abraxane en cÁncer de mama lucía gonzález-cortijo hospital universitario quirón madrid madrid,...
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ABRAXANE EN CÁNCERDE MAMA
Lucía González-CortijoHospital Universitario Quirón Madrid
Madrid, 11 de febrero de 2015
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INTRODUCTION TO
TAXANES
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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)
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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
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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)
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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)
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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
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ACTIVITY
Effectiveness in the initial therapy of earlier stages of
cancer
Curative treatment
in certain types of cancer
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BREAST CANCERTrends in survival for patients with recurrent breast
cancer diagnosed from 1974 through 2000
Taxanes
anti-HER2drugs
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INTRODUCTION TO
nab-PACLITAXEL
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HISTORICAL OVERVIEW OF TAXANES FOR THE TREATMENT OF BREAST
CANCER
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HISTORICAL OVERVIEW OF TAXANES FOR THE TREATMENT OF BREAST
CANCER
US approval
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nab-PACLITAXEL
• Albumin-bound paclitaxel particle with a mean size of 130 nm Solvent free
• Different mechanism to deliver paclitaxel to tumors
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nab-PACLITAXEL
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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
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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
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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
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nab-Paclitaxel improved ORR independent
of line of therapy and accross various subgroups
Gradishar et al. J Clin Oncol. 2005;23:7794–7803
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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
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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
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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
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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
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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;
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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
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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
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nab-PACLITAXEL FOR TAXANE-EXPOSED PATIENTS
•nab-paclitaxel and trastuzumab was started
•After 4 months of treatment...
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nab-PACLITAXEL FOR TAXANE-EXPOSED PATIENTS
•Response was mantained for 18 months...
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nab-PACLITAXELIN THE NEOADJUVANT
SETTING
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GEPARSEPTO(SABCS 2014)
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Geparsepto: Study design
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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?
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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)
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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
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Geparsepto: Study design
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Weeky comparison Abraxane vs paclitaxel
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Study Endpoints
•pCR (ypT0 ypN0)
•ypT0is ypN0; ypT0 ypN 0/+
•Toxicity and compliance
•pCR rates by SPARC
Primary Endpoint
Secondary Endpoints
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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
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Primary endpoint: pCR: ypT0 ypN0
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pCR in Subgroups
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pCR in Stratified Subgroups
> 20%
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Secondary Endpoints: pCR rates according to other
definitions
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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)
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Hematological toxicity
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Non hematological toxicity
Approximately 200patients treated with
150 mg/m2/w
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TRIALS IN PROGRESSIN THE NEOADJUVANT
SETTING
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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
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CONCLUSIONSnab-PACLITAXEL
IN BREAST CANCER
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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
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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)
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CONCLUSIONS: nab-Paclitaxel
•Superior to CrEL-paclitaxel in the metastatic breast cancer
•Superior to CrEL-paclitaxel in the neoadjuvant setting
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Gracias
Peter Plateau - LH-hCG Effect in Human Assisted Fertility - II Simposio Reproducción Asistida Quirón
“My life today creates tomorrow” C.E.I.P Virgen del Cortijo - Madrid - Spain School year 2013 - 2014
Francisco Zaragoza - Un Biosimilar Es Igual a Un Original - II Simposio Reproducción Asistida Quirón