ABRAXANE EN CÁNCERDE MAMA

Lucía González-CortijoHospital Universitario Quirón Madrid

Madrid, 11 de febrero de 2015

INTRODUCTION TO

TAXANES

HISTORY AND CHEMISTRY• Discovered as part of

NCI program in which extracts of thousands of plants were screened for anticancer activity in the 1960s

• Initially supplied from the bark of the scarce Pacific yew, Taxus brevifolia, which had deleterious long-term environmental implications

PACLITAXEL

Summaries of Product Characteristics for paclitaxel (Accord Healthcare Ltd, Actavis UK Ltd, Hospira UK Ltd., Medac GmbH)

HISTORY AND CHEMISTRY

• 1980s: more potent semisynthetic derivative of paclitaxel

• Derived from the extracts from the needless of the European yew tree, Taxus baccata

DOCETAXEL

Summaries of Product Characteristics for Taxotere/docetaxel (Sanofi-Aventis

MECHANISM OF ACTION

•Inhibition of microtubules dynamics that promote microtubule polymerisation and inhibit depolymerisation

•Results in “cell cycle arrest” in G2 and M phase leading to CELL DEATH

Summaries of Product Characteristics for paclitaxel (Accord Healthcare Ltd, Actavis UK Ltd, Hospira UK Ltd., Medac GmbH) and Taxotere/docetaxel (Sanofi-Aventis)

TAXANE DRUG FORMULATION

Taxanes are highly hydrophobic.Commercial formulations include synthetic

solvents to enable parenteral administration

TaxaneSynthetic Solvents

PaclitaxelCremophor EL

(polyoxyethylated castor oil)

Docetaxel Tween 80(polysorbate 80)

Summaries of Product Characteristics for paclitaxel (Accord Healthcare Ltd, Actavis UK Ltd, Hospira UK Ltd., Medac GmbH) and Taxotere/docetaxel (Sanofi-Aventis)

ACTIVITY

•The most important addition to the chemotherapeutic armamentarium against cancer over the past several decades

•Unique ability to palliate the symptoms of many types of advanced cancers, including carcinoma of the ovary, lung, head and neck, bladder, and esophagus

ACTIVITY

Effectiveness in the initial therapy of earlier stages of

cancer

Curative treatment

in certain types of cancer

BREAST CANCERTrends in survival for patients with recurrent breast

cancer diagnosed from 1974 through 2000

Taxanes

anti-HER2drugs

INTRODUCTION TO

nab-PACLITAXEL

HISTORICAL OVERVIEW OF TAXANES FOR THE TREATMENT OF BREAST

CANCER

HISTORICAL OVERVIEW OF TAXANES FOR THE TREATMENT OF BREAST

CANCER

US approval

nab-PACLITAXEL

• Albumin-bound paclitaxel particle with a mean size of 130 nm Solvent free

• Different mechanism to deliver paclitaxel to tumors

nab-PACLITAXEL

nab-PACLITAXEL

• Initially designed to minimize toxic effects of taxane treatment and improve tolerability

• More effective formulation

EMA approval in 2008 Nab-paclitaxel (260 mg/m2 once every 3 weeks) approved for the treatment of

metastatic breast cancer in adult patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline containing therapy is not

indicated

nab-Paclitaxel superior to standardpaclitaxel: phase III study

Randomization (1:1)n=460

Taxane naive MBC

nab-paclitaxel 260 /m2/q3w No standard

premedicationPaclitaxel 175/m2/q3w

Standard premedication

Gradishar et al. J Clin Oncol. 2005;23:7794–7803

nab-Paclitaxel significantly prolonged OS

in >1st-line patients

Randomization (1:1)n=460

Taxane naive MBC

nab-paclitaxel 260 /m2/q3w No standard

premedicationPaclitaxel 175/m2/q3w

Standard premedication

Gradishar et al. J Clin Oncol. 2005;23:7794–7803

nab-Paclitaxel improved ORR independent

of line of therapy and accross various subgroups

Gradishar et al. J Clin Oncol. 2005;23:7794–7803

Efficacy in head-to-head trials of taxanes

Data from different studies (cross-trial comparison) cannot be used to determine the relative effects of different treatments. No phase 3 head-to-head study comparing nab-

paclitaxel and docetaxel has been undertaken

Table adapted from Gradishar WJ. Breast Cancer (Auckl). 2012;6:159-71; 1. Jones SE, et al. J Clin Oncol. 2005;23(24):5542–51; 2. Gradishar WJ, et al. J Clin Oncol. 2005;23(31):7794–803

Safety in head-to-head trials of taxanes

(grade 3/4 adverse events)

Data from different studies (cross-trial comparison) cannot be used to determine the relative effects of different treatments. No phase 3 head-to-head study comparing nab-

paclitaxel and docetaxel has been undertaken

Table adapted from Gradishar WJ. Breast Cancer (Auckl). 2012;6:159-71; 1. Jones SE, et al. J Clin Oncol. 2005;23(24):5542–51; 2. Gradishar WJ, et al. J Clin Oncol. 2005;23(31):7794–803

RETREATMENT WITH TAXANES

•Most patients with breast cancer receive taxanes in the adjuvant setting

•Higher number of patients with refractory or resistant disease in the metastatic setting

Blum et al. Clin Breast Cancer. 2007; 7(11): 850-6Im et al. J Clin Oncol (Meeting Abstracts). 2011; 29: abstr 1088

RETREATMENT WITH TAXANES

•ORR to taxanes in previously treated patients in the metastatic setting: 15-25%

•ORR to taxanes in previously treated patients in the neoadjuvant and adjuvant setting: 34%- 63% (dependant on disease free interval)

Guo X, et al. Breast Care. 2011;6(4): 279-83

nab-PACLITAXEL FOR TAXANE-EXPOSED PATIENTS

•ORR to nab-paclitaxel in previously treated patients in the metastatic setting: 15-25%

•Superiority of nab-paclitaxel vs CrEL-paclitaxel in metastatic disease progressed during treatment with other agents: ORR 27% vs 13%,

•OS 56.4 vs 46.7 weeks. Gradishar et al. J Clin Oncol. 2005;23:7794–7803 Blum et al. Clin Breast Cancer. 2007; 7(11): 850-6Gradishar WJ. Breast Cancer (Auckl). 2012;6:159-71;

nab-PACLITAXEL FOR TAXANE-EXPOSED PATIENTS

•27 year-old patient diagnosed with metastatic breast cancer (liver metastasis)

•HR - , HER2 positive disease

•Initially treated with weekly paclitaxel-carboplatinum and trastuzumab

nab-PACLITAXEL FOR TAXANE-EXPOSED PATIENTS

•4 years after diagnosis the patient had progressed to 6 lines of therapy

•Anthracycline resistant disease

•Disease progression in the liver

nab-PACLITAXEL FOR TAXANE-EXPOSED PATIENTS

•nab-paclitaxel and trastuzumab was started

•After 4 months of treatment...

nab-PACLITAXEL FOR TAXANE-EXPOSED PATIENTS

•Response was mantained for 18 months...

nab-PACLITAXELIN THE NEOADJUVANT

SETTING

GEPARSEPTO(SABCS 2014)

Geparsepto: Study design

Adverse events reported to date

Grade

CP + EC, %(n=30)

Nab-P + EC, %(n=30)

Grade

CP + EC, %(n=30)

Nab-P + EC, %(n=30)

Any AE 3-4 8 41 Skin rash* Any 8 30

Leukopenia Any 35 85 HFS* Any 11 15

Leukopenia 3-4 0 7 Allergic reaction* Any 15 30

Neutropenia Any 4 81 PNP Any 38 70

Neutropenia 3-4 4 27 PNP** 3-4 0 11

Increased AP Any 0 27 Myalgia* Any 23 33

Increased AP 3-4 0 7 Epistaxis* Any 31 26

Increased AST Any 31 26 Dyspnoea Any 11 7

Increased AST** 3-4 0 4 Dyspnoea 3-4 4 0

Increased creatinine* Any 0 18 Infection Any 38 44

Fatigue* Any 58 78 Infection** 3-4 4 11

Headache* Any 15 37 Mucositis* Any 23 30

Nausea* Any 23 37 Pulmonary embolism** 3-4 0 4

Untch et al. St Gallen 2013 (poster 249)*No Grade 3-4; **SAE; AP, alkaline phosphatase; AST, aspartate

transaminase; HFS, hand-foot-syndrome; PNP, Peripheral neuropathy; SAE, serious adverse event

• More AEs (mainly Grade 1/2) occurred in the nab-P group vs the CP group• 7 SAEs reported in taxane-treated patients; 6 in the nab-P group vs 1 in the

CP group

NOTE: % values reported in the table don’t seem to align with no of SAEs reported?

Compliance to taxane treatment

Taxane discontinuation Taxane dose reduction

CP + EC, %(n=30)

Nab-P + EC, %(n=30) P value

CP + EC, %(n=30)

Nab-P + EC, %(n=30) P value

Any reason 4 30 0.02 8 35 0.038

Haematological toxicity 0 4 - 4 8 1.00

Non-haematological toxicity 0 22 - 8 31 0.075

Untch et al. St Gallen 2013 (poster 249)

GeparSepto protocol amend

• Based on a review of these preliminary data, a protocol amend has been implemented

• 12 weeks of nab-paclitaxel 125 mg/m2 QW (instead of 150 mg/m2)

• Taxane dose modifications for peripheral neuropathy:

• Grade 0-1: No change

• Grade 2:

• Treatment held until Grade 1

• Subsequent taxane treatment at dose level -1 QW 3/4*

• If resolution to Grade 1 not achieved within 3 weeks, taxane discontinued

• Grade 3/4: Taxane discontinued

*Nab-paclitaxel dose level -1 = 100 mg/m2

DMC, data monitoring committee; GBG, German Breast Group Celgene data on file 2013

Geparsepto: Study design

Weeky comparison Abraxane vs paclitaxel

Study Endpoints

•pCR (ypT0 ypN0)

•ypT0is ypN0; ypT0 ypN 0/+

•Toxicity and compliance

•pCR rates by SPARC

Primary Endpoint

Secondary Endpoints

Main Eligibility Criteria

•Unilateral o bilateral primary breast cancer

•Operable or inoperable

•Stages: cT2-cT4a-d; cT1c and cN1 or pN(sn+) or ER- and PR- or Ki 67>20% or HER2 +

•FFPE tissue centrally available for HR, HER2, Ki 67 and SPARC testing

Primary endpoint: pCR: ypT0 ypN0

pCR in Subgroups

pCR in Stratified Subgroups

> 20%

Secondary Endpoints: pCR rates according to other

definitions

Pathologic Complete Response

In patients with triple negative disease nab-Paclitaxel

improves pCR by the same magnitude (22.5%) approximately than a targeted therapy

in HER2 disease

- Trastuzumab~20% (NOHA Study) - Pertuzumab 18%3 (NeoSPHERE) - Lapatinib 10%-25%(NeoALTO Study)

Hematological toxicity

Non hematological toxicity

Approximately 200patients treated with

150 mg/m2/w

TRIALS IN PROGRESSIN THE NEOADJUVANT

SETTING

ETNA: Phase III study design (Michelangelo /GEICAM)

4x 28d cycles:Nab-paclitaxel

125 mg/m2 QW 3/4

R1:1

4x 28d cycles:Conventional

paclitaxel90 mg/m2 QW 3/4

• HER2-negative non metastatic unilateral breast cancer at risk of disease recurrence

• ECOG PS 0-1• No prior radiotherapy, chemotherapy, biotherapy and/or hormonal therapy

for current BC• One of the following stages:

• T2, T3, T4 disease, triple negative (HER2, ER, PgR)• T2, T3, T4 disease, ER or PgR positive and moderately /poorly

differentiated (G II-III)

4x 21d cycles:AC or EC or FEC

4x 21d cycles:AC or EC or FEC

SURGERY

FOLLOW-UP: 10 years after randomization of last patient

BIOPSY

BIOPSY

BIOPSY

BIOPSY

BIOPSY

BIOPSY

NCT01822314. Available at: www.clinicaltrials.gov

Primary EP : pCR (absence of invasive disease in breast and nodes (ypT0/ypTis, ypN0)

N=632Recruitme

nt finished

CONCLUSIONSnab-PACLITAXEL

IN BREAST CANCER

CONCLUSIONS: nab-Paclitaxel

•First approved solvent-free taxane for metastatic breast cancer

•Albumin-bound paclitaxel particle with a mean size of 130 nm

•Different mechanism to deliver paclitaxel to tumors

CONCLUSIONS: nab-Paclitaxel

•Safe and active in different dosages and schedules

•Should be considered in taxane-exposed patients, especially in those with long disease free intervals

Excluding patients with previous hypersensitivity to paclitaxel (per the contraindications in theSmPC for nab-paclitaxel)

CONCLUSIONS: nab-Paclitaxel

•Superior to CrEL-paclitaxel in the metastatic breast cancer

•Superior to CrEL-paclitaxel in the neoadjuvant setting

Gracias