The Food and Drug Administration has approved a new cetuximab indication in colorectal cancer along with a genetic test to rule out patients who carry a KRAS mutation and therefore would not benefit from treatment.
The new indication supports use of cetuximab (Erbitux) combined with the three-drug FOLFIRI chemotherapy regimen as a first-line treatment for patients with metastatic colorectal cancer that expresses the epidermal growth factor receptor (EGFR) targeted by cetuximab. The indication is contingent on the patients not having a KRAS mutation, since cetuximab does not work in those patients.
Concurrently, the agency approved the therascreen KRAS RGQ PCR Kit, which provides information about KRAS mutations in patients with metastatic colorectal cancer, and "provides a reliable way to identify these subsets of patients with colon cancer," according to the FDA announcement.
The genetic assay, manufactured by Qiagen, is a real-time polymerase chain reaction assay that detects 7 different mutations of the KRAS gene in a tumor specimen, the agency said on July 6.
"The approval of this new Erbitux indication with the concurrent approval of a genetic test provides clear guidance on selecting patients who will optimally benefit," Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, is quoted in the agency’s announcement.
"Clinical trial data leading to the approval of this new indication support the recommendation to treat those patients whose colorectal tumors do not have KRAS mutations and to avoid treating those with KRAS mutations," he added.
Approval of the indication for cetuximab with FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) is based on retrospective analyses of subsets of patients in three trials: the CRYSTAL study and two supportive studies (CA225025 and EMR 62 202-047 [OPUS]), which determined that the benefits of cetuximab "were limited to patients whose tumors did not have one of the seven KRAS mutations detected by the test," according to the FDA statement.
Treatment with cetuximab was associated with improvements in overall survival, progression-free survival, and overall response rates in the subset of patients with KRAS wild-type tumors, but among those with KRAS mutant tumors, "there was no benefit or potential harm." the FDA said.
In the open-label, randomized controlled CRYSTAL trial patients with EGFR-expressing metastatic colorectal cancer received FOLFIRI with or without cetuximab. A retrospective analysis found that 63% of patients had KRAS wild-type tumors, while the remaining 37% had KRAS mutations.
Overall survival reached a median of 23.5 months with cetuximab and FOLFIRI in the wild-type patients vs. 19.5 months with FOLFIRI alone. Median progression-free survival also was longer with the combination at 9.5 months vs. 8.1 months. No significant improvements were seen in patients with KRAS mutations.
The CA225025 and OPUS trials added cetuximab to best supportive care and to the FOLFOX regimen, respectively. In both studies the benefit from cetuximab was limited to patients with wild type KRAS.
Safety data in these studies was consistent with the adverse event profiles of cetuximab and the chemotherapy regimens, according to the announcement.
The FDA recommends that cetuximab be administered at 400 mg/m2 intravenously as a 120-minute infusion initially followed by 250 mg/m2 infused over 30 minutes weekly in combination with FOLFIRI. It said cetuximab administration should be completed 1 hour prior to FOLFIRI.
Cetuximab, marketed as Erbitux by ImClone, received accelerated approval in 2004 to treat late-stage colorectal cancer in patients who had stopped responding to irinotecan-based chemotherapy. In 2007, the FDA granted regular approval for single-agent cetuximab "for the treatment of patients with EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based chemotherapy regimens."
It also is approved in the treatment of head and neck cancers.
The genetic test kit was developed by Qiagen of Manchester, England. Erbitux is marketed by Bristol-Myers Squibb and Eli Lilly.
Click here to view the updated cetuximab label.