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Amgen Becomes Early MiSeqDx Adopter for Vectibix CDx; Illumina Plans for Shared 'Onco Panels'

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Originally published Jan. 17.

Less than five years ago, Amgen was facing criticism from researchers and industry experts for waiting too long to pursue a biomarker strategy to limit the indication for its colorectal cancer drug Vectibix, since in their view, the scientific literature had clearly shown that patients with KRAS mutations wouldn't respond to the drug.

However, this week, Amgen became an early adopter of advanced genomic technologies. While most pharmaceutical companies are still using complex, next-generation sequencing tests largely in the discovery setting, Amgen is among the first in the industry to publicize that it will use the technology to develop a companion test for Vectibix (panitumumab).

Specifically, Amgen will work with Illumina to advance a companion diagnostic for Vectibix on the MiSeqDx, the first commercial sequencing instrument with the US Food and Drug Administration's blessing. The test will identify patients' RAS mutation status. The latest research by Amgen suggests that not just KRAS mutations, but other mutations in the RAS family of genes limit colorectal cancer patients' ability to respond to Vectibix.

“Multigene NGS panels provide a more complete genetic picture of each patient’s tumor, which can better inform critical treatment decisions,” Illumina's chief medical officer Rick Klausner said in a statement announcing the deal. “We see the development of multigene diagnostic tests as a natural evolution to improve cancer care and outcomes.”

Other drug developers, such as Clovis Oncology, BioMarin, and PharmaMar, have said they are exploring using NGS-based tests to identify best responders to investigational drugs, but none of them is FDA-cleared or approved. One of the major barriers holding drug developers back from using NGS technologies for companion diagnostic testing has been the uncertainty around regulation and reimbursement. Moreover, an FDA-cleared or approved kit, using less complex technologies such as florescent in situ hybridization or immunohistochemistry, is cheaper for laboratories to adopt than putting in a new NGS system.

Despite these challenges, the importance of genomic data in drug development is an unavoidable and increasingly complex reality for pharmaceutical firms, particularly in the oncology market. During an Illumina investor's meeting held this week to announce new product launches and research efforts in 2014, Klausner estimated an $11 billion market opportunity for Illumina in the cancer treatment space, particularly in the development of companion tests for therapeutics. Noting that the personalized medicine field is moving away from the era of companion diagnostics to companion therapeutics, Klausner said that “only NGS is poised to handle the range and extent and complexity … of not only the development of molecularly targeted drugs, but ultimately [their] use.”

In order to lift some of the barriers currently stopping drugmakers from using NGS to personalize their drugs, Illumina is talking with the FDA about developing a universal, single platform that will gauge all molecular alterations that pharma partners are investigating for drugs in their late-stage pipelines. As Klausner described it, the drug companies will have to “subscribe” or partner with Illumina to include their genomic markers of interest in these so-called Onco Panels, which Illumina will take through 510(k) clearance. Once cleared, these pharma subscribers can use the NGS instrument to investigate best responders to their drugs and, eventually, file for pre-market approval for a companion test through what Illumina hopes will be a more efficient pathway.

This program “allows the setting of standards for how to measure those molecular changes on a single, reproducible platform,” Klausner said. “And … it offers a streamlined and regulatory pathway.” He added that because the platform will be shared by multiple drug companies, and the content won't be “owned” by any one entity, it will facilitate investigations of personalized cancer drug combinations that target complex genomic tumor profiles.

Illumina's deal with Amgen to develop an NGS-based companion test can be seen as a precursor to future Onco Panels. The partners together will validate the test. Illumina will be responsible for garnering approval for and commercializing the test in the US and in Europe.

The companies did not disclose the financial terms of the deal. Representatives from Illumina and Amgen declined to comment on their companion diagnostic partnership for this article beyond the information in a press release announcing the deal.

Ahead of the curve

Amgen, like the rest of the pharmaceutical industry, has been on a learning curve when it comes to developing molecularly targeted personalized drugs. The company had a rocky start.

At the American Society of Clinical Oncology's annual meeting in 2008, researchers reported results from a large, multinational prospective trial showing that patients with metastatic colorectal cancer whose tumors carry the wild-type version of the KRAS gene were much more likely than patients with the mutated form of the gene to benefit from Erbitux (cetuximab), a drug in the same class as Vectibix. The results from the study led Eric Van Cutsem of the University Hospital Gasthuisberg in Leuven, Belgium, to recommend that “KRAS testing be routinely conducted in all colorectal cancer patients immediately after diagnosis to ensure the best treatment strategies for the individual patient.”

Then, in 2009, at a conference hosted by the Partners Healthcare Center for Personalized Genetic Medicine at Harvard University, leading researchers and healthcare industry stakeholders questioned whether Amgen knew – well in advance of the study reported by Cutsem et al. and even before it received a negative regulatory decision on its Vectibix marketing application from the European regulators in May 2007 – that patients with mutated KRAS genes would not respond to the drug, but pursued an indication in the broader colorectal cancer population anyway. Some industry experts at the conference accused Amgen of unethical behavior, pointing out that the company was able to resubmit its marketing application to the European Medicines Agency with KRAS-related drug response data within a month of receiving a negative opinion from health regulators.

Amgen has denied these accusations and company officials have explained that while there may have been early signs that a subpopulation of patients was not responding to Vectibix, there wasn't robust clinical evidence definitively showing KRAS mutations as the culprits hindering response.

In 2009, the FDA updated the label for Vectibix and Erbitux to inform doctors and patients that those with certain KRAS mutations would not respond to these drugs. However, five years after the class labeling change, the agency has approved Qiagen's Therascreen KRAS RGQ PCR Kit to identify best responders to Erbitux, but there is still no FDA-approved companion test for Vectibix. Industry observers have previously said that by not moving quickly to characterize the pharmacogenetics of Vectibix, Amgen missed an opportunity to differentiate its drug from Erbitux, currently the market leader in colorectal cancer.

While Amgen and Qiagen continue to work together to develop a similar diagnostic for Vectibix, the drug developer has simultaneously taken a lead in advancing knowledge around the genomic underpinnings of colorectal cancer and Vectibix response. In May last year, Amgen developed a CE-IVD test in collaboration with Transgenomic, called CRC RAScan, to screen patients with metastatic colorectal cancer for KRAS and NRAS mutations. The test, which uses Transgenomic's Surveyor-Wave technology, is marketed for commercial use in Europe and available for research use in the US.

Using this test, researchers from Amgen and elsewhere conducted a prospective-retrospective pharmacogenetic analysis of metastatic colorectal cancer patients enrolled in the PRIME trial, in which they were randomized to receive either Vectibix and FOLFOX4 or just FOLFOX4. The study, published in September in the New England Journal of Medicine, showed that among approximately 500 patients without RAS mutations (KRAS or NRAS), overall survival was 26 months on Vectibix/FOLFOX4 versus 20.2 months on FOLFOX4.

Approximately 17 percent of the patients with wild-type KRAS had other RAS mutations. “These mutations were associated with inferior progression-free survival and overall survival with panitumumab–FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2,” reported researchers led by Jean-Yves Douillard of Institut de Cancérologie de l'Ouest in France. The study also found that BRAF mutations were a negative prognostic factor.

The deal between Amgen and Illumina to advance an NGS-based companion test that gauges RAS mutations evolved from the findings of this study. Based on Illumina's description of the companion diagnostic it is developing for Vectibix, the test will likely gauge mutations in the RAS family of genes (i.e. NRAS, KRAS, and HRAS), but wouldn't pick up mutations in genes in the RAS-RAF pathway, such as BRAF, which other studies have suggested may negatively impact patients' response to Vectibix and Erbitux.

“This initial product … is a reflection of the recent NEJM paper [by Douillard et al.] that substantiated the clinical value of broadening the search beyond KRAS codons 12/13,” Howard McLeod, medical director of Moffitt Cancer Center's DeBartolo Family Personalized Medicine Institute, told PGx Reporter in an email. “BRAF status was part of the Douillard paper, but did not convincingly add any clinical value to the prediction of response to panitumumab (beyond that with FOLFOX chemotherapy alone)."

NGS advantages for pharma

Based on the complex pharmacogenetic characteristics of EGFR-inhibiting monoclonal antibodies, it perhaps only makes sense that Amgen would invest in NGS technology that would allow testing for multiple mutations in a panel of genes. McLeod characterized Amgen's decision to develop a companion test using MiSeqDx as a “natural evolution” based on “robust” clinical data and noted that, given the nature of the field, this test probably won't be the final version.

However, as genomic advances reveal the complexity of tumors and the biological mechanisms driving them, McLeod suggested that drug developers need regulatory mechanisms that allow them to update drug labels quickly based on new findings and advanced diagnostic technologies such as NGS.

While Amgen's regulatory pathway for the Vectibix companion test is somewhat less uncertain using an FDA-cleared NGS instrument, the drug developer will be pursuing a new intended use for the platform, and as such will likely need to submit for premarket approval. “It certainly does help that the platform has gained clearance but it does not preclude the sponsor from having to seek FDA's premarket approval for the specific companion diagnostic indication,” Lakshman Ramamurthy, director of FDA Regulatory & Policy at Avalere Health, a healthcare strategic advisory firm, said in an email.

“An FDA-cleared platform does mean that the agency is familiar with the overall analytical performance of the platform so the sponsor can focus more on the clinical validation of the specific markers for which the approval is sought,” explained Ramamurthy, former senior reviewer and policy advisor at FDA's diagnostics division. “It does not, however, entirely exempt one from having to submit analytical studies. One would still have to demonstrate analytical precision of the sample type and the relevant pre-extraction details, and prevalence of [a] mutation (or absence of one) will vary for each marker or tumor type.

In a recent interview with PGx Reporter Alberto Gutierrez, director of FDA's Office of In Vitro Diagnostics and Radiological Health, and Elizabeth Mansfield, director of personalized medicine at the agency, noted that the MiSeqDx platform has Class II status exempting test developers using the same platform for the same intended use from having to submit premarket notification. However, Gutierrez said that test developers that want to develop and market the platform for new intended uses would need to submit applications for regulatory approval or clearance.

In this regard, Illumina's universal Onco Panels may ease the way for drug developers to use NGS in a commercial setting to identify best responders to their drugs. In talks with Illumina, “the FDA has agreed that … we will expand the FDA's allowance of the ... performance standards across the panel so that you go into your companion diagnostic on a platform that has 510(k) [clearance],” Klausner said during the Investor Day meeting. “Then we'll work with the company and the FDA so that whenever a company has a claim to be attached … there will be a rapid and simple process to go from a 510(k) to a PMA.”

According to Klausner, Illumina has been discussing the development of these “shared and open” Onco Panels with all major drug companies. “It's a la the Amgen announcement, but expanded over a larger panel of genes,” he told investors. “We're very optimistic that this is going to have a lot of traction over this year.”

Uncertainty around reimbursement of NGS-based tests is another reason most drug developers haven't jumped at using the technology to advance companion tests for their drugs. To date, insurers have paid for NGS-based testing on a case-by-case basis.

And once an NGS-based companion test is marketed, it may be difficult to convince some healthcare providers and labs to adopt the FDA-approved version of the test in place of the platform they're already using. This was a major challenge for Roche when it launched the personalized melanoma drug Zelboraf with a PCR-based companion test for gauging BRAF mutations in patients.

This may not be such a big issue for NGS technologies, particularly if the price is right for gauging hundreds of markers at once in order to fully characterize a patient's disease and treatment response. “NGS systems do offer large providers and hospitals the opportunity to invest in a single platform and run various FDA-approved biomarkers on it. It will be almost like choosing an operating system,” Ramamurthy said. “Additionally, for large reference labs or hospital labs having an FDA-cleared NGS platform will allow them the freedom to create laboratory-developed tests for specific conditions.”

However, he noted that “for all of these technologies the payment scenarios are yet to be fully ironed out.”

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