Erbitux significantly extends survival by 7.5 Months in mCRC RAS wild-type patients when compared with Bevacizumab: New analysis of FIRE-3 AIO study

Date: Oct-01-2013Merck Serono, the biopharmaceutical division of Merck, has announced that the German cooperative investigator group AIO (Arbeitsgemeinschaft Internistische Onkologie) reported new data from the Phase III head-to-head clinical trial FIRE-3, which show a clinically relevant improvement from Erbitux® (cetuximab) plus FOLFIRI versus bevacizumab plus FOLFIRI as 1st line treatment in metastatic colorectal cancer (mCRC) in patients with RAS wild-type tumors.[1]

The new data, from a preplanned exploratory analysis, were presented at the European Cancer Congress 2013 (ECCO-ESMO-ESTRO). The analysis shows a 7.5-month increase in median overall survival (OS) in mCRC patients with RAS wild- type tumors ((n=342); defined as having no mutations in exons 2, 3 and 4 of KRAS and NRAS), receiving 1st line Erbitux plus FOLFIRI compared with patients receiving bevacizumab plus FOLFIRI (OS: 33.1 months vs. 25.6 months, respectively; hazard ratio [HR]: 0.70; p=0.011). In a post hoc analysis of the patient group with any RAS mutations (n=178), patients who received Erbitux plus FOLFIRI 1st line reached an OS of 20.3 months vs. 20.6 months in the group that was treated with bevacizumab plus FOLFIRI (HR: 1.09; p=0.60).[1]

As previously presented at the annual meeting of the American Society of Clinical Oncology (ASCO) 2013 and at the World Congress on Gastrointestinal Cancer 2013, the primary endpoint of the trial, objective response rate based on investigators' read in patients with KRAS exon 2 wild-type tumors, was not met.2,3 In the patient group with KRAS exon 2 wild-type tumors, an expected and balanced cross-over or continuation beyond progression with regard to subsequent biologic treatments in 2nd line therapy (either EGFR antibody or bevacizumab) was observed. Also, no major imbalances were noted with regard to chemotherapies used in 2nd line treatment. It is important to note that this result is not fully mature (57% event rate in the "intent-to-treat" KRAS exon 2 wild-type population) and will be updated in due course.[2]

"These new data from the Phase III study FIRE-3 show a 7.5-month increase in median overall survival to 33.1 months when using 1st line Erbitux plus FOLFIRI as compared to using bevacizumab plus FOLFIRI in metastatic colorectal cancer. Such a prolongation is a paradigm shift in mCRC treatment since the introduction of monoclonal antibodies," said Professor Volker Heinemann from the Ludwig- Maximilians University, Munich, and FIRE-3 principal investigator. "Together with insights from other recent relevant studies, these results suggest that 1st line treatment of RAS wild-type patients should include an anti-EGFR therapy."

"These results continue to reinforce the value of Erbitux as a 1st line treatment for metastatic colorectal cancer and show that RAS tumor status is likely to help to identify those patients who are most likely to benefit from Erbitux," said Dr. Annalisa Jenkins, Head of Global Drug Development and Medical for Merck Serono. "Additional biomarker analyses are being conducted on data from the pivotal Erbitux studies, CRYSTAL and OPUS to help shed additional light on the role of RAS mutations in these patients."
About the FIRE-3 study

FIRE-3 is an independent, randomized, controlled, head-to-head Phase III trial led by Ludwig-Maximilians University in Munich, Germany. Merck Serono GmbH has financially supported the study. The FIRE-3 trial is being conducted in Europe, including 752 mCRC patients of whom 592 patients had confirmed KRAS exon 2 wild- type tumors. Of these, 297 patients were randomized to Erbitux plus FOLFIRI and 295 to bevacizumab plus FOLFIRI.[2] 113 patients had confirmed KRAS exon 2 mutations.

Initial data from the FIRE-3 study "intent-to-treat" population were presented at ASCO 2013. The primary endpoint, objective response rate (ORR) based on investigators' read, of the FIRE-3 trial was not met (62% for Erbitux vs. 58% for bevacizumab; odds ratio 1.18).[2]
Analysis of RAS tumor status[1]

In the population with samples available for further RAS mutation analyses (n=407; KRAS exons 3 or 4, NRAS exons 2, 3, or 4), 84% of patients have RAS wild-type tumors and 16% RAS mutant tumors (other than KRAS exon 2).

Median OS was 33.1 months in mCRC patients with RAS wild-type tumors (n=342) receiving 1st line Erbitux plus FOLFIRI compared with 25.6 months in patients receiving bevacizumab plus FOLFIRI (HR: 0.70; 95% confidence interval [CI]: 0.53 - 0.92; p=0.011). ORR was substantially improved (65.5% for Erbitux plus FOLFIRI vs. 59.6% for bevacizumab plus FOLFIRI p=0.157). Progression-free survival (PFS) was similar in the two treatment groups (median PFS 10.4 months for Erbitux plus FOLFIRI vs. 10.2 months for bevacizumab plus FOLFIRI; HR: 0.93; 95% CI: 0.74 - 1.17; p=0.54).

In the group of patients with any RAS mutations (n=178), patients who received Erbitux plus FOLFIRI 1st line reached an OS of 20.3 months vs. 20.6 months in the group that was treated with bevacizumab plus FOLFIRI (HR=1.09; 95% CI: 0.78 - 1.52; p=0.60). For patients in the Erbitux plus FOLFIRI arm, median PFS was 7.5 months compared with 10.1 months in the bevacizumab plus FOLFIRI arm (HR=1.31; 95% CI: 0.98 - 1.78; p=0.085), and ORR was 38.0% vs. 51.2% (p=0.097), respectively.

No new safety concerns were reported in the trial in either treatment arm and toxicity profiles were as expected and manageable for both combinations.
About Colorectal Cancer

Colorectal cancer (CRC) is the fourth most common cancer worldwide, with an estimated incidence of more than 1.2 million cases globally.[4] An estimated 608,000 deaths from CRC occur worldwide each year, accounting for 8% of all cancer deaths and making it the fourth most common cause of death from cancer.[4] Almost 60% of the cases occur in developed regions, and incidence and mortality rates are substantially higher in men than in women.[5] In Europe alone, an estimated 436,000 people develop CRC every year, with approximately 212,000 people dying from the disease annually.[5]
Courtesy: Medical News Today Note: Any medical information available in this news section is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional.