Chemotherapy plus cetuximab benefited colorectal cancer patients4 Jul 2015
Patients with metastatic colorectal cancer (mCRC) showed significant benefit from continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression following first-line chemotherapy and an anti-EGFR monoclonal antibody. According to the study results, the patients must be mutation-free in the following genes: KRAS, NRAS, BRAF and PIK3CA.
CAPRI-GOIM is a non-profit, academic, phase 2 trial enrolling 340 patients with mCRC and KRAS exon 2 wild-type tumors. All patients received standard first-line treatment of FOLFIRI plus cetuximab until disease progression or unacceptable toxicity.
Based on the genes, two patient populations were detected
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 sole FOLFOX (Arm B; n=79). The primary endpoint of the study was progression-free survival (PFS) and secondary endpoints were overall survival (OS), response rate and safety.
The investigators used the Ion AmpliSeq™ Colon and Lung cancer panel, comprising 500 hotspot mutations in 22 genes, and Ion Reporter™ Software, showing that:
- NGS was possible in 76.5% patients and revealed that 66 patients had "all RAS" wild-type tumors with no mutations in KRAS; NRAS; BRAF; or PIK3CA genes and
- 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.
A detrimental effect from FOLFOX plus cetuximab
"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 4 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": commented Prof Fortunato Ciardiello from Seconda Università degli Studi di Napoli, Italy. He added that the results showed:
- Whereas the mutation free, quadruple wild-type population showed significantly prolonged PFS, and improved OS 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 PFS in patients with quadruple wild-type tumors, while the median PFS in arm A was nearly half that of arm B shorter in patients with a mutation in any of the 4 EGFR-dependant genes.
“Patients showing no mutation do benefit from this approach"
An important finding from this study is that those patients with tumors which were multiple wild type, meaning no mutation in the KRAS, NRAS, BRAF and PIK3CA genes, 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.
Prof Andrés Cervantes, Biomedical Research Institute, INCLIVA, University of Valencia, Spain, ESMO spokesperson, not involved in the study, commented: "this is a new understanding of how to treat a select group of patients. There is no benefit from this treatment, however the patients showing no mutation do benefit from this approach."
However, these results generate a very important signal that deserves to be further explored in a larger, randomized, phase 3 study.
Source: Science Daily