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.
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.
Antwerp University Hospital and University of Antwerp, Edegem, Belgium. Marc.Peeters@uza.be.
Marc
M
Peeters
Amgen Inc., Thousand Oaks, California, USA.
Kelly S
KS
Oliner
Queen Elizabeth Hospital and University of Adelaide, Woodville, Australia.
Timothy J
TJ
Price
Biomedical Research Institute INCLIVA, University of Valencia, Spain.
Andrés
A
Cervantes
Ospedale San Martino, Genova, Italy.
Alberto F
AF
Sobrero
Institut Gustave Roussy, Villejuif, and Paris-Sud University, Le Kremlin Bicêtre, Paris, France.
Michel
M
Ducreux
Uzhgorod National University, Uzhgorod, Ukraine.
Yevhen
Y
Hotko
Hôpital Saint Antoine and Université Pierre et Marie Curie (UMPC; Paris VI), Paris, France.
Thierry
T
André
Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Emily
E
Chan
University Cancer Center, Leipzig, Germany.
Florian
F
Lordick
Academic Medical Center, Amsterdam, the Netherlands.
Cornelis J A
CJ
Punt
Monash Medical Center, East Bentleigh, Australia.
Andrew H
AH
Strickland
Christie Hospital, Manchester, United Kingdom.
Gregory
G
Wilson
Institutul Oncologic Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu, Cluj Napoca, Romania.
Tudor E
TE
Ciuleanu
Leningrad Regional Oncology Dispensary, Saint Petersburg, Russia.
Laslo
L
Roman
University Hospitals and KU Leuven, Leuven, Belgium.
Eric
E
Van Cutsem
Amgen Inc., Thousand Oaks, California, USA.
Pei
P
He
Amgen Inc., Thousand Oaks, California, USA.
Hua
H
Yu
Amgen (Europe) GmbH, Zug, Switzerland.
Reija
R
Koukakis
Amgen (Europe) GmbH, Zug, Switzerland.
Jan-Henrik
JH
Terwey
Amgen Inc., Thousand Oaks, California, USA.
Andre S
AS
Jung
Amgen Inc., Thousand Oaks, California, USA.
Roger
R
Sidhu
Amgen Inc., Thousand Oaks, California, USA.
Scott D
SD
Patterson
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use; D011905:Genes, ras; D006801:Humans; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D000077544:Panitumumab; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019233:Retreatment; D016019:Survival Analysis; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D000077544:Panitumumab; D048493:Proto-Oncogene Proteins B-raf; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin