RAS Mutations Ready for Prime Time in mCRC

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.

The median OS with panitumumab was 26.0 months compared with 20.2 months with FOLFOX alone in patients with wild-type RAS (HR = 0.78; P = .04). Moreover, this study demonstrated that patients with RAS mutations had a 3.6-month worse median OS with panitumumab compared with FOLFOX alone (15.6 vs 19.2 months; HR = 1.25; P = .04).

PEAK Trial Findings

The second analysis came from a subanalysis of the phase II PEAK study, which specifically examined KRAS and NRAS mutations.⁴ In this trial, FOLFOX6 plus panitumumab or bevacizumab was examined as a first-line treatment in patients with mCRC. These results were similar to the PRIME study, demonstrating an improvement in outcomes with panitumumab for patients with wild-type RAS tumors.

The median PFS with panitumumab was 13.1 months compared with 9.5 months with bevacizumab in patients with wild-type RAS (HR = 0.63; P = .02). By traditional KRAS criteria, the median PFS was 7.8 months with panitumumab and 8.9 months with bevacizumab (HR = 1.31; P = .44).

“The data are compelling when you look at PRIME, when you look at FIRE-3, when you look at PEAK,” Marwan G. Fakih, MD, said in the discussion. “The differential of improvement is increasing with a RAS wild-type signature.”

Evidence from the FIRE-3 study and other retrospective RAS analyses suggest that cetuximab could be superior to bevacizumab as a frontline therapy, specifically when utilizing the expanded testing. As a result, the EGFR inhibitors have moved forward in the treatment paradigm for patients with wild-type RAS, some of the panelists suggested. “There may be a differential benefit from antiangiogenesis therapy versus anti-EGFR therapy along the lines of treatment,” Fakih believes. “If you miss on antiangiogenesis during your whole treatment duration, it may not be as important as missing an anti-EGFR treatment.”

However, until conclusive prospective evidence is presented that one therapy is more effective in the frontline setting, some of the panelists plan to continue the frontline administration of bevacizumab for patients with RAS wild-type metastatic CRC. This decision is based largely upon the comparison of side effects between the two drugs, with a particular emphasis on dermatologic toxicity.

“I think you need to test and you need to consider this as a treatment option, discuss it with your patients. I think you cannot just ignore it,” Heinz-Josef Lenz, MD, said during the discussion. “This does not mean that every patient gets it. There are a lot of different balances to discuss. Toxicity is one of the major issues, but I think I discuss this issue in the first-line [setting].”

Putting RAS Testing Into Practice

The collection of mutational analyses has provided ample evidence to begin utilizing the expanded RAS testing in the community setting. However, putting this new testing strategy into practice requires multidisciplinary collaboration, since pathologists generally order the tests, Marshall pointed out during the talk. The current reflex for testing is KRAS exon 2 codon 12 and 13 alone, which should be expanded to include KRAS exon 3 and 4 and NRAS exon 2 and 3 mutations, panelists agree.

“In my practice, what I’ve been encouraging physicians to do within our centers, is to go ahead and order the expanded KRAS testing,” Johanna Bendell, MD, said during the conversation. “I think what we do know is that from the data we’ve seen, there’s a suggestion that if you treat those patients with KRAS mutation, especially with the expanded KRAS mutation, you could actually do harm to them by treating them with an anti-EGFR inhibitor.”

Despite the desire to adopt this approach today, future studies are still required to discover the optimal approach to RAS testing. With the increased sensitivity of testing, finite levels of alterations can now be detected. This places further emphasis on the study of functional heterogeneity within the RAS pathway, in order to identify meaningful criteria to use for predicting response to EGFR inhibitors.

“I think where confusion comes in is how do we implement this test. What technologies do we use, because with the standard technologies we can pick up probably 10 out of 100 cells or 20 out of 100 cells.

Technology has now become available [that] is now detecting 1 out of 10,000,” Lenz notes. “Now, the big clinical question is whether that is the same clinically meaningful mutation data or not.”

Outside of retesting for patients currently on EGFR inhibitors who were deemed eligible by standard KRAS testing, the appearance of a treatment- related skin rash could indicate whether or not a patient is responding to EGFR inhibition. If a rash has not developed, it may be safe to discontinue therapy or retest using the expanded criteria for patients who were already on EGFR inhibitors before expanded testing was available.

“If they have a bad rash I’d probably continue the treatment. If they don’t have a rash at all, I might stop it—again, the pharmacodynamics of the rash reflecting some biology,” Venook notes. “I’m hoping we can get there with further information, really to drill down.”

Reimbursement Issues Loom

As many institutions begin to switch to the expanded criteria, the issue of reimbursement for testing has begun to represent a possible challenge in some settings. A second hurdle is present in the form of the education required in order to accurately interpret the expanded results.

“The practical issue, of course, is will insurers cover the expanded testing. And you need to be careful about that,” Venook said. “The other issue is knowing how to interpret the results. And so you need to find a way to do the testing and make sure you understand what the results will mean.”

References

1. Heinemann V, von Weikersthal LF, Decker T, et al. Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). J Clin Oncol. 2013;31(suppl; abstr LBA3506).
2. Stintzing S, Jung A, Rossius L, et al. Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: a randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. Presented at: European Cancer Congress 2013; September 27- October 1, 2013; Amsterdam, The Netherlands. Abstract LBA17.
3. Oliner KS, Douillard J-Y, Siena S, et al. Analysis of KRAS/NRAS and BRAF mutations in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC). J Clin Oncol. 2013;31(suppl; abstr 3511).
4. Schwartzberg LS, Rivera F, Karthaus M, et al. Analysis of KRAS/ NRAS mutations in PEAK: a randomized phase II study of FOLFOX6 plus panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC). J Clin Oncol. 2013;31(suppl; abstr 3631).