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

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Presentation on theme: "ABRAXANE EN CÁNCER DE MAMA Lucía González-Cortijo Hospital Universitario Quirón Madrid Madrid, 11 de febrero de 2015."— 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 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)

4 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

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 TaxaneSynthetic 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 Taxan es anti- HER2 drugs drugs

10 INTRODUCTION TO nab-PACLITAXEL

11 HISTORICAL OVERVIEW OF TAXANES FOR THE TREATMENT OF BREAST CANCER

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

18 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): 279-83

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 Grade CP + EC, % (n=30) Nab-P + EC, % (n=30)Grade CP + EC, % (n=30) Nab-P + EC, % (n=30) Any AE3-4841Skin rash*Any830 LeukopeniaAny3585HFS*Any1115 Leukopenia3-407Allergic reaction*Any1530 NeutropeniaAny481PNPAny3870 Neutropenia3-4427PNP**3-4011 Increased APAny027Myalgia*Any2333 Increased AP3-407Epistaxis*Any3126 Increased ASTAny3126DyspnoeaAny117 Increased AST**3-404Dyspnoea3-440 Increased creatinine*Any018InfectionAny3844 Fatigue*Any5878Infection**3-4411 Headache*Any1537Mucositis*Any2330 Nausea*Any2337Pulmonary embolism**3-404 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?

43 Compliance to taxane treatment Taxane discontinuationTaxane 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 reason4300.028350.038 Haematological toxicity04-481.00 Non-haematological toxicity022-8310.075 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/m 2 QW (instead of 150 mg/m 2 ) 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/m 2 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 pCR (ypT0 ypN0) ypT0is ypN0; ypT0 ypN 0/+ Toxicity and compliance pCR rates by SPARC Primary Endpoint 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) 4x 28d cycles: Nab-paclitaxel 125 mg/m 2 QW 3/4 R 1:1 4x 28d cycles: Conventional paclitaxel 90 mg/m 2 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 NCT01822314. Available at: www.clinicaltrials.gov Primary EP Primary EP : pCR (absence of invasive disease in breast and nodes (ypT0/ypTis, ypN0) N=632 Recruitment finished

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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