With the European launch of a companion diagnostic for Vectibix, Amgen’s drug for advanced bowel cancer, UK-based diagnostics developer DxS stands to benefit from being one of the only players in the market with a CE-marked KRAS test.
Amgen UK and Lab21 announced last month a partnership to introduce a real-time PCR-based companion diagnostic for Vectibix, also known as panitumumab. The assay, which was used in the pivotal clinical trial for the drug, will be available in 22 EU countries, DxS officials told Pharmacogenomics Reporter this week.
“We know that Vectibix will only be effective in those patients whose cancers are positive for non-mutated (wild type) KRAS. It means that we can exclude those patients in whom the agent will not be beneficial, thereby avoiding unnecessary exposure and the concomitant risk of side-effects,” Amgen said in a statement to Pharmacogenomics Reporter. “We believe that targeted therapies like this will be critical for the future if society is going to be able to afford innovative drugs.”
“As far as we know we are the only CE-marked KRAS test available” in Europe, DxS CEO Steven Little told Pharmacogenomics Reporter.
Sweden’s Biotage markets a KRAS test on its PyroMark platform for research use in the EU. Additionally, Italy-based DiaSorin and partner Dana Farber-Brigham and Women’s Cancer Center are developing a KRAS assay based on a real-time PCR, FLourescent Amplicon Generation (FLAG) technology.
A US Food and Drug Administration-approved KRAS test is not currently available in the US for Vectibix. However, if Amgen decided to introduce a similar companion diagnostic for panitumumab in the US, DxS stands to be one of the first companies to introduce a test in this market.
The KRAS gene is located on chromosome 12 (12p12). Other than by real-time PCR, an alternative way of doing a KRAS test is through sequencing, which is the way it is done at most academic hospitals.
Vectibix was approved in the UK earlier this year and is indicated for the treatment of metastatic bowel cancer for patients who have failed standard chemotherapy and have a specific gene mutation. Biomarker analysis of the patient population in a pivotal clinical trial for Vectibix using DxS’ assay appears to have saved the drug from failing to reach the market.
In May the European Committee for Medicinal Products for Human Use had initially decided not to recommend the drug for marketing in the EU, reasoning that a pivotal clinical trial did not show a favorable risk-benefit ratio. CHMP decided to recommend Vectibix after a second review in September, during which Amgen showed that patients with a non-mutated, wild type Kirsten Rat Sarcoma 2 viral oncogene homolog benefited from the drug.
“We developed a set of biomarker products and put it out on the market at the beginning of last year,” Little said, adding that its KRAS assay was used to stratify patients in a pivotal clinical trial for Vectibix. “When it became apparent that KRAS was a very useful biomarker for Vectibix, and it became apparent that Amgen required a biomarker, that was when we upgraded the biomarker to the companion diagnostic.”
At the American Society of Clinical Oncology Gastrointestinal Cancers Symposium in January, Amgen reported results from a biomarker analysis of a Phase III, randomized controlled trial, comparing Vectibix monotherapy with best standard care versus best standard care alone in 463 patients with metastatic colorectal cancer.
“You have to have a good reason for not using our assay. There will be competition, but I think we’re in a very good position at the moment.”
The study revealed that Vectibix plus BSC improved median progression-free survival in patients with wild-type KRAS to 12.3 weeks compared with patients with mutated KRAS, whose median progression-free survival was 7.3 weeks. Standardized time-to-tumor assessment showed median PFS at 16 weeks for patients with non-mutated KRAS versus 8 weeks for those with mutated KRAS.
As part of this study, researchers also looked at overall survival by KRAS status and treatment. While overall survival was longer in patients with non-mutated KRAS compared with mutated KRAS, there were no differences in overall survival between Vectibix and BSC in either KRAS subgroup “due to a high rate of crossover from BSC to Vectibix after progression, and similar efficacy of Vectibix in these patients,” Amgen said in a statement.
With the launch of the KRAS companion diagnostic, “it is the first time that the European Commission has licensed a bowel cancer product with the stipulation that a predictive test should be carried out,” Lab21 said in a statement.
Over 36,000 people in Britain are afflicted with bowel cancer every year. According to the NCI, in the US, there are approximately 149,000 new cases of colorectal cancer each year, and as many as 50,000 people die of the disease each year.
Although Amgen will not be able to market the drug to all bowel cancer patients, the company still stands to capture a large portion of the market, since 60 percent of advanced bowel cancer patients have wild-type KRAS.
Is KRAS Greener in US?
In the US, where panitumumab was approved in 2006 as a third-stage metastatic colorectal cancer drug following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens, there is yet to be an FDA-approved KRAS companion test.
According to the DxS officials, if there is a KRAS test for Vectibix in the US, there is a good chance DxS’ test will be the first one there.
“Our assay was widely used in [Vectibix’s] clinical trials, so it wouldn’t make a great deal of sense to have a different platform in a different part of the world because you want consistency and comparability of data,” Peter Collins, DxS’ business development director, told Pharmacogenomics Reporter last week.
“So, if there is to be a KRAS diagnostic in the US associated with Vectibix then it would be difficult to not see it being the same one that [Amgen] has effectively endorsed in other countries,” Collins added.
“You have to have a good reason for not using our assay,” Little said. “There will be competition, but I think we’re in a very good position at the moment.”
While the European regulatory authority recommended Vectibix for bowel cancer patients with non-mutated KRAS based on retrospective data, the FDA is waiting for prospective data from Amgen, according to a report in BioCentury. DxS said it will likely take any KRAS test for the US market through the FDA.
Amgen has said it is integrating KRAS testing into the endpoints for ongoing studies in first- and second-line colorectal cancer.
For the time being, although DxS’ KRAS test appears to be the only CE-marked test of its kind sold in Europe, there are other research-use products that may soon compete with it.
Biotage’s “research use only” test PyroMark KRAS can be used to genotype codons 12 and 13 of the KRAS gene, as well as quantify alleles at individual positions in the same codons. On its website, Biotage highlights that its test includes negative controls, which allows for it to detect additional rare mutations.
“After the run, peak heights from all dispensations can be imported into an Excel worksheet for further analysis by an Excel macro,” the company states. “By this extra evaluation step, rare mutations in codons 12 and 13 can be detected that are not included in the pre-defined ‘Sequence to Analyze.’” Additionally, a second primer set in the test allows for the detection of rare mutations in codon 61.
In contrast, DiaSorin adapted its investigational FLAG technology for “simultaneously amplifying mutated codon 12 KRAS sequences, [for] monitoring in real-time the amplification, and [for] genotyping the exact nucleotide alteration,” researchers for the company said in an article published in the October issue of Nucleic Acids Research.
“FLAG enables high-throughput, closed-tube KRAS mutation detection down to ~0.1% mutant-to-wild type,” the study authors wrote. “The assay was validated on model systems and compared with allele-specific PCR sequencing for screening 27 cancer specimens. Diverse applications of FLAG for real-time PCR or genotyping applications in cancer, virology, or infectious diseases are envisioned.”
DxS’ product combines its ARMS (allele-specific PCR) technology with its Scorpions real-time PCR technology to detect seven mutations in the K-RAS gene, including Gly12Asp (GGT>GAT); Gly12Ala (GGT>GCT); Gly12Val (GGT>GTT); Gly12Ser (GGT>AGT); Gly12Arg (GGT>CGT); Gly12Cys (GGT>TGT); and Gly13Asp (GGC>GAC).
“After DNA extraction, real time PCR assays are performed to detect the target molecule. By comparing control and mutant sample reactions, users can detect and estimate low levels of mutation,” the company describes on its website. “No further sample processing is necessary and the time-to-result is [less than] three hours.”
According to the company, the KRAS test is compatible with most real-time PCR machines, and used DNA samples from fresh or frozen tumor tissue and PET samples.
“What we’ve tried to do … is create a product that does not need to be run in a particularly sophisticated molecular diagnostics lab,” Little said. “It’s one that can also go into a pathology lab. We’ve used real-time PCR to try to make the product as simple as we possibly can for the customer.”