Altre evidenze con NAB-paclitaxel: melanoma

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Altre evidenze con NAB-paclitaxel melanoma
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Phase 3 Study of nab-Paclitaxel vs Dacarbazine
in Chemotherapy-naïve Patients with Metastatic
Malignant Melanoma
Evan M. Hersh,1 Michele Del Vecchio,2 Michael P.
Brown,3 Richard Kefford,4 Carmen Loquai,5
Alessandro Testori,6 Shailender Bhatia,7 Ralf
Gutzmer,8 Andrew Haydon,9 Caroline Robert,10
Alicia Clawson,11 Ileana Elias,11 Markus F
Renschler,11 Axel Hauschild12
1 Arizona Cancer Center, Tucson, AZ, USA 2
Istituto Nazionale Tumori, Milano, Italy 3 Royal
Adelaide Hospital, Australia 4 Westmead Hospital
and Melanoma Institude, Australia 5
Universitätsmedizin Mainz, Germany 6 Istituto
Europeo di Oncologia, Milano, Italy 7 Seattle
Cancer Care Alliance, USA 8 Medizinische
Hochschule Hannover, Germany 9 Alfred Hospital,
Melbourne, Australia 10 IGR Centre de Lutte
Contre le Canc, Villejuif, France 11 Celgene,
Summit, NJ, USA 12 Universitätsklinkum
Schleswig-Holstein, Kiel, Germany
Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.
3
nab-Paclitaxel Distinct Pharmacokinetics and
Biodistribution

• Compared with solvent-based paclitaxel,
  nab-paclitaxel exhibits
• Linear pharmacokinetics 1
• 10-fold increase in Cmax and 3-fold higher AUC
  of unbound paclitaxel 2
• Potential binding to albumin-binding proteins
• Enhanced transport across endothelial cell
  monolayers 3
• 33 higher paclitaxel concentration in tumor
  xenografts 3

Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.
1. Nyman, JCO, 2005 2. Gardner, CCR, 2008
3. Desai, CCR, 2006
4

• nab-Paclitaxel Phase I and II Studies

• No premedication No special tubing No acute
  toxicities typical of taxanes
• While cremophor-paclitaxel 1,2 or
  docosahexaenoic acid-paclitaxel 3 produced
  limited clinical benefit, nab-paclitaxel produced
  promising efficacy

nab-Paclitaxel, 30-min IV infusion, weekly 3 of 4 weeks nab-Paclitaxel, 30-min IV infusion, weekly 3 of 4 weeks
Phase 1, Advanced Solid Tumors 4 (14 Melanoma pts) 80-200 mg/m2 weekly N 39
DCR, 38
The 150 mg/m2 dose level was well tolerated in lightly pretreated patients The 150 mg/m2 dose level was well tolerated in lightly pretreated patients
Phase 2, Metastatic Melanoma 5 150 mg/m2 Chemo-naïve N 37
PR, DCR, PFS, median month OS, median month 22 49 4.5 9.6
DCR, disease control rate OS, overall survival
PFS, progression-free survival PR, partial
response

1. Walker, Melanoma Res, 2005
2. Pfugfelder, Plos Once, 2011
3. Bedikian, Ann Oncol, 2011
4. Nyman, JCO, 2005
5. Hersh, Cancer. 2010

Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.
5
Phase III Study Design

• 11 randomization stratified by
• metastatic stage (M1a, M1b, and M1c)
• region (Australia, North America, Western
  Europe)
• baseline LDH (lt 0.8 x ULN, 0.81.1 x ULN, gt1.1-2
  x ULN)

• CT scan every 8 weeks in both arms
• Enrollment period April 2009 June 2011 Data
  cut-off June 30, 2012
• Treatment until disease progression or
  unacceptable toxicity, patient/investigator
  discretion

Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.
ECOG, Eastern Cooperative Oncology Group LDH,
lactate dehydrogenase ULN, upper limit of normal
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Study Endpoints

• Primary Efficacy Endpoint
• PFS per blinded radiology assessment, RECIST v1.0
  
• Secondary Efficacy Endpoint
• OS
• Other Endpoints Included
• ORR, DCR
• Safety/tolerability using NCI CTCAE v3

Statistical Analyses

• For PFS, 514 with 379 events patients provided
  80 power to detect a HR of 0.750 (two sided
  alpha of 0.049)
• Interim survival analysis was planned at PFS
  final analysis
• Treatment differences in PFS and OS were tested
  using stratified log-rank ORR and DCR were
  tested using chi-squared test
• The ITT population was evaluated for efficacy,
  the treated population for safety

ITT, intent-to-treat NCI CITCAE, National Cancer
Institute Common Terminology Criteria for Adverse
Events HR, hazard ratio ORR, objective response
rate RECIST, Response Evaluation Criteria In
Solid Tumors
Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.
7
Baseline Characteristics
Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.
8
PFS by Independent Radiology Review
Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.
CI, confidence interval
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OS Planned Interim Analysis
Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.
10
PFS and Interim OS by BRAF Status
BRAF Status BRAF Status nab-Paclitaxel(n 264) Dacarbazine(n 265) HR(nab-P/DTIC) P-value
Wild Type N Median PFS, months Median OS, months 116 5.4 12.7 108 2.5 11.1 0.715 0.845 0.088 0.330
V600E Mutation N Median PFS, months Median OS, months 65 5.3 16.9 67 3.5 11.2 0.883 0.688 0.656 0.132
Unknown N Median PFS, months Median OS, months 83 3.7 11.1 90 2.2 9.9 0.684 0.837 0.066 0.381
Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.
11
Other Efficacy Endpoints
Blinded Radiology Assessment nab-Paclitaxel(n 264) Dacarbazine(n 265) Response Rate Ratio(Pnab-P/PDTIC) P-value
ORR, (95 CI) 15 (10.5, 19.1) 11 (7.5, 15.1) 1.305 (0.837, 2.035) 0.239
DCR, (95 CI) 39 (32.8, 44.5) 27 (21.5, 32.1) 1.442 (1.123, 1.852) 0.004
PR, 15 11
SD 16 weeks, 24 15
Best Response 0.0017
PR, 15 11
SD, 25 16
PD, 35 48 0.005
Not Evaluable, 25 25
Includes confirmed PR SD PD Comparison
of PD rate between arms
Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.
P, proportion of improved patients PD,
progressive, disease SD, stable disease
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PFS by Independent Review Subgroups
Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.
13
OS Interim Analysis Subgroups
Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.
14
Target Tumor Responses by Patient
Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.
15
Treatment Exposure, Dose Reductions
Variable nab-Paclitaxel(n 257) Dacarbazine(n 258)
Planned Protocol Dose , median Min, Max 97.7 49.9, 105.0 100.0 48.0, 105.0
Dose Intensity, median mg/m2/week Min, Max 146.5 74.9, 157.5 333.3 160.1, 350.0
Duration of Treatment, median weeks Min, Max 11.1 0, 88 6.4 0, 106
Patients with at least 1 Dose Reduction, 32 20
nab-paclitaxel 28-day cycle dacarbazine
21-day cycle
Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.
16
Grade 3 Treatment-related Adverse Events (TRAEs)
in 5 Patients
Preferred Term nab-Paclitaxel(n 257) Dacarbazine(n 258)
Patients with at least 1 TRAE, Patients with at least 1 serious TRAE, 50 9 28 7
Hematologic Adverse events, Neutropenia Leukopenia Lymphocytopenia Thrombocytopenia Anemia 20 12 8 0 2 10 7 11 6 5
Nonhematologic Adverse Events, Peripheral Neuropathy Fatigue Alopecia 25 8 5 0 2 0
Neuropathy, median days Time to Onset Time to Improvement by 1 grade Time to Improvement to grade 1 101 28 67 - - -
Except for lymphocytopenia, all events P lt
0.05 All but 2 neuropathy cases were grade 3
Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.
17
Conclusions
Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.
18
Acknowledgments

• We thank all the patients and investigators who
  participated in this phase 3 trial
• Other investigators who enrolled patients were
• Robert Conry, Vanna Chiarion Sileni, Scott Ernst,
  Jade Homsi, Jean Jacques Grob, Kari Kendra,
  Sanjiv Agarwala, Alexander Guminski, Teresa
  Petrella, Neville Davidson, Lawrence Flaherty,
  Rene Gonzalez, Kenneth Scott Wilson, Ana Arance,
  John Wagstaff, Michael Gordon, Viran
  (Roger)Holden, Paolo Ascierto, Michele Maio,
  Ruggero Ridolfi, William Kruit, Oscar B. Goodman,
  Gary Pansegrau, Bernard Guillot, Antonella
  Romanini, James Larkin, Stephen P. Anthony,
  Bartosz Chmielowski, Arkadiiusz Dudek, Timothy
  Webb, Evan Bayliss, Stephen Begbie, Tina Cheng,
  Michele Guida, Paola Queirolo, Laura Hutchins,
  Rosemary Harrup, Thomas Jouary, Laurent Mortier,
  Anja Gesierich, Theodore Logan, John Richart,
  Takamo Sato, Catalin Mihalcioiu, Sudha Rajagopal,
  Michael Smylie, Celeste Lebbe, Marie-Therese
  Leccia, Jean Paul Ortonne, Peter Altmeyer,
  Jessica Hassel, Annette Stein, Uwe Trefzer, Angus
  Dalgleish, Sarah Danson, Satish Kumar, Timothy
  Collins, Lynn Feun, Troy Guthrie, Graydon W.
  Harker, Edward McClay, Anton Melnyk, Sushma
  Nakka, Greg Dueck, Vincent Young, Eve Maubec,
  Cornelia Mauch, Dirk Schadendorf, Sabine Sell,
  J.J.H. van der Hoeven, Yolanda Garcia, Murray A.
  Brunt, Simon Grumett, Poulam Patel, John
  Nemunaitis, Isaac Tafur, Eric Whitman

Hersh, et al. Phase 3 Study of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma. Presented at The
Society of Melanoma Reserach November 8-11,
2012 Los Angeles, CA.