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ABRAXANE EN CÁNCER DE MAMA

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Presentation on theme: "ABRAXANE EN CÁNCER DE MAMA"— Presentation transcript:

1 ABRAXANE EN CÁNCER DE MAMA
Lucía González-Cortijo Hospital Universitario Quirón Madrid Madrid, 11 de febrero de 2015

2 INTRODUCTION TO TAXANES

3 HISTORY AND CHEMISTRY PACLITAXEL
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 Summaries of Product Characteristics for paclitaxel (Accord Healthcare Ltd, Actavis UK Ltd, Hospira UK Ltd., Medac GmbH)

4 HISTORY AND CHEMISTRY DOCETAXEL
1980s: more potent semisynthetic derivative of paclitaxel Derived from the extracts from the needless of the European yew tree, Taxus baccata Summaries of Product Characteristics for Taxotere/docetaxel (Sanofi-Aventis

5 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)

6 TAXANE DRUG FORMULATION
Taxanes are highly hydrophobic. Commercial formulations include synthetic solvents to enable parenteral administration Taxane Synthetic Solvents Paclitaxel Cremophor 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)

7 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

8 ACTIVITY Effectiveness in the initial therapy of earlier stages of cancer Curative treatment in certain types of cancer

9 BREAST CANCER Trends in survival for patients with recurrent breast cancer diagnosed from 1974 through 2000 Taxanes anti-HER2 drugs

10 INTRODUCTION TO nab-PACLITAXEL

11 HISTORICAL OVERVIEW OF TAXANES FOR THE TREATMENT OF BREAST CANCER

12 HISTORICAL OVERVIEW OF TAXANES FOR THE TREATMENT OF BREAST CANCER
A Phase III pivotal trial of a tocopherol-based Cremophor-free formulation of paclitaxel (TOCOSOL® paclitaxel)1 in women with metastatic breast cancer did not meet its primary endpoint of noninferiority on objective response rate compared with CrEL paclitaxel.2DHA-paclitaxel was studied in women with breast cancer previously treated with an anthracycline containing regimen: the objective response rate was comparable to that seen with other taxanes in this disease setting; however, grade IV neutropenia was seen in 26 of 37 patients.3 A search of clinicaltrials.gov on May 31, 2011 shows 10 trials of DHA paclitaxel in a variety of tumor types, but not breast cancer.4A conjugate of paclitaxel and poly-L-glutamate was studied in a small phase II study of patients with HER2-negative MBC who had received 0 or 1 prior lines of chemotherapy: although the compound had activity, neurotoxicity and hypersensitivity reactions were more frequent than expected and led to early termination of the trial5A phase II trial of a Cremophor-free, polymeric micelle formulation of paclitaxel in patients with MBC demonstrated overall response rate of 58.5% with 5 complete responses and 19 partial responses6 and additional trials are studying paclitaxel-loaded polymeric micelle in patients with breast cancer7 US approval

13 nab-PACLITAXEL Albumin-bound paclitaxel particle with a mean size of 130 nm Solvent free Different mechanism to deliver paclitaxel to tumors

14 nab-PACLITAXEL

15 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

16 nab-Paclitaxel superior to standard paclitaxel: phase III study
nab-paclitaxel 260 /m2/q3w No standard premedication Randomization (1:1) n=460 Taxane naive MBC Paclitaxel 175/m2/q3w Standard premedication Gradishar et al. J Clin Oncol. 2005;23:7794–7803

17 nab-Paclitaxel significantly prolonged OS in >1st-line patients
nab-paclitaxel 260 /m2/q3w No standard premedication Randomization (1:1) n=460 Taxane naive MBC Paclitaxel 175/m2/q3w Standard premedication Gradishar et al. J Clin Oncol. 2005;23:7794–7803

18 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

19 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

20 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

21 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): 850-6 Im et al. J Clin Oncol (Meeting Abstracts). 2011; 29: abstr 1088

22 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):

23 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): 850-6 Gradishar WJ. Breast Cancer (Auckl). 2012;6:159-71;

24 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

25 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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29 nab-PACLITAXEL FOR TAXANE-EXPOSED PATIENTS
nab-paclitaxel and trastuzumab was started After 4 months of treatment...

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37 nab-PACLITAXEL FOR TAXANE-EXPOSED PATIENTS
Response was mantained for 18 months...

38 nab-PACLITAXEL IN THE NEOADJUVANT SETTING

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40 GEPARSEPTO (SABCS 2014)

41 Geparsepto: Study design

42 Adverse events reported to date
NOTE: % values reported in the table don’t seem to align with no of SAEs reported? Adverse events reported to date 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 Grade CP + EC, % (n=30) Nab-P + EC, % (n=30) Any AE 3-4 8 41 Skin rash* Any 30 Leukopenia 35 85 HFS* 11 15 7 Allergic reaction* Neutropenia 4 81 PNP 38 70 27 PNP** Increased AP Myalgia* 23 33 Epistaxis* 31 26 Increased AST Dyspnoea Increased AST** Increased creatinine* 18 Infection 44 Fatigue* 58 78 Infection** Headache* 37 Mucositis* Nausea* Pulmonary embolism** *No Grade 3-4; **SAE; AP, alkaline phosphatase; AST, aspartate transaminase; HFS, hand-foot-syndrome; PNP, Peripheral neuropathy; SAE, serious adverse event Untch et al. St Gallen 2013 (poster 249)

43 Compliance to taxane treatment
Taxane discontinuation Taxane dose reduction CP + EC, % (n=30) Nab-P + EC, % (n=30) P value Any reason 4 30 0.02 8 35 0.038 Haematological toxicity - 1.00 Non-haematological toxicity 22 31 0.075 Untch et al. St Gallen 2013 (poster 249)

44 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

45 Geparsepto: Study design

46 Weeky comparison Abraxane vs paclitaxel

47 Study Endpoints Primary Endpoint pCR (ypT0 ypN0)
ypT0is ypN0; ypT0 ypN 0/+ Toxicity and compliance pCR rates by SPARC Secondary Endpoints

48 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

49 Primary endpoint: pCR: ypT0 ypN0

50 pCR in Subgroups

51 pCR in Stratified Subgroups
> 20%

52 Secondary Endpoints: pCR rates according to other definitions

53 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)

54 Hematological toxicity

55 Non hematological toxicity
Approximately 200 patients treated with 150 mg/m2/w

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57 TRIALS IN PROGRESS IN THE NEOADJUVANT SETTING

58 ETNA: Phase III study design (Michelangelo /GEICAM)
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) BIOPSY BIOPSY 4x 28d cycles: Nab-paclitaxel 125 mg/m2 QW 3/4 R 4x 28d cycles: Conventional paclitaxel 90 mg/m2 QW 3/4 1:1 BIOPSY BIOPSY 4x 21d cycles: AC or EC or FEC N=632 Recruitment finished 4x 21d cycles: AC or EC or FEC BIOPSY SURGERY BIOPSY FOLLOW-UP: 10 years after randomization of last patient Primary EP : pCR (absence of invasive disease in breast and nodes (ypT0/ypTis, ypN0) NCT Available at:

59 CONCLUSIONS nab-PACLITAXEL IN BREAST CANCER

60 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

61 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 the SmPC for nab-paclitaxel)

62 CONCLUSIONS: nab-Paclitaxel
Superior to CrEL-paclitaxel in the metastatic breast cancer Superior to CrEL-paclitaxel in the neoadjuvant setting

63 Gracias


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