1. Highlights in the Management of Breast Cancer Nanoparticles incapsulated drugs Alessandra Fabi Medical Oncology Rome, 10 May 2013 Mediterranean School of Oncology

2. Trasmission electronic Microscopy of nab- paclitaxel nanoparticles Piccart, APJOH 2009

3. Nab-paclitaxel is Albumin-bound Cremophor- free Paclitaxel Paclitaxel Albumin Mean = 130 nm cryo-TEM Concentration dependent dissociation into individual paclitaxel- bound albumin molecules Paclitaxel exists in the albumin particle in an non- crystalline, amorphous state

4. Desai N, et al. Clin Cancer Res 2006;12(4), 1317-24 Athymic mice with human xenografts (n = 10 per group; daily administration for 5 days) Breast MX-1 tumor model equidose paclitaxel comparison Preclinical Finding: Replacing Cremophor with Albumin Enhanced the Efficacy of Paclitaxel in Breast Cancer

5. Nab-paclitaxel Results in Higher Intra-tumoral Concentration Compared to Taxol ABI-007 = 1.33 X Taxol Desai et al. Clin Can Res, 2006. Intratumor paclitaxel levels following equal doses ABI-007 and Taxol in nude mice bearing MX-1 human breast cancer xenografts

6. Nab-paclitaxel ✔ Clinical data mono and combination: efficacy and toxicity in breast cancer ✔ Is there the patient ? ✔ Is there the patient who could better benefit? ✔ Future directions ✔ The other clinical fields

7. StudiesStudy ArmStandard ArmEnd- point Patients Gradishar 05 Fase III NAB-P; 260 mg/mq q3W Paclitaxel 175 mg/mq q3w ORR1-2+ line; Previous Anthracycline No previous taxanes Gradishar 09 R Fase II NAB-P 300 mg/mq q3w 100 mg/mq 3q4w 150 mg/mq 3q4w Docetaxel 100mg/mq q3w ORR1 line; No previous therapy; Adjuvant 1 year before clinical data in BC Nab-paclitaxel as single agent

8. Phase III Random (1:1) n = 460 nab-paclitaxel 260 mg/m 2 Every 3 weeks n = 233 paclitaxel 175 mg/m 2 Every 3 weeks n = 227 Misurable disease No taxanes for metastatic disease DFI >1 y from adjuvant taxanes Gradishar et al. J Clin Oncol 2005; 23:7794-803 Primary end point: ORr, Safety Secondary end-poit: PFS, OS

9. Previous Therapies nab- Paclitaxel n=229 Paclitaxel n=225 Taxanes Adjuvant or metastatic with taxanes 0% Adjuvant or metastatic Anthracyclines 77%78% Metastatic Anthracycline 50%58% Previous MBC CT Nihil 1 2 ≥ 3 42% 41% 10% 7% 40% 43% 16% 2% Gradishar et al. J Clin Oncol 2005; 23:7794-803

10. Response rate nab-paclitaxel:22997132176176 paclitaxel:22589136175182 ORR, tasso di risposta globale All patientsI lineII lineanthracyclinesvisceral disease P=0,001 0 10 20 30 40 50 60 33,2% 27,0% 42,3% 18,7% P=0,029 26,5% 13,2% P=0,006 34,1% 18,3% 33,5% P=0,002 18,7% ORR (± IC al 95%) Gradishar et al. J Clin Oncol 2005; 23:7794-803

11. 1.00 0.75 0.50 0.25 0.00 Time To disease Progression Note: P value log-rank test NAB-P (n = 229) Solvent-based paclitaxel (n = 224) Median = 23.0 wks (19.4–26.1) Mediana = 16.9 wks (15.1–20.9) P = 0.006 HR = 0.75 Proportion wthout progression weeks 081624324048566472808896104112120 Gradishar et al. J Clin Oncol 2005; 23:7794-803

12. Overall Survival Gradishar et al. J Clin Oncol. 2005; 23: 7794–7803 Note: P value log-rank test Median = 65.0 wks (52.1–76.9) NAB-P (n = 229) Solvent-based paclitaxel (n = 225) 1.00 0.75 0.50 0.25 0.00 Probability of survival weeks 081624324048566472808896104112120128136144 Median = 55.7 wks (48.0–66.4) P = 0.374 HR = 0.90

13. 1.00 0.75 0.50 0.25 0.00 weeks 081624324048566472808896104112120128136144 Overall Survival in pts ≥ 2a-line Note: P value log-rank test Nab-P (n = 131) Solvent-based paclitaxel (n = 136) P = 0.024 HR = 0.73 Median = 46.7 wks (39.0–55.3) Median = 56.4 wks (45.1–76.9) Gradishar et al. J Clin Oncol. 2005; 23: 7794–7803 Probability of survival

14. Safety nab-Paclitaxel n=229 Paclitaxel n=225 AE (%)Grade 3434p Neutropenia2593222< 0,001 Thrombocytopenia< 10 00,290 Anemia< 1 0 0,279 Febbrile Neutropenia< 1 00,491 Death for sepsis00– Gradishar et al. J Clin Oncol 2005; 23:7794-803 nab-Paclitaxel n=229 Paclitaxel n=225 AE (%)Grade p 234234 Ipersensibility † < 1000100,150 Hot flash< 100500< 0,001 Sensorial Neuropaty20100 20< 0,001 Fatigue138< 1163< 10,062 Mialgie127015200,567 Emesis43< 14100,022 Aedema200< 1 00,851

15. Neuropaty and nab-paclitaxel : time of duration 1,00 0,75 0,50 0,25 0,00 Days from grade 3 to 1 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 % of unresolved cases nab-Paclitaxel (n=24) + + + + ● ●improvement: medain 22 days (95%CI 17-22) vs 79 days of paclitaxel ● ● 3% of pts (6/233) discontinued therapy with nab-paclitaxel due to sensorial neuropaty. No case of motor neuropaty Gradishar et al. J Clin Oncol 2005; 23:7794-803

16. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for MBC 302 MBC pts in I line therapy Braccio A (n = 76):nab-paclitaxel 300 mg/m 2 ogni 3 settimane Braccio B (n = 76):nab-paclitaxel 100 mg/m 2 alla settimana x 3/ogni 4 settimane Braccio C (n = 74):nab-paclitaxel 150 mg/m 2 alla settimana x 3/ogni 4 settimane Braccio D (n = 74):docetaxel 100 mg/m 2 ogni 3 settimane RANDOMIZERANDOMIZE nab-paclitaxel versus docetaxel (A,B,C vs D) nab-paclitaxel qw versus q3w (B,C vs A) nab-paclitaxel bassa vs alta dose qw (B vs C) Comparing Endpoint primario: ORR Arms A, C e D somministrati alla MTD 3q4w, ripetuta wkly per 3 wks / 4 Gradishar et al. J Clin Oncol 2009;27:3611–3619

17. Response Rate Gradishar et al. J Clin Oncol 2009;27:3611–3619 P=0.024 P<0.001 P=0.002 % of patients nab-Paclitaxel Docetaxel n=302 * ° nab-paclitaxel 150 mg/m 2 versus docetaxel P = 0,001 * nab-paclitaxel 100 mg/m 2 versus docetaxel P = 0,002

18. Progression Free Survival Gradishar et al. J Clin Oncol 2009;27:3611–3619

19. Overall Survival 1.00 0.75 0.50 0.25 0 1020 30 40 50 Probability of Survival Months 0 HR = 0.688 1. Gradishar et al. ASCO Breast Cancer Symposium. 2011 [Abstract 275]. 2. Gradishar et al. J Clin Oncol. 2009;27(22):3611-3619. The 150 mg/m 2 qw NAB-paclitaxel arm demonstrated a numerically longer OS versus docetaxel (not statistically significant) NAB-paclitaxel 300 mg/m 2 q3w and 100 mg/m 2 qw arms not shown OS calculated when 58% of patients had died. HR, hazard ratio; OS, overall survival; qw 3/4, first 3 of 4 weeks; q3w, every 3 weeks. NAB-paclitaxel 150 mg/m 2 qw 3/4 (n = 74) Docetaxel 100 mg/m 2 q3w (n = 74) 26.633.8 For the purpose of clarity, only these 2 (out of 4) patient groups were included here. + 7.2

20. qw or q3w ABRAXANE ® vs q3w docetaxel: toxicity † Gradishar W, et al. J Clin Oncol, 2009; 27(22): 3611-3619. ABRAXANE ® Docetaxel 300 mg/m 2 q3w (n = 76) 100 mg/m 2 qw (n = 76) 150 mg/m 2 qw (n = 74) 100 mg/m 2 q3w (n = 74) Neuropatia, n (%) grade 217 (22)11 (14)19 (26)14 (19) grade 313 (17)6 (8)10 (14)9 (12) grade 40 (0) Fatigue, n (%) grade 217 (22)5 (7)15 (20)12 (16) grade 34 (5)0 (0)2 (3)14 (19) grade 40 (0) † reported in ≥ 25% of patients

21. ASCO Breast Symposium, Abstract # 275 nab-paclitaxel 150 mg/m2 qw ¾ demonstreted the best as I line MBC Final Overall Survival Analysis of a Randomized Phase 2 Trial

22. O’Shaughnessy et al, Poster P1-12-07, San Antonio 2012 Who patients could better benefit Visceral metastases Short DFI

23. Weekly nab-paclitaxel is safe and effective in 65 years old patients with metastatic breast cancer: A post-hoc analysis Matti Aapro, Sergei Tjulandin, Paul Bhar, William Gradishar

24. ORr - DCR In the phase 2 study ORRnab-paclitaxel 22%300 mg/m2 q3w 64% 100 mg/m2 weekly 60% 150 mg/m2 weekly docetaxel32% 100 mg/m2 q3w In the phase 3 study ORRnab-paclitaxel 27%260 mg/m2 q3w paclitaxel19% 175 mg/m2 q3w Aapro M et al, The Breast 2011 In the phase 2 study DCR nab-paclitaxel 56% 300 mg/m2 q3w 86%100 mg/m2 weekly 90%150 mg/m2 weekly docetaxel79% 100 mg/m2 q3w In the phase 3 study DCRnab-paclitaxel 53 % 260 mg/m2 q3w paclitaxel41%175 mg/m2 q3w

25. PFS In the phase 3 study PFS median nab-paclitaxel 5.6 260 mg/m2 q3w paclitaxel 3.5 175 mg/m2 q3w Aapro M et al, The Breast 2011 In the phase 2 study PFS median nab-paclitaxel 13.8 300 mg/m2 q3w 9.2 100 mg/m2 weekly 18.9 150 mg/m2 weekly docetaxel 8.5 100 mg/m2 q3w

26. Combination therapy

27. Phase II combinations Nab-P + gemcitabine I line ORr 50% PFS 7.9 mos Roy et al. Ann Oncol 2009;20:449–453 Nab-P + capecitabine I line ORr 61% PFS 8.2 mos Somer et al. Presented at ASCO Meeting 2007; Abstract 1053 Nab-P + trastuzumab + carboplatin I line HER2+ ORr 63% PFS 16.6 mos Conlin et al. Clin Breast Cancer 2010; 281-7 Nab-P + lapatinibII line HER2+ ORr 54% PFS 9.3. mos Yardley et al. SABCS 2011 Nab-P + Bevacizumab I line ORr 75.9% PFS 10.7 mos Lobo et al. Breast Cancer Res Treat 2010

28. Considerations The actual indication of NAB-paclitaxel is at three-weekly schedule (260 mg/m 2 ), but the evidences justify the weekly administration (150, 125, 100 mg/m 2 ) Clinical data support the use of NAB-paclitaxel in MBC from the 1- line, also for pts pretreated with taxanes in adjuvant setting, relapsed or refractory The sensorial neuropaty usual occur late in course of treatment, and it can be manage with dose reduction, short drug interruption and rapidly improve Future marker will be evaluated, such as caveolin and SPARC

29. Future Directions Targeted therapy Piccart, APJOH 2009

30. Phase III in first - line NSCLC: nab-Paclitaxel + carboplatin demonstrated improved activity vs conventional paclitaxel + carboplatin ORr: 41% vs 24% (p=.005) higher in squamous subtype Lung Cancer Phase III in first-line metastatic melanoma: nab-paclitaxel vs dacarbazine PFS: 4.8 vs 2.5 mos (p=.04) Melanoma Breast Cancer First approved in the US in 2005 and in the EU in 2008 for the treatment of MBC. nab ® -Paclitaxel Improves Clinical Outcomes Across Multiple Tumor Types, Including Historically Non- Taxane Sensitive Tumors 1-9 Pancreatic Cancer Phase III trial IMPACT: nab- paclitaxel + gemcitabine vs gemcitabine alone. OS: 14.8 vs 11.5 mos (p=.0000015) (p=.0000015) nab ® is a registered trademark of Celgene Corporation. 1.Gradishar et al. J Clin Oncol. 2009;27(22):3611-3618. 2.Gradishar et al. J Clin Oncol. 2005;23(31):7794-7803. 3.Gradishar et al. ASCO Breast Cancer Symposium. 2011 [Abstract 275]. 4.Von Hoff et al. Published online ahead of print October 3, 2011. J Clin Oncol. doi: 10.1200/JCO.2011.36.5742. 5.Burris et al. J Clin Oncol. 1997;15(6):2403-2413. 6.Hersh et al. Cancer. 2010;116(1):155-163. 7.Boasberg et al. ASCO. 2011 [Abstract 8543]. 8.Kottschade et al. ASCO. 2011 [Abstract 8532]. 9.Socinski et al. ASCO. 2010 [Abstract LBA7511].

31. Comparing views of patients with those of doctors, nurses and general public Slevin ML, Br Med J 300:1458, 1990 Respondents accepting intensive treatments with a supposed minimum chance of effectiveness

32. Thanks for attention