Adding Cetuximab to First-Line FOLFIRI Does Not Benefit Metastatic Colorectal Cancer Patients With RAS Mutations


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Eric Van Cutsem, MD, PhD

Cetuximab/FOLFIRI and RAS Mutation Status in Colorectal Cancer

Our study supports the use of FOLFIRI plus cetuximab in patients with RAS wild-type tumors and, on the basis of a lack of observed benefit, suggests the exclusion of patients with other RAS mutations.

—Eric Van Cutsem, MD, PhD, and colleagues

The phase III CRYSTAL trial showed that the addition of cetuximab (Erbitux) to first-line FOLFIRI (fluorouracil, leucovorin, and irinotecan) significantly improved overall survival, progression-free survival, and objective response rates in patients with KRAS codon 12/13 (exon 2) wild-type metastatic colorectal cancer.1,2 According to a post hoc analysis conducted in the CRYSTAL population and reported in the  Journal of Clinical Oncology, Eric Van Cutsem, MD, PhD, of University Hospitals Gasthuisberg/Leuven, and colleagues found that cetuximab was not of benefit among patients in the trial with RAS mutations at exon 2 or other loci.3

Study Details

In the CRYSTAL trial, patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer were randomly assigned to receive 14-day cycles of FOLFIRI plus weekly cetuximab or FOLFIRI alone as first-line treatment. In the current study, DNA samples from CRYSTAL patients with KRAS exon 2 wild-type tumors were reanalyzed for other RAS mutations in four additional KRAS codons (exons 3 and 4) and six NRAS codons (exons 2, 3, and 4) using beads, emulsion, amplification, and magnetics technology; no tissue microdissection was performed.

In total, RAS mutation status was assessable in 430 (65%) of the 666 patients with KRAS exon 2 wild-type tumors, including 210 in the cetuximab/FOLFIRI group and 220 in the FOLFIRI-alone group. Other RAS mutations, using a 5% mutant/wild-type cutoff, were found in 63 (15%) of the 430 patients, including 32 patients in the cetuximab/FOLFIRI group and 31 in the FOLFIRI group.

Outcomes According to RAS Status

Among all 430 RAS-assessable patients with wild-type KRAS exon 2 tumors, median overall survival was 26.1 months with cetuximab/FOLFIRI vs 20.2 months with FOLFIRI alone (hazard ratio [HR] = 0.75, P = .008), median progression-free survival was 11.3 vs 7.7 months (HR = 0.58, P < .001), and objective response rate was 61% vs 38% (P < .001).

Among the 367 patients with wild-type RAS at all loci, overall survival was 28.4 months with cetuximab/FOLFIRI vs 20.2 months with FOLFIRI (hazard ratio [HR] = 0.69, P = .0024), progression-free survival was 11.4 vs 8.4 months (HR = 0.56, P < .001), and objective response rate was 66% vs 39% (P < .001).

Among the 63 patients with RAS mutations, overall survival was 18.2 months with cetuximab/FOLFIRI vs 20.7 months with FOLFIRI (HR = 1.22, P = .50), progression-free survival was 7.2 vs 6.9 months (HR = 0.81, P = .56), and objective response rate was 34% vs 35% (P = .97).

Finally, in a population of 460 patients with any RAS mutation, consisting of the 63 patients with other RAS mutation and 397 previously identified with KRAS exon 2 mutation in the ­CRYSTAL population, overall survival was 16.4 months with cetuximab/­FOLFIRI vs 17.7 months with ­FOLFIRI (HR = 1.05, P = .64), progression-free survival was 7.4 vs 7.5 months (HR = 1.10, P = .47), and objective response rate was 32% vs 36% (P = .40).

Conclusions

The investigators concluded: “In the first-line treatment of [metastatic colorectal cancer], patients with RAS wild-type tumors derived a significant benefit from the addition of cetuximab to FOLFIRI; patients with RAS tumor mutations did not…. [O]ur study supports the use of FOLFIRI plus cetuximab in patients with RAS wild-type tumors and, on the basis of a lack of observed benefit, suggests the exclusion of patients with other RAS mutations. Reserving such first-line treatment for a RAS wild-type population allows the definition of a subgroup more likely to benefit from the addition of cetuximab to FOLFIRI. Molecular testing of tumors for all activating mutations in KRAS and NRAS before considering anti-EGFR therapy is therefore essential in selecting the most effective treatment for patients with [metastatic colorectal cancer].” ■

Disclosure: The study was supported by Merck KGaA. Dr. Van Cutsem has received research funding from Amgen, Bayer, Boehringer Ingelheim, Eli Lilly, Merck Serono, Novartis, Roche, and sanofi-aventis, all via his institution. For full disclosures of the study authors, visit jco.ascopubs.org.

References

1. Van Cutsem E, Köhne CH, Hitre E, et al: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360:1408-1417, 2009.

2. Van Cutsem E, Köhne CH, Láng I, 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. J Clin Oncol 29:2011-2019, 2011.

3. Van Cutsem E, Lenz H-J, Köhne C-H, et al: Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 33:692-700, 2015.

See commentary by Brandon G. Smaglo, MD.


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