1. Phase III Trial (MPACT) of Weekly nab-Paclitaxel Plus Gemcitabine in Metastatic Pancreatic Cancer: Influence of Prognostic Factors of Survival
J Tabernero, DD Von Hoff, MJ Moore, T Ervin, FP Arena,
EG Chiorean, JR Infante, SR Hingorani, V Ganju, CD Weekes,
W Scheithauer, RK Ramanathan, D Goldstein, X Wei, A Romano

2. nab-Paclitaxel + Gemcitabine in Pancreatic Cancer
Preclinical models1,2
nab-Paclitaxel active as single agent
Synergizes with gemcitabine
Phase I/II trial of nab-paclitaxel + gemcitabine (N = 67)1
MTD: nab-paclitaxel 125 mg/m2 + gemcitabine 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
MTD, maximum tolerated dose; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.
1. Von Hoff DD, et al. J Clin Oncol. 2011:29: Frese KK, et al. Cancer Discov. 2012;2:

3. Study Design and Objective of Prognostic Factor Analysis
nab-Paclitaxel
125 mg/m2 IV qw 3/4 +
Gemcitabine
1000 mg/m2 IV qw 3/4
Planned N = 842a
Stage IV
No prior treatment for metastatic disease
KPS ≥ 70
Measurable disease
Total bilirubin ≤ ULN
No age limitation
Primary endpoint: OS
Secondary endpoints: PFS, ORR by independent review (RECIST), safety
Objective of analysis: To evaluate the potential influence of prognostic factors on the primary efficacy endpoint of OS in this phase III trial
1:1, stratified by KPS, region, liver metastasis
Gemcitabine
1000 mg/m2 IV qw 7/8
then qw 3/4
a A total of 861 patients were randomized between May 2009 and April 2012 in 151 community and academic centers from 11 countries
KPS, Karnofsky performance status; qw 3/4, first 3 of 4 weeks; qw 7/8, first 7 of 8 weeks; RECIST, Response Criteria In Solid Tumors; ULN, upper limit of normal.
Tabernero J, et al. 15th World Congress on Gastrointestinal Cancer; July 3 - 6, 2013; Barcelona, Spain. [abstract O-0001].

4. Potential Prognostic Factors for OS and PFS
A prespecified analysis to assess the potential influence of the following prognostic factors on OS and PFS was performeda
Age (< 65 and ≥ 65 years)
Sex (male and female)
KPS ( and )
Pancreatic cancer primary location (head and other)
Peritoneal carcinomatosis (yes and no)
Presence of liver metastases (yes and no)
Presence of pulmonary metastases (yes and no)
Geographic region
Presence of biliary stent at baseline (yes and no)
Previous Whipple procedure (yes and no)
Number of metastatic sites (1, 2, 3, and > 3)
Stage at diagnosis (IV and other)
CA19-9 level (within normal limit, ULN, < 59 × ULN, and ≥ 59 × ULN)
a A Cox proportional hazard model was used to identify potential prognostic factors using a step-wise multivariate analysis with a significance level for entry of 0.2 and for stay of 0.1
CA19-9, carbohydrate antigen 19-9.
Tabernero J, et al. 15th World Congress on Gastrointestinal Cancer; July 3 - 6, 2013; Barcelona, Spain. [abstract O-0001].

5. Baseline Patient Characteristics
Variable
nab-P + Gem
(n = 431)
Gem
(n = 430)
All Patients
(N = 861)
Age
Median years (min, max)
62 (27, 86)
63 (32, 88)
63 (27, 88)
≥ 65 years, % 41 44 42
Sex, %
Male 57 60 58
Region, %
North America 62 63
Australia 14
Eastern Europe 15
Western Europe 9
KPS, % 38 40
Stage IV at primary diagnosis, %
Yes 78 82 80
Pancreatic primary tumor location, %
Head 43
Body 31 32
Tail 24 26 25
Gem, gemcitabine; max, maximum; min, minimum; nab-P, nab-paclitaxel.
Tabernero J, et al. 15th World Congress on Gastrointestinal Cancer; July 3 - 6, 2013; Barcelona, Spain. [abstract O-0001].

6. Baseline Patient Characteristics (Cont)
Variable
nab-P + Gem
(n = 431)
Gem
(n = 430)
All Patients
(N = 861)
Current site(s) of metastasis, %
Lung 35 43 39
Liver 85 84
Peritoneal carcinomatosis 4 2 3
Number of metastatic sites, % 1 8 5 6 47 48
≥ 3 45 46
Previous Whipple procedure, %
Yes 7
Biliary stent, % 19 16 17
CA19-9, %
Normal 14 13
> ULN but < 59 ×ULN 28
≥ 59 × ULN
Tabernero J, et al. 15th World Congress on Gastrointestinal Cancer; July 3 - 6, 2013; Barcelona, Spain. [abstract O-0001].

7. Proportion of Survival
OS in ITT Population
OS, months
Events, n/N (%)
Median (95% CI)
75th Percentile
333/431 (77)
8.5 ( )
14.8
359/430 (83)
6.7 ( )
11.4
1.0
0.9
0.8
nab-P + Gem
Gem
0.7
0.6
Proportion of Survival
0.5
0.4
HR = 0.72
95% CI,
P =
0.3
0.2
0.1
0.0 3 6 9 12 15 18 21 24 27 30 33 36 39
Months
Pts at Risk
nab-P + Gem:
Gem:
431
430
357
340
269
220
169
124
108 69 67 40 26 27 15 16 7 9 3 4 1
HR, hazard ratio; Pts, patients.
Tabernero J, et al. 15th World Congress on Gastrointestinal Cancer; July 3 - 6, 2013; Barcelona, Spain. [abstract O-0001].

8. OS in Prespecified Subgroups
nab-P + Gem
Events, n/N
Gem HR
333/431
359/430
0.72
188/254
209/242
0.65
145/177
150/188
0.81
138/186
141/173
195/245
218/257
142/179
146/161
0.61
187/248
212/268
0.75
142/191
155/180
0.59
188/237
201/246
0.80
290/365
309/360
0.69
43/66
50/70
0.86
21/33
16/21
0.41
159/202
163/206
104/136
121/140
0.79
49/60
59/63
0.50
47/60
43/56
1.07
96/122
95/120
0.83
151/197
171/195
50/61
53/59
0.67
62/64
59/62
0.84
14/38
17/38
207/268
230/271
0.68
Group HR
0.125
0.25
0.5
1.0
2.0
All patients
Age < 65 years
Age ≥ 65 years
Female
Male
KPS
KPS
Australia
Western Europe
North America
Eastern Europe
Primary tumor location: head
Primary tumor location: other
No liver metastases
Liver metastases
Normal CA19-9 level
CA19-9 ULN to < 59 x ULN
CA19-9 ≥ 59 x ULN
> 3 Metastatic sites
1 Metastatic site
3 Metastatic sites
2 Metastatic sites
Favors nab-P + Gem
Favors Gem
Tabernero J, et al. 15th World Congress on Gastrointestinal Cancer; July 3 - 6, 2013; Barcelona, Spain. [abstract O-0001].

9. Stepwise Multivariate Analysis for Predictors of OS
Factors Predictive of OS HR
95% CI
P Valuea
Treatment (nab-P + Gem vs Gem)
0.72
0.0001
KPS ( vs )
1.60
<
Liver metastases (yes vs no)
1.81
Age (< 65 vs ≥ 65 years)
0.81
0.0190
Region (Eastern Europe vs North America)
1.22
0.0765
Number of metastatic sites (1, 2, 3, > 3)
1.08
0.0864
KPS, presence of liver metastases, age, region, and number of metastatic sites were found to be the most important predictors of survival
After adding known prognostic factors into the model, the effect of treatment on OS remained significant and favored nab-paclitaxel treatment
Baseline CA19-9 level was found to be a predictor of OS by univariate analysis; however, in the stepwise procedure, after selecting for the above factors, CA19-9 did not remain in the model as an independent predictor of survival
a For Cox proportional hazard model, P ≤ 0.1 considered statistically significant.
Tabernero J, et al. 15th World Congress on Gastrointestinal Cancer; July 3 - 6, 2013; Barcelona, Spain. [abstract O-0001].

10. Overall Survival in Subgroups
Patient Subgroups
nab-P + Gem
Gem HR
P Value n
Median OS, months
Region
North America
268
8.7
271
6.8
0.68
<
Eastern Europe 64
7.7 62
5.9
0.84
0.3715
Age
< 65 years
254
9.2
242
0.65
≥ 65 years
177
7.8
188
6.6
0.81
0.0816
KPS 70 30
3.9 33
2.8
0.99
0.9632 80
149
8.1
128
5.6
0.55 90
179
8.9
199
7.1
0.72
0.0058
100 69
12.6
10.9
0.92
0.6966
Liver metastases
Yes
365
8.3
360
0.69 No 66
11.0
10.7
0.86
0.4940
Number of metastatic sites 1
13.5 21
9.0
0.41
0.0212 2
202
206
0.75
0.0150 3
136
8.0
140
0.79
0.0929
> 3 60
8.6 63
5.0
0.50
0.0011
Tabernero J, et al. 15th World Congress on Gastrointestinal Cancer; July 3 - 6, 2013; Barcelona, Spain. [abstract O-0001].

11. Stepwise Multivariate Analysis for Predictors of PFS
Factors Predictive of PFS HR
95% CI
P Valuea
Treatment (nab-P + Gem vs Gem)
0.66
<
KPS ( vs )
1.56
Liver metastases (yes vs no)
1.79
0.0002
Age (< 65 vs ≥ 65 years)
0.83
0.0519
Region (Australia vs North America)
1.25
0.0928
After adding known prognostic factors into the models, the effect of treatment on OS (HR 0.72; 95% CI, ; P < ) and PFS (HR 0.66; 95% CI, ; P < ) remained significant and favored nab-P treatment
a For Cox proportional hazard model, P ≤ 0.1 considered statistically significant.
Tabernero J, et al. 15th World Congress on Gastrointestinal Cancer; July 3 - 6, 2013; Barcelona, Spain. [abstract O-0001].

12. Conclusions
In the phase III MPACT trial, KPS, presence of liver metastases, age, region, and number of metastatic sites were found to be the most important predictors of survival
Baseline CA19-9 level was not an independent predictor of OS in the multivariate analysis
After correcting for known prognostic factors, treatment with nab-P + Gem remained an independent, highly significant predictor of improved survival (HR 0.72; P < ) and disease progression (HR 0.66; P < ) in patients with metastatic pancreatic cancer
Tabernero J, et al. 15th World Congress on Gastrointestinal Cancer; July 3 - 6, 2013; Barcelona, Spain. [abstract O-0001].

13. THANK YOU
A special thank you to the patients and their families and the MPACT study investigators