Transcript Slide 1

Altre evidenze con
NAB-paclitaxel:
melanoma
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 Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
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]
1. Nyman, JCO, 2005
2. Gardner, CCR, 2008
3. Desai, CCR, 2006
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
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
Phase 1, Advanced Solid Tumors [4]
(14 Melanoma pts)
DCR, %
80-200 mg/m2 weekly
N = 39
38
The 150 mg/m2 dose level was well tolerated in lightly pretreated patients
Phase 2, Metastatic Melanoma [5]
PR, %
DCR, %
PFS, median month
OS, median month
150 mg/m2
Chemo-naïve N = 37
22
49
4.5
9.6
DCR, disease control rate; OS, overall survival; PFS, progression-free survival; PR, partial response
1.
2.
3.
4.
5.
Walker, Melanoma Res, 2005
Pfugfelder, Plos Once, 2011
Bedikian, Ann Oncol, 2011
Nyman, JCO, 2005
Hersh, Cancer. 2010
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Phase III Study Design
nab-Paclitaxel (nab-P)
150 mg/m2 IV
days 1, 8, and 15, 28-day cycle
Planned N = 514
Chemo-naïve
ECOG PS 0-1
Stage IV cutaneous
Measurable disease
LDH levels ≤2.0 x ULN
No current brain mets
1:1 randomization stratified by:
• metastatic stage (M1a, M1b, and M1c)
• region (Australia, North America, Western Europe)
• baseline LDH (< 0.8 x ULN, 0.8–1.1 x ULN, >1.1-2 x ULN)
Dacarbazine (DTIC)
1000 mg/m2 IV, day 1, 21-day cycle
• 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
ECOG, Eastern Cooperative Oncology Group;
LDH, lactate dehydrogenase; ULN, upper limit of normal
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
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 Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Baseline Characteristics
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
PFS by Independent Radiology Review
CI, confidence interval
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
OS: Planned Interim Analysis
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
PFS and Interim OS by BRAF Status
BRAF Status
N
Wild Type Median PFS, months
Median OS, months
V600E
Mutation
Unknown
nab-Paclitaxel Dacarbazine
(n = 264)
(n = 265)
HR
P-value
(nab-P/DTIC)
116
5.4
12.7
108
2.5
11.1
0.715
0.845
0.088
0.330
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
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 Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Other Efficacy Endpoints
Blinded Radiology nab-Paclitaxel Dacarbazine
Assessment
(n = 264)
(n = 265)
Response Rate
Ratio
P-value
(Pnab-P/PDTIC)
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, %
SD ≥16 weeks, %
15
24
11
15
Best Response
0.0017*
PR, %
15
11
SD, %
PD, %
Not Evaluable, %
25
35
25
16
48
25
0.005**
* Includes confirmed PR + SD + PD
** Comparison of PD rate between arms
P, proportion of improved patients; PD, progressive, disease; SD,
stable disease
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
PFS by Independent Review – Subgroups
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
OS Interim Analysis – Subgroups
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Target Tumor Responses by Patient
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Treatment Exposure, Dose Reductions
nab-Paclitaxel Dacarbazine
(n = 257)
(n = 258)
Variable
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
11.1
0, 88
6.4
0, 106
32
20
Duration of Treatment, median weeks*
Min, Max
Patients with at least 1 Dose Reduction, %
* nab-paclitaxel: 28-day cycle; dacarbazine: 21-day cycle
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Grade ≥3 Treatment-related Adverse Events
(TRAEs) in ≥ 5% Patients
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
-
Preferred Term
* Except for lymphocytopenia, all events P < 0.05
** All but 2 neuropathy cases were grade 3
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
Conclusions
Hersh, et al. Phase 3 Study of nab®-Paclitaxel vs Dacarbazine in Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
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, MarieTherese 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 Chemotherapynaïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of
Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.