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

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.

[1]  W. Scheithauer,et al.  Mutations within the EGFR signaling pathway: Influence on efficacy in FIRE-3—A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. , 2014 .

[2]  J. Tabernero,et al.  Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. , 2013, The New England journal of medicine.

[3]  G. Fasola,et al.  Analysis of KRAS/NRAS mutations in PEAK: A randomized phase II study of FOLFOX6 plus panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC). , 2013 .

[4]  B. Tops,et al.  Abstract 36: The OncoNetwork Consortium: A European Collaborative Research study on the development of an Ion AmpliSeq gene panel targeting hot spots in colon and lung cancers. , 2013 .

[5]  P. A. Futreal,et al.  Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. , 2012, The New England journal of medicine.

[6]  A. Marchetti,et al.  KRAS Mutations Testing in Colorectal Carcinoma Patients in Italy: From Guidelines to External Quality Assessment , 2011, PloS one.

[7]  Sabine Tejpar,et al.  KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. , 2011, The Lancet. Oncology.

[8]  Renzo Boldorini,et al.  Increased Detection Sensitivity for KRAS Mutations Enhances the Prediction of Anti-EGFR Monoclonal Antibody Resistance in Metastatic Colorectal Cancer , 2011, Clinical Cancer Research.

[9]  E. Van Cutsem,et al.  Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  P. Laurent-Puig,et al.  External quality assessment for KRAS testing is needed: setup of a European program and report of the first joined regional quality assessment rounds. , 2011, The oncologist.

[11]  Josep Tabernero,et al.  Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  Sabine Tejpar,et al.  Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. , 2010, The Lancet. Oncology.

[13]  F. J. Ramos,et al.  Pharmacogenomic and pharmacoproteomic studies of cetuximab in metastatic colorectal cancer: biomarker analysis of a phase I dose-escalation study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  E. Van Cutsem,et al.  Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. , 2009, The New England journal of medicine.

[15]  L. Mazzucchelli,et al.  Multi-Determinants Analysis of Molecular Alterations for Predicting Clinical Benefit to EGFR-Targeted Monoclonal Antibodies in Colorectal Cancer , 2009, PloS one.

[16]  Sabine Tejpar,et al.  Implications for KRAS status and EGFR-targeted therapies in metastatic CRC , 2009, Nature Reviews Clinical Oncology.

[17]  G. Tortora,et al.  EGFR antagonists in cancer treatment. , 2008, The New England journal of medicine.