Vectibix® (Panitumumab) Granted Approval for Expanded Indications in the European Union

Amgen (NASDAQ: AMGN) today announced that the European Commission (EC) has approved a variation to the marketing authorization for Vectibix® (panitumumab) to include indications for the treatment of patients with wild-type KRAS metastatic colorectal cancer (mCRC) in first-line in combination with FOLFOX and in second-line in combination with FOLFIRI in patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan). This approval of Vectibix applies to all 27 European Union (EU) member states. Prior to this approval, Vectibix had received conditional approval in the EU as monotherapy. The monotherapy indication was also further revised to state that Vectibix is indicated for the treatment of patients with wild-type KRAS mCRC as monotherapy after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

Colorectal cancer is the second most common cancer in women worldwide and the third most common cancer in men. 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.(1)

“Colorectal cancer can have a devastating impact on the lives of patients affected by this disease,” said Professor Jean-Yves Douillard, director of Clinical and Translational Research, ICO Centre R Gauducheau, France. “This European Commission approval for Vectibix earlier in the treatment continuum marks a welcome and important addition of treatment choice in an area where few targeted agents have shown to be effective when used with chemotherapy.”

Data from studies 20050203 (PRIME) and 20050181 (‘181) showed that adding Vectibix to either FOLFOX or FOLFIRI chemotherapy improved progression-free survival (PFS) versus chemotherapy alone for patients with wild-type KRAS mCRC. Additionally, the overall response rate (ORR) of Vectibix plus chemotherapy was higher than chemotherapy alone. Although numerically greater, the improvement in median overall survival (OS) did not achieve statistical significance in the Vectibix arm of either trial.(2)(3) The Amgen PRIME and ‘181 studies were among the first Phase 3 studies to prospectively analyze the effect of an anti-epidermal growth factor receptor (EGFR) inhibitor based on KRAS status in patients with mCRC.

Adverse events in the PRIME and ‘181 studies included known toxicities associated with EGFR therapy, such as rash, diarrhea, and hypomagnesemia. The incidence of grade 3/4 infusion reactions in the treatment arms for the two trials was approximately one percent. In patients with mutated KRAS tumors, outcomes were inferior for those receiving Vectibix plus FOLFOX versus FOLFOX alone. Vectibix should only be used in those patients in whom wild-type KRAS status has been confirmed.

“Today’s decision by the EC to extend the therapeutic indications for Vectibix marks a promising step forward for those patients facing an aggressive disease where limited treatment options are available,” said Willard H. Dere, M.D., senior vice president and international chief medical officer at Amgen. “This is a significant milestone for Amgen and highlights our commitment to deliver medicines that make a real difference to the lives of patients.”

Vectibix is already approved and established in more than 40 countries as a monotherapy treatment for patients with wild-type KRAS mCRC, when standard chemotherapy is no longer effective. In the United States (U.S.), Vectibix received accelerated approval 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 use of Vectibix is not recommended in patients whose tumors have KRAS mutations in codon 12 or 13. In Russia, Japan and Israel, Vectibix is also approved for use in combination with chemotherapy for patients with wild-type KRAS mCRC.

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.(4) 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 to 50 percent of mCRC patients.(5)(6)

About Vectibix

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 U.S. in September 2006 as a single agent for the treatment of patients with EGFR-expressing mCRC with 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 PFS. More than half of patients who receive Vectibix monotherapy respond to treatment with an average six month PFS benefit. 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 mCRC with these mutations.(7)

Important U.S. Product Safety Information (Monotherapy)

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 one 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

• Vectibix has been approved in the European Union for the treatment of patients with wild-type KRAS metastatic colorectal cancer (mCRC):
• in first-line in combination with FOLFOX
• in second-line in combination with FOLFIRI for patients who have received first-line fluoropyrimidine-based chemotherapy (excluding irinotecan)
• as monotherapy 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. Vectibix should not be administered in combination with oxaliplatin-containing chemotherapy to mCRC patients with mutant KRAS tumors or for whom KRAS tumor status is unknown.
• Adverse events of special importance associated with Vectibix and/or EGFR monoclonal antibody therapies include dermatologic-related reactions, pulmonary complications, electrolyte disturbances, infusion-related reactions (including rare reports with fatal outcome) and ocular toxicities. Acute renal failure has been observed in patients who develop severe diarrhea and dehydration. These events should be monitored carefully, see Summary of Product Characteristics for information on appropriate management of these adverse events.
• Vectibix should not be used in combination with IFL chemotherapy or in combination with bevacizumab containing chemotherapy. For patients with ECOG 2 performance status, assessment of benefit-risk is recommended prior to initiation of Vectibix in combination with chemotherapy for treatment of mCRC.

References

1. Jemal. Global Cancer Statistics. CA CANCER J CLIN 2011;61:69-90
2. Douillard, JE et al. Randomized, Phase 3 Study (PRIME) of Panitumumab with FOLFOX4 versus FOLFOX4 Alone as First-Line Treatment in Patients With Previously Untreated Metastatic Colorectal Cancer. J Clin Oncol 28. 2010.
3. Peeters, M et al. Randomized Phase III Study of Panitumumab With Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) Compared With FOLFIRI Alone As Second-Line Treatment in Patients With Metastatic Colorectal Cancer. J Clin Oncol 28, 2010.
4. Malumbres, M. and Barbacid, M. RAS oncogenes: the first 30 years. Nature Reviews Cancer. 3:459-65, 2003
5. Karapentis C, S. Snell, L, E. The Laboratory Assessment of KRAS Mutation Status in Colorectal Cancer. Asia, PacificJournal of Oncology and Hematology. 2010.
6. Friday BB and Adjei AA. K-ras as a target for cancer therapy. Biochim. Biophys. Acta 1756: 127-144, 2005
7. Vectibix (panitumumab) [prescribing information]. Thousand Oaks, Calif: Amgen; 2011.