On July 6, 2012 , the U. S. Food and Drug Administration granted approval to cetuximab (Erbitux, ImClone LLC, a wholly owned subsidiary of Eli Lilly and Co) for use in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment of patients with K-ras mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use.

FDA also approved the Therascreen KRAS RGQ PCR Kit (QIAGEN Manchester, Ltd) concurrent with this cetuximab approval.

This approval was based on retrospective analyses in the patient subsets according to K-ras mutation status in tumour samples from patients enrolled in the CRYSTAL trial and in two supportive studies, CA225025 and EMR 62 202-047 (OPUS).

The addition of cetuximab to chemotherapy or best supportive care (BSC) resulted in improved survival (OS), progression-free survival (PFS), and overall responses rates (ORR) in the subset with K-ras wild-type tumours; whereas, there was no benefit or potential harm in patients with K-ras mutant tumours.

The approval of the companion diagnostic, the QIAGEN Therascreen KRAS RGQ PCR Kit, provides a reliable way to identify these subsets of patients with colon cancer. This QIAGEN test, a genetic assay, is a real-time polymerase chain reaction assay detecting 7 different mutations of the K-ras gene in a tumour specimen. Tumours that are K-ras mutation-negative in this assay are commonly referred to as K-ras wild-type.

CRYSTAL was an open-label, randomised, controlled trial in patients with EGFR-expressing mCRC who had not received prior chemotherapy for metastatic disease. A total of 1217 patients, irrespective of K-ras mutation status, were randomised (1:1) to receive either cetuximab in combination with FOLFIRI or FOLFIRI alone. PFS was the primary efficacy endpoint.

A statistically significant improvement in PFS was observed with cetuximab plus FOLFIRI arm compared to the FOLFIRI alone [median PFS 8.9 vs. 8.1 months, HR 0.85, (95% CI: 0.74, 0.99), p-value=0.036] in the overall population.

OS, a secondary endpoint, was not significant in the planned analysis [HR 0.93, (95% CI: 0.82, 1.07), p-value 0.327, 838 events]. In an updated analysis with an additional 162 events, the median OS was 19.6 compared to 18.5 months for cetuximab-containing arm and FOLFIRI alone arm [HR 0.88 (95% CI: 0.78, 1.00)].

Retrospective efficacy analyses in patient subsets with K-ras wild-type and mutant tumours, demonstrated that in the wild-type subgroup, the addition of cetuximab to FOLFIRI resulted in a favorable effect on OS, PFS and ORR. Tumour tissue was evaluable for K-ras mutation status assessment in 89% of the patients (N=1079/1217); 676 (63%) had wild-type and 403 (37%) had mutant tumours.

The median OS for the wild-type subgroup was 23.5 versus 19.5 months for the cetuximab plus FOLFIRI and FOLFIRI alone, respectively [HR 0.80 (95% CI: 0.67, 0.94)]. PFS and ORR findings in the K-ras wild-type subgroup supported the efficacy of cetuximab in combination with FOLFIRI; the median PFS was 9.5 versus 8.1 months for cetuximab plus FOLFIRI and FOLFIRI alone, respectively [HR 0.70 (95% CI: 0.57, 0.86)]. ORR was 57% with cetuximab plus FOLFIRI compared to 39% with FOLFIRI alone. In the mutant subgroup, improvements in OS, PFS or ORR were not observed with the addition of cetuximab to FOLFIRI compared to FOLFIRI alone.

Retrospective analyses of two supportive studies, CA225025 and OPUS by tumour K-ras mutation status supported cetuximab’s efficacy in the wild-type subgroup:

CA225025 was an open-label, randomised, trial comparing cetuximab plus best supportive care (BSC) with BSC alone in patients with previously treated EGFR-expressing mCRC. CA225025 demonstrated a statistically significant improvement in OS in the cetuximab plus BSC arm compared to BSC alone. The planned efficacy results served as the basis for the full approval of cetuximab in October 2007 as a single agent for EGFR-expressing mCRC after failure of both irinotecan- and oxaliplatin-based regimens or in patients intolerant to irinotecan-based regimens.

Tumour tissue was evaluable for K-ras mutation status in 79% of patients (N=453/572). In the wild-type subgroup, cetuximab plus BSC resulted in an improvement in OS compared to those receiving BSC alone [HR 0.63 (95% CI: 0.47, 0.84)].

The median OS was 8.6 versus 5.0 months in the cetuximab plus BSC and BSC arms, respectively. The median PFS was 3.8 and 1.9 months for the cetuximab plus BSC and the BSC alone, respectively [HR 0.42 (95% CI: 0.32, 0.56)]. In the mutant subgroup, no improvements in OS, PFS or ORR were observed with the addition of cetuximab to BSC compared to BSC alone.

OPUS was a randomised, open-label, phase 2 study comparing cetuximab in combination with 5-flourouracil, folinic acid, and oxaliplatin (FOLFOX-4) to FOLFOX-4 alone as first-line treatment of EGFR-expressing mCRC.

Tumour tissue was evaluable for retrospective K-ras mutation status analysis in 93% of patients (N=315/337). ORR was the trial’s primary endpoint. In the wild-type subgroup (N=179/315, 57%), ORR was 57% (95% CI: 46, 68) in the cetuximab plus FOLFOX-4 arm compared to 34% (95% CI: 25, 44) with FOLFOX-4. A numerical improvement in PFS was noted in the wild-type subgroup [HR 0.57 (95% CI: 0.38, 0.86)].

The median PFS was 8.3 compared to 7.2 months favoring the cetuximab-containing arm. A numerical OS improvement was also observed in the wild-type subgroup [HR 0.86 (95% CI: 0.60, 1.22)]. The median OS for the cetuximab-containing arm was 22.8 versus 18.5 months in the control arm. In the K-ras mutant subgroup (N=136/315, 43%), improvement in OS, PFS or ORR were not observed with cetuximab plus FOLFOX-4 compared to FOLFOX-4 alone.

Safety data were evaluated in 317 patients in the wild-type subgroup who received cetuximab in combination with FOLFIRI in the CRYSTAL study and in 118 patients with wild-type tumors who received cetuximab monotherapy in CA225025.

The frequency and nature of the adverse events, including adverse events associated with cetuximab (acne-like rash, infusion reactions, cardiac events, and hypomagnesemia) observed in CRYSTAL, CA225025, and OPUS in the wild-type population were consistent with the known adverse drug reaction profiles of either cetuximab, chemotherapy agents, or the underlying disease. No significant differences between the wild-type, mutant and the overall safety populations have been noted.

The recommended dose and schedule for cetuximab is 400 mg/m2 administered intravenously as a 120-minute infusion as an initial dose, followed by 250 mg/m2 infused over 30 minutes weekly in combination with FOLFIRI. Cetuximab administration should be completed 1 hour prior to FOLFIRI.

Product labeling for cetuximab provides “Limitation of Use” information specifying that cetuximab is not indicated for treatment of K-ras mutation-positive colorectal cancer.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125084s225lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Source: FDA