ASCO_2013_files/Von Hoff MPACT oral ASCO 2013

Report
Results of a Randomized Phase III Trial
(MPACT) of Weekly nab-Paclitaxel Plus
Gemcitabine vs Gemcitabine Alone for
Patients With Metastatic Adenocarcinoma of
the Pancreas With PET and CA19-9
Correlates
Daniel D. Von Hoff,1 Thomas Ervin,2 Francis P. Arena,3 E. Gabriela Chiorean,4 Jeffrey Infante,5
Malcolm Moore,6 Thomas Seay,7 Sergey A. Tjulandin,8 WenWee Ma,9 Mansoor N. Saleh,10 Marion
Harris,11 Michele Reni,12 Ramesh K. Ramanathan,1 Josep Tabernero,13 Manuel Hidalgo,14 Eric Van
Cutsem,15 David Goldstein,16 Xinyu Wei,17 Jose Iglesias,18 Markus F. Renschler 17
1TGen,
Scottsdale Healthcare, AZ, USA; 2Florida Cancer Specialists/Sarah Cannon Research Institute, Englewood, FL; 3Arena Oncology
Associates, Lake Success, NY, USA; 4University of Washington, Seattle, WA, USA; 5Sarah Cannon Research Institute/Tennessee Oncology,
PLLC, Nashville, TN; 6Princess Margaret Hospital, Toronto, Canada; 7Atlanta Cancer Care, GA, USA; 8Blokhin Cancer Research Center,
Moscow, Russia; 9Roswell Park Cancer Institute, Buffalo, NY, USA; 10Cancer Specialists, Atlanta, GA, USA; 11Southern Health, East Bentleigh,
VIC, Australia; 12San Raffaele Scientific Institute, Milan, Italy; 13Vall d'Hebron University Hospital, Barcelona, Spain; 14Centro Integral
Oncológico Clara Campal, Madrid, Spain; 15Leuven University, Belgium; 16Prince of Wales Hospital, Sydney, NSW, Australia; 17Celgene
Corporation, Summit, NJ, USA; 18Bionomics, Thebarton, Australia
Disclosures
This study was sponsored by Celgene Corporation
Von Hoff: consultant or advisory role, honoraria, and research
funding, Celgene; Ervin: research funding, Celgene; Arena:
research funding, Clinical Research Alliance and Celgene;
Chiorean: research funding, Celgene; Moore: consultant or
advisory role and research funding, Celgene; Seay: research
funding, Celgene; Tjulandin: research funding, Celgene; Ma:
research funding, Celgene; Saleh: research funding, Celgene;
Reni: consultant or advisory role, honoraria, and research funding,
Celgene; Ramanathan: consultant or advisory role, honoraria, and
research funding, Celgene; Tabernero: consultant or advisory role
and honoraria, Celgene; Hidalgo: consultant or advisory role,
honoraria, and research funding, Celgene; Van Cutsem: research
funding, Celgene; Goldstein: consultant or advisory role and
research funding, Celgene; Wei: employment or leadership
position and stock ownership, Celgene; Iglesias: employment or
leadership position at Bionomics and stock ownership, Celgene;
Renschler: employment or leadership position and stock
ownership, Celgene; Infante, Harris: nothing to disclose.
Von Hoff et al. ASCO 2013.
2
nab-Paclitaxel + Gemcitabine
in Pancreatic Cancer
1. Preclinical models1,2:
•
•
nab-Paclitaxel (nab-P) active as single agent
Synergizes with gemcitabine (Gem)
2. In a 67-patient phase I/II trial of nab-P + Gem1
• MTD: nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and
15 every 28 days
• Promising activity at MTD
• ORR: 48%
• Median PFS: 7.9 months
• Median OS: 12.2 months
1.
2.
Von Hoff DD, et al. J Clin Oncol. 2011;29:4548-4554.
Frese KK, et al. Cancer Discov. 2012;2:260-269.
Von Hoff et al. ASCO 2013.
3
Study Design
nab-P
Planned N = 842
• Stage IV
• No prior treatment for
metastatic disease
• KPS ≥ 70
• Measurable disease
• Total bilirubin ≤ ULN
• No age limitation



Primary endpoint
– OS
Secondary endpoints
– PFS and ORR by
independent review
(RECIST)
Safety and tolerability
– By NCI CTCAE v3.0
125 mg/m2 IV qw 3/4
+
Gem
1000 mg/m2 IV qw 3/4
1:1, stratified by KPS, region, liver metastasis
Gem
1000 mg/m2 IV qw 7/8
then qw 3/4
• With 608 events, 90% power to detect
OS; HR = 0.769 (2-sided α = 0.049)
• Treat until progression
• CT scans every 8 weeks
• PET scans in an initial cohort of
patients at baseline and weeks 8 and 16
• CA19-9 measurements at baseline and
every 8 weeks
Von Hoff et al. ASCO 2013.
4
MPACT (CA046) Phase III Trial
Country
nab-P + Gem, n Gem, n
All, n (%)
USA
Australia
Russia
Canada
Italy
Ukraine
Spain
Germany
Austria
France
Belgium
235
61
50
33
21
14
6
3
3
4
1
241
59
50
30
16
12
10
5
3
2
2
476 (55)
120 (14)
100 (12)
63 (7)
37 (4)
26 (3)
16 (2)
8 (1)
6 (1)
6 (1)
3 (< 1)
Total
431
430
861 (100)
Total of 151 sites enrolled 861 patients between May 8, 2009, and April 17, 2012
Von Hoff et al. ASCO 2013.
5
Baseline Characteristics
nab-P + Gem
(n = 431)
Gem
(n = 430)
All Patients
(N = 861)
62 (27, 86)
63 (32, 88)
63 (27, 88)
≥ 65 years old, %
41
44
42
Male, %
57
60
58
90-100, %
58
62
60
70-80, %
42
38
40
Head, %
44
42
43
Body, %
31
32
31
Tail, %
24
26
25
Lung, %
35
43
39
Liver, %
85
84
84
1, %
8
5
6
2, %
47
48
47
≥ 3, %
45
47
46
Previous Whipple
Yes, %
7
7
7
Biliary stent
Yes, %
19
16
17
Normal, %
14
13
13
> ULN-< 59 ×ULN, %
28
28
28
≥ 59 × ULN, %
46
45
46
Variable
Age
Sex
KPS
Pancreatic primary
location
Current site(s) of
metastasis
No. of metastatic
sites
CA19-9a
Median years (min, max)
ULN, upper limit of normal.
a CA19-9 at baseline was unknown in 13% of patients.
Von Hoff et al. ASCO 2013.
6
Overall Survival
OS, months
1.0
Median (95% CI)
75th
Percentile
nab-P + Gem 333/431 (77)
8.5 (7.89-9.53)
14.8
Gem
6.7 (6.01-7.23)
11.4
Proportion of Survival
0.9
Events/n (%)
0.8
0.7
359/430 (83)
0.6
0.5
0.4
HR = 0.72
95% CI (0.617-0.835)
P = 0.000015
0.3
0.2
0.1
0.0
0
3
6
9
12
15
•
•
•
21
24
27
30
33
36
39
16
7
9
3
4
1
1
0
1
0
0
0
Months
Pts at risk
nab-P + Gem: 431
Gem: 430
18
357
340
269
220
169
124
108
69
67
40
40
26
27
15
Subsequent therapy: 38% for nab-P + Gem and 42% for Gem
OS censored at time of secondary therapy: 9.4 vs 6.8 months; HR 0.68; P = 0.00007
Trial conclusions not impacted by secondary therapies
Von Hoff et al. ASCO 2013. 7
Overall Survival Rate
nab-P + Gem
Time Points,
months
Survival, %
Gem
Survival, % Increase, % P Value
6
67
55
22
0.00074
9
48
36
33
0.00067
12
35
22
59
0.00020
18
16
9
78
0.00803
24
9
4
125
0.02123
Von Hoff et al. ASCO 2013. 8
OS—Prespecified Subgroups
nab-P + Gem
Events/n
Gem
Events/n
HR
All patients
Age < 65 years
333/431
359/430
0.72
188/254
209/242
0.65
Age ≥ 65 years
145/177
138/186
195/245
150/188
141/173
218/257
0.81
0.72
0.72
142/179
146/161
0.61
187/248
212/268
0.75
142/191
188/237
290/365
155/180
201/246
309/360
0.59
0.80
0.69
43/66
50/70
0.86
21/33
16/21
0.41
159/202
163/206
0.75
104/136
121/140
0.79
49/60
47/60
96/122
151/197
50/61
62/64
14/38
207/268
59/63
43/56
95/120
171/195
53/59
59/62
17/38
230/271
0.50
1.07
0.83
0.61
0.67
0.84
0.72
0.68
Group
HR
Female
Male
KPS 70-80
KPS 90-100
Primary tumor location: head
Primary tumor location: other
Liver metastases
No liver metastases
1 metastatic site
2 metastatic sites
3 metastatic sites
> 3 metastatic sites
Normal CA19-9
CA19-9 ULN to < 59 x ULN
CA19-9 ≥ 59 x ULN
Australia
Eastern Europe
Western Europe
North America
0.125
0.25
0.5
1.0
2.0
Favors nab-P + Gem Favors Gem
Von Hoff et al. ASCO 2013. 9
PFS by Independent Review
PFS, months
1.0
Median (95% CI)
75th
Percentile
nab-P + Gem 277/431 (64)
5.5 (4.47-5.95)
9.2
Gem
3.7 (3.61-4.04)
5.9
Proportion of
Progression-Free Survival
0.9
Events/n (%)
0.8
0.7
265/430 (62)
0.6
0.5
HR = 0.69
95% CI (0.581-0.821)
P = 0.000024
0.4
0.3
0.2
0.1
0.0
0
3
6
9
Pts at Risk
nab-P + Gem: 431
Gem: 430
PFS Rate at
12
15
18
21
24
8
6
4
4
2
0
0
0
Months
281
209
122
51
62
23
24
10
nab-P + Gem
Gem
Increase
6 months
44%
25%
76%
12 months
16%
9%
78%
Von Hoff et al. ASCO 2013. 10
Response Rates
nab-P + Gem
(n = 431)
Gem
(n = 430)
P Value
Overall response rate
Independent review, %
(95% CI)
Investigator assessment, %
(95% CI)
23
(19.1-27.2)
29
(25.0-33.8)
7
(5.0-10.1)
8
(5.3-10.6)
1.1 x 10−10
Disease control rate by independent review,a %
(95% CI)
48
(43.0-52.6)
33
(28.4-37.5)
7.2 x 10−6
Variable
a
3.3 x 10−16
Includes CR + PR + SD ≥ 16 weeks.
Von Hoff et al. ASCO 2013. 11
Treatment Exposure
nab-P + Gem
(n = 421)
Gem
(n = 402)
Treatment duration, median months (min, max)
≥ 6 months, %
3.9 (0.1, 21.9)
32
2.7 (0.1, 21.5)
15
Relative dose intensity (%), median (min, max)
nab-P
Gem
80.6 (16.7, 100.0)
75.2 (14.3, 97.7)
-84.6 (14.1, 100.0)
Cumulative dose, median mg/m²
nab-P
Gem
1425.0
11,400.0
-9000.0
nab-P doses at 125 mg/m², n (%)
Gem doses at 1000 mg/m², n (%)
4116.0 (71)
3731.0 (63)
-3762.0 (79)
Variable
Von Hoff et al. ASCO 2013. 12
Safety
nab-P + Gem
(n = 421)
Gem
(n = 402)
Pts with at least 1 AE leading to death, %
4
4
Grade ≥ 3 hematologic AEs,a %
Neutropenia
Thrombocytopenia
Anemia
38
13
13
27
9
12
Pts who received growth factors, %
26
15
Febrile neutropenia,b %
3
1
Grade ≥ 3 nonhematologic AEsb in > 5% pts, %
Fatigue
Peripheral neuropathyc
Diarrhea
17
17
6
7
<1
1
Grade ≥ 3 neuropathy
Time to onset, median days
Time to improvement by 1 grade, median days
Time to improvement to grade ≤ 1, median days
Pts who resumed nab-P, %
140
21
29
44
113
29
---
Preferred Term
a
Based on laboratory values; b Based on investigator assessment of treatment-related events; c Grouped term.
Von Hoff et al. ASCO 2013. 13
Metabolic Response by PET by
Independent Review
• PET scans were performed in the first 257 patients
randomized to receive treatment at PET-equipped centers
nab-P + Gem
(n = 130)a
Gem
(n = 127)a
HR
P Value
Metabolic response
by PET,b %
63
38
-
0.000051
ORR by CT scan, %
31
11
-
0.0001
10.5
8.3
0.71
0.0096
Outcome
Median OS in PET
cohort, mo
a
b
Follow-up scans at 8 weeks (n = 222) and 16 weeks (n = 134).
PET evaluated by EORTC criteria (Young H, et al. Eur J Cancer. 1999;35:1773-1782).
Von Hoff et al. ASCO 2013. 14
CA19-9 Best Response and
Landmark OS Analyses
• Best Decrease in CA19-9 During Study
nab-P + Gem
(n = 379)
Gem
(n = 371)
P Value
Patients with a ≥ 20%
decrease, n (%)
230 (61)
162 (44)
< 0.0001
Patients with a ≥ 90%
decrease, n (%)
117 (31)
51 (14)
< 0.0001
Decrease in CA19-9 level
• Predictive Value of CA19-9 Response at Week 8 on OS: Landmark Analyses
Decrease in CA19-9
Level at Week 8
nab-P + Gem
Gem
HR
P Value
n
Median OS, mo
n
Median OS, mo
≥ 20%
197
13.2
141
9.4
0.59
< 0.0001
≥ 90%
59
13.4
34
9.8
0.47
0.0053
Detailed analysis presented by Chiorean et al. (abstract 4058)
Von Hoff et al. ASCO 2013. 15
Conclusions from MPACT
1. MPACT study – a large, multi-center, international study
performed at community and academic centers
2. OS, PFS, and ORR were superior for nab-P + Gem vs Gem
a) Improvement in OS across the entire curve, including
median, 1-year, and 2-year survival rates
3. Metabolic response rate by PET and CA19-9 response
rates were higher for nab-P + Gem vs Gem alone
a) Both were predictors for longer OS
Von Hoff et al., ASCO 2013 16
Conclusions from MPACT (cont)
4. Serious life threatening toxicity not increased; AEs
acceptable and manageable
5. nab-P + Gem, a new standard for the treatment of
patients with metastatic pancreatic cancer, is
superior to Gem alone and could become the
backbone for new regimens
6. A phase III study of nab-P + Gem in the adjuvant setting
is currently in development
Von Hoff et al., ASCO 2013 17
MPACT Team
Von Hoff et al. ASCO 2013. 18

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