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Home , Eribulin, Etirinotecan pegol, Vinflunine

Eribulina: Supervivencia después de la primera línea

Javier Cortes, Hospital Universitario Ramon y Cajal Madrid Systemic Therapy for Metastatic

• is incurable and remains an important medical problem • Treatment is palliative • Endocrine treatment: best effect in ER/PgR positive • in HR-negative or HR-positive and resistant or fast progressive disease (liver/lung mets) • Median OS once chemotherapy is indicated: 15-25 mos • HER2 positive: different options 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 , , …)

Ixabepilone New Compounds

MeO 1 H O O HO O O H H O 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 , eribulin, gemcitabine, ixabepilone, nab-, • 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 Probability Survival 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. ASCO 2015 Eribulin Mesylate (E7389): A Novel Tubulin Targeted Agent

• Eribulin mesylate (E7389), a non-taxane dynamics inhibitor with a novel , is a structurally simplified synthetic analog of the marine halichondrin B1,2

1Jordan MA, et al. Mol Cancer Ther. 2005;4:1086-1095. 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 EMBRACE Study: Endpoints

• Primary endpoint: Overall Survival

• Secondary endpoints: – Progression-free survival (PFS) – Overall response rate (ORR) – Response duration • Other assessments: Safety

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 EMBRACE Prior Chemotherapy Sub-analysis: Overall Survival

● Subgroup analysis of the influence of the number of prior regimens on overall survival among eribulin- treated patients identified consistently longer median overall survival with eribulin vs. TPC in patients who received ≤3 prior chemotherapy regimens

● The study was not powered to show statistical significance for this subgroup analysis

≤3 Chemo Regimens > 3 Chemo Regimens previously received previously received Overall Survival (95% CI) 13.3 months 11.7 months Eribulin-treated Patients (404 days [365.0, 454.0]) (355 days [282.0, 380.0]) n=362 n=106 10.7 months 10.0 months TPC-treated Patients (326 days [282.0, 380.0]) (304 days [191.0, 547.0]) n=162 n=51 2.6 months 1.7 months Median Survival Difference (78 days) (51 days) P-value 0.039 0.607 0.774 0.899 Hazard Ratio (95% CI) (0.606, 0.988) (0.600, 1.348)

NB: The primary analysis of the EMBRACE trial demonstrated that treatment with eribulin significantly prolonged overall survival in patients with late-stage breast cancer when compared with TPC (p=0.041, HR=0.809, 95% CI: 0.660, 0.991). Median OS for eribulin = 13.12 months, for TPC = 10.65 months. This subgroup analysis was carried out using the primary analysis of OS, and not the updated analysis.

TPC, treatment of physician’s choice Blum JL, et al. San Antonio Breast Cancer Symposium 2010. Abstract No. P6-13-01. 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

Kaplan-Meier graphs of overall survival for receptor status subgroups: HER2-negative

CI, confidence interval

Kaplan-Meier graphs of overall survival for receptor status subgroups: triple-negative

CI, confidence interval 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 One dose of Eribulin induces small capillaries, increase perfusion and eliminates hypoxia

Funahashi Y, et al. Cancer Sci 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 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 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

Pooled Analysis: Overall Survival in the Intent to Treat Population

Median OS 1.0 (months)

0.9 Eribulin (n=1062) 15.2 2.4 months 0.8 Control (n=802) 12.8 difference

0.7 HR 0.85

0.6 95% CI 0.77, 0.95

0.5 P value 0.003

0.4

Proportion ofsurvival Proportion 0.3

0.2

0.1

0.0 Number of subjects at risk 1062 1021 957 870 785 690 623 554 462 385 327 276 227 189 158 130 105 79 52 38 32 26 22 15 13 9 7 2 2 0 802 750 672 604 545 486 414 370 324 275 242 216 181 151 134 113 83 62 42 33 27 23 17 13 12 10 2 2 1 0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 Time (months)

Hazard ratio stratified by region, HER2 status, prior capecitabine use and study Overall survival curves adjusted by study 305 study data is updated 77% event analysis

1. Twelves et al, 2014 ASCO, Abstract No. 631. Poster #95 Patient selection for eribulin (i)

Younger or older patients? Pooled analysis form the two large phase 2 studies and the two randomised phase 3 studies (EMBRACE and 301, eribulin arm only) N OS (months) Patient age group

All patients 827 13.2

< 50 years 253 11.8 50-69 289 12.3 60-69 206 11.7 > 70 79 12.5 P 0.82

No overall effect of age on incidence of AEs Muss et al, et al. Oncologist ; 2014 Patient selection for eribulin (ii)

Less or more heavily pre-treated patients? – In EMBRACE OS benefit more apparent in patients who had received < 3 lines of prior chemotherapy – In 301 eribulin and capecitabine appeared to have very similar efficacy in the 1st, 2nd and 3rd line settings – Treatment is likely to be better tolerated – Limits of “attrition” over successive lines of treatment 100 90 80 1st line 70 2nd line 60 3rd line % who receive 50 chemotherapy 4th line 40 5th line 30 6th line 20 10 0 Evaluation of synergy between novel PI3K-pathway inhibitors and microtubule-targeting agents in HER2-negative breast cancer

Albert Gris, Cristina Saura, Mafalda Oliveira, Alex Piris, Yasir Ibrahim, Ludmila Prudkin, Paolo Nuciforo, Javier Cortés & Violeta Serra

Gris-Oliver et al., unpublished results Inhibition of PI3K reverts PIK3CA-mutant eribulin-resistance in vivo PI3K inhibition enhances eribulin’s antitumoral activity in PIK3CA mutated TNBC in vivo models

BKM120 27.5mg/kg 6IW • Patient 44: paclitaxel 3/w Eribulin 0.1mg/kg 3IW non-progressing patient

**, p<0.01; ***, p<0.001. ANOVA with Bonferroni’s post-test Conclusions In 34 years, only 16 studies have been conducted in MBC with OS

Prior MBC therapy Author Regimen No prior A Prior adjuvant A A T Canellos et al.1976 CMF > L-PAM ✓ Engelsman et al. 1991 PO CMF > IV CMF ✓ Stewart et al. 1997 FAC > CMF ✓ Bishop et al. 1999 P > CMFP ✓ Jassem et al. 2001 AP > FAC ✓ Feher et al. 2005 E > Gem ✓ Bontenbal et al. 2005 AD > FAC ✓ Albain et al. 2008 Gem-P > P ✓ Slamon et al. 2001 AC or P + H > AC or P ✓ Marty et al. 2005 D + H > D ✓ Jones et al. 1995 Vinorelbine > ✓ ✓ Nabholtz et al. 1999 D > mitomycin/ ✓ ✓ O’Shaughnessy et al. 2002 D+X > D ✓ ✓ Jones et al. 2005 D > P ✓ ✓ Seidman et al. 2008 P weekly > P q3wk ✓ ✓ Cortes et al. 2011 Eribulin > TPC ✓ ✓ ✓

A = doxorubicin (or anthracycline); C = ; D = docetaxel; E = ; F = 5-; Gem = gemcitabine; H = trastuzumab; M = ; OS = overall survival; P = paclitaxel; TPC = treatment of physician’s choice; X = capecitabine; MBC = metastatic breast cancer Conclusions

• Eribulin as single agent demonstrated statistically significantThese improvement results in OS in late -haveline MBC – Improvement of median OS was 2.7 months established– Clinically significant difference eribulin in heavily pretreated patients as the • Secondary endpoints were consistent with primary bestendpoint option for second-line • These benefits were achieved with a predictable safety profileand beyond of patients • EMBRACE is the first Phase III single-agent study in late- line MBC to meetwith its primary MBC endpoint of OS