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KRAS Dx Market Emerges In US as ASCO Data Support Companion Testing for Colon Cancer

A market for KRAS mutation testing is beginning to take shape in the US following positive results from clinical trials presented at the American Society of Clinical Oncology’s annual meeting in June.
At ASCO’s annual meeting, Eric Van Cutsem, a professor at the University Hospital Gasthuisberg in Leuven, Belgium, and colleagues presented data from a large, multinational prospective clinical trial showing that metastatic colorectal cancer patients who carry the wildtype version of the KRAS gene are much more likely than patients with the mutated form of the gene to benefit from the monoclonal antibody Erbitux [see PGx Reporter 06-04-2008].
“KRAS testing should be routinely conducted in all colorectal cancer patients immediately after diagnosis to ensure the best treatment strategies for the individual patient,” Van Cutsem said during an ASCO news conference.
Coinciding with the presentation of this data, UK-based personalized medicine company DxS penned a deal with Roche to ensure that its TheraScreen K-RAS Mutation test is sold worldwide, after European regulators narrowed the indication for the metastatic CRC drug Vectibix to include only patients whose tumor carries the wildtype KRAS gene. The European Medicines Agency has issued a similar recommendation for Erbitux.
Meantime, across the Atlantic, the US Food and Drug Administration said it is awaiting prospective clinical trial data before deciding whether to update the labels for these anti-EGFR colorectal cancer drugs to recommend companion KRAS testing.
Betting that the FDA will eventually recommend such a move, two companies last week announced they were launching new tests in this market. The first was ViennaLab, which launched its KRAS StripAssay, a CE-marked IVD test kit in Europe that Oasis Diagnostics will market as a homebrew test in the US. The second shop, Caris Diagnostics, last week said it has begun to offer KRAS testing as part of its Target Now oncology testing service.
The KRAS gene is mutated in between 35 percent and 45 percent of metastatic CRC patients. Studies have shown that KRAS testing can better define which CRC patients will benefit from treatment with epidermal growth factor receptor-inhibiting monoclonal antibodies, such as Amgen’s Vectibix (panitumumab) and Imclone/Bristol-Myers Squibb’s Erbitux (cetuximab).
The two drugs are competitors in the CRC market. In the US, Vectibix is indicated for the treatment of metastatic CRC following standard chemotherapy, while Erbitux, in combination with the chemotherapy irinotecan, is indicated for the treatment of EGFR-expressing, metastatic CRC in irinotecan-refractory patients. As a single agent, Erbitux is indicated for the treatment of metastatic CRC in patients who are intolerant to irinotecan-based chemotherapy.
With positive data presented at ASCO and a blessing from EMEA to test CRC patients for KRAS mutations before prescribing Erbitux or Vectibix, it appears that diagnostic companies are not waiting around for a nod from the FDA to begin selling their KRAS tests in the US.
A labeling change for Vectibix and Erbitux by the FDA “is definitely important,” Fritz Kury, managing director at ViennaLab, told Pharmacogenomics Reporter this week. “However, even without the labeling change, we are seeing a strong interest in KRAS testing.”
Although ViennaLab will initially launch the StripAssay as a homebrew test in the US, the company plans to eventually submit the test for FDA clearance.
DxS is currently collecting prospective clinical data to support a submission for FDA approval of its TheraScreen KRAS test. The test, CE-marked in Europe, is considered a high-risk Class III device in the US. Therefore, if it is to be used as a predictive test for Vectibix or Erbitux, “the labeling [change] is crucial,” Peter Collins, DxS business development director, told Pharmacogenomics Reporter this week.
“However, it’s clear that after ASCO and the recent [World Gastro-Intestinal Cancer] conference in Barcelona, the physicians have already embraced the need for genotyping metastatic colorectal cancer patients for KRAS before using anti-EGFR therapies,” Collins added.
Despite the excitement over KRAS testing, reimbursement remains an outstanding issue. And although several presentations at ASCO’s annual meeting have begun to generate interest in the physician community regarding this new technology, ASCO’s 2006 guidelines still consider KRAS testing for colorectal cancer experimental. 
However, as seen with Genomic Health’s experience with Oncotype DX, recommendations from professional societies like ASCO to use gene-based diagnostics to help guide treatment options can greatly improve a test’s chances of being reimbursed.
KRAS Is Greener
The main area of differentiation between the various KRAS tests appear to be in the mutations they detect: DxS’ TheraScreen detects seven mutations in codons 12 and 13 of the K-RAS oncogene; ViennaLab’s StripAssay detects 10 mutations in the KRAS codons 12 and 13; while Caris Dx says that its test gauges “any and all nucleotide changes” at the three validated KRAS codons 12, 13, and 61.
Caris Dx, based in Irving, Texas, said its KRAS assay “offers a distinct advantage over other laboratories that may only screen for a few specific mutations in codons 12 and 13.”
However, DxS questioned some of Caris Dx’s claims. “The DxS test covers the seven most common mutations in codons 12 and 13. In CRC, this provides 99.5 percent coverage of all the known mutations,” DxS’ Collins said in an e-mail.
“How Caris Dx can claim to be more ‘comprehensive’ than 99.5 percent in CRC is a mystery, particularly as there are other very low-frequency mutations besides codon 61, such as A146R, that they would appear not to pick up.”
DxS’ K-RAS test “has been used to provide high-quality data for both Vectibix and Erbitux trials,” Collins added. “Any drug requiring a label change such as Vectibix and Erbitux will need a companion diagnostic product, not a service.”

“Any drug requiring a label change such as Vectibix and Erbitux will need a companion diagnostic product, not a service.”

Caris Dx did not respond to questions regarding its KRAS test and the Target Now oncology testing service.
Meanwhile, ViennaLab is touting the sensitivity of its assay. The company said its StripAssay has a relative sensitivity of 0.5 percent for mutated sequences, and an absolute detection limit of less than 10 copies of mutated sequences.
However, in a study published in the Journal of Clinical Oncology by Amado et al., the sensitivity cut-off for the StripAssay was set at 1 percent of mutant DNA.
Despite this, Kury said the StripAssay “is significantly more sensitive than widely used sequencing, which has only a sensitivity of about 20 percent for mutant DNA, 5 percent at most.”
For its part, DxS claims on its website that its TheraScreen assay “can detect 1 percent of mutant [DNA] in a background of wildtype genomic DNA.” 
Another difference may be the technology platform on which the various assays are built. The TheraScreen assay combines ARMS allele-specific PCR with the Scorpions real-time PCR technology to detect KRAS mutations. ViennaLab’s test is based on mutant-enrichment PCR followed by reverse hybridization; the technology is proprietary to the company.
Caris Dx’s Target Now oncology testing service, meantime, uses microarrays, advanced immunohistochemistry, fluorescent in situ hybridization, and sequencing analysis. It was not immediately clear which technologies would be applied to KRAS screening.
According to Caris Dx, patients enrolled in the Target Now program receive a report on the molecular targets present in their cancer specimen, and which treatments may be associated with those targets, based on published literature.
Distribution Channels
One of the main advantages of DxS in the KRAS-testing market will be the distribution muscle of marketing partner Roche Molecular Diagnostics.
Although there is yet to be a recommendation from the FDA regarding KRAS testing for colorectal cancer patients treated with EGFR-inhibiting antibodies, “the US represents an important additional market opportunity for KRAS testing,” Melinda Baker, director of global communications at Roche Molecular Diagnostics, previously told Pharmacogenomics Reporter.
In “our partnership with Roche Molecular Diagnostics … we are currently tailoring a comprehensive package to deal with the unique environment in the US,” DxS’ Collins said. Roche will market the DxS TheraScreen tests to a range of laboratories in the US, including large reference labs and smaller regional and local pathology laboratories. 
Separately, DxS announced this week that it is launching its KRAS test in Australia, after the test met the compliance standards of that country’s Therapeutic Goods Administration.
Caris Dx’ marketing advantage will be its existing relationships with physicians. The company provides pathology services to physicians who treat patients in the community setting and claims that as many as 1,500 doctors in the US use its services.
Also, at the beginning of this year, Caris Dx acquired Caris MPI in order to add molecular testing services to its overall physician-consultation business. According to the company, it provides medical opinions on more than 1,000 gastrointestinal biopsies per day.
"Given our leading position in gastrointestinal pathology, it is not only natural, but also imperative for us to offer our clinicians this critical information for their treatment decisions," David Halbert, Caris Dx chairman, said in a statement. "We have been predicting the convergence of anatomic pathology and molecular testing for some time. With our ability to perform the KRAS analysis on the biopsies that we receive for initial cancer diagnosis each week, the paths of anatomic and molecular test are now united.”
Additionally, Caris Dx highlights that it has “strategic relationships” with the International Genomics Consortium, US Oncology, the Translational Genomics Research Institute, and the Biodesign Institute of Arizona State University, whose physician networks it could use to market its oncology testing service.
For ViennaLab, in addition to having its KRAS test marketed in Europe, US, and Canada, the company plans to eventually launch the test in China and Japan. 
“ViennaLab will use its existing network of … distribution partners in Europe and our partner Oasis Diagnostics,” Kury said. “In Asia, contacts have been made with interested partners for the test’s marketing.” He did not elaborate on who these potential partners were.
ViennaLab intends to expand the use of the StripAssay into DPD and UGT1A1 mutation testing. This test will be launched in the “near future,” Kury said.
DxS also offers a CE-marked EGFR 29-Mutation Test kit under its TheraScreen brand of assays, which may help better define the patient population for tyrosine kinase inhibitors such as AstraZeneca’s Iressa and Genentech’s Tarceva.
Roche has exclusive worldwide distribution rights to the test except in North America and Hong Kong.
Additionally, Genzyme Genetics has been marketing a KRAS test for non-small cell lung cancer since 2006.
Genomic Health also presented data at ASCO from a study it conducted as part of a collaboration with research partners Bristol-Myers Squibb and Imclone to discover and validate markers associated with disease control and improved progression-free survival in colon cancer patients treated with Erbitux. The study could lead to the development of a predictive test based on Genomic Health’s Oncotype DX platform [see PGx Reporter 06-11-2008]. 
Reimbursement Question
While diagnostic developers may be excited about the KRAS testing market in the US, insurers don’t appear to share their enthusiasm. And based on past examples, even a nod from the FDA may not be enough to stir insurers into covering a particular test.
Although the FDA has approved several gene-based tests that detect patients likely to suffer serious adverse reactions when treated with the anticoagulant warfarin, many large insurers have yet to cover the test, arguing that studies have yet to show the clinical utility of warfarin testing [see PGx Reporter 09-26-2007]. 
ViennaLab’s StripAssay test “is very new,” Kury said. “We will be beginning the dialog with reimbursement agencies very soon.”
DxS has begun discussions with insurers, according to Collins. “Recent comments … suggest [insurers] will embrace the idea of reimbursing a test that provides value to patient, physician, and payor alike and ensure money follows the most efficacious path,” he said.
In the US, very few pharmacogenetic tests are covered by major insurance companies, which have largely held that there is little evidence to suggest that gene-based personalized medicine reduces healthcare costs [see PGx Reporter 12-19-2007].
One payor, WellPoint, did not outline its current position on KRAS testing. However, a spokesperson noted that the company, which covers 34 million lives in the US and is the largest member of the BlueCross BlueShield Association, believes “it is important to consider the merits of genetic testing on a case-by-case basis as the use of some genetic tests have not been shown to lead to positive health outcomes.”
An Aetna spokesperson told Pharmacogenomics Reporter this week that it “currently considers testing for KRAS mutations experimental for persons diagnosed with colorectal cancer.” The insurer, which covers 15 million lives nationwide, said its policy regarding KRAS testing is supported by current guidelines from ASCO.
According to its most recent recommendations for the use of tumor markers in gastrointestinal cancers, ASCO recommends carcinoembryonic antigen (CEA) screening for colorecteal cancer patients. “CEA is the marker of choice for monitoring the response of metastatic disease to systemic therapy,” ASCO states in its guidelines. “Data are insufficient to recommend the routine use of p53, RAS, thymidine synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, microsatellite instability, 18q loss of heterozygosity, or deleted in colon cancer (DCC) protein in the management of patients with colorectal cancer.”
According to the Aetna spokesperson, the payor “will continue to review the emerging literature for KRAS testing as it becomes available from sources, including peer-reviewed published studies and evidence-based guidelines from nationally recognized professional healthcare organizations and public health agencies.”
It is unclear whether ASCO intends to update its guidelines in light of new data presented at its annual meeting regarding KRAS testing. However, a recommendation for genetic testing in the treatment guidelines of professional societies like ASCO can certainly improve a test’s chances for reimbursement.
A prime example is Genomic Health’s experience in garnering reimbursement for its breast cancer recurrence test Oncotype DX. Company officials have said that insurers have been much more willing to cover the test after ASCO and the National Comprehensive Cancer Network updated their breast cancer treatment guidelines to recommend screening with Oncotype DX [see PGx Reporter 10-31-2007]. 
None of companies revealed the price of their KRAS tests.

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