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nab-paclitaxel in combinazione Dati clinici e safety

nab-paclitaxel in combinazione Dati clinici e safety. nab-paclitaxel IN BREAST CANCER Essential Concepts. Better efficacy and safety than TAX in MBC: In Q3W schedule –Ph III trial (CA012) Better efficacy and safety than Q3W TXT in MBC: In Q1W schedule –Ph II randomized trial (CA024)

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nab-paclitaxel in combinazione Dati clinici e safety

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  1. nab-paclitaxel in combinazioneDati clinici e safety

  2. nab-paclitaxel IN BREAST CANCEREssential Concepts • Better efficacy and safety than TAX in MBC: • In Q3W schedule –Ph III trial (CA012) • Better efficacy and safety than Q3W TXT in MBC: • In Q1W schedule –Ph II randomized trial (CA024) • Combinable with large number of drug partners without compromise in efficacy or safety – several studies • Promising activity when combined with GEM + BEV in Q2W schedule (Lobo) • Not feasible and probably unnecessary to run Ph III for registration vs. Q3W TXT • Not feasible to run a Ph III adjuvant study in unselected pt populations • No more neoadjuvant studies to be done in unselected patient populations • Mammaprint study may open door for early breast cancer positioning Ibrahim NK et al. J Clin Oncol. 2005; 23: 6019−6026

  3. nab-Paclitaxel - studi di combinazione *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 everynab-paclitaxel is not approved for use in combination chemotherapy

  4. nab-paclitaxel in MBC – Synoptic Table *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

  5. nab-paclitaxel in combinazione con:GemcitabineCapecitabineTrastuzumabBevacizumab

  6. NCCTG Phase II Trial N0531 of Weekly nab-Paclitaxel in Combination with Gemcitabine in Patients with Metastatic Breast Cancer V. Roy, B. R. LaPlant, G. G. Gross, C. L. Bane, F. M. Palmieri, E. A. Perez, on behalf of the North Central Cancer Treatment Group Roy V, et al. Ann Oncol 2009; 20(3):449-453

  7. Study Rationale • nab-paclitaxel significantly reduced acute toxicity and showed superior efficacy to solvent-based paclitaxel¹ • A phase III study of GEM + TAX demonstrated superior antitumor activity in anthracycline-pretreated patients with MBC with 41% vs. 26% ORR for (doublet vs. TAX alone)² • This study was to evaluate the combination of nab-paclitaxel and gemcitabine for MBC • Gradishar et al, J Clin Oncol 2005 2) Albain et al, J Clin Oncol 2008 • Roy V, et al. Ann Oncol 2009; 20(3):449-453

  8. Patient Eligibility • Key Inclusion Criteria • Age ≥18 years of age • Confirmed histological and cytological invasive breast cancer with clinical evidence of metastatic disease • ECOG PS 0-1 • No previous chemotherapy for MBC • Previous taxanes allowed if completed >6 mo before • Key Exclusion Criteria • No active CNS metastasis • No >grade 1 peripheral neuropathy Roy V, et al. Ann Oncol 2009; 20(3):449-453

  9. Study Design & Treatment • Open-label, multicenter phase II study conducted through the North Central Cancer Treatment Group (NCCTG) • Primary Endpoint: • Response rate (RR) • Secondary Endpoints: • Overall survival (OS) • Progression-free survival (PFS) • Duration of Response nab-paclitaxel125 mg/m2IV over 30 minDays 1 and 8 every 21 days Gemcitabine 1000 mg/m2IV over 30 minDays 1 and 8 every 21 days Roy V, et al. Ann Oncol 2009; 20(3):449-453

  10. Efficacy Results (N = 50) Roy V, et al. Ann Oncol 2009; 20(3):449-453

  11. Adverse Events (AEs) occurring in >5% of patients N = 50 AST, aspartate aminotransferase Roy V, et al. Ann Oncol 2009; 20(3):449-453

  12. Conclusions • Weekly nab-paclitaxel in combination with gemcitabine demonstrated significant activity as first-line therapy in patients with MBC • Toxicities were manageable; neutropenia was the most common AE • No significant nonhematologic toxicities were encountered • Grade 3 neuropathy occurred in 3 (6%) patients Roy V, et al. Ann Oncol 2009; 20(3):449-453

  13. Phase II Trial of nab-Paclitaxel + Capecitabine in First-line Treatment of Metastatic Breast Cancer B. G. Somer, L.S. Schwartzberg, F. Arena, D. Mintzer, A. Epperson, D. Fu, B.V. Fortner Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053

  14. Study Rationale • nab-Paclitaxel and capecitabine have substantial single agent activity in MB1-4 • Taxane and anti-metabolite doublets improve RR and TTP compared with single agent therapy5 • Weekly nab-paclitaxel has an excellent safety and efficacy profile with maintenance of dose intensity6 • This study was designed to evaluate the safety and efficacy of nab-paclitaxel and capecitabine given in a novel combination schedule 1) Gradishar et al, J Clin Oncol 2005 2) Talbot et al, Br J Cancer 2002 3) O’Shaughnessy et al, Ann Oncol 2001 4) Bajetta et al, J Clin Oncol 2005 5) Miles et al, Clin Breast Cancer 2004 6) Blum et al, Proc ASCO 2003 Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053

  15. Study Design & Treatment • This was a phase II, multicenter, open-label study • Treatment • nab-Paclitaxel 125 mg/m2 IV on days 1 and 8 q3w without premedication • capecitabine 825 mg/m2 orally bid on days 1-14 q3w • Primary endpoint: • RR • Secondary endpoints: • PFS • OS • Safety Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053

  16. Select Patient Characteristics Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053

  17. Tumor Response • 4 out of 50 patients were not evaluable for response • ORR: 28 (60.9%) patients • CR: 2 (4.3%) patients • PR: 26 (56.5%) patients • SD: 10 (21.5%) patients • PD: 8 (17.4%) patients Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053

  18. Progression-free Survival Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053

  19. Overall Survival Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053

  20. GRADE 3/4 Adverse Events Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053

  21. Dose Modifications Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053

  22. Conclusion • nab-Paclitaxel and capecitabine is a highly active combination regimen in first-line MBC with an ORR of 61% • Days 1 and 8 nab-paclitaxel at 125 mg/m2 plus capecitabine 825 mg/m2 bid days 1-14 q3w is well tolerated • A favorable PFS with a median of 270 days was observed with this combination regimen Somer, et al. Presented at ASCO Meeting 2007; Abstract 1053

  23. nab-paclitaxel + Trastuzumab

  24. nab-paclitaxel qw + trastuzumab have shown first-line efficacy in MBC • Include details from 2 phase II studies in first line MBC: • Conlin 2010 (nab-paclitaxel + carboplatin + trastuzumab) • ORR: 62.5% • ORR + SD>16 weeks: 81% • Mirtsching 2011 (nab-paclitaxel ± trastuzumab) • ORR 42.2% (52% in HER2+) • Overall benefit (ORR +SD): 68.8% Conlin et al. Clin Breast Cancer 2010;10:281-287; Mirtsching et al. Clin Breast Cancer 2011; Jan 11:1-8 (Epub)

  25. Phase II Trial of Weekly Nanoparticle Albumin-Bound Paclitaxel With Carboplatin and Trastuzumab as First-line Therapy for Women With HER2-Overexpressing Metastatic Breast Cancer AK. Conlin, AD. Seidman, A. Bach, D. Lake, M. Dickler, G. D’Andrea, T. Traina, M. Danso, AM. Brufsky, M. Saleh, A. Clawson, CA. Hudis Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.

  26. Study Rationale • Carbo improves ORR and TTP when added to q3w TAX+ HER as first-line therapy for HER2+ MBC¹ • Qw TAX + HER is highly active and safe as first-line treatment of HER2+ MBC² • Qw TAX + carbo + HER is highly active and is better tolerated than q3w TAX³ • Weekly nab-paclitaxel is more active than q3w in first-line MBC patients4 • Robert et al, J Clin Oncol 2006 • Seidman et al, J Clin Oncol 2001, Seidman et al, J Clin Oncol, 2008 • Perez et al, Clin Breast Cancer, 2005 • Gradishar et al, CJ Clin Oncol, ASCO 2009

  27. Patient Eligibility • Key Inclusion Criteria • Females >18 years of age • Stage IV adenocarcinoma • Measurable disease (≥1 lesion with diameter ≥2 cm by conventional techniques or ≥1 cm by spiral CT) • HER2 overexpressing (IHC 3+) or amplified (FISH+) disease • ≥4 weeks since radiotherapy or major surgery • Adequate hepatic/renal function • Normal LVEF Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.

  28. Patient Eligibility • Key Exclusion Criteria • Prior chemotherapy for MBC • < 9 months since prior taxanes • Concurrent immunotherapy or hormone therapy • Parenchymal brain metastases (unless stable for at least 6 mo) • Pregnant or breast feeding Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.

  29. Study Design & Treatment • Phase II, open-label, multi-centre • Planned N = 50 • Primary Endpoints: • ORR (CR + PR) • Safety/Tolerability • Secondary Endpoints: • SD >16 weeks + CR or PR • TTP and PFS • Response duration • OS Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.

  30. nab-Paclitaxel 100 mg/m2 Carboplatin AUC = 2 Trastuzumab 2 mg/kg after loading dose of 4 mg/kg Original Phase II Schema Admin: HER  ABX  Carbo Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.

  31. nab-Paclitaxel 100 mg/m2 Carboplatin AUC = 6 Trastuzumab 2 mg/kg after loading dose of 4 mg/kg Revised Phase II Schema(due to hypersensitivity to Qw carbo) Admin: HER  ABX  Carbo Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.

  32. Results: Patient Treatment • 32 patients treated • 17 treated solely on original regimen • 3 switched from original to revised regimen • 12 treated only on revised regimen Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.

  33. Select Patient Demographics • Median age: 52.0 yrs (range 29-76) • 78% postmenopausal • ECOG PS: 0: 59%, 1: 38%, 2: 3% • Sites of metastases: • Lymph node: 75% • Soft tissue/breast: 66% • Liver: 47% • Lung: 59% • Bone: 69% • Prior adjuvant or neoadjuvant chemotherapy: • Prior anthracycline: 44% • Prior taxane: 34% Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.

  34. Results • Median PFS: 16.6 months (95% CI, 7.5-26.5 months) • OS (monitored q3mo for 2 yr): 10 pts (31%) had died at time of reporting *CR + PR +SD ≥ 16 wk Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.

  35. Results – PFS in Treated Population • Median PFS: 16.6 months (95% CI, 7.5-26.5 months) Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.

  36. Results: Response by regimen • Original regimen only (n = 17) • 11/17 (65%) had confirmed responses • Revised regimen only (n = 12) • 8/12 (67%) had confirmed responses • Original + revised (n = 3) • 1/3 (33%) responded after switching Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.

  37. Safety (pooled) Incidence (%) of Therapy-Related Adverse Events Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase A Based on laboratory data graded by National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. B 1 episode of febrile neutropenia was observed Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.

  38. Hypersensitivity Reactions • Total of 9 hypersensitivity reactions • Carboplatin: 5 patients (none during monthly regimen) • Trastuzumab: 4 patients • nab-paclitaxel: none Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.

  39. Safety: Dose Reductions • At least 1 dose reduction • nab-Paclitaxel: 22 (69%) • Carboplatin: 19 (59%): 2 due to hypersensitivity reactions • 95% for hematologic toxicity (each drug) • At least 1 dose delay • 69% pts • 82% were for hematologic toxicities • None for peripheral neuropathy • Dose interruption • nab-paclitaxel: 2 pts • Trastuzumab: 6 pts had at least 1 missed dose Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.

  40. Drug Exposure • The median dose intensity: • nab-paclitaxel: 76% of the planned dose • Carboplatin: 62% of the planned dose • Median number of cycles: 8 (range, 2-39 cycles) • 8 patients who responded and had at least 6 cycles of nab-paclitaxel and carboplatin were continued on trastuzumab alone until progression of disease. Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.

  41. Conclusion • Weekly ABX+ HER+ Carbo (weekly or monthly) is active as first-line therapy for HER2+ MBC • HS reactions to weekly Carbo (generally on infusion #6-8) make monthly dosing preferable • Regimen (perhaps in a lower dose to avoid hematologic toxicities), may be preferred for patients with HER2+ MBC who need or want to avoid premedication Conlin et al. Clin Breast Cancer. 2010 Aug 1;10(4):281-7.

  42. nab-paclitaxel + Bevacizumab

  43. nab-Paclitaxel Phase II Trials in Combination with Bevacizumab • 3 different dosing schedules of nab-paclitaxel + bevacizumab as first line treatment in MBC (Conlin/Seidman) • Retrospective Analysis: nab-paclitaxel + bevacizumab in heavily pretreated MBC (Link) • nab-Paclitaxel + gemcitabine + bevacizumab as first-line treatment in MBC (Lobo/Gluck)

  44. Final Results of a Phase 2 Study of nab-Paclitaxel, Bevacizumab, and Gemcitabine as First-line Therapy for Patients with HER2-Negative Metastatic Breast Cancer C. Lobo, G. Lopes, O. Baez, A. Castrellon, Ferrell, C. Higgins, E. Hurley, J. Hurley, I. Reis, S. Richman, P. Seo, O. Silva, J. Slingerland, K. Tukia, C. Welsh, S. Gluck Breast Cancer Res Treat (2010) 123:427–435

  45. Study Features • Objective: efficacy of combination therapy with nab-paclitaxel, BEV + GEM as 1st line treatment for MBC patients • Design: Multi-centre, open label Phase II study • Patients: untreated HER2-negative MBC or metastases diagnosed ≥ 6 months after adjuvant or neo-adjuvant systemic treatment • Primary endpoint: • Progression-free survival (PFS) • Secondary endpoints • Overall Survival (OS) • Response rate (CR or PR) • Safety • Toxicity Breast Cancer Res Treat (2010) 123:427–435

  46. Study Design Gemcitabine1500 mg/m2 nab-paclitaxel150 mg/m2 Bevacizumab 10 mg/kg • Evaluate response • After 2 cycles • Treatment continued until • Disease progression • Unacceptable toxicity • Patient withdrawal Day 1 15 28 CT scans every 2 cycles Cycle 1 Additional cycles Breast Cancer Res Treat (2010) 123:427–435

  47. Patient Characteristics and Demographics Breast Cancer Res Treat (2010) 123:427–435

  48. Chemotherapy Delivery Breast Cancer Res Treat (2010) 123:427–435

  49. Best Response to Treatment Breast Cancer Res Treat (2010) 123:427–435

  50. Progression-Free Survival Breast Cancer Res Treat (2010) 123:427–435

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