RAS Mutations Ready for Prime Time in mCRC

Silas Inman
Published Online: Thursday, June 12, 2014
Dr. John L. Marshall

John L. Marshall, MD

A multitude of studies presented over the course of the past year have emphasized the importance of broader RAS mutational analyses outside of traditional KRAS testing for patients with metastatic colorectal cancer (mCRC).

In a recent OncLive Peer Exchange® roundtable entitled “Treatment Considerations in Refractory CRC,” moderator John L. Marshall, MD, led a discussion focused on the treatments available in the second- and later-line settings for patients with mCRC, with an in-depth discussion focused on the new mutational analyses needed for treatment selection.

Until recently, KRAS mutation testing included only exon 2 at codons 12 and 13. However, a better understanding of the pathway and improvements in detection tools demonstrated that mutations in KRAS exon 3 and 4, including NRAS exon 2 and 3, are predictive of response to EGFR inhibitors in CRC. As a result of these findings, the number of patients with CRC who should receive EGFR inhibitors has been reduced to approximately 40% of the total population.

“It appears that somewhere only between a third and 25% of patients who seem suitable for EGFR antibodies are receiving them,” Alan P. Venook, MD, said in the discussion. “So my hope would be that we’d be at 40%, which is probably the right percentage of patients, give or take, who should receive it of the total group.”

Bevacizumab Versus Cetuximab

The lackluster percentage of eligible patients receiving EGFR inhibitors could be a direct result of other available options, such as the VEGF inhibitor bevacizumab (Avastin). At this point, bevacizumab and the EGFR inhibitor cetuximab (Erbitux) both have been approved in combination with chemotherapy as a frontline treatment for patients with mCRC for over a decade.

Various studies have been formed to compare these agents, including the CALGB/SWOG 80405 study. This study began accruing patients nearly 10 years ago, with results presented at the 2014 ASCO Annual Meeting. In this study, frontline therapy with bevacizumab or cetuximab combined with either FOLFOX or FOLFIRI yielded a comparable survival in patients with KRAS wild-type mCRC.

At a median follow-up of 24 months, OS was 29 months (95% CI, 25.7-31.2) in the bevacizumab arm and 29.9 months (95% CI 27.0-32.9) in the cetuximab arm (HR = 0.925; 95% CI, 0.78-1.09; P = .34). With the secondary endpoint of progression-free survival (PFS), disease progression was delayed by a median of 10.8 months (95% CI, 9.7-11.4) in patients receiving bevacizumab compared with 10.4 months (95% CI, 9.6-11.3) in the cetuximab group (HR = 1.04; 95% CI, 0.91-1.17; P = .55). A RAS analysis from this study is not yet available.

As the 80405 trial enrolled patients, the FIRE-3 study was completed, which compared upfront FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab in patients with KRAS wild-type mCRC. The overall response rate and PFS were similar between the two arms in FIRE-3. However, there was a 3.8-month overall survival (OS) benefit in favor of cetuximab compared with bevacizumab.1 Interestingly, the Kaplan-Meier curves for OS did not split until the 20-month mark. Given these inconsistent results, investigators are exploring the second, third, and fourth lines of therapy.

“There was a lot of information we didn’t have and still don’t have about FIRE-3 such as subsequent therapies, the recommendation or not of what the second-line therapy should be,” Venook said. “A number of issues that were unclear I thought raised some doubts about the study.”

Benefits of Broader RAS Testing

Adding to the dilemma, when the broader definition of RAS mutations was applied to the FIRE-3 trial, the OS advantage improved 7.2 months for cetuximab with the same split in the curves at 20 months.2 These findings are difficult to explain biologically, suggesting that treatment sequencing may be the cause.

“The most fascinating finding in the study, which is extremely hard to explain biologically, is that the survival benefit accrued almost 2 years after the start of the patients’ entry on the study,” Venook said. “When they do the all-RAS analysis, there’s a 7-month improvement in overall survival. Again, the curves diverge at the same time but it’s 7 months.”

PRIME Trial Results

One of the first studies to uncover the enhanced benefits of broader RAS testing was the phase III PRIME study that explored panitumumab (Vectibix) plus FOLFOX as a first-line treatment for patients with mCRC.3 This trial found a higher survival benefit in patients with wild-type RAS treated with the EGFR inhibitor.

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