Patients With Mutant K-Ras Gene Do Not Benefit From Cetuximab Treatment for Colorectal Cancer: Presented at ESMO

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Title: Patients With Mutant K-Ras Gene Do Not Benefit From Cetuximab Treatment for Colorectal Cancer: Presented at ESMO
URL: http://www.pslgroup.com/dg/22C692.htm
Doctor's Guide
September 16, 2008

By Janet Fricker

STOCKHOLM, Sweden -- September 16, 2008 -- K-ras mutation status should be considered the "new standard of care" for selecting patients suitable for the targeted therapy cetuximab in the treatment of colorectal cancer, according to a study presented here on at the 33rd European Society for Medical Oncology Congress (ESMO).

Presented on September 16, the study, by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) and the Australasian Gastro-Intestinal Trials Group (AGITG), demonstrates that patients with the wild-type gene who take cetuximab live almost twice as long as those with the mutant K-ras gene.

K-ras genes, explained presenter Christos Karapetis, MD, Flinders University, Adelaide, Australia, play an important role in cell-growth regulation and oncogenesis. Studies have shown that anti-epidermal growth factor receptor (anti-EGRF) therapies -- such as cetuximab -- work by blocking the activation of the receptor, thereby inhibiting downstream events leading to cancer-cell signalling, including the K-ras protein that plays a key role in regulating cell growth and proliferation.

In patients with tumours harbouring a mutated K-ras gene, however, the K-ras gene is always turned "on," regardless of whether the receptor has been therapeutically inhibited. "So we had a good rationale for thinking that the presence of the K-ras mutation might predict the patients who would not benefit from treatment," Dr. Karapetis explained, adding that K-ras gene mutations occur in 35% of colorectal cancers.

Following a phase 3 clinical trial of cetuximab plus best supportive care (BSC) versus BSC alone, which only showed a modest improvement in median overall survival of 1.5 months.(1) Dr. Karapetis and coinvestigators decided to reanalyse tumour samples for K-ras status.

In the original study, patients with pretreated metastatic EGFR-positive colorectal cancer were randomised to receive cetuximab (400 mg/m² IV for the first week, then 250 mg/m² IV weekly) plus BSC or BSC alone.

The current study involved genetic analysis of tumour samples taken from 394 patients (69%) taking part in the initial study.

The investigators found that 42% of patients had cancers with K-ras mutations, while 60% had wild-type K-ras, without mutations.

For the patients with K-ras mutations, overall survival was 4.6 months for those receiving cetuximab and BSC compared to 4.5 months for BSC alone (HR = 0.98; P = .89). In contrast, for patients with wild-type cancers (without K-ras mutations) median overall survival was 9.5 months for those receiving cetuximab and BSC compared to 4.8 months for those receiving BSC alone (HR = 0.55; P < .0001).

Furthermore, for patients with mutant K-ras, median progression-free survival was 1.8 months for those receiving cetuximab and BSC, compared with 1.8 months for those receiving BSC alone (HR = 0.99; P = .96). Wild-type patients (without the K-ras mutation) however, experienced median progression-free survival of 3.8 months for those receiving cetuximab and BSC, compared to 1.9 months for those receiving BSC alone (HR = 0.40; P < .0001).

"Our results show that cetuximab only helps patients live longer if they have the wild type K-ras, and that there are no advantages to giving therapy to patients with K-ras mutations," the researchers noted.

The possibility that K-ras mutations might themselves be prognostic markers can be discounted, Dr. Karapetis added, since no differences in overall survival were found between the mutated and unmutated (wild-type) patients who received only BSC.

It has been predicted at ESMO that, by the end of the year, most colorectal cancer clinicians will have access to K-ras testing.

1. Jonker DJ et al. N Engl J Med. 2007;357:2040-2048.

[Presentation title: KRAS Mutation Status Is a Predictive Biomarker for Cetuximab Benefit in the Treatment of Advanced Colorectal Cancer -- Results From NCIC CTC co.17: A Phase III trial of Cetuximab Versus Best Supportive Care. Abstract LBA6]

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