nab-paclitaxel: La pratica clinica

Il carcinoma mammario metastatico oggi Malgrado i progressi compiuti nell’ambito del trattamento delle pazienti affette da carcinoma mammario metastatico, esistono necessità mediche non ancora soddisfatte, fra cui: Tassi più alti di sopravvivenza globale, dato che la maggior parte delle pazienti manifesta una progressione della malattia, malgrado le terapie disponibili in commercio Compromissione minore della qualità di vita durante il trattamento, in associazione a un aumento del livello di soddisfazione della paziente

Il carcinoma mammario metastatico oggi Malgrado i progressi compiuti nell’ambito del trattamento delle pazienti affette da carcinoma mammario metastatico, esistono necessità mediche non ancora soddisfatte, fra cui: Miglioramento dell’indice terapeutico, aumentando l’efficacia e riducendo la tossicità dei farmaci Migliore comprensione dei profili delle pazienti, terapie appropriate, specialmente con molecole nuove

Obiettivi del trattamento in MBC Cure No single drug or combination cures MBC N 2 Prolong Survival Few drugs or combinations have proved the capacity to prolong overall survival of MBC N 3 Improve QoL Hormones better therapeutic index than Chemotherapy Chemo combos more effective, but more toxic than single agent Targeted treatment improve Chemo Symptom relief Prevent complications of MBC Minimize AEs from treatments Palliative

Informazioni necessarie per la scelta del trattamento Età e comorbidità Estensione della Malattia Organi Coinvolti Caratteristiche Biologiche (neoplasia primaria e/o metastasi): ER, PgR, HER2 DFS Precedenti trattamenti Preferenze della paziente

Survival of Patients with Metastatic Breast Cancer 1974 - 2000 Giordano SH, et al, Cancer 100:44-52, 2004

Caratterizzazione Biologica e Carcinoma Mammario Metastatico

Metastatic Behavior of Breast Cancer Subtypes 3726 patients Median follow-up time 14.8 years Diagnosed between 1986 and 1992 Referred to the British Columbia Cancer Agency Archive Tissue Available H Kennecke, JCO 2010

Metastatic Behavior of Breast Cancer Subtypes ER/PR Ki67 HER2 EGFR and CK 5/6 Luminal A ER and/or PR positive < 14% negative - Luminal B > 14% Luminal/HER2 positive HER2 enriched Basal Like EGFR and/or CK 5/6 positive TN non basal EGFR and CK 5/6 negative H Kennecke, JCO 2010

Metastatic Behavior of Breast Cancer Subtypes Ten-year Survival Median Duration of Survival from mts (years) 15-year distant relapse rate Luminal A 70% 2.2 27.8% Luminal B 54.4% 1.6 42.9% Luminal/HER2 46.1% 1.3 47.9% HER2 enriched 48.1% 0.7 51.4% Basal Like 52.6% 0.5 43.1% TN non basal 62.6% 0.9 35.1% H Kennecke, JCO 2010

Metastatic Behavior of Breast Cancer Subtypes Frequency among pts who developed mts(%) Brain Liver Lung Bone Distant Nodes Pleura /peritoneum Luminal A 7.6 28.6 23.8 66.6 15.9 28.2 Luminal B 10.8 32.0 30.4 71.4 23.3 35.2 Luminal/HER2 15.4 44.4 36.8 65.0 22.2 34.2 HER2 enriched 28.7 45.6 47.1 59.6 25.0 31.6 Basal Like 25.2 21.4 42.8 39.0 39.6 29.6 TN non basal 22.0 32.1 35.8 43.1 28.4 Pearson’s Chi-square test showed p <0.001 in all cases H Kennecke, JCO 2010

Survival curve percentiles and their corresponding scenarios 6.3 months 11.9 months 36.2 months 55.8 months Survival curve percentiles and their corresponding scenarios. Kiely B E et al. JCO 2011;29:456-463 ©2011 by American Society of Clinical Oncology

Le Linee-Guida: nab-paclitaxel e altri taxani Paclitaxel viene raccomandato in prima linea in monoterapia o in associazione a bevacizumab Raccomandato anche l’utilizzo di nab paclitaxel alla posologia di 100-150 mg/m2 ev ai giorni 1, 8 e 15 ogni 28 giorni, o alla posologia di 260 mg/m2 ev ogni 21 giorni Terapia di prima linea con paclitaxel settimale in monoterapia, paclitaxel associato ad antraciclina (doxorubicina, epirubicina), a gemcitabina, vinorelbina o carboplatino. Le Linee-guida ESMO suggeriscono anche l’impiego del nuovo farmaco nab-paclitaxel Nell’aggiornamento 2010 delle linee guida AIOM nab paclitaxel è stato inserito tra i farmaci molto attivi in monoterapia; si sottolinea infatti che nab paclitaxel ha dimostrato di migliorare significativamente la percentuale di risposte obiettive, TTP e OS nelle donne con carcinoma mammario metastatico rispetto a paclitaxel disciolto in solvente

Linee-Guida AIOM e nab-paclitaxel Tra le più recenti novità terapeutiche, le Linee Guida AIOM citano nab-paclitaxel: “Nab-paclitaxel, una formulazione di paclitaxel a nanoparticelle legate ad albumina senza solventi chimici e che pertanto non richiede una premedicazione, ha migliorato significativamente la percentuale di risposte obiettive, il tempo alla progressione e la sopravvivenza globale rispetto a paclitaxel in uno studio di fase III”

NCCN: Linee-guida MBC HER2 - HER2 + No compelling evidence that combination regimens are superior to sequential agents HER2 - HER2 + 16 preferred single agents/combinations listed with no sequencing guidance Relatively clearer guidance for HER2+ patients Anthracyclines Taxanes Anti-metabolites First Line (Herceptin Naïve) HERCEPTIN Exposed Doxorubicin Paclitaxel Albumin-bound Paclitaxel Capecitabine Capecitabine + lapatinib Pegylated Liposomal Doxorubicin Herceptin + Paclitaxel +/- Carboplatin Gemcitabine Herceptin + Capecitabine Epirubicin Docetaxel Herceptin + Docetaxel Combo/Other Herceptin + lapatinib Vinorelbine AC DC Herceptin + Vinorelbine FAC/CAF AT GP Herceptin + HER2- recommended therapy FEC CMF Other Herceptin + Capecitabine Bevacizumab

NCCN: nab-paclitaxel tra le monochemioterapie raccomandate in prima linea

Taxanes Sequential preferred

nab-paclitaxel e Tecnologia nab™ “nab-paclitaxel non è semplicemente un altro taxano: è la prima chemioterapia target che rappresenta un passo avanti per il trattamento delle pazienti affette da carcinoma mammario metastatico” Piccart M., nab™-Paclitaxel: A Targeted Chemotherapy to Improve Outcomes in Metastatic Breast Cancer, APJOH 2009.

nab-paclitaxel: una chemioterapia mirata il nab-paclitaxel, grazie alla tecnologia nab sfrutta le proprietà peculiari di trasporto dell’albumina (gp60, CAV-1 e SPARC) per rilasciare alte concentrazioni di farmaci direttamente nel tumore Speaker Notes: Taxanes are a recognized part of the standard of care for the treatment of early-stage and metastatic breast cancer.1 Weekly dosing, not higher dosing, has been the only effective strategy that enhances the efficacy endpoints of solvent-based (sb)-paclitaxel. 2,3 Docetaxel has greater efficacy when compared to paclitaxel on a Q3W dosing schedule, although the former was associated with significantly more toxicities.4 nab®Paclitaxel was shown to have superior efficacy when compared to sb-paclitaxel in a phase III study of patients with metastatic breast cancer.5 Because the optimal dosing schedule for nab®paclitaxel was not known prior to this study, multiple arms were assigned to nab®paclitaxel at varying doses and schedules. References: Conlin AK, Seidman AD: Taxanes in breast cancer: An update. Curr Oncol Rep 9:22-30, 2007 Winer EP, Berry DA, Woolf S, et al: Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: Cancer and Leukemia Group B trial 9342. J Clin Oncol 22:2061-2068, 2004 Verrill MW, Lee J, Cameron DA, et al: Anglo-Celtic IV: first results of a UK National Cancer Research Network randomised phase 3 pharmacogenetic trial of weekly versus 3 weekly paclitaxel in patients with locally advanced or metastatic breast cancer (ABC). J Clin Oncol 25:33s, 2007 (suppl; abstr LBA1005) Jones SE, Erban J, Overmoyer B, et al: Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 23:5542-5551, 2005 Gradishar WJ, Tjulandin S, Davidson N, et al: Phase III Trial of Nanoparticle Albumin-Bound Paclitaxel Compared With Polyethylated Castor Oil-Based Paclitaxel in Women With Breast Cancer. J Clin Oncol 23:7794-803, 2005 Citotossico: paclitaxel Albumina 130 nm Dissociazione in singoli complessi paclitaxel-albumina 21

nab-paclitaxel: meccanismo d’azione nab-paclitaxel è la prima nano-chemioterapia target1 Dissociazione in singoli complessi di paclitaxel albumina Legame recettoriale attivo e mirato tra paclitaxel albumina e recettori gp60, con attivazione di caveolina-1 1 2 Incremento della transcitosi attraverso le membrane cellulari endoteliali Incremento dell’accumulo a livello tumorale di paclitaxel albumina attraverso il legame con la proteina SPARC 3 4 1. Piccart M., APJOH 2009. 22

Differenze tra nab-paclitaxel e gli altri taxani Parametri Paclitaxel Docetaxel nab-paclitaxel Formulazione Solvente Cremophor e Ethanol Tween 80 e Ethanol Solvent free Premedicazione Corticosteroidi Antistaminici H2 Antagonisti Non richiesta Dose & efficacia Più basse dosi richieste Più alte dosi possibili Reazioni Ipersensitività Secondarie a solvente Ridotte Tempo di Infusione 3 ore 1 ora ~30 minuti IV tubing Non-PVC tubing PVC or non-PVC tubing nab™-paclitaxel therapy for metastatic breast cancer offers several advantages over standard paclitaxel treatment. It has become increasingly recognized that formulation vehicles may be responsible for some of the “taxane-associated toxicity,” particularly fluid retention and hypersensitivity which require pre-medication with antihistamines and moderate-to-high doses of corticosteroids to manage. nab-paclitaxelTM is solvent-free and does not require pre-medication with corticosteroids to prevent hypersensitivity reactions. nab-paclitaxelTM is dosed “higher.” This is possible because of less time for R/T plateau. It is in large part because of the toxicities associated with the current formulations of taxanes that strategies such as nab-paclitaxel have been developed to enhance the therapeutic index of these agents. Since nab-paclitaxel is solvent free, the potential for hypersensitivity reactions to occur in patients who are administered nab-paclitaxel is greatly reduced. This in turn means that no pre-medication with antihistamines or steroids is needed. As a result, the chair time for drug administration is reduced considerably. For Internal Use Only. Not for Distribution

nab-paclitaxel, da febbraio 2011 anche in Italia Testo testo 1 febbraio 2011 TUMORE DEL SENO, APPROVATA LA RIMBORSABILITÀ DI PACLITAXEL ALBUMINA È disponibile anche in Italia paclitaxel albumina (nab-paclitaxel, formulazione di paclitaxel legato all’albumina in nanoparticelle privo di solventi) per il trattamento del tumore metastatico della mammella in pazienti adulte nelle quali il trattamento di prima linea per la malattia metastatica ha fallito e la terapia standard, contenente antraciclina, non è indicata. Il farmaco è già stato approvato dall’EMA e il regime di rimborsabilità (in fascia H) è stabilito nella Gazzetta Ufficiale del 14 ottobre 2010. Il nuovo farmaco è soggetto a prescrizione limitativa, utilizzabile esclusivamente in ambiente ospedaliero o in struttura ad esso assimilabile (OSP) al dosaggio unico di 100 mg.

GU nab-paclitaxel (14/10/2010)

Nuova GU nab-paclitaxel (13/05/2011)

nab-paclitaxel: Indicazioni a confronto USA – EU - Italia nab-paclitaxel is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated nab-paclitaxel monotherapy is indicated 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 La monoterapia con nab-paclitaxel è indicata nel trattamento del tumore metastatico della mammella in pazienti adulti che hanno fallito il trattamento di prima linea per la malattia metastatica e per i quali la terapia standard, contenente antraciclina, non è indicata

Studi in malattia metastatica Studio Braccio Sperimentale Braccio Standard End-point Pazienti Gradishar, Fase III NAB-P; 260 mg/mq q3W Paclitaxel 175 mg/mq q3w ORR 1-2+ linea trattamento; Antracicline pretrattamento No pretrattamento taxani Fase II rand NAB-P 300 mg/mq q3w 100 mg/mq 3q4w 150 mg/mq 3q4w Docetaxel 100mg/mq q3w 1 linea; Nessun pretrattamento; Adiuvante un anno prima CALGB/ NCCTG 150 mg/mq qw + Bevacizumab 90 mg/mq qw Ixabepilone 16 mg/mq qw PFS Localmente avanzato; 1 linea metastatico

nab-Paclitaxel - studi di combinazione Dual Phase II open-label n=50 first-line + gemcitabine Roy et al. Ann Oncol 2009;20:449–453 + capecitabine Somer et al. Presented at ASCO Meeting 2007; Abstract 1053 Dose comparison Target n=225 + bevacizumab Conlin et al. Presented at ASCO 2009; Abstract 1006 Danso et al. Presented at ASCO Meeting 2008; Abstract 1075 Retrospective subgroup analysis n=40 heavily pretreated Link et al. Clin Breast Cancer 2007;7: 779–783 n. 72 first line + trastuzumab Mirtsching et al. Clin Breast Cancer 2011; 1-8 Triple n=25 + gemcitabine + bevacizumab Lobo, Gluck et al. Breast Cancer Res 2010; 123: 427-435 Target n=50 HER2+ve + carboplatin + trastuzumab Conlin et al. Clin Breast Cancer 2010; 281-7 *nab-paclitaxel monotherapy is indicated 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. The recommended dose of nab-paclitaxel is 260 mg/m2 administered intravenously over 30 minutes every nab-paclitaxel is not approved for use in combination chemotherapy 29

nab-paclitaxel in MBC – Synoptic Table Conlin Lobo Roy Somer N 50 73 78 29 mg/m2 100 q1w 260 q3w 130 q1w 150 q2w 125 q1w Partner Drug Carbo Her Bev Gem Bev Gem Xel Age 52.0 < 65 54.0 56.0 59.0 ORR 63% 44% 46% 75.9% 50% 60.9% CR 9% 1% 27.6% 8% 4.3% PR 54% 43% 45% 48.3% 42% 56.5% PFS 16.6 mo NR 10.4 mo 7.9 mo 270 days TTP 7.7 mo 9.0 mo OS Not reached Toxicities (Grade 3 + 4 only) ANC 2% FN 0% FN 55% 10% PLT 3% 12% PN 30% 39% 6% Fatigue 16% 17% 0% 29% *nab-paclitaxel monotherapy is indicated 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. The recommended dose of nab-paclitaxel is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. nab-paclitaxel is not approved for use in first-line chemotherapy, weekly regimen or combination chemotherapy

Posizionamento di nab-paclitaxel Proposte

HER2 positivity as a major driver in the Decision Making Process HER2 +/ HR - Prev adjuvant Trastuzumab Taxane (incl nab-paclitaxel) or Vinorelbine +Trastuzumab Lapatinib and Capecitabine NO Prev adjuvant Trastuzumab Si può somministrare nab-paclitaxel come nello studio di Gradishar, ma ci sono anche dati che sostengono le combinazione di nab-paclitaxel con altre molecole. I green box si riferiscono agli studi di fase 2. I blu box comprendono anche i risultati dello studio di Gradishar (di fase 3). Green BOX = interesting results for nab-paclitaxel Blue BOX = nab-paclitaxel as studied in the Gradishar Trial and interesting results for combinations

HER2 positivity as a major driver in the Decision Making Process HER2 +/ HR + Prev adjuvant T Taxane (incl nab-paclitaxel) or Vinorelbine +T Lapatinb and Capecitabine Anti-HE2 and Aromatase Inhibitor Taxane (incl nab-paclitaxel) or Vinorelbine + T Anti -HER2 combinations Anti HER2 + CT NO Prev adjuvant T Lapatinib and Capecitabine Anti-HER2 and Aromatase Inhibitor Anti -HER2 Combinations Si può somministrare nab-paclitaxel come nello studio di Gradishar, ma ci sono anche dati che sostengono le combinazione di nab-paclitaxel con altre molecole. I green box si riferiscono agli studi di fase 2. I blu box comprendono anche i risultati dello studio di Gradishar (di fase 3). Green BOX = interesting results for nab-paclitaxel Blue BOX = nab-paclitaxel as studied in the Gradishar Trial and interesting results for combinations

HER2 negativity corresponds to a major heterogeneity HR+ Amenable with HT Sequential Lines of HT Candidate for CT HR-

The dilemma of choosing CT for HER2-/HR+ HER2 -/ HR +/ Candidate for Chemotherapy Rapid Control of the Disease Growth is Needed No Adjuvant CT or CMF Anthra/taxane Anthracycline Taxane (incl nab-paclitaxel) +/- Antimetabolite nab-paclitaxel Capecitabine and /or Vinorelbine ** Adjuvant Anthracyclines Taxane (incl nab-paclitaxel) +/- Antimetabolite Anthracyclines rechallenge Taxane (incl nab-paclitaxel) + Beva Capecitabine and/or Vinorelbine nab-paclitaxell Antrhacycline Rechallenge Capecitabine and or Vinorelbine ** Adjuvant Anthracyclines and Taxanes Anthacycline Rechallenge Taxane Rechallenge (+/- Beva) Capecitabine and or Vinorelbine nab-paclitaxel (+/-Beva)* Capecitabine and or Vinorelbine** Rapid Control of the Disease Growth is NOT Needed Green BOX = interesting results for nab-paclitaxel Blue BOX = nab-paclitaxel as studied in the Gradishar Trial and interesting results for combinations * Adjuvant Taxane stopped at least 6 months before ** If not previously employed in first line Si può somministrare nab-paclitaxel come nello studio di Gradishar, ma ci sono anche dati che sostengono le combinazione di nab-paclitaxel con altre molecole. I green box si riferiscono agli studi di fase 2. I blu box comprendono anche i risultati dello studio di Gradishar (di fase 3).

The dilemma of choosing CT for HER2-/HR+ HER2 -/ HR +/ Candidate for Chemotherapy Rapid Control of the Disease Growth is NOT Needed No Adjuvant CT or CMF MonoCT (anthra, taxane*, vinorelbine, capecitabine) nab-paclitaxel MonoCT (nab-paclitaxel, vinorelbine, capecitabine)** Adjuvant Anthracyclines MonoCT (taxane, vinorelbine, capecitabine) Adjuvant Anthracyclines and Taxanes MonoCT (vinorelbine, capecitabine) nab-paclitaxel* Rapid Control of the Disease Growth is Needed Green BOX = interesting results for nab-paclitaxel Blue BOX = nab-paclitaxel as studied in the Gradishar Trial and interesting results for combinations * Adjuvant Taxane stopped at least 6 months before ** If not previously employed in first line Si può somministrare nab-paclitaxel come nello studio di Gradishar, ma ci sono anche dati che sostengono le combinazione di nab-paclitaxel con altre molecole. I green box si riferiscono agli studi di fase 2. I blu box comprendono anche i risultati dello studio di Gradishar (di fase 3).

“Triple Negative” MBC Blue BOX = HER2 -/ HR- No adjuvant CT or CMF Anthra/taxane Anthracycline Taxane (incl nab-paclitaxel) +/- Antimetabolite nab-paclitaxel Capecitabine and /or Vinorelbine ** Adjuvant Anthracyclines Anthracyclines rechallenge Taxane (incl nab-paclitaxel) + Beva Capecitabine and/or Vinorelbine Antrhacycline Rechallenge Capecitabine and or Vinorelbine ** Adjuvant Anthhracyclines and Taxanes Anthacycline Rechallenge Taxane Rechallenge (+/- Beva) Capecitabine and or Vinorelbine nab-paclitaxel (+/-Beva)* Capecitabine and or Vinorelbine** * Adjuvant Taxane stopped at least 6 months before ** If not previously employed in first line Blue BOX = nab-paclitaxel as studied in the Gradishar Trial and interesting results for combinations Si può somministrare nab-paclitaxel come nello studio di Gradishar, ma ci sono anche dati che sostengono le combinazione di nab-paclitaxel con altre molecole. I green box si riferiscono agli studi di fase 2. I blu box comprendono anche i risultati dello studio di Gradishar (di fase 3).

Ogni flacone contiene 100mg nab-paclitaxel Dose Raccomandata nab-paclitaxel 260 mg/m2 IV in 30 minuti ogni 3 settimane Ogni flacone contiene 100mg nab-paclitaxel e 900mg albumina umana nab-paclitaxel™ (nab-paclitaxel) is indicated in Canada for the treatment of first-line metastatic breast cancer. The approved dose is nab-paclitaxelTM 260mg/m2 administered by IV over 30 minutes every 3 weeks. For an average BSA = 1.7m2, the dosing volume is approximately 90 mls. Reference: nab-paclitaxel™ Canadian Product Monograph. June 2006, Richmond Hill, Canada. For Internal Use Only. Not for Distribution

nab-paclitaxel: NO SCHEDA AIFA

nab-paclitaxel: modalità di somministrazione

Informazioni per la somministrazione La soluzione ricostituita è una soluzione lattescente omogenea Stabilità 8 ore (temperatura ambiente o refrigerata) Infusione in 30 minuti; set d’infusione solo con normali soluzioni saline nab-paclitaxelTM reconstituted solution is a milky, homogenous solution that is stabile for 8 hours (room temperature or refrigerated). The reconstituted solution is infused 30 minutes. As nab-paclitaxelTM is solvent-free, no special IV tubing is required (no filters, non-PVC or PVC tubing is allowed with nab-paclitaxelTM infusion). Premedications are not required with nab-paclitaxelTM as it is a solvent-free taxane preparation. nab-paclitaxelTM is classified as an irritant; it is important to monitor site for injection reactions. nab-paclitaxelTM is only compatible with normal saline solution; flushing pre and post with normal saline is possible. For Internal Use Only. Not for Distribution