First-line Treatment with Panitumumab + FOLFOX in Patients with Wild-type KRAS Metastatic Colorectal Cancer Approved

The U.S. Food and Drug Administration (FDA) has approved panitumumab (Vectibix®, Amgen) for use in combination with FOLFOX, an oxaliplatin-based chemotherapy regimen, as first-line treatment in patients with wild-type KRAS (exon 2) metastatic colorectal cancer (mCRC). 

With an estimated number of 96,830 colon and 40,000 rectal cases and 50,310 deaths from colon and rectal cancer in the United States in 2014, colorectal cancer is the third most common cancer found in both men and women in the U.S., and is the second leading cause of cancer deaths.[1][2] Approximately 1,2 million cases of colorectal cancer or CRC are expected to occur globally. [3]

Research has shown that an estimated 50%–60% of patients diagnosed with CRC will develop metastases during the course of their disease while about 15%–25% of patients present with metastasis at the time of diagnosis.[4][5] Hence, today's announcement is good news for patients diagnosed with (m)CRC. The approval reinforces Amgen commitment to personalized medicine and their drug, panitumumab, is the first fully human anti-EGFR antibody approved by the FDA for treatment of mCRC.

Panitumumab is the first approved biologic to show a significant survival benefit when combined with FOLFOX as a first-line treatment...

Panitumumab was initially approved in the U.S. in September 2006 as a monotherapy for the treatment of patients with EGFR-expressing mCRC after disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy.  

As a result of this added approval, panitumumab becomes the first and only biologic to offer a significant survival benefit as a first-line treatment with FOLFOX, one of the most commonly used chemotherapy regimens in the first-line setting for patients with wild-type KRAS mCRC. This approval further converts the accelerated monotherapy approval to a full approval for panitumumab.

Companion test
In addition to the approval of panitumumab in combination with FOLFOX, the FDA also approved the therascreen® KRAS RGQ PCR Kit, developed as companion diagnostic for panitumumab. The test, developed by The Netherlands based Qiagen, a provider of sample and assay technologies for molecular diagnostics, applied testing, academic and pharmaceutical research, is a qualitative real-time PCR assay for the detection of specific mutations in the KRAS oncogene and includes reagents optimized for rapid and sensitive detection of 7 somatic mutations.

Research has shown that mutations in the KRAS oncogene, an effector molecule responsible for signal transduction from ligand-bound EGFR to the nucleus, are frequently found in human cancers. The presence of these mutations correlates with a lack of response to certain EGFR inhibitor cancer therapies in patients with metastatic colorectal cancer (mCRC). These mutations in the KRAS oncogene are present in around 40% of all cases. As a result, routine testing of all patients with CRC for KRAS mutations is now recommended. Screening colorectal cancer patients with the therascreen KRAS companion test detects the most frequent mutations in the KRAS gene and helps physicians in treatment planning decisions. Only those patients harboring wild-type KRAS should be candidates for therapies which improves outcomes, and minimizes unnecessary toxicity and cost. [6][7][8]

Personalized medicine
The FDA's approval is the latest milestone in Amgen’s pioneering cancer biomarker research, designed to help oncologists personalize cancer treatment to improve patient outcomes. Biomarkers are biological characteristics that demonstrate the likelihood of an individual’s response or lack of response to a particular therapy and are a key element in personalized medicine that can help oncologists choose treatments for patients who are most likely to benefit. 

“Because every patient with cancer is unique, we have made it our mission to focus on identifying treatment options for patients based on their cancer’s genetic makeup,” noted Sean E. Harper, M.D., executive vice president of Research and Development at Amgen.

"In essence, personalized medicine is the ability to understand the makeup of a patient's cancer and the genetics and pathways involved.  Using the latest technologies to understand this science helps us to understand how a specific cancer works in an individual patient" explained Rodger Sidhu, Executive Medical Director, Global Development, Hematology/Oncology. "This helps tailor treatments in such a way that it is most likely to benefit the patient."

"Our research team was among the first to establish that KRAS is a strong predictor of resistance to EGFR-targeted treatments. The FDA's approval offers a new treatment option," Sidhu concludes.

“Approval of Vectibix in combination with FOLFOX for first-line treatment of patients with wild-type KRAS metastatic colorectal cancer is an example of the advancements that can be made through a greater understanding of distinct genetic markers associated with difficult-to-treat diseases,” Harper adds.

Trial results
The approval of panitumumab is based on results from the PRIME (‘203) and ASPECCT (‘763) trials. The PRIME Phase III study showed that patients with wild-type KRAS tumors in exon 2 achieved statistically significant improvement in progression-free survival or PFS with panitumumab and FOLFOX versus FOLFOX alone (9.6 versus 8.0 months, p=0.02) and a significant 4.4 month improvement in overall survival (OS) versus FOLFOX alone (23.8 versus 19.4 months).

Additionally, the Phase III ASPECCT study met its primary endpoint of non-inferiority for improving overall survival in patients taking panitumumab versus cetuximab (Erbitux®; ImClone) as a single agent for the treatment of mCRC in patients with wild-type KRAS tumors who have not responded to chemotherapy. [9]

The authors of an article published in May 2014 discussing the ASPECCT study concluded that these findings show that panitumumab and cetuximab provide similar overall survival benefit in this specific population of patients. Furthermore, the authors conclude that both agents had toxicity profiles that were to be expected. They finally concluded that based on the consistency in efficacy and toxicity seen, small but meaningful differences in the rate of grade 3-4 infusion reactions and differences in dose scheduling will guide a physician's choice of anti-EGFR treatment. [9]

“Vectibix is now the first approved biologic to show a significant survival benefit when combined with FOLFOX as a first-line treatment,” said Lee S. Schwartzberg, M.D., medical director of The West Clinic, Memphis, Tenn. “Vectibix has shown a significant benefit to patients with wild-type KRAS metastatic colorectal cancer when used with FOLFOX, which gives us a valuable new treatment option as we help patients fight this devastating disease.”

For more information:
[1] Colorectal Cancer Facts and Figures. American Cancer Society. Last accessed, March 25, 2013.[Website]
[2] Colorectal Cancer Prevention (PDQ®). National Cancer Institute. Accessed March 25, 2013. [Website]
[3] Jemal. Global Cancer Statistics. CA Cancer J Clin. 2011;61:69-90.
[4] Van Cutsem E, Nordlinger B, Adam R, et al. Towards a pan-European consensus on the treatment of patients with colorectal liver metastases Eur J Cancer 42(14):2212–2221, 2006. [PubMed]
[5] Alberts SR, Horvath WL, Sternfeld WC, et al. Oxaliplatin, fluorouracil, and leucovorin for patients with liver-only metastases from colorectal cancer: A North Central Cancer Treatment Group phase II study. J Clin Oncol 23(36):9243–9249, 2005.[PubMed]
[6] Di Fiore F1, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP, et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer. 2007 Apr 23;96(8):1166-9. Epub 2007 Mar 20. [Article][PubMed]
[7] De Roock W, De Schutter J, De Hertogh G, Janssens M, Biesmans B, Personeni N, Geboes K, Verslype C, Van Cutsem E, Tejpar S KRAS mutations preclude tumor shrinkage of colorectal cancers treated with cetuximab Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).Vol 25, No 18S (June 20 Supplement), 2007: 4132 [Abstract]
[8] Markman B, Javier Ramos F, Capdevila J, Tabernero J. EGFR and KRAS in colorectal cancer. Adv Clin Chem. 2010;51:71-119.[PubMed]
[9] Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A,et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014 May;15(6):569-79. doi: 10.1016/S1470-2045(14)70118-4. Epub 2014 Apr 14.[Article][PubMed]

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