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.

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.

• Authors: Marc Peeters, Kelly S Oliner, Timothy J Price, Andrés Cervantes, Alberto F Sobrero, Michel Ducreux, Yevhen Hotko, Thierry André, Emily Chan, Florian Lordick, Cornelis J A Punt, Andrew H Strickland, Gregory Wilson, Tudor E Ciuleanu, Laslo Roman, Eric Van Cutsem, Pei He, Hua Yu, Reija Koukakis, Jan-Henrik Terwey, Andre S Jung, Roger Sidhu, Scott D Patterson
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 24 Pg. 5469-79 (12 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 26341920 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• Panitumumab
• Proto-Oncogene Proteins B-raf
• Leucovorin
• Fluorouracil
• Camptothecin

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Camptothecin (adverse effects, analogs & derivatives, therapeutic use)
• Colorectal Neoplasms (drug therapy, genetics, mortality, pathology)
• DNA Mutational Analysis
• Exons
• Female
• Fluorouracil (adverse effects, therapeutic use)
• Genes, ras
• Humans
• Leucovorin (adverse effects, therapeutic use)
• Male
• Middle Aged
• Mutation
• Neoplasm Metastasis
• Panitumumab
• Proportional Hazards Models
• Proto-Oncogene Proteins B-raf (genetics)
• Retreatment
• Survival Analysis
• Treatment Outcome