Reference Detail

Ref Type

Journal Article

PMID

(26341920)

Authors

Peeters M, Oliner KS, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, He P, Yu H, Koukakis R, Terwey JH, Jung AS, Sidhu R, Patterson SD

Title

Analysis of KRAS/NRAS Mutations in a Phase III Study of Panitumumab with FOLFIRI Compared with FOLFIRI Alone as Second-line Treatment for Metastatic Colorectal Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	21	24	2015 12 15	5469-79	Clin Cancer Res

URL

Abstract Text

We evaluated the influence of RAS mutation status on the treatment effect of panitumumab in a prospective-retrospective analysis of a randomized, multicenter phase III study of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) versus FOLFIRI alone as second-line therapy in patients with metastatic colorectal cancer (mCRC; ClinicalTrials.gov, NCT0039183).Outcomes were from the study's primary analysis. RAS mutations beyond KRAS exon 2 (KRAS exons 3, 4; NRAS exons 2, 3, 4; BRAF exon 15) were detected by bidirectional Sanger sequencing in wild-type KRAS exon 2 tumor specimens. Progression-free survival (PFS) and overall survival (OS) were coprimary endpoints.The RAS ascertainment rate was 85%; 18% of wild-type KRAS exon 2 tumors harbored other RAS mutations. For PFS and OS, the hazard ratio (HR) for panitumumab plus FOLFIRI versus FOLFIRI alone more strongly favored panitumumab in the wild-type RAS population than in the wild-type KRAS exon 2 population [PFS HR, 0.70 (95% confidence interval [CI], 0.54-0.91); P = 0.007 vs. 0.73 (95% CI, 0.59-0.90); P = 0.004; OS HR, 0.81 (95% CI, 0.63-1.03); P = 0.08 vs. 0.85 (95% CI, 0.70-1.04); P = 0.12]. Patients with RAS mutations were unlikely to benefit from panitumumab. Among RAS wild-type patients, the objective response rate was 41% in the panitumumab-FOLFIRI group versus 10% in the FOLFIRI group.Patients with RAS mutations were unlikely to benefit from panitumumab-FOLFIRI and the benefit-risk of panitumumab-FOLFIRI was improved in the wild-type RAS population compared with the wild-type KRAS exon 2 population. These findings support RAS testing for patients with mCRC. Clin Cancer Res; 21(24); 5469-79. ©2015 AACR.See related commentary by Salazar and Ciardiello, p. 5415.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS wild-type	colorectal cancer	predicted - sensitive	Fluorouracil + Irinotecan + Leucovorin + Panitumumab	Phase III	Actionable	In a Phase III clinical trial, the combination of Vectibix (panitumumab) and FOLFIRI improved progression-free survival and median overall survival in patients with RAS wild-type colorectal cancer compared to FOLFIRI treatment alone (PMID: 26341920).	26341920