Jean-Yves Douillard, MD, PhD
The presence or absence of RAS
mutations should dictate use of panitumumab (Vectibix) in combination with FOLFOX chemotherapy for patients with metastatic colorectal cancer (mCRC), two analyses of phase III data demonstrated.1,2
Patients whose tumors had wild-type RAS
lived almost 6 months longer when they received the anti-EGFR antibody in addition to four cycles of FOLFOX. Tumors with RAS
mutations were associated with significantly worse progression-free survival (PFS) and overall survival (OS) with panitumumab.
Even among patients with wild-type exon 2, a subgroup had mutations in other RAS
exons, which was associated with significantly worse survival with panitumumab plus FOLFOX4 versus FOLFOX4 alone.
“These results suggest that RAS
mutation status beyond KRAS
may be predictive of negative outcomes in patients receiving panitumumab plus FOLFOX4 in metastatic colorectal cancer,” concluded Kelly Oliner, PhD, principal scientist for in vitro diagnostics at Amgen, and colleagues, in a poster presentation at the 2013 ASCO Annual Meeting.
“Panitumumab plus oxaliplatin-containing regimens should not be used in patients with mutant RAS
metastatic colorectal cancer tumors,” they added. “By excluding patients with mutant RAS
metastatic colorectal tumors, the benefit-risk profile of panitumumab plus FOLFOX4 is improved.”
A second analysis of the phase III study also showed significant improvement in OS among patients with wild-type KRAS
exon 2 mCRC treated with panitumumab plus FOLFOX4, and confirmed the inferior survival in patients with mutant KRAS exon 2.
Both analyses involved data from the PRIME randomized trial of FOLFOX4 plus panitumumab versus FOLFOX4 alone as first-line therapy for mCRC. As previously reported, the primary results showed a statistically significant 1.6-month improvement in PFS in the panitumumab arm and a trend toward improved OS in patients with wild-type KRAS
exon 2 tumors. Patients with KRAS
-mutant tumors had worse PFS and OS (Douillard et al. J Clin Oncol.
A phase III trial of panitumumab monotherapy in mCRC also suggested lack of efficacy for anti-EGFR therapy in patients with mCRC tumors harboring mutations in KRAS
Oliner and colleagues presented findings from a prospectively defined retrospective comprehensive biomarker analysis, including KRAS, NRAS, and BRAF. The primary objective was to evaluate the efficacy and safety of panitumumab in patients with mutant and wild-type tumors.
PRIME involved 1083 patients. Mutation ascertainment was 90% for RAS
in both treatment arms, 52% for BRAF
and 89% for RAS/BRAF
. Oliner reported that 325 patients in the panitumumab arm had wild-type KRAS
exon 2 (codons 12/13), as did 331 in the control arm. Additionally, 221 patients in the panitumumab arm had mutant tumors, as well as 219 in the control group.
Testing for other RAS
mutations and for BRAF
mutations showed that 108 wild-type KRAS
exon 2 tumors (17%) had other mutations, most commonly BRAF
exon 15 odon 600 (9%), followed by KRAS
exon 4 (6%), KRAS
exon 3 (4%), NRAS
exon 3 (4%), and NRAS
exon 2 (3%).
Patients with any RAS
mutation or a BRAF
mutation had worse PFS and worse OS with panitumumab. In contrast, wild-type KRAS
exon 2 tumors were associated with a 5.8-month improvement in OS among patients who received panitumumab in addition to FOLFOX4 (hazard ratio [HR] = 0.78; 95% CI, 0.62-0.99; P
The second analysis of PRIME results involved the most mature OS data reported to date. Previous analyses occurred after 54% and 68% of survival events had occurred. The updated analysis reflected 82% of patients with a survival event, reported Jean-Yves Douillard, MD, PhD, director of Clinical and Translational Research at the Integrated Oncology Centers in Saint-Herblain, France.
The exploratory analysis showed a median OS of 23.8 months in patients with wild-type KRAS
exon 2 tumors treated with panitumumab versus 19.4 months in patients treated with FOLFOX4 alone (HR = 0.83; P
= .03). Consistent with previous analyses, the data showed a trend toward worse survival with panitumumab in patients with mutant KRAS
exon 2 tumors (15.5 vs 19.2 months; HR = 1.16; P
Oliner KS, Douillard J-Y, Salvatore S, et al. Analysis of KRAS/NRAS and BRAF mutations in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC). J Clin Oncol. 2013;31(suppl; abstr 3511).
Douillard J-Y, Siena S, Tabernero J, et al. Overall survival (OS) analysis from PRIME: randomized phase III study of panitumumab (pmab) with FOLFOX4 for first-line metastatic colorectal cancer (mCRC). J Clin Oncol. 2013;31(suppl; abstr 3620).