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Ann Oncol. 2014 Sep;25(9):1756-61. doi: 10.1093/annonc/mdu230. Epub 2014 Jun 18.

Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next-generation sequencing: findings from the CAPRI-GOIM trial.

Author information

  • 1Department of Clinical and Experimental Medicine 'F. Magrassi', Medical Oncology, Second University of Naples, Naples fortunato.ciardiello@unina2.it.
  • 2Cell Biology and Biotherapy Unit, National Cancer Institute 'Fondazione Giovanni Pascale', Naples.
  • 3Medical Oncology, Hospital Casa Sollievo Della Sofferenza-San Giovanni Rotondo (Foggia), San Giovanni Rotondo.
  • 4Department of Clinical and Experimental Medicine 'F. Magrassi', Medical Oncology, Second University of Naples, Naples.
  • 5Department of Medical Oncology, Hospital SS. Annunziata, Taranto.
  • 6Department of Medical Oncology, National Cancer Institute Giovanni Paolo II, Bari.
  • 7Department of Medical Oncology, University Hospital A. Gemelli, Rome.
  • 8Department of Medical Oncology, Hospital 'A. Cardarelli', Naples.
  • 9Department of Medical Oncology, Hospital Monaldi- Azienda Ospedaliera dei Colli, Napoles.
  • 10Department of Medical Oncology, Univeristy Hospital Campus Bio-Medico di Rome, Rome.
  • 11Department of Medical Oncology, Hospital A. Perrino, Brindisi.
  • 12Department of Medical Oncology, Hospital Garibaldi, Nesima, Catania.
  • 13Department of Medical Oncology, Hospital Sacro Cuore di Gesù, Fatebenefratelli, Benevento.
  • 14Department of Medical Oncology, Hospital Polo Occidentale, Castellaneta, Bari.
  • 15Department of Pathology, National Cancer Institute 'Fondazione Giovanni Pascale', Naples, Italy.

Abstract

BACKGROUND:

Treatment with antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies has been restricted to metastatic colorectal cancer (mCRC) patients with RAS wild-type tumors. Next-generation sequencing (NGS) allows the assessment in a single analysis of a large number of gene alterations and might provide important predictive and prognostic information.

PATIENTS AND METHODS:

In the CAPRI-GOIM trial, 340 KRAS exon 2 wild-type mCRC patients received first-line FOLFIRI plus cetuximab. Tumor samples (182/340, 53.5%) were assessed by NGS to search for mutations in 22 genes involved in colon cancer.

RESULTS:

Objective responses in the NGS cohort were observed in 104/182 patients [overall response rate (ORR) 57.1%; 95% confidence interval (95% CI) 52% to 66.4%] with a median progression-free survival (mPFS) of 9.8 (95% CI 8.7-11.5) months. NGS analysis was successfully completed in all 182 samples. One or more gene mutations (up to five) were detected in 124/182 (68.1%) tumors within 14/22 genes for a total of 206 mutations. KRAS exon 2 mutations were identified in 29/182 (15.9%) samples, defined as wild type by local laboratory assessment. Frequently mutated genes were: TP53 (39.6%), KRAS exons 3/4 (8.8%), NRAS exons 2/3 (7.1%), PIK3CA exons 9/20 (13.2%), BRAF (8.2%). FOLFIRI plus cetuximab treatment determined ORR of 62.0% (95% CI 55.5% to 74.6%) with mPFS of 11.1 (95% CI 9.2-12.8) months in patients with KRAS and NRAS wild-type tumors. Conversely, ORR was 46.6% (95% CI 39.9-57.5%) with mPFS of 8.9 (95% CI 7.4-9.6) months in patients with KRAS or NRAS mutations. Similarly, the subgroup of patients carrying KRAS, NRAS, BRAF, or PIK3CA mutations showed a worse outcome, although this might be due to a prognostic effect.

CONCLUSIONS:

This study demonstrates that NGS analysis in mCRC is feasible, reveals high level of intra and intertumor heterogeneity, and identifies patients that might benefit of FOLFIRI plus cetuximab treatment.

© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

KEYWORDS:

BRAF; KSA/NRAS; PIK3CA; cetuximab; colorectal cancer; next-generation sequencing

PMID:
24942275
[PubMed - indexed for MEDLINE]
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