Two Pivotal Vectibix® Phase 3 Studies in First and Second-Line Treatment of Metastatic Colorectal Cancer Published in the Journal of Clinical Oncology

THOUSAND OAKS, Calif., Oct. 4 /PRNewswire-FirstCall/ -- Amgen (Nasdaq: AMGN) today announced that results from the PRIME '203' and '181' pivotal Phase 3 trials evaluating Vectibix® (panitumumab) in combination with chemotherapy (FOLFOX or FOLFIRI) as a first and second-line treatment for metastatic colorectal cancer (mCRC), respectively, were published online in the Journal of Clinical Oncology.

"Both studies demonstrated that Vectibix administered with chemotherapy significantly improved progression-free survival in patients with wild-type KRAS mCRC," said Marc Peeters, M.D., Ph.D., Professor of Oncology, Antwerp University Hospital and '181' trial lead investigator and study author. "The adverse event profiles in both trials were as expected for an anti-EGFR antibody treatment used in combination with these types of chemotherapy regimens. Additionally, these data reinforce that KRAS status should be known when choosing treatment strategies."

PRIME '203' Results in First-Line mCRC Demonstrate Vectibix Combined with Chemotherapy (FOLFOX) Helped Patients with Wild-type KRAS mCRC Live Longer Without their Disease Worsening (Progression-Free Survival or PFS)

• The addition of Vectibix to FOLFOX (an oxaliplatin-based chemotherapy) significantly improved PFS (median 9.6 months for Vectibix plus FOLFOX versus 8.0 months for patients treated with FOLFOX alone, hazard ratio 0.80; 95 percent CI: 0.66-0.97; p=0.02) in the first-line treatment of patients with wild-type KRAS mCRC.  
• Although numerically greater (23.9 months versus 19.7 months, hazard ratio 0.83; 95 percent CI: 0.67-1.02), the improvement in overall survival (OS) (secondary endpoint) in the Vectibix arm did not achieve statistical significance (p=0.072) in the same patient population.
• 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 versus 8.8 months with FOLFOX alone (hazard ratio 1.29; 95 percent CI: 1.04-1.62; p=0.02).
• These data confirm previous findings when oxaliplatin-based chemotherapy and an anti-EGFR antibody were combined in patients bearing tumors with activating KRAS mutations.
• The response rate of Vectibix plus chemotherapy was higher than chemotherapy alone in the wild-type KRAS patient population as measured by blinded central review (55 percent versus 48 percent in the FOLFOX only arm).
• Tumor KRAS status was ascertained in 93 percent of the 1,183 patients enrolled in the PRIME '203' trial, the highest number ever prospectively reported for a first-line trial.

"The outcome of this high quality trial demonstrated that Vectibix, which was administered every two weeks, improved progression-free survival as a first-line metastatic colorectal cancer treatment in a selected patient population," said Jean Yves-Douillard, M.D., Ph.D., director Clinical and Translational Research, Medical Oncology Branch, Centre R Gauducheau, France and PRIME '203' trial lead investigator and study author.

'181' Results in Second-Line mCRC Demonstrate Vectibix Combined with Chemotherapy (FOLFIRI) Helped Patients with Wild-type KRAS mCRC Live Longer Without their Disease Worsening (PFS)

• Results of the '181' trial showed that the addition of Vectibix to FOLFIRI (an irinotecan-based chemotherapy) significantly improved PFS (co-primary endpoint) (median 5.9 months for Vectibix plus FOLFIRI versus 3.9 months for patients treated with FOLFIRI alone, hazard ratio 0.73; 95 percent CI: 0.59-0.90; p=0.004) in the second-line treatment of patients with wild-type KRAS mCRC.
• Although numerically greater (median 14.5 months versus 12.5 months; hazard ratio 0.85; 95 percent CI: 0.70-1.04), the improvement in overall survival (co-primary endpoint) in the Vectibix arm did not achieve statistical significance (p=0.12) in the same patient population.
• The addition of Vectibix to chemotherapy in the '181' trial resulted in greater than a three-fold improvement (35 percent versus 10 percent) in response rate in the wild-type KRAS patient population, as measured by a blinded central review.
• Tumor KRAS status was ascertained in 91 percent of the 1,186 patients enrolled in the '181' trial, the highest number ever prospectively reported for a second-line trial.
• In this study, the addition of Vectibix had no positive or negative effect on PFS or OS in patients with tumors harboring activating KRAS mutations.

"The response rate seen in the '181' trial is among the highest ever reported in the second-line metastatic colorectal cancer setting," said Emily Chan, M.D., Ph.D., Assistant Professor of Medicine, Vanderbilt-Ingram Cancer Center and '181' study investigator and author. "Additionally, the tissue acquisition from both the '181' and '203' studies has yielded a large repository of informative data regarding the KRAS biomarker, and holds the potential of providing even more information in the future."

In general, adverse events rates were comparable across arms in both studies, with the exception of known toxicities associated with anti-EGFR therapy, such as rash, diarrhea, and hypomagnesemia. Vectibix-related grade 3/4 infusion reactions were reported in less than one percent of patients.

Originally designed to compare the treatment effect in the overall mCRC patient population, both studies were amended to analyze outcomes with respect to the presence or absence of activating mutations in KRAS in the tumor itself. These are the first Phase 3 studies to prospectively analyze the effect of an EGFR inhibitor based on KRAS status in patients with previously treated mCRC.

Results from both trials were previously presented at Europe's largest cancer conference, ECCO 15 – ESMO 34, in September 2009, at the 2010 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in January, and at the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting in June.

About the PRIME '203' Trial

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 was progression-free survival by KRAS status and secondary endpoints included overall survival, objective response rate, time to progression, duration of response and safety. Long-term follow up for overall survival is ongoing.

About the '181' Trial

The '181' trial is a global, multicenter, randomized Phase 3 study. Patients enrolled in the study were randomized to receive either 6.0 mg/kg of Vectibix and FOLFIRI Q2W or FOLFIRI alone Q2W. The co-primary endpoints were progression-free survival (which was independently tested) and overall survival. Secondary endpoints included objective response rate, time to progression, duration of response and safety by KRAS status.

About KRAS

Results from studies performed over the last 25 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 inhibiting the activation of EGFR, thereby inhibiting downstream events that lead to malignant signaling. However, 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 patients.

About Colorectal Cancer

Colorectal cancer is the fourth most common cancer in men and the third most common cancer in women worldwide. Approximately 1.2 million cases of colorectal cancer are expected to occur globally. With more than 630,000 deaths worldwide per year, it is the third 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 Southeast Asia. Rates are substantially higher in men than in women.

About Vectibix

Vectibix is the first fully human anti-EGFR antibody approved by the United States (U.S.) Food and Drug Administration (FDA) for the treatment of mCRC. Vectibix was approved in the U.S. 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 mCRC is based on progression-free survival. Currently no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Vectibix.

Retrospective subset analyses of mCRC trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations.

In December 2007, the European Medicine Agency (EMA) granted a conditional marketing authorization for Vectibix as a monotherapy for the treatment of patients with EGFR-expressing mCRC with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. Vectibix has been launched in more than 20 European Union countries, Russia, Israel, Switzerland, Australia, Canada and Japan. Applications in the rest of the world are pending.

Important U.S. Product Safety Information

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS

Dermatologic Toxicity: Dermatologic toxicities occurred in 89 percent of patients and were severe (NCI-CTC grade 3 or higher) in 12 percent of patients receiving Vectibix monotherapy. [See Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

Infusion Reactions: Severe infusion reactions occurred in approximately 1 percent of patients. Fatal infusion reactions occurred in postmarketing experience [See Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)].

The most common adverse events of Vectibix are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration.

Important European Product Safety Information

For full prescribing information please see the Summary of Product Characteristics.

Vectibix is indicated as monotherapy for the treatment of patients with EGFR-expressing, metastatic colorectal carcinoma (mCRC) with nonmutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

Vectibix is contraindicated in patients with a history of severe or life-threatening hypersensitivity reactions to the product and in patients with interstitial pneumonitis or pulmonary fibrosis.

Other common adverse events of special importance associated with Vectibix and/or EGFR monoclonal antibody therapies include dermatologic-related reactions, pulmonary complications, electrolyte disturbances and infusion-related reactions (including rare reports with fatal outcome). These events should be monitored carefully, see Summary of Product Characteristics for information on appropriate management of these adverse events. Acute renal failure has been observed in patients who develop severe diarrhoea and dehydration.

Vectibix should not be used in combination with IFL [bolus 5-fluorouracil (500 mg/m2), leucovorin (20 mg/m2) and irinotecan (125 mg/m2)] or in combination with bevacizumab containing chemotherapy.

Vectibix should not be administered in combination with oxaliplatin-containing chemotherapy to mCRC patients with mutant KRAS tumours or for whom KRAS tumour status is unknown.

About Amgen

Amgen discovers, develops, manufactures and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science's promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people's lives. To learn more about our pioneering science and our vital medicines, visit http://www.amgen.com.

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