Analysis of the large randomized Phase II OPUSa study (OxaliPlatin and CetUximab in First-line Treatment of MetaStatic Colorectal Cancer) demonstrating an association between early tumor shrinkage and long-term median overall survival (OS) of more than 2 years for patients with KRAS wild-type metastatic colorectal cancer (mCRC) treated with cetuximab ( Erbitux?, ImClone, Bristol-Myers Squibb Company and Merck KGga), plus FOLFOX standard chemotherapy. This correlation was not seen in the chemotherapy-alone arm of the study.[1 ] The study will be presented at the annual Gastrointestinal (GI) Cancers Symposium of the American Society of Clinical Oncology (ASCO) which will take place on January 20-22, 2011 in San Francisco, CA.

Cetuximab is a first-in-class and highly active IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR). As a monoclonal antibody, the mode of action of cetuximab is distinct from standard non-selective chemotherapy treatments in that it specifically targets and binds to the EGFR. This binding inhibits the activation of the receptor and the subsequent signal-transduction pathway, which results in reducing both the invasion of normal tissues by tumor cells and the spread of tumors to new sites. It is also believed to inhibit the ability of tumor cells to repair the damage caused by chemotherapy and radiotherapy and to inhibit the formation of new blood vessels inside tumors, which appears to lead to an overall suppression of tumor growth.

The latest analysis shows that the majority of patients (69%) with KRAS wild-type mCRC demonstrated tumor shrinkage of 20% or more in the first 8 weeks of 1st line treatment with cetuximab and FOLFOX. These patients experienced a long-term median OS of 26.2 months. Patients treated with FOLFOX chemotherapy alone whose tumors shrank by 20% or more in the same period (46%) experienced median OS of only 21.8 months. [1]

These results support recent findings from the Phase III CRYSTALb trial (Cetuximab combined with iRinotecan in 1st line therapY for metaSTatic colorectAL cancer), which found that early tumor shrinkage achieved with cetuximab in combination with FOLFIRI standard chemotherapy led to a long-term median OS of 2.4 years (28.3 months).[2]

?The OPUS and CRYSTAL studies show, for the first time in colorectal cancer, that there is a correlation between early tumor shrinkage during the first weeks of treatment and extended survival. This effect seems to be unique to treatment with chemotherapy and cetuximab since a similar association was not observed with chemotherapy alone in this analysis, nor has it been proved for any other colorectal cancer treatment,? said Professor Carsten Bokemeyer, lead investigator of the OPUS trial, Head of the Department for Oncology, Hematology and Bone Marrow Transplantation in the Center for Internal Medicine at the University Medical Center in Hamburg, Germany. ?The result is both scientifically of extreme interest and immediately medically relevant for improving patient care through the personalized medicine approach with Erbitux.?

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Further cetuximab data to emerge from ASCO GI came from the randomized Phase II CORE.1.2.002 study that included 152 patients. The results showed that administration of cetuximab every second week in combination with FOLFOX resulted in sustained efficacy and safety in the treatment of mCRC patients with KRAS wild-type tumors, which were equivalent to the results demonstrated with the weekly administration.[3] Response rates of 51% and 63% were seen in the weekly administration arm and in the arm where cetuximab was given every second week, respectively. There was no significant difference between the two arms.

?Results from both the CORE.1.2.002 and OPUS studies confirm the high activity of cetuximab with the standard FOLFOX oxaliplatin-based chemotherapy regimen,? said Dr. Wolfgang Wein, Executive Vice President, Oncology, Merck Serono. ?The latest long-term survival data from the OPUS and CRYSTAL studies, using the FOLFOX and FOLFIRI standard chemotherapies respectively, show that the strong tumor shrinkage of Erbitux directly translates into extended survival for patients.?

[1] Piessevaux H, Bokemeyer C, Schlichting M, Heeger S, Tejpar S, et al. Impact of early tumor shrinkage on long-term outcome in metastatic colorectal cancer (mCRC) treated with FOLFOX4 with or without cetuximab: Lessons from the OPUS trial. J Clin Oncol 29: 2011 (suppl 4; abstr 398)
[2] Piessevaux H, et al. Early tumor shrinkage for the prediction of efficacy of cetuximab in metastatic colorectal cancer (MCRC): Analysis from the CRYSTAL study ESMO Congress 2010. Abstract No. 596P.
[3] Ciuleanu T, Nikolic V, Shmueli E, Vrbanec D, Plate S, Krmpotic ZM, et al. Cetuximab weekly (q1w) versus every two weeks (q2w) plus FOLFOX4 as first-line therapy in patients (pts) with KRAS wild-type (wt) metastatic colorectal cancer (mCRC).J Clin Oncol 29: 2011 (suppl 4; abstr 494)

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