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Clin Cancer Res. 2015 Dec 15;21(24):5469-79. doi: 10.1158/1078-0432.CCR-15-0526. Epub 2015 Sep 4.

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.

Author information

1
Antwerp University Hospital and University of Antwerp, Edegem, Belgium. Marc.Peeters@uza.be.
2
Amgen Inc., Thousand Oaks, California, USA.
3
Queen Elizabeth Hospital and University of Adelaide, Woodville, Australia.
4
Biomedical Research Institute INCLIVA, University of Valencia, Spain.
5
Ospedale San Martino, Genova, Italy.
6
Institut Gustave Roussy, Villejuif, and Paris-Sud University, Le Kremlin Bicêtre, Paris, France.
7
Uzhgorod National University, Uzhgorod, Ukraine.
8
Hôpital Saint Antoine and Université Pierre et Marie Curie (UMPC; Paris VI), Paris, France.
9
Vanderbilt University Medical Center, Nashville, Tennessee, USA.
10
University Cancer Center, Leipzig, Germany.
11
Academic Medical Center, Amsterdam, the Netherlands.
12
Monash Medical Center, East Bentleigh, Australia.
13
Christie Hospital, Manchester, United Kingdom.
14
Institutul Oncologic Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu, Cluj Napoca, Romania.
15
Leningrad Regional Oncology Dispensary, Saint Petersburg, Russia.
16
University Hospitals and KU Leuven, Leuven, Belgium.
17
Amgen (Europe) GmbH, Zug, Switzerland.

Abstract

PURPOSE:

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).

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSIONS:

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.

Comment in

PMID:
26341920
DOI:
10.1158/1078-0432.CCR-15-0526
[Indexed for MEDLINE]
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