Anti-EGFR Therapy Worsens Survival in Patients With RAS Mutations

Roxanne Nelson

September 11, 2013

There might now be a better way to predict clinical response to panitumumab (Vectibix), according to a new study.

In patients with metastatic colorectal cancer, KRAS mutations have been established as a predictive biomarker of resistance to antiepidermal growth-factor receptor (EGFR) therapy, but other RAS mutations are also predictive.

In fact, the data suggest that patients with other RAS mutations have worse survival when panitumumab is added to a standard chemotherapy regimen.

Patients with nonmutated wild-type KRAS exon 2 who harbored other RAS mutations had inferior progression-free and overall survival when treated with panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) than when treated with FOLFOX4 alone.

This is consistent with findings in patients with KRAS mutations in exon 2, report Jean-Yves Douillard, MD, PhD, from the Institut de Cancérologie de l'Ouest in Nantes, France, and colleagues. In other words, when a patient has a KRAS mutation in exon 2 or other RAS mutations, they will not benefit from panitumumab.

Conversely, for those without RAS mutations, progression-free and overall survival were better with panitumumab plus FOLFOX4 than with FOLFOX4 alone.

Results from the Panitumumab Randomized Trial in Combination with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) were published in the September 12 issue of the New England Journal of Medicine.

Detrimental Effect

In PRIME, the researchers looked at the effect of RAS (KRAS or NRAS) or BRAF mutations on the efficacy and safety of panitumumab plus FOLFOX4 and FOLFOX4 alone.

For patients with no RAS mutations, progression-free survival was better when panitumumab was added to FOLFOX4 (10.1 vs 7.9 months; hazard ratio [HR] for progression or death, 0.72; P = .004). Overall survival was also better with panitumumab (25.8 vs 20.2 months; HR for death, 0.78; P = .04).

However, panitumumab did not improve survival in patients with RAS mutations; it actually had a detrimental effect.

For patients with no KRAS mutation in exon 2 who had other RAS mutations, progression-free survival was worse when panitumumab was added to FOLFOX4 (7.3 vs 8.0 months). Overall survival was also worse (17.1 vs 17.8 months).

Clinical Implications

So what does this mean clinically?

In an accompanying editorial, Jordan Berlin, MD, from the Vanderbilt–Ingram Cancer Center in Nashville, Tennessee, notes that the benefit of excluding patients with RAS mutations from anti-EGFR antibody therapy is "logical and expected," but the harm was not anticipated.

Even though data from this study are "not definitive enough to require a change from the limited KRAS exon 2 testing currently performed" to broadly assess RAS status, "presuming other analyses support these results, it would be difficult to justify taking a long time to change practices," writes Dr. Berlin.

He adds that because the PRIME results show that panitumumab plus FOLFOX4 is less effective than FOLFOX4 alone in the presence of other RAS mutations, the need to quickly confirm or refute these data is "even greater."

"The PRIME study aroused concern that a subgroup of patients may be harmed by the combination of an anti-EGFR therapy with FOLFOX4," he continues. "Thus, it will be difficult to recommend incorporation of these regimens into first-line therapy in metastatic colorectal cancer."

These data might also complicate the integration of forthcoming results from head-to-head comparison trials of bevacizumab and anti-EGFR therapy into daily clinical practice, Dr. Berlin points out.

"Therefore, the reanalysis of the PRIME study is the next important step in the development of a biomarker for the efficacy of anti-EGFR antibody therapy in colorectal cancer," he concludes.

Study Details

Dr. Douillard and colleagues conducted a prospective–retrospective biomarker analysis of 1183 patients with metastatic colorectal cancer.

Of the 1060 patients (90%) with RAS status available, 512 (48%) had tumors with nonmutated RAS and 548 (52%) had tumors with mutated RAS (any KRAS or NRAS mutation in exon 2, 3, or 4). In addition, 108 of the patients who had no KRAS mutations in exon 2 had other RAS mutations.

RAS and BRAF status was ascertained in 1047 of the 1183 patients (89%). Of the 619 patients with no KRAS mutation in exon 2 who were evaluated for BRAF, 53 (9%) had V600E mutations.

For patients with no RAS or BRAF mutation, the improvement in progression-free survival was 1.6 months when panitumumab was added to FOLFOX4, and the improvement in overall survival was 7.4 months.

The researchers note that there were "minor differences" in the 2 treatment groups for patients with BRAF mutations but no RAS mutations, but these were not significant.

In patients treated with panitumumab plus FOLFOX4, adverse events were similar in patients with no RAS mutations and in those with no KRAS mutations in exon 2 (from a previous analysis reported in J Clin Oncol. 2010;28:4697-4705). Similarly, the safety profile was similar in patients with RAS mutations and in those with KRAS mutations in exon 2.

The study was supported by Amgen and by grants from the Royal Marsden Hospital and the Institute of Cancer Research, the National Institute for Health Research, the Biomedical Research Centre, and the Oncologia Ca' Granda Onlus Fondazione.

N Engl J Med. 2013;369:1023-1034, 1059-1060. Abstract, Editorial

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