Further, the addition of Vectibix to chemotherapy also improved response rate in the KRAS wild-type patient population as measured by blinded central review (55 percent versus 48 percent in the FOLFOX only arm).
"I am very pleased with the outcome of this high quality trial which demonstrated that Vectibix improved progression-free survival and appeared to be well tolerated as a first-line metastatic colorectal cancer treatment in a selected patient population," said Jean-Yves Douillard, director Clinical and Translational Research, Medical Oncology Branch, Centre R Gauducheau, France and the study's principal investigator. "This is the first prospective Phase 3 data to demonstrate the importance of KRAS mutation as a predictive biomarker for Vectibix treatment in the first-line setting, providing definitive support for the use of the KRAS biomarker for selection of patients eligible for anti-EGFR therapy."
Importantly, in patients with tumors harboring activating KRAS mutations, PFS was significantly inferior in the Vectibix arm. For patients with mutant KRAS tumors, median PFS was 7.3 months with Vectibix in combination with FOLFOX vs. 8.8 months with FOLFOX alone (hazard ratio 1.29, p=0.02). These data confirm previous findings when oxaliplatin-based chemotherapy and an anti-epidermal growth factor receptor (EGFR) antibody are combined in patients bearing tumors with activating KRAS mutations.
Consistent with the PFS data, an interim analysis of overall survival, a secondary endpoint, demonstrated a reduction in overall survival in patients with KRAS mutant tumors receiving Vectibix. The median overall survival for patients with KRAS wild-type mCRC has not yet been reached. Long-term follow-up for survival continues and the primary analysis is expected in the fourth quarter of 2009.
Adverse event rates were comparable across arms with the exception of known toxicities associated with anti-epidermal growth factor receptor (EGFR) therapy such as rash, diarrhea and hypomagnesemia. Vectibix-related grade 3 infusion reactions were reported for two patients (less than 1 percent).
Originally designed to compare the treatment effect in the overall population, the study was amended to analyze outcomes with respect to the presence or absence of activating mutations in KRAS in the tumor itself. Tumor KRAS status was ascertained in 93 percent of the 1,183 patients enrolled in the trial, the highest percentage ever reported. Tumor KRAS tests were finalized after the completion of enrollment and prior to the primary analysis.
Earlier this week, data were presented from the '181' trial which showed that Vectibix administered in combination with FOLFIRI (an irinotecan-based chemotherapy) prolonged PFS by 2 months in patients with KRAS wild-type mCRC, compared to treatment with FOLFIRI alone (Abstract Number 14LBA).
An analyst/investor event will also be held from the Congress on September 24th, at 6:30 a.m. Eastern Time to discuss data presented at ECCO-ESMO. A webcast of the event can be found on Amgen's Web site at www.amgen.com, under Investors. The audio webcast will be archived and available for replay for at least 72 hours.
Patients enrolled in the '203' or PRIME trial (Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy) were randomized to receive either 6.0 mg/kg of Vectibix and FOLFOX4 once every two weeks (Q2W) or FOLFOX4 alone Q2W. The primary endpoint of the study is progression-free survival by KRAS status and secondary endpoints include overall survival, objective response rate, time to progression, duration of response and safety. Long-term follow up for overall survival is ongoing.
Results from studies performed over the last twenty-five years indicate that KRAS plays an important role in cell growth regulation. In mCRC, EGFR transmits signals through a set of intracellular proteins. Upon reaching the nucleus, these signals instruct the cancer cell to reproduce and metastasize, leading to cancer progression. Anti-EGFR antibody therapies work by blocking the activation of EGFR, thereby inhibiting downstream events that lead to malignant signaling. However, it is hypothesized that in patients whose tumors harbor a mutated KRAS gene, the KRAS protein is always turned "on," regardless of whether the EGFR has been activated or therapeutically inhibited. KRAS mutations occur in approximately 40-50 percent of mCRC.
About Colorectal Cancer
Colorectal cancer is the fourth most common cancer in men and the third most common cancer in women worldwide. In 2007, approximately 1.2 million cases of colorectal cancer were expected to occur globally. With more than 630,000 deaths worldwide per year, it is the second leading cause of cancer-related death in the Western world. The highest incidence rates are found in Japan, North America, parts of Europe, New Zealand, and Australia, and rates are low in Africa and South-East Asia. Rates are substantially higher in men than in women.
Vectibix is the first fully human anti-EGFR antibody approved by the U.S. Food and Drug Administration (FDA) for the treatment of mCRC. Vectibix was approved in the United States in September 2006 as a monotherapy for the treatment of patients with EGFR expressing mCRC after disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.
The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progression-free survival. Currently no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Vectibix. Vectibix has not shown a treatment benefit for patients whose tumors had KRAS mutations in codon 12 or 13.
In December 2007, the EMEA granted a conditional marketing authorization for Vectibix as monotherapy for the treatment of patients with EGFR-expressing mCRC with wild-type KRAS genes after failure of standard chemotherapy regimens. Vectibix has been launched in over 20 countries, Switzerland, Australia and Canada. Applications in the rest of the world, including Japan, are pending.
Important Product Safety Information
Dermatologic Toxicity: Dermatologic toxicities occurred in 89 percent of patients and were severe (NCI-CTC grade 3 and higher) in 12 percent of patients receiving Vectibix monotherapy. Withhold Vectibix for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to greater than or equal to grade 2 within 1 month, permanently discontinue Vectibix. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage were reported.
Infusion Reactions: Severe infusion reactions occurred in approximately 1 percent of patients. Severe infusion reactions included anaphylactic reactions, bronchospasm, and hypotension. Although not reported with Vectibix, fatal infusion reactions have occurred with other monoclonal antibody products. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix.
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