Transcript ASCO_2013_files/Von Hoff MPACT oral ASCO 2013
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 Malcolm Moore, 6 Thomas Ervin, Thomas Seay, 7 2 Francis P. Arena, 3 Sergey A. Tjulandin, 8 E. Gabriela Chiorean, WenWee Ma, 9 4 Jeffrey Infante, 5 Mansoor N. Saleh, 10 Marion Harris, 11 Michele Reni, Cutsem, 15 12 Ramesh K. Ramanathan, 1 David Goldstein, 16 Xinyu Wei, 17 Josep Tabernero, Jose Iglesias, 18 13 Manuel Hidalgo, 14 Markus F. Renschler 17 Eric Van 1 TGen, Scottsdale Healthcare, AZ, USA; 2 Florida Cancer Specialists/Sarah Cannon Research Institute, Englewood, FL; 3 Arena Oncology Associates, Lake Success, NY, USA; 4 University of Washington, Seattle, WA, USA; 5 Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; 6 Princess Margaret Hospital, Toronto, Canada; 7 Atlanta Cancer Care, GA, USA; 8 Blokhin Cancer Research Center, Moscow, Russia; 9 Roswell Park Cancer Institute, Buffalo, NY, USA; 10 Cancer Specialists, Atlanta, GA, USA; 11 Southern Health, East Bentleigh, VIC, Australia; 12 San Raffaele Scientific Institute, Milan, Italy; 13 Vall d'Hebron University Hospital, Barcelona, Spain; 14 Centro Integral Oncológico Clara Campal, Madrid, Spain; 15 Leuven University, Belgium; 16 Prince of Wales Hospital, Sydney, NSW, Australia; 17 Celgene Corporation, Summit, NJ, USA; 18 Bionomics, 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; Renschler: ownership, Celgene; Infante, Harris : Iglesias : employment or leadership position at Bionomics and stock ownership, Celgene; employment or leadership position and stock nothing to disclose.
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nab-Paclitaxel + Gemcitabine
in Pancreatic Cancer
1. Preclinical models 1,2 :
• •
nab-Paclitaxel (nab-P) active as single agent Synergizes with gemcitabine (Gem) 2. In a 67-patient phase I/II trial of nab-P + Gem 1
•
MTD: nab-P 125 mg/m 2 + Gem 1000 mg/m 2 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.
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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
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PFS and ORR by independent review (RECIST) Safety and tolerability
–
By NCI CTCAE v3.0
Study Design
nab-P 125 mg/m 2 IV qw 3/4 + Gem 1000 mg/m 2 IV qw 3/4 1:1, stratified by KPS, region, liver metastasis
• • • • •
Gem 1000 mg/m 2 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
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MPACT (CA046) Phase III Trial
Country nab-P + Gem, n Gem, n USA Australia Russia Canada Italy Ukraine Spain Germany Austria France Belgium Total 235 6 3 3 4 1 61 50 33 21 14 431 241 10 5 3 2 2 59 50 30 16 12 430 All, n (%) 476 (55) 120 (14) 100 (12) 63 (7) 37 (4) 26 (3) 16 (2) 8 (1) 6 (1) 6 (1) 3 (< 1) 861 (100) Total of 151 sites enrolled 861 patients between May 8, 2009, and April 17, 2012
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Baseline Characteristics
Variable Age Sex KPS Median years (min, max) ≥ 65 years old, % Male, % 90-100, % 70-80, % Pancreatic primary location Current site(s) of metastasis No. of metastatic sites Previous Whipple Biliary stent Head, % Body, % Tail, % Lung, % Liver, % 1, % 2, % ≥ 3, % Yes, % Yes, % CA19-9 a Normal, % > ULN-< 59
×
ULN, % ≥ 59
×
ULN, %
ULN, upper limit of normal.
a CA19-9 at baseline was unknown in 13% of patients.
nab-P + Gem (n = 431) 62 (27, 86) 41 57 58 42 44 31 24 35 85 8 47 45 7 19 14 28 46 Gem (n = 430) 63 (32, 88) 44 60 62 38 42 32 26 43 84 5 48 47 7 16 13 28 45 All Patients (N = 861) 63 (27, 88) 42 58 60 40 43 31 25 39 84 6 47 46 7 17 13 28 46
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Overall Survival
1.0
0.9
0.8
0.7
0.6
Events/n (%) nab-P + Gem Gem 333/431 (77) 359/430 (83) OS, months Median (95% CI) 8.5 (7.89-9.53) 6.7 (6.01-7.23) 75th Percentile 14.8
11.4
0.5
0.4
0.3
0.2
0.1
HR = 0.72
95% CI (0.617-0.835) P = 0.000015
0.0
0 Pts at risk nab-P + Gem: Gem: 431 430 3 357 340 6 269 220 9 169 124 12 108 69 15 67 40 18 Months 40 26 21 27 15 24 16 7 27 9 3 30 4 1 33 1 0 36 1 0 39 0 0
• 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
• Trial conclusions not impacted by secondary therapies = 0.00007
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Overall Survival
Rate
Time Points, months 6 9 12 18 24 nab-P + Gem Survival, % Gem Survival, % Increase, % P Value 67 48 35 16 9 55 36 22 9 4 22 33 59 78 125 0.00074
0.00067 0.00020
0.00803
0.02123
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OS —Prespecified Subgroups
Group All patients Age < 65 years Age ≥ 65 years 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
HR nab-P + Gem Events/n 333/431 188/254 145/177 138/186 195/245 142/179 187/248 142/191 188/237 290/365 43/66 21/33 159/202 104/136 49/60 47/60 96/122 151/197 50/61 62/64 14/38 207/268 0.25
0.5
Favors nab-P + Gem 1.0
2.0
Favors Gem Gem Events/n 359/430 209/242 150/188 141/173 218/257 146/161 212/268 155/180 201/246 309/360 50/70 16/21 163/206 121/140 59/63 43/56 95/120 171/195 53/59 59/62 17/38 230/271
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HR 0.72
0.65
0.81
0.72
0.72
0.61
0.75
0.59
0.80
0.69
0.86
0.41
0.75
0.79
0.50
1.07
0.83
0.61
0.67
0.84
0.72
0.68
PFS by Independent Review
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 Pts at Risk nab-P + Gem: Gem: 431 430 PFS Rate at 6 months 12 months 3 281 209 Events/n (%) nab-P + Gem 277/431 (64) Gem 265/430 (62) PFS, months Median (95% CI) 5.5 (4.47-5.95) 3.7 (3.61-4.04) 75th Percentile 9.2
5.9
6 9 122 51 nab-P + Gem 44% 16% 62 23 12 Months 24 10 Gem 25% 9% 15 HR = 0.69
95% CI (0.581-0.821) P = 0.000024 18 21 24 8 6 4 4 2 0 0 0 Increase 76% 78%
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Response Rates
Variable nab-P + Gem (n = 431) Gem (n = 430) P Value Overall response rate
Independent review, % (95% CI) Investigator assessment, % (95% CI)
Disease control rate by independent review, a %
(95% CI) a Includes CR + PR + SD ≥ 16 weeks.
23 (19.1-27.2) 29 (25.0-33.8) 48 (43.0-52.6) 7 (5.0-10.1) 8 (5.3-10.6) 1.1 x 10 −10 3.3 x 10 −16 33 (28.4-37.5) 7.2 x 10 − 6
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Treatment Exposure
Variable Treatment duration, median months (min, max)
≥ 6 months, %
Relative dose intensity (%), median (min, max)
nab
-P Gem
Cumulative dose, median mg/m ²
nab
-P Gem
nab-P
doses at 125 mg/m², n (%) Gem doses at 1000 mg/m², n (%) nab-P + Gem (n = 421) 3.9
(0.1, 21.9) 32 1425.0
11,400.0
4116.0 ( 71 ) 3731.0 (63) Gem (n = 402) 2.7
(0.1, 21.5) 15 80.6
(16.7, 100.0) 75.2 (14.3, 97.7) - 84.6 (14.1, 100.0) - 9000.0
- 3762.0 (79)
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Safety
Preferred Term Pts with at least 1 AE leading to death, % Grade ≥ 3 hematologic AEs,
a Neutropenia Thrombocytopenia Anemia
% nab-P + Gem (n = 421) 4 38 13 13 Gem (n = 402) 4 27 9 12 Pts who received growth factors, % Febrile neutropenia,
b
% Grade ≥ 3 nonhematologic AEs
b Fatigue Peripheral neuropathy c Diarrhea
in > 5% pts, % 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, %
26 3 17 17 6 140 21 29 44 15 1 7 < 1 1 113 29 - --
a Based on laboratory values; b Based on investigator assessment of treatment-related events; c Grouped term. Von Hoff et al. ASCO 2013.
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Metabolic Response by PET by Independent Review
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PET scans were performed in the first 257 patients randomized to receive treatment at PET-equipped centers Outcome nab-P + Gem (n = 130) a Gem (n = 127) a HR P Value Metabolic response by PET, b % 63 38 ORR by CT scan, % 31 11 Median OS in PET cohort, mo 10.5
8.3
a Follow-up scans at 8 weeks (n = 222) and 16 weeks (n = 134).
b PET evaluated by EORTC criteria (Young H, et al.
Eur J Cancer
. 1999;35:1773-1782).
0.71
0.000051
0.0001
0.0096
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CA19-9
Best Response and Landmark OS Analyses
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Best Decrease in CA19-9 During Study Decrease in CA19-9 level nab-P + Gem (n = 379) Patients with a decrease, n (%) ≥ 20% Patients with a decrease, n (%) ≥ 90% 230 (61) 117 (31) Gem (n = 371) 162 (44) 51 (14) P Value < 0.0001
< 0.0001
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Predictive Value of CA19-9 Response at Week 8 on OS: Landmark Analyses nab-P + Gem Gem HR P Value Decrease in CA19-9 Level at Week 8 n Median OS, mo n Median OS, mo ≥ 20% ≥ 90% 197 59 13.2
13.4
141 34 9.4
9.8
0.59
0.47
< 0.0001
0.0053
Detailed analysis presented by Chiorean et al. (abstract 4058)
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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
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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
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MPACT Team
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