Abstract A57: Extended RAS analysis in patients (pts) with untreated metastatic colorectal cancer (mCRC): Results from the PRIME and PEAK studies
Authors: Hecht J. Randolph , Douillard Jean-Yves , Schwartzberg Lee , Siena Salvatore , Tabernero Josep , Karthaus Meinholf , Rivera Fernando , Oliner Kelly S. , Yu Hua , Tian Ying , Jung Scott , Go Will 
Published: May 2015

Abstract
Background: PRIME was a randomized phase 3 study of panitumumab (pmab)+FOLFOX4 vs FOLFOX4 in the 1st-line treatment (tx) of pts with mCRC by KRAS exon 2 status. PEAK was a randomized phase 2 study of pmab+mFOLFOX6 or bevacizumab (bev)+mFOLFOX6 in the 1st-line tx of pts with wild-type (WT) KRAS exon 2 mCRC. Prespecified analyses in these studies indicated that RAS mutations, beyond those in KRAS exon 2, were negative predictive factors for pmab tx for progression-free survival (PFS) and overall survival (OS). We report the objective response rates (ORRs) and PFS and OS results for pts whose tumors underwent extended RAS analysis (exons 2, 3, and 4 of KRAS and NRAS).
Methods: Pts were randomized 1:1 to receive FOLFOX4±pmab 6.0 mg/kg Q2W in PRIME and mFOLFOX6 with either pmab 6.0 mg/kg or bev 5.0 mg/kg Q2W in PEAK. The primary endpoint for both studies was PFS. For PRIME, results from the primary analysis are presented. For PEAK, PFS and ORR results are from the primary analysis. OS results are from an additional follow-up approximately 1 year from the last patient enrolled with 130 (46%) deaths reported. For prespecified extended RAS analysis, mutations in KRAS exons 3 and 4 and NRAS exons 2, 3, and 4 were identified by independently conducted bidirectional Sanger sequencing and WAVE-based SURVEYOR® from Transgenomic which yielded consistent results.
Results: The RAS ascertainment rate was 90% (1060/1183) of pts in PRIME and 82% (233/285) in PEAK. In pts with WT RAS mCRC (WT for exons 2, 3, and 4 of KRAS and NRAS), median PFS in PRIME was 10.1 months in the pmab+FOLFOX4 arm and 7.9 months in the FOLFOX4 arm (HR=0.72; 95% CI, 0.58-0.90; P=0.004) and in PEAK 13.0 months in the pmab+mFOLFOX6 arm and 9.5 months in the bev+mFOLFOX6 arm (HR=0.65; 95% CI, 0.44-0.96; P=0.029). Median OS in PRIME was 26.0 months in the pmab+FOLFOX4 arm and 20.2 months in the FOLFOX4 arm (HR=0.78; 95% CI, 0.62-0.99; P=0.043) and in PEAK 41.3 months in the pmab+mFOLFOX6 arm and 28.9 months in the bev+mFOLFOX6 arm (HR=0.63; 95% CI, 0.39-1.02; P=0.058). For the WT RAS subgroup, ORRs in PRIME were 59% and 46% in the pmab+FOLFOX4 and FOLFOX4 arms, respectively. ORRs in PEAK were 64% and 60% in the pmab+mFOLFOX6 and bev+mFOLFOX6 arms, respectively.
17% of pts (108/641) were WT KRAS exon 2/mutant in other RAS exons in PRIME and 22% (51/227) in PEAK. In this subset, median PFS in PRIME was 7.3 months in the pmab+FOLFOX4 arm and 8.0 months in the FOLFOX4 arm (HR=1.28; 95% CI, 0.79-2.07; P=0.326) and in PEAK 7.8 months in the pmab+mFOLFOX6 arm and 8.9 months in the bev+mFOLFOX6 arm (HR=1.39; 95% CI, 0.73-2.64; P=0.318). Median OS in PRIME was 17.1 months in the pmab+FOLFOX4 arm and 18.3 months in the FOLFOX4 arm (HR=1.29; 95% CI, 0.79-2.10; P=0.305) and in PEAK 27.0 months in the pmab+mFOLFOX6 arm and 16.6 months in the bev+mFOLFOX6 arm (HR=0.41; 95% CI, 0.19-0.87; P=0.020). For the WT KRAS exon 2/mutant in other RAS subgroup, ORRs in PRIME were 40% and 54% in the pmab+FOLFOX4 and FOLFOX4 arms, respectively. ORRs in PEAK were 58% and 56% in the pmab+mFOLFOX6 and bev+mFOLFOX6 arms, respectively.
No new safety signals were identified.
In both studies, PFS results for prespecified subset analyses by exon indicate that individual WT RAS exons favor the pmab-containing arms and will be presented.
Conclusions: Extended RAS analyses in the phase 3 PRIME and phase 2 PEAK studies indicate that pts with WT RAS mCRC have improved PFS, OS, and ORR in 1st-line tx regimens containing pmab. Consistent with KRAS exon 2 mutations, negative outcomes are associated with pmab+oxaliplatin tx regimens for pts whose tumors harbor RAS mutations beyond KRAS exon 2.
Citation Format: J. Randolph Hecht, Jean-Yves Douillard, Lee Schwartzberg, Salvatore Siena, Josep Tabernero, Meinholf Karthaus, Fernando Rivera, Kelly S. Oliner, Hua Yu, Ying Tian, Scott Jung, Will Go. Extended RAS analysis in patients (pts) with untreated metastatic colorectal cancer (mCRC): Results from the PRIME and PEAK studies. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A57. doi: 10.1158/1557-3125.RASONC14-A57