taxanes – 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. , liposomal , , …)

USO INTERNO ORR Independent of Line of Therapy and Across Various Subgroups

60 P = .001 P = .029 P = .006 P = .002 P = .002

50 42.3% 40

% % CI) 33.2% 34.1% 33.5% 95

30 27.0% 26.5% ± 20 18.7% 18.3% 18.7%

13.2% ORR ORR ( 10

0 All First-Line ≥ Second-Line Anthracycline Visceral Patients Therapy Therapy Exposed Disease nab-: 229 97 132 176 176 Solvent-based paclitaxel: 225 89 136 175 182

Gradishar WJ, et al. J Clin Oncol. 2005;23(31):7794-7803. nab-Paclitaxel vs : Results

1.00

Investigator-Assessed Survival

0.75

0.50

0.25 Probability Probability of Survival nab-Paclitaxel 150 mg/m2 q3w (n = 74) – 33.8 months nab-Paclitaxel 300 mg/m2 q3w (n = 76) – 27.7 months Docetaxel 100 mg/m2 q3w (n = 74) – 26.6 months nab-Paclitaxel 100 mg/m2 q3w (n = 76) – 22.2 months 0.00 0 10 20 30 40 50 Months Gradishar WJ, et al. J Clin Oncol. 2011;29(Suppl 27): Abstract 275. CALGB 40502: Trial Design

Stratified by receipt of adjuvant Disease progression† taxanes and HR status

Paclitaxel 90 mg/m2/wk + Bevacizumab* 10 mg/kg q2w (n = 283)

Treatment-naïve patients nab-paclitaxel 150 mg/m2/wk + with locally recurrent or Bevacizumab* 10 mg/kg q2w (n = 271) (N = 799)

Ixabepilone 16 mg/m2/wk + Bevacizumab* 10 mg/kg q2w (n = 245)

Note: All chemotherapy given for 3 wks on, 1 wk off. *Protocol amended in March 2011 (n = 669) to allow optional use of bevacizumab following ODAC recommendation that approval be withdrawn for metastatic breast cancer; 98% of all patients received bevacizumab. †Patients with SD or responding disease after 6 cycles could discontinue chemotherapy and continue bevacizumab alone.

Rugo HS, et al. J Clin Oncol. 2012;30(Suppl): Abstract CRA1002. CALGB 40502 PFS by Treatment Arm

1

0.8 Comparison HR P Value 95% CI Nab vs Pac 1.19 .12 0.96-1.49 Ixa vs Pac 1.53 <.0001 1.24-1.90 0.6

0.4

0.2 Paclitaxel nab-Paclitaxel Proportion Proportion Progression Free 0 0 10 20 30 Months Agent N Median PFS, Months from Study Entry Paclitaxel 283 10.6 nab-Paclitaxel 271 9.2 Ixabepilone 245 7.6

Rugo HS, et al. J Clin Oncol. 2012;30(Suppl): Abstract CRA1002. CALGB 40502 PFS by Treatment Arm

Rugo HS, et al. J Clin Oncol. 2012;30(Suppl): Abstract CRA1002. Capecitabine in Anthracycline-Taxane-pretreated Metastatic Breast Cancer

Disease Median Control Median Median CR + Response Study N (CR + TTP, Surviva PR, % Duration PR + mos l, mos , mos SD), % Blum et al.1-2 162 20 63 7.9 3.0 11.6 Blum et al.3 74 26 57 8.3 3.2 12.2 Reichardt et al.4 136 15 62 7.4 3.5 10.1 Fumoleau et al.5 126 25 54 5.0 4.6 15.2

1. Blum JL, et al. J Clin Oncol. 1999;17:485-493. 2. Blum JL et al. Eur J Cancer 001;37:S190 (Abstract 693) 3. Blum JL et al. Cancer 2001;92:1759-1768. 4. Reichardt P et al. Ann Oncol. 200311 ;14:1227-1233. 5. Fumoleau P et al. Eur J Cancer. 2004;40:536-542. Nab-paclitaxel in taxane-refractory patients

• Albumin-bound paclitaxel, nanoparticle formulation • Phase II trial, taxane-refractory MBC (N = 106) – 100 mg/m2 weekly, Days 1, 8, and 15 every 28 days – Objective PR in 16 pts (15%); PR+SD ≥ 16 wks, 32 (30%) – Probability of surviving to 12 months, 38% – Well tolerated without steroids or G-CSF prophylaxis • Grade 4 neutropenia, 1%; grade 3, 14% • Grade 3 sensory neuropathy, 4%

1. Blum JL et al., Proc Am Soc Clin Oncol. 2004. Abstract 543. Ixabepilone New Compounds

MeO 1 H O O HO O O H H O Eribulin mesylate H3N O O O MsO Me H O Eribulin Mesylate

Etirinotecan Pegol

Vinflunine BEACON Phase 3 Study Design

Single-Agent Locally recurrent or 2 Primary Endpoint metastatic breast cancer 145 mg/m every 3 weeks (n=852) (n=429) • Overall Survival • Prior treatment with Secondary Endpoints anthracycline, a taxane, • PFS, ORR, CBR, and capecitabine R DoR, HRQoL • ECOG PS 0-1 Single-Agent Treatment of Exploratory Endpoints • 2-5 prior Physician’s Choice (TPC) for advanced disease • PD Markers in CTC, others Docetaxel, eribulin, gemcitabine, ixabepilone, nab-paclitaxel, • Stable brain mets allowed paclitaxel or vinorelbine (n=423)

Stratification: 135 centers in US, Canada, Belgium, France, Germany, • Geographic region Italy, Korea, Russia, Spain, The Netherlands, UK • Prior eribulin use • Receptor status Enrollment: Dec 2011 – Aug 2013 Event cutoff: Dec 2014

Perez E, et al. Lancet Oncol 2015 Primary Efficacy Endpoint: Overall Survival

Events OS (95% CI) Etirinotecan Pegol (n=429) 318 12.4 mo (11.0-13.6) 1.0 TPC (n=423) 329 10.3 mo (9.0-11.3)

0.8

HR (95% CI): 0.872 (0.747-1.019) 0.6 Log-rank P-value = 0.0835

0.4 Survival ProbabilitySurvival 0.2

0.0 Number at Risk: 429 392 331 276 219 161 91 53 25 10 3 423 371 301 229 177 142 93 52 25 9 2

0 3 6 9 12 15 18 21 24 27 30 Months from Randomization

Perez E, et al. Lancet Oncol 2015 Overall Survival in Patients With History of Brain Metastases (n=67)

Events OS (95% CI)

1.0 72.2% (54.5-84.0) Etirinotecan Pegol (n=36) 31 10.0 mo (7.8-15.7) 45.2% (27.4-61.4) TPC (n=31) 29 4.8 mo (3.7-7.3) 0.8

44.4% (28.0-59.6) 19.4% (7.9-34.6) 0.6 HR (95% CI): 0.511 (0.304-0.858) Log-rank P-value = 0.0099

0.4 Survival Probability Survival 0.2

0.0 Number at Risk: 36 33 26 22 16 13 4 3 2 1 0 31 27 14 7 6 4 2 2 1 0

0 3 6 9 12 15 18 21 24 27 30 Months from Randomization

Perez E, et al. Lancet Oncol 2015 : Phase III Study Design

Cortes J, et al. ASCO 2015 VINFLUNINE: OS

Median OS Vinflunine 9.7 AA 9.3

HR 0.99 (95% CI 0.82, 1.22) p value=0.99

Cortes J, et al. Ann Oncol 2018 Eribulin Mesylate

• Halichondrins ― a new class of antineoplastic agents Me Me MeO H H H 1 O O O H H O H O O HO O O HO O O O O O O HO H H H H H H H O H O H O O H3N O HO Me O O O MsO Me O Me H H O O Halichondrin B Eribulin Mesylate Halichondria okadai

• Eribulin is an synthetic analog of halichondrin B, a found in marine sponges • Non-taxane dynamics inhibitor – Inhibits through a novel mode of action distinct from other tubulin-targeting agents • Potent antiproliferative agent against many human cancer types in vitro and in vivo • Active against β-tubulin mutated cell lines • Unusually wide therapeutic window for a chemotherapeutic agent • Eribulin induces less neuropathy in mice than paclitaxel or ixabepilone

Towle et al 2001; Jordan et al 2005; Kuznetsov et al 2004; Okouneva et al 2008; Smith et al 2010 EMBRACE Study Design

Global, randomized, open-label Patients (n=762) Phase III trial (Study 305) • Locally recurrent or metastatic breast cancer Eribulin mesylate • 2-5 prior chemotherapies 1.4 mg/m2, 2-5 min IV bolus – ≥2 for advanced disease Day 1, 8 q21 days – Prior anthracycline and R taxane Treatment of Physician’s Choice (TPC) • Progression on or within 2:1 Any monotherapy (chemotherapy, 6 months of last hormonal, biological)* or supportive chemotherapy care only† • Neuropathy ≤grade 2 Stratification • Geographic region • ECOG ≤2 • Prior capecitabine treatment • HER2/neu status ACCRUAL: Nov 2006 – Nov 2008

* Approved for treatment of cancer and administered according to local practice, if applicable. †Or palliative treatment or radiotherapy.

Cortes J, et al. Lancet. 2011 TPC Treatment Received

96% of patients were treated with chemotherapy 30%

25% 25% Total pts = 247

19% 20% 18% 15% 15%

% of Patients of % 10% 10% 10%

5% 4%

n=61 n=46 n=44 n=39 n=24 n=25 n=9 0%

No patients received only best supportive care or biological therapies

Taxanes: paclitaxel, docetaxel, Abraxane Anthracyclines: doxorubicin, , liposomal doxorubicin Cortes J, et al. Lancet. 2011 EMBRACE Updated Survival Analysis: Overall Survival

Treatment Eribulin (n=325) TPC (n=163)

HER2, human epidermal growth factor receptor type 2; HR, hazard ratio; CI, confidence intervals; TPC, treatment of physician’s choice †HR Cox model including geographic region, HER2/neu status, and prior capecitabine therapy as strata ‡Nominal p value from stratified log-rank test.

Twelves C, et al. San Antonio Breast Cancer Symposium 2010. Abstract P6-14-08 Study Design (Study 301)

 Global, randomized, open-label Phase III trial (Study 301)

Patients (N=1102) Co-primary endpoint Locally advanced or MBC Eribulin mesylate • OS and PFS • ≤3 prior chemotherapy 1.4 mg/m2† 2- to 5-min IV regimens (≤2 for Day 1 & 8 q21 days Secondary endpoints advanced disease) • Quality of life • Prior anthracycline and taxane in (neo)adjuvant Randomization 1:1 • ORR • Duration of response setting or for locally 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 only)

 Stratification: – Geographical region, HER2 status

†Equivalent to 1.23 mg/m2 eribulin Kaufman P, et al. SABCS 2012 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 Kaufman P, et al. SABCS 2012 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 Kaufman P, et al. SABCS 2012 Non-Hematologic Adverse Events†

Eribulin Capecitabine (n=544) (n=546)

All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 % % % % % % Hand-foot syndrome <1 0 0 45 14 0 Alopecia 35 - - 4 - - Diarrhea 14 1 0 29 5 <1 Nausea 22 <1 0 24 2 0 Vomiting 12 <1 <1 17 2 0 Fatigue 17 2 0 15 2 <1 Asthenia 15 4 <1 15 4 0 Decreased appetite 13 <1 0 15 2 0 Peripheral sensory neuropathy 13 4 0 7 <1 0 Pyrexia 13 <1 0 6 <1 0 Headache 13 <1 0 10 <1 <1 Dyspnea 10 2 <1‡ 11 3 <1‡ Back pain 10 2 0 8 <1 0

Safety population †Incidence >10% (all grades) or 1% (Grade 3 or higher) in either arm; ‡Grade 5 events also occurred in 0.7% and 0.5% of patients, respectively If a subject had two or more AEs in the same system organ class or with the same preferred term with different CTCAE grades, then the event with the highest grade was used for that subject This presentation is the intellectual property of the author. Pre-Specified Subgroup Analysis

Kaufman P, et al. SABCS 2012 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 Kaufman P, et al. SABCS 2012 The Pooled Analysis

Study 3051 • Global, open-label, randomised, pivotal Phase III EMBRACE (Eisai Metastatic trial Breast Cancer Study Assessing • First presented 2010 Treatment of Physician’s Choice • Used for the regulatory approval of Halaven in (TPC) versus Eribulin E7389) over 55 countries • Global, open-label, randomised, two-parallel- arm, pivotal Phase III trial • First presented 2012 Study 3012 • Didn’t reach primary endpoint • European Medicines Agency requested further evaluation • Pooled analysis requested by EMA as supplementary information for review of eribulin • Final decision by EMA based on two Phase III (305 and 301) trials as separate entities1-2

Efficacy of eribulin in MBC by HER2 and triple negative status

Overall HER2− HER2+ TNR

Eribulin C Eribulin C Eribulin C Eribulin C

n 1062 802 748 572 169 123 243 185

HR 0.85 (0.77, 0.95) 0.84 (0.72, 0.93) 0.82 (0.62, 1.06) 0.74 (0.60, 0.92) (95% CI)a p 0.003 0.002 0.135 0.006 Eribulin´s Mechanisms of Action

1. Tubulin-based Antimitotic Effects 2. Complex Non-Mitotic Effects on Tumor Biology* 1. Tumor Vasculature Remodeling 2. Reversal of EMT 3. Decrease Capacity for Migration and Invasion

*As shown in preclinical studies Eribulin blocks mitotic spindle formation, causing cell death by

Towle MJ, et al. Cancer Res 2001; Kuznetsov G, et al. Cancer Res 2004 After a single dose of Eribulin, Perfusion becomes uniform across tumor core and rim

Funahashi Y, et al. Cancer Sci 2014 Eribulin induces epithelial morphology in surviving breast cancer cells in vitro

Yoshida T, et al. Br J Cancer 2014 Eribulin reverses EMT in Tumors in vivo

Yoshida T, et al. Br J Cancer 2014 Eribulin decreases in vitro migration and invasion

Yoshida T, et al. Br J Cancer 2014 Experimental metastases in mice

www.benchmarks.cancer.gov Eribulin prevents experimental metastasis and increases survival in mice

Yoshida T, et al. Br J Cancer 2014 Eribulin Mesylate: Ongoing Programme NeoEribulin: A Phase II, open-label, single-arm, pharmacogenomic study of single agent E7389 (eribulin mesylate) as neoadjuvant treatment for operable Stage I-IIIA HER2 non-overexpressing breast cancer

Pharmacogenomic Study of Eribulin in HER2-ve BC -EISAI

Phase II, open-label, single-arm exploratory study of the safety and pharmacogenomics of single agent E7389 (eribulin mesylate) in patients with operable Stage I-IIIA HER2 non-overexpressing breast cancer (J. Cortés)

N200 S U I and IIIA Post-Surgery ERIBULIN R Operable 1.4 mg/m2 D1, D8 Q21days Treatment HER2 4 Cycles G as per Negative Investigator E (Anthracyline- R based therapy recommended) Core or Day 21 Y Incisional Core Biopsy ORR Biopsy PE BORR Imaging Dx Mammo/US/MRI pCRB pCR BL DFS Gene BCR Expression Eribulin Safety > 60% Profile

C O N F I D E N T I A L Eribulin Mesylate: Ongoing Clinical Trial Programme

Prat A, et al. SABCS 2015 Use and Duration of Chemotherapy in Patients With Metastatic Breast Cancer According to Tumor Subtype and Line of Therapy

Number of lines of chemotherapy Median duration of chemotherapy by line and subtype according to line and subtype

Seah DSE et al. J Natl Compr Canc Netw 2014 CASCADE STUDY: Patient Prevalence decay per line of treatment and tumour immunotype Chemo-based Treatment Approach for HER2- Negative, Metastatic Breast Cancer

Metastatic Breast Cancer

Scientific approach Regulatory approach •Anthracyclines and taxanes pretreated •Anthracyclines and taxanes pretreated

Eribulin (TNMBC) Capecitabine (HER2 neg?) Gemcitabine /IF capecitabine decided) Vinorelbine

Progression of disease (after 1 lines) If disease progresses, Second/third-line chemo therapy Eribulin