SAN FRANCISCO – Patients with metastatic colorectal cancer should be broadly tested for RAS mutations before being treated with panitumumab, according to new data from a phase III trial.
"Patients with tumors mutated in the RAS genes are unlikely to benefit from the addition of panitumumab to FOLFIRI, similar to what was seen in the patients with only a KRAS exon 2 mutation," study investigator Dr. Marc Peeters said in a press briefing.
The investigators performed genetic testing of 597 patients who had participated in an Amgen-sponsored second-line trial and whose tumors were wild type (negative) for KRAS exon 2 mutations – about 55% of the entire trial population, he reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.
Almost one-fifth of the patients were found to have tumor mutations in other KRAS exons or in NRAS exons, noted Dr. Peeters, professor of oncology at Antwerp University Hospital in Edegem, Belgium.
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The trial randomized patients to FOLFIRI alone or in combination with panitumumab (Vectibix). Vectibix is manufactured by Amgen and approved by the Food and Drug Administration for the treatment of progressive EGFR-expressing metastatic colorectal cancer.
The investigators tested the banked tumor samples for other RAS mutations – specifically mutations in KRAS exons 3 and 4 and NRAS exons 2, 3, and 4.
Results showed that adding panitumumab improved the response rate among all patients whose tumors were wild type at KRAS exon 2, compared with FOLFIRI therapy alone (35% vs. 10%, respectively). Adding panitumumab to FOLFIRI therapy in patients whose tumors were also wild type for all of the RAS mutations, compared with FOLFIRI therapy alone, garnered an even higher response rate (41% vs. 10%), Dr. Peeters reported.
Also, the previously reported lack of panitumumab efficacy on response among patients whose tumors harbored KRAS exon 2 mutations, compared with those who did not harbor the mutation (13% vs. 14%), was also evident in those whose tumors harbored mutations in any of the other RAS mutations assessed, compared those who did nor harbor the mutation (15% vs. 13%), he said.
Panitumumab had a progression-free survival benefit among all patients whose tumors were wild type for KRAS exon 2 (median, 5.9 vs. 3.9 months; hazard ratio, 0.73; P = .004), but benefit was greater among those whose tumors were also wild type for all of the RAS mutations (median, 6.4 vs. 4.4 months; HR, 0.69; P = .006).
The addition of panitumumab did not significantly improve overall survival among patients whose tumors were wild type for KRAS exon 2, but there was a trend toward improvement among patients whose tumors were also wild type for all of the other RAS mutations (median, 16.2 vs. 13.9 months; HR, 0.80; P = .077).
"These results clearly support the fact that we need RAS testing when we want to treat our patients with panitumumab in the setting of metastatic colorectal cancer," said Dr. Peeters.
The trial’s findings were similar to those of PRIME (Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy), noted press briefing moderator Dr. Smitha Krishnamurthi, associate professor at Case Western Reserve University in Cleveland.
PRIME tested the addition of panitumumab to FOLFOX in the first-line setting, and recent analyses showed that RAS mutations were a negative predictor of panitumumab benefit (N. Engl. J. Med. 2013;369:1023-34).
"These results [presented by Dr. Peeters], as well as those from the PRIME and FIRE trials ... indicate that expanded RAS testing should become the standard of care in order to best identify patients who will benefit from anti-EGFR therapy," Dr. Krishnamurthi noted.
The current trial was sponsored by Amgen. Dr. Peeters disclosed that he is a consultant/advisor to and receives honoraria and research funding from Amgen. Dr. Krishnamurthi did not report having any conflicts of interest.
This article was updated 1/27/2014.
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