ESMO World GI 2015: Second-Line Cetuximab Active Beyond Progression in Metastatic Colorectal Cancer
Patients with metastatic colorectal cancer that are free of mutations in the KRAS, NRAS, BRAF, and PIK3CA genes showed a significant benefit from continuing antiepidermal growth factor receptor (EGFR) therapy beyond progression following first-line chemotherapy and an anti-EGFR monoclonal antibody. These study results were presented July 4 at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer in Barcelona, Spain (Abstract LBA-09).
Fortunato Ciardiello, MD, PhD, Head of the Laboratory of Experimental Therapeutics, Head of the Division of Medical Oncology, and Professor of Medical Oncology at Seconda Università degli Studi di Napoli, presented results from the CAPRI-GOIM study on the efficacy of cetuximab (Erbitux) plus FOLFOX (leucovorin, fluorouracil [5-FU], oxaliplatin) chemotherapy as second-line treatment for patients with metastatic colorectal cancer that progressed following FOLFIRI (leucovorin, 5-FU, irinotecan) chemotherapy and cetuximab.
Study Details
CAPRI-GOIM is a nonprofit, academic, phase II trial enrolling 340 patients with metastatic colorectal cancer and KRAS exon 2 wild-type tumors. All patients received standard first-line treatment of FOLFIRI plus cetuximab, until disease progression or unacceptable toxicity, as previously reported by Ciardiello et al.
Following first-line treatment, patients experiencing disease progression were randomized 1:1 to receive second-line treatment of FOLFOX plus cetuximab (arm A; n = 74) or FOLFOX alone (arm B; n = 79). The primary endpoint of the study was progression-free survival, and secondary endpoints were overall survival, response rate, and safety.
Analysis of these data in the overall intent-to-treat population showed an advantage in progression-free survival favoring arm A that did not reach statistical significance; median progression-free survival was 6.4 months in the FOLFOX plus cetuximab arm A, compared with 4.5 months in the FOLFOX arm B (hazard ratio = 0.81; 95% confidence interval = 0.58, 1.12; log-rank test, P = .19).
Genetic Sequencing
“We therefore looked for patient characteristics that would account for this result; next generation sequencing of the genes of interest was performed on the archival tissue samples from the patients' primary tumors,” explained Dr. Ciardiello.
The investigators used the Ion AmpliSeq Colon and Lung Cancer Panel, comprising 500 hotspot mutations in 22 genes, and Ion Reporter Software. Next-generation sequencing was possible in 117 (76.5%) patients. It revealed that 66 patients had “all RAS” wild-type tumors, with no mutations in KRAS, NRAS, BRAF, or PIK3CA genes; 51 patients had tumors harboring a mutation in at least one of these genes. KRAS exon 2 mutations were found in approximately 15% of the tumors that were originally identified as wild-type.
“The most important thing we found was that when we considered patients regarding the KRAS, NRAS, BRAF, and PIK3CA genes, we could have two patient populations: one that was multiple wild-type and normal for all four genes and another of patients that were mutated in at least one of these genes. In the patients with at least one mutation in one of these genes, there was a detrimental effect from FOLFOX plus cetuximab in progression-free survival, response rate, and overall survival,” Dr. Ciardiello commented.
Whereas the mutation-free, quadruple wild-type population showed significantly prolonged progression-free survival and improved overall survival and response rates with second-line cetuximab/FOLFOX, this treatment had the opposite effect upon patients with genetic mutations in the EGFR pathway. Cetuximab/FOLFOX demonstrated significantly longer progression-free survival in patients with quadruple wild-type tumors, whereas the median progression-free survival in arm A was nearly half that of arm B shorter in patients with a mutation in any of the four EGFR-dependent genes.
Second-line FOLFOX plus cetuximab is feasible past progression in patients with metastatic colorectal cancer and an EGFR-dependent tumor.
“An important finding from this study is those patients with tumors which were multiple wild type were most likely to be EGFR-dependent; in fact, these patients had significantly better progression-free survival when treated with cetuximab and chemotherapy than when treated with chemotherapy alone, with a hazard ratio of 0.56, which was significant (P = .025). Response rate was also improved, as was overall survival, with a hazard ratio of 0.57 (P = .056),” said Dr. Ciardiello.
Conclusions
Andrés Cervantes, MD, PhD, of the Biomedical Research Institute, INCLIVA, University of Valencia, Spain, and ESMO spokesperson, commented, “This is a new understanding of how to treat a select group of patients that are wild-type for the KRAS, NRAS, BRAF, and PIK3CA genes, who can be treated with the same anti-EGFR antibody and a change in chemotherapy following progression. In the intent-to-treat analysis there is no benefit from this treatment, however the patients showing no mutation do benefit from this approach.”
“This is a new finding, that these patients can have an advantage from rechallenge with the same antibody,” Dr. Cervantes remarked.
“CAPRI is the first study to evaluate cetuximab as second line beyond progression in patients with metastatic colorectal cancer in a randomized phase II study. Results suggest tumors with multiple wild-type KRAS, NRAS, BRAF, and PIK3CA genes are likely to benefit from chemotherapy plus cetuximab and to demonstrate significantly better progression-free survival, response rate, and overall survival than with chemotherapy alone,” commented Dr. Ciardiello.
He continued, “A word of caution; these results generate a very important signal that deserves to be further explored in a larger, randomized, phase III study, that continuing anti-EGFR treatment while switching the chemotherapy backbone in second line is feasible past progression and by identifying patients whose tumor is EGFR-dependent; that by identifying wild-type status for KRAS, NRAS, BRAF, and PIK3CA genes, also identifies patients responsive to this treatment.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
