FOLFOX/Cetuximab Prolonged Survival in Mutation-Free Colorectal Cancer

July 6, 2015

Treatment with FOLFOX plus cetuximab resulted in improved PFS vs FOLFOX alone in patients with metastatic colorectal cancer with “all-RAS” wild-type tumors.

Combination treatment with FOLFOX plus cetuximab resulted in improved progression-free survival compared with FOLFOX alone in patients with metastatic colorectal cancer with “all-RAS” wild-type tumors who had progressed after first-line FOLFIRI plus cetuximab.

However, patients who had tumors with a mutation in KRAS, NRAS, BRAF, and/or PIK3CA genes had a detrimental effect from the combination of FOLFOX plus cetuximab, according to the results of the CAPRI-GOIM study (abstract LBA-09) presented at the European Society for Medical Oncology (ESMO) 17th World Congress on Gastrointestinal Cancer in Barcelona.

“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,” said Fortunato Ciardiello, MD, PhD, from Seconda Università degli Studi di Napoli in Naples Italy, in a prepared statement.

The phase II trial included 340 patients with metastatic colorectal cancer and KRAS exon 2 wild-type tumors treated with first-line FOLFIRI plus cetuximab until disease progression or unacceptable toxicity. After progression, these patients were randomly assigned to treatment with FOLFOX plus cetuximab (n = 74) or FOLFOX alone (n = 79). The primary endpoint was progression-free survival.

According to the study results, the median progression-free survival of the intention-to-treat population was 6.4 months for FOLFOX plus cetuximab compared with 4.5 months for FOLFOX alone (hazard ratio [HR] = 0.81; 95% confidence interval [CI], 0.58–1.12; P = .19).

The researchers performed next-generation sequencing in about 75% of cases; 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.

The median progression-free survival for patients identified as all-RAS wild-type was 6.8 months with combination treatment compared with 5.5 months for FOLFOX alone (HR = 0.80; 95% CI, 0.50–1.29; P = .36). Median progression-free survival in the RAS-mutated population was 2.7 months for FOLFOX plus cetuximab compared with 4.1 months for FOLFOX alone (HR = 1.53; 95% CI, 0.79–2.96; P = .2).

When the researchers looked at those patients considered to be quadruple wild-type, the median progression-free survival was 6.9 months for combination therapy compared with 5.3 months for FOLFOX alone, a significant difference (HR = 0.56; 95% CI, 0.33–0.94; P = .025). In contrast, for patients with any mutation in KRAS, NRAS, BRAF, or PIK3CA, the median progression-free survival was longer for FOLFOX alone compared with combination treatment (4.4 months vs 2.7 months; HR = 1.70; 95% CI, 0.94–3.05; P = .07).

ESMO spokesperson Andrés Cervantes, of University Hospital Valencia in Spain, who was not involved in the study, commented in a press release: “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.”