In patients with metastatic colorectal cancer, the presence of a RAS mutation predicts harm from the addition of panitumumab to traditional FOLFOX4 therapy, according to a retrospective analysis of the large prospective, randomized PRIME (Panitumumab Randomized Trial in Combination with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) study.
In the study, published in the New England Journal of Medicine (2013;369-1023-1034), the presence of both KRAS and NRAS mutations better identified the right target population to be treated with oxaliplatin, fluorouracil, and leucovorin (FOLFOX) plus panitumumab in first-line treatment of metastatic colorectal cancer than using the presence of just the KRAS mutation.
“We have clearly demonstrated that patients harboring any of these mutations do not benefit from the addition of panitumumab, and may even experience a detrimental effect—a nice illustration of the concept of personalized medicine,” PRIME lead investigator Jean-Yves Douillard, MD, PhD, Professor of Medical Oncology of Institut de Cancerologie de l'Ouest Rene Gauducheau in Nantes, France, said in an interview.
“These findings will be practice changing in terms of the best identification of the RAS mutational status for these patients, and should be rapidly implemented.”
He noted that the European Medicine Agency has already refined the prescribing information for panitumumab to the treatment of adult patients with wild-type RAS metastatic colorectal cancer. The U.S. Food and Drug Administration has as yet made no such adjustments.
Asked for his opinion for this article, GI cancer specialist David Ilson, MD, Attending Physician at Memorial Sloan-Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College, commented: “This is an important study. Patients with any type of activating RAS mutations do not benefit from epidermal growth factor receptor targeted antibodies in metastatic colorectal cancer. The use of these drugs should be limited to wild-type patients.”
The predefined, retrospective subset analysis of the PRIME study assessed the safety and efficacy of panitumumab plus FOLFOX compared with FOLFOX alone, based on RAS or BRAF mutation status. More precisely narrowing the pool of patients treated with panitumumab plus FOLFOX to those with wild-type RAS resulted in greater improvements in both overall and progression-free survival.
Previous data had found that overall survival was improved by 4.4 months in patients with wild-type KRAS. In the new study, the additional narrowing to patients with wild-type RAS resulted in an improvement of 5.8 months in overall survival.
The study was supported by funding from Amgen, which makes panitumumab (Vectibix), along with several institutional and organizational grants. Among 512 patients without RAS mutations in the EGFR signaling pathway, overall survival was 26 months in the panitumumab plus conventional FOLFOX chemotherapy group compared with 20 months in those given FOLFOX alone. Similarly, the combination therapy had a significantly longer progression-free survival time (10.1 months) compared with the chemotherapy-alone group (7.9 months).
A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following:
* KRAS exon 3 or 4;
* NRAS exon 2, 3, or 4;
* BRAF exon 15.
The overall rate of ascertainment of RAS status was 90 percent.
Douillard noted that previous PRIME results showed that patients with KRAS mutations in exon 2 had significantly shorter survival when panitumumab was given along with a FOLFOX4 regimen. In addition, similar results were found in colorectal cancer patients and KRAS mutations treated with another anti-EGFR agent, cetuximab.
“By excluding results for patients with mutated KRAS from outcomes measures, it has become clear that anti-EGFR agents have greater efficacy in fighting metastatic colorectal cancer than previously thought when their use is confined to those with wild-type KRAS as both a first- and second-line treatment,” he said.
“Before a clinician decides on the use of a given regimen, the full analysis of KRAS and NRAS should be documented, and FOLFOX-panitumumab should be restricted to wild-type patients. Additional data within this setting in a smaller randomized Phase II study—PEAK—have already shown a very strong signal of superior efficacy of progression-free and overall survival.”
He said he expected that these data from another randomized Phase III trial (FIRE-3) would be confirmed when reported at the then-upcoming European Cancer Congress.
In the NEJM study, 108 patients (17%) with non-mutated KRAS exon 2 were found to have other RAS mutations. “These mutations were associated with inferior PFS and overall survival with panitumumab-FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2,” he said.
The researchers also looked at the effects of BRAF mutations, and found shorter progression-free survival times in both treatment groups, suggesting that this, too, was a negative prognostic factor.
No new safety signals were identified, he added.
“While the KRAS exon 2 biomarker is well known and has facilitated selection of patients who are more likely to respond to anti-EGFR treatment, we found that there were still some patients who didn't benefit from treatment. This analysis furthers our understanding of tumor genetics and allows physicians to more accurately match patients to effective treatments.
“Personalized treatment improves outcome. NRAS and KRAS testing should be performed before a treatment decision is made in first-line metastatic colorectal cancer.”
Ilson commented that the survival benefits for panitumumab plus FOLFOX in wild-type disease were “significant,” although the benefits remain modest. “Still, a significant proportion of patients will benefit. This interesting observation extends biomarker selections beyond EGFR antibodies,” he said.
While current clinical practice involves investigating KRAS in exon2 mutations, particularly codons 12 and 13, other genes are also potentially mutated, he said. “Activating RAS mutations can also render tumors resistant to upstream blockade of EGFR receptors, such as less common NRAS and RAS mutations.
“These other RAS mutations appear to have a negative effect when you look at the pooled analysis of all patients with RAS mutations. When the researchers combined KRAS exon 2 and other mutations, they saw significant detriments in PFS and overall survival in those patients who received panitumumab. The detriment was limited to not just KRAS exon 2 mutations, but also those harboring any RAS mutations when given EFGR antibodies. This shows the potential to treat more patients with EFGR drugs by extending treatment to those with RAS mutations.”
Ilson noted that KRAS mutational status has no effect when patients are given chemotherapy alone, and therefore is not a prognostic test but rather, a predictive biomarker for which patients should get EGFR antibodies.
In addition, he said, BRAF is a negative prognostic marker in metastatic disease and should not be used as a measure to exclude patients with colon cancer from receiving EGFR-targeted therapies.
The data do need to be validated in other studies, he said, which he hoped would answer some outstanding questions: “Should we extend the definition of treatment to RAS mutations, which are rarer than the already well-characterized KRAS mutations? Considering the costs, is this concept commercially viable? And how will the FDA interpret the data?” he asked, adding that more diagnostics are needed before instituting global RAS-status testing.
He said that nevertheless, he believes the data will “likely have a significant impact. There will be a move to study rare RAS mutations to identify patients who should not be treated.”
Practicing oncologists should “keep their ears to the ground about the availability of mutational testing to include rare RAS mutations. These data make a compelling argument that any RAS mutation should lead to exclusion of these patients taking drugs that target EGFR receptors.”