Statistical Methods

1. Prognostic Factors of Survival in a Randomized Phase III Trial (MPACT) of Weekly nab-Paclitaxel Plus Gemcitabine vs Gemcitabine Alone in Patients With Metastatic Pancreatic Cancer Abstract #4059 nab-P + Gem Gem Malcolm J. Moore,1 Daniel D. Von Hoff,2 Thomas J. Ervin,3 Francis P. Arena,4 E. Gabriela Chiorean,5Jeffrey R. Infante,6 Jeremy K. Hon,7 Mikhail Yu Biakhov,8 Sunil R. Hingorani,9Vinod Ganju,10 Colin D. Weekes,11 Werner Scheithauer,12 Ramesh K. Ramanathan,2JosepTabernero,13 David Goldstein,14Xinyu Wei,15 Alfred Romano15 1 Princess Margaret Hospital, Toronto, ON, Canada; 2 Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, Scottsdale, AZ; 3 Florida Cancer Specialists, Englewood, FL; 4 Arena Oncology Associates, Lake Success, NY;5University of Washington, Seattle, WA; 6 Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; 7Clearview Cancer Institute, Huntsville, AL; 8Semashko Central Clinical Hospital, Moscow, Russia; 9 Fred Hutchinson Cancer Research Center, Seattle, WA; 10 Peninsula Oncology Centre, Frankston, VIC, Australia; 11 University of Colorado Cancer Center, Aurora, CO; 12MedizinischeUniversität Wien, Wien, Austria; 13Valld'Hebron University Hospital, Barcelona, Spain; 14 Prince of Wales Hospital, Sydney, Australia; 15CelgeneCorporation, Summit, NJ Australia Eastern Europe INTRODUCTION Statistical Methods • A prespecified analyses to assess the potential influence of the following prognostic factors on OS and PFS was performed • 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) • 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, upper limit of normal (ULN) to < 59 ULN, and ≥ 59 ULN) • Geographic region • 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 • Median OS for nab-P + Gem was significantly longer vs Gem (Figure 2) • A step-wise multivariate analysis for predictors of OS and PFS are shown in Table 2. • After adding known prognostic factors into the model, 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-paclitaxel treatment across the majority of subgroups. Median OS across subgroups is show in Table 3 Table 3. OS in Subgroups Western Europe North America Figure 2. OS in the ITT Population Primary Tumor Location: Head Primary Tumor Location: Other • Compared with solvent-based paclitaxel, albumin-bound paclitaxel (nab®-paclitaxel [nab-P], Celgene, Summit, NJ), • Exhibits 10-fold higher mean Cmax of free paclitaxel1 • Delivers 33% higher drug concentration to tumors in preclinical xenograft models2 • Demonstrates enhanced transport across endothelial cell monolayers2 • In this phase III trial (MPACT) of patients with metastatic PC, nab-P + G demonstrated superior efficacy vsG alone • Median overall survival (OS): 8.5 vs 6.7 months; HR 0.72; P = 0.000015 • Median progression-free survival (PFS): 5.5 vs 3.7 months; HR 0.69; P = 0.000024 • Overall response rate (ORR): 23% vs 7%; P = 1.1 × 10−10 • In this analysis, the potential influence of prognostic factors on the primary efficacy endpoint of OS was assessed Liver Metastases No Liver Metastases 1 Metastatic Site 2 Metastatic Sites 3 Metastatic Sites 1.0 > 3 Metastatic Sites Table 2. Stepwise Multivariate Analysis for Predictors of OS and PFS 0.9 Normal CA19-9 CA19-9 ULN to < 59 × ULN 0.8 CA19-9 ≥ 59 × ULN 0.125 0.25 0.5 1.0 2.0 0.7 0.6 HR = 0.72 95% CI (0.617 - 0.835) P= 0.000015 0.5 Proportion of Survival 0.4 0.3 0.2 0.1 0.0 Patients at Risk RESULTS 0 3 6 9 12 15 18 21 24 27 30 33 36 39 nab-P + Gem: 431 357 269 169 108 67 40 27 16 9 4 1 1 0 nab® is a registered trademark of Celgene Corporation. Months Gem: 430 340 220 124 69 40 26 15 7 3 1 0 0 0 conclusions study design Table 1. Baseline Characteristics • 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 was not an independent predictor of OS in the multivariate analysis; however, the effect of treatment on OS remained significant after baseline CA19-9 was added into the model (HR 0.67; P < 0.0001) • 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 Figure 1. Planned Trial Design • Treatment effect on OS was consistent across patient subgroups (Figure 3) Group HR nab-P125 mg/m2IV qw 3/4 + Gem 1000 mg/m2 IV qw 3/4 All Patients Figure 3. OS - Prespecified Subgroups Age < 65 Years Age ≥ 65 Years • Planned N = 842 • Stage IV • No prior treatment for metastatic disease • KPS ≥ 70 • Measurable disease • Total bilirubin ≤ ULN Female Male • 1:1 randomization stratified by: • KPS • Region • Liver metastasis KPS 70-80 KPS 90-100 ACKNOWLEDGMENTS The authors acknowledge the financial support for this study from Celgene Corporation and the production support from MediTech Media, Ltd. Gem 1000 mg/m2 IV qw 7/8, then qw 3/4 DISCLOSURES MJM: consultant or advisory role and research funding, Celgene Corp.; DDVH: consultant or advisory role, honoraria, and research funding, Celgene Corp.; TJE: Research funding, Celgene Corp.; FPA: research funding, Clinical Research Alliance and CelgeneCorp.; EGC: research funding, CelgeneCorp.; JRI: nothing to disclose; JKH: nothing to disclose; MYB: research funding, Celgene Corp.; SRH: nothing to disclose; VG: nothing to disclose; CDW: consultant or advisory role and honoraria, Celgene Corp.; WS: consultant or advisory role, honoraria, and research funding, Celgene Corp.; RKR: consultant or advisory role, honoraria, and research funding, CelgeneCorp.; JT: Consultant or advisory role and honoraria, CelgeneCorp.; DG: Consultant or advisory role and research funding, CelgeneCorp.; XW: employment or leadership position and stock ownership, CelgeneCorp.; AR: employment or leadership position and stock ownership, CelgeneCorp. • A total of 861 patients were randomized between May, 2009 and April, 2012 in 151 community and academic centers from 11 countries • With 608 events, 90% power to detect OS HR = 0.769 (2-sided α = 0.049) • Treat until disease progression REFERENCES • Gardner ER, et al. Clin Cancer Res. 2008;14:4200-4205. • Desai N, et al. Clin Cancer Res. 2006;12:1317-1324. • Therasse P, et al. J Natl Cancer Inst. 2000;92:205-216. • Baseline CA19-9 was found to be a predictor of OS by univariate analysis; however, after correcting for the above factors CA19-9 was not an independent predictor of OS in the multivariate analysis • The effect of treatment on OS remained significant after baseline CA19-9 was added into the model (HR 0.67; 95% CI 0.573 - 0.794, P < 0.0001) Endpoints • Primary: OS • Secondary: PFS and ORR by independent review using RECIST v1.03 criteria, safety Favors Gem Favors nab-P + Gem Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO® and the author of this poster KPS, Karnofskyperformance status; qw 3/4, first 3 of 4 weeks; qw 7/8, first 7 of 8 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; ULN, upper limit of normal.