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Final Results from Study 181: Randomized Phase 3 Study of FOLFIRI +/- Panitumumab for the Treatment of 2 nd ‑line Metastatic Colorectal Cancer. A. Sobrero , 1 M. Peeters, 2 T. Price, 3 Y. Hotko, 4 A. Cervantes, 5 M. Ducreux, 6 T. André, 7 E. Chan, 8 F. Lordick 9 Y. Tian, 10 R. Sidhu 10
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Final Results from Study 181: Randomized Phase 3 Study of FOLFIRI +/- Panitumumab for the Treatment of 2nd‑line Metastatic Colorectal Cancer A. Sobrero,1 M. Peeters,2 T. Price,3 Y. Hotko,4 A. Cervantes,5 M. Ducreux,6 T. André,7E. Chan,8 F. Lordick9 Y. Tian,10 R. Sidhu10 1Ospedale San Martino, Genoa, Italy; 2University Hospital Antwerp, Antwerp, Belgium; 3Queen Elizabeth Hospital, Woodville, Australia; 4Uzhgorod National University, Uzhgorod, Ukraine; 5Hospital Clínico, University of Valencia, Spain; 6Institut GustaveRoussy, Villejuif, France; 7Hôpital Pitié-Salpêtrière, Paris, France; 8Vanderbilt University Medical Center, Nashville, Tennessee; 9Nationales Centrum fürTumorerkrankungen, Heidelberg, Germany; 10Amgen Inc., Thousand Oaks, California
Conflicts of interest • This study was funded by Amgen • A. Sobrero: consultant/advisory role for Amgen, Merck-Serono and Roche and received honoraria • M. Peeters: consultant/advisory role for Amgen and also received honoraria and research funding • T. Price: consultant/advisory role for Amgen and received honoraria • Y. Hotko: None • A. Cervantes: consultant/advisory role for Amgen and also received honoraria • M. Ducreux: consultant/advisory role for Amgen and Roche and also received honoraria and research funding • T. André: consultant/advisory role for Amgen and Roche and received honoraria • E. Chan: consultant/advisory role and received honoraria from Amgen, Genentech, ImClone Systems, Bristol-Myers Squibb and Celgene and research funding from Amgen, ImClone Systems, Pfizer, Roche, Plexxilon, Idera Pharmaceuticals, EMD Serono, Genentech, Bristol-Myers Squibb, and Eli Lilley • F. Lordick: received honoraria from Amgen and Merck KGaA and also received research funding from the latter • Y. Tian: employed by Amgen • R. Sidhu: employed by Amgen
Study Schema and Stratification LONG TERM FOLLOW UP • Randomization stratification: • ECOG PS: 0-1 vs 2 • Prior oxaliplatin exposure • Prior bevacizumab exposure END OF TREATMENT Treatment arm 1: Pmab6.0 mg/kg Q 2 weeks + FOLFIRI Q 2 weeks ENROLLMENT SCREENING Treatment arm 2: FOLFIRI Q 2 weeks Disease assessments every 8 weeks Enrollment target 1100 patients
Introduction • The primary analysis of the 181 trial showed:1 • Significantly improved PFS and RR • A trend towards improved OS • Here we present • A pre-specified descriptive efficacy analysis planned for 30 months after the last patient enrolled(No formal hypothesis testing was planned) • Efficacy outcomes were analyzed by skin toxicity (ST) Grade (0-1 vs 2-4) to investigate a possible correlation among patients who were alive without PD at day 28 1Peeters et al. J ClinOncol 2010; 28: 4706-13
Objective Response Rate (Central Review) All responses were required to be confirmed at least 28 days after the response criteria were first met.
PFS (Central Review) WT MT 100 100 Pmab + FOLFIRI (n=238) Pmab + FOLFIRI (n=303) 80 80 FOLFIRI alone (n=294) FOLFIRI alone (n=248) 60 60 Proportion event free (%) Proportion event free (%) 40 40 20 20 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Months Months
OS WT MT 100 100 Pmab + FOLFIRI (n=238) Pmab + FOLFIRI (n=303) 80 80 FOLFIRI alone (n=248) FOLFIRI alone (n=294) 60 60 Proportion event free (%) Proportion event free (%) 40 40 20 20 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Months Months
Grade 3/4 Adverse Events (AEs) of Interest aIncludes one Grade 5 AE; bIncludes two Grade 5 AEs; cRates of infusion reactions reported as an AE are shown
Efficacy by ST Grade – WT KRAS PFS OS 100 100 Worst ST Grade 2-4 in Pmabarm (n=208) Worst ST Grade 2-4 in Pmabarm (n=208) Worst ST Grade 0-1 in Pmabarm (n=83) Worst ST Grade 0-1 in Pmabarm (n=83) 80 80 FOLFIRI alone (n=288) FOLFIRI alone (n=288) 60 60 Proportion event free (%) Proportion event free (%) 40 40 20 20 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Months Months Events, n (%) 198 (95)81 (98)271 (94) Median (95% CI), months 7.4 (6.7, 8.5)4.0 (3.7, 5.5)5.1 (3.8, 5.5) Events, n (%) 187 (90)76 (92)254 (88) Median (95% CI), months 16.6 (14.9, 19.4)8.4 (6.7, 11.3)12.7 (11.3, 14.3) Worst ST Grade 2-4 in Pmab arm Worst ST Grade 2-4 in Pmab arm Worst ST Grade 0-1 in Pmab arm Worst ST Grade 0-1 in Pmab arm FOLFIRI alone FOLFIRI alone ST 2-4 vs FOLFIRI (95% CI): HR=0.72 (0.60, 0.87); p=0.0006 ST 0-1 vs FOLFIRI (95% CI): HR=1.15 (0.89, 1.48); p=0.28 ST 2-4 vs 0.1 (95% CI): HR=0.60 (0.46, 0.80); p=0.0003 ST 2-4 vs FOLFIRI (95% CI): HR=0.80 (0.66, 0.97); p=0.025 ST 0-1 vs FOLFIRI (95% CI): HR=1.48 (1.14, 1.93); p=0.003 ST 2-4 vs 0.1 (95% CI): HR=0.50 (0.38, 0.66); p<0.0001
PRIME: PFS and OS by ST Grade WT KRAS and OS ≥ 28 Days Worst Grade ST Grade WT KRAS and PFS ≥ 28 Days Worst Grade ST Grade
Conclusions • Results of the primary analysis confirmed that in K/RAS wt: • Significantly improved PFS • Trend towards improved OS • Significantly improved RR • No new safety signals • One-third of patients in the FOLFIRI alone arm received subsequent anti-EGFR therapy, with potential impact on OS • Patients with WT KRAS tumors receiving Pmab + FOLFIRI with Grade 2-4 skin toxicity demonstrated improved PFS and OS, compared with those receiving FOLFIRI alone, or those receiving Pmab + FOLFIRI with Grade 0-1 skin toxicity • The inability to mount a skin reaction to anti EGFR seems to be associated with a shorter overall survival
Acknowledgments • The authors wish to thank: • The patients and their families • The investigators and their study staff worldwide • The study team at Amgen
