Phase III Trial (MPACT) of Weekly nab-Paclitaxel Plus Gemcitabine in Metastatic Pancreatic Cancer: Influence of Prognostic Factors of Survival J Tabernero,

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Presentation transcript:

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

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. 2011:29:4548-4554. 2. Frese KK, et al. Cancer Discov. 2012;2:260-269.

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].

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 (70 - 80 and 90 - 100) 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].

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, % 90 - 100 70 - 80 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].

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].

Proportion of Survival OS in ITT Population OS, months Events, n/N (%) Median (95% CI) 75th Percentile 333/431 (77) 8.5 (7.89 - 9.53) 14.8 359/430 (83) 6.7 (6.01 - 7.23) 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, 0.617 - 0.835 P = 0.000015 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].

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 70 - 80 KPS 90 - 100 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].

Stepwise Multivariate Analysis for Predictors of OS Factors Predictive of OS HR 95% CI P Valuea Treatment (nab-P + Gem vs Gem) 0.72 0.605 - 0.849 0.0001 KPS (70 - 80 vs 90 - 100) 1.60 1.346 - 1.895 < 0.0001 Liver metastases (yes vs no) 1.81 1.404 - 2.332 Age (< 65 vs ≥ 65 years) 0.81 0.686 - 0.967 0.0190 Region (Eastern Europe vs North America) 1.22 0.979 - 1.516 0.0765 Number of metastatic sites (1, 2, 3, > 3) 1.08 0.988 - 1.191 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].

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 < 0.0001 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].

Stepwise Multivariate Analysis for Predictors of PFS Factors Predictive of PFS HR 95% CI P Valuea Treatment (nab-P + Gem vs Gem) 0.66 0.544 - 0.796 < 0.0001 KPS (70 - 80 vs 90 - 100) 1.56 1.288 - 1.879 Liver metastases (yes vs no) 1.79 1.323 - 2.424 0.0002 Age (< 65 vs ≥ 65 years) 0.83 0.683 - 1.002 0.0519 Region (Australia vs North America) 1.25 0.963 - 1.631 0.0928 After adding known prognostic factors into the models, the effect of treatment on OS (HR 0.72; 95% CI, 0.605 - 0.849; P < 0.0001) and PFS (HR 0.66; 95% CI, 0.544 - 0.796; P < 0.0001) 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].

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 < 0.0001) and disease progression (HR 0.66; P < 0.0001) 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].

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