Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next generation sequencing: findings from the CAPRI-GOIM trial
Menée sur 104 patients atteints d'un cancer colorectal métastatique et inclus dans l'essai CAPRI-GOIM, cette étude évalue la faisabilité et les résultats d'une méthode de séquençage à haut débit ciblée sur 22 gènes pour identifier les patients susceptibles de bénéficier d'un traitement combinant cetuximab et chimiothérapie FOLFIRI
Background : Treatment with anti-epidermal growth factor receptor (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), 52-66.4%] 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 5) 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, 55.5-74.6%) 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 either 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 inter-tumor heterogeneity, and identifies patients that might benefit of FOLFIRI plus cetuximab treatment.
Annals of Oncology , résumé, 2014