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With New Indication for Vectibix, FDA Approves Qiagen's Therascreen KRAS Test as Companion Diagnostic

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Originally published May 27.

NEW YORK (GenomeWeb) – The US Food and Drug Administration last week approved Amgen's Vectibix as a frontline treatment for metastatic colorectal cancer (CRC) alongside Qiagen's Therascreen KRAS test as companion diagnostic that can determine which patients are most likely to benefit from the drug.

These simultaneous Rx/Dx approvals are the long-awaited result of regulatory actions that began five years ago, after researchers first presented data at a medical conference showing that CRC patients with KRAS gene mutations in codons 12 or 13 would not respond to EGFR-inhibiting monoclonal antibodies, such as Vectibix and Bristol-Myers Squibb/Lilly's Erbitux (cetuximab). This data came two years after the agency had already granted accelerated approval to Vectibix based on the results of a single study that showed the drug in combination with best supportive care improved progression-free survival in EGFR-expressing metastatic CRC compared to patients who had received just best supportive care. The agency granted accelerated approval to Erbitux in 2004 for metastatic CRC.

The emerging PGx data on Vectibix and Erbitux presented an early learning opportunity for drugmakers, diagnostics firms, and the FDA, navigating the regulatory framework for drug/diagnostic codevelopment. The agency held advisory committee meetings in 2008 to publicly discuss the regulatory requirements for updating the labels for Vectibix and Erbitux with PGx information. Based on the advice of the expert committee, the FDA updated the drugs' labels a year later based on retrospective data submitted by the sponsors and recommended against administration of these drugs in patients with KRAS mutations.

The latest FDA action on Vectibix converts its 2006 accelerated approval into a full approval. The drug is now indicated in combination with oxaliplatin-based chemotherapy as a first-line treatment for patients with metastatic CRC tumors characterized by the wild-type or normal version of the KRAS gene. The FDA approved the new indication based on data from two Phase III studies, called PRIME and ASPECT.

In PRIME, patients with wild-type KRAS tumors experienced significant improvement in progression-free survival when treated with Vectibix and oxaliplatin-based chemo versus just chemo – 9.6 months versus 8 months. Overall survival in the Vectibix-containing arm was 23.8 months compared to 19.4 months in the chemo only arm, imparting a survival advantage of 4.4 months. The Phase III ASPECT study reported that Vectibix as a single agent was non-inferior to Erbitux in improving overall survival in metastatic CRC patients who harbor wild-type KRAS tumors and have not responded to chemotherapy.

The Vectibix approval comes two years after FDA in 2012 approved a new indication for Erbitux as a first-line metastatic CRC drug with the chemotherapy regimen irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI), alongside Qiagen's Therascreen KRAS test. In order to garner the new indication for Erbitux, BMS/Lilly conducted retrospective analysis of the 1,200-patient CRYSTAL trial and showed that study participants treated with Erbitux plus FOLFIRI who had KRAS-mutated tumors experienced median survival of 23.5 months compared to 19.5 months for those who received just FOLFIRI. Patients with KRAS mutations did not derive a survival advantage with the addition of Erbitux to FOLFIRI.

Vectibix and Erbitux are competing therapies on the metastatic CRC market. Last year, Vectibix netted global sales of $389 million, compared to $359 million in 2012, an 8 percent increase. BMS' Erbitux (cetuximab) had $696 million in worldwide revenues in 2013, a 1 percent decrease from $702 million in 2012.

Qiagen, meanwhile, has been steadily expanding its companion diagnostics business and has launched a number of tests in the US and overseas markets. Its Rx/Dx collaborations with the sponsors of Vectibix and Erbitux to develop KRAS companion tests, however, were the company's first publicly announced forays into the CDx space after its 2009 acquisition of DxS.

The company pursued the modular pre-market approval pathway in both instances. And company officials have in the past described how closely they have had to work with the FDA to navigate "uncharted territory" in terms of the regulatory requirements and timelines the company needed to meet for its KRAS tests.

In a difficult reimbursement environment for molecular tests, Qiagen has also been on the front lines pushing for differential Medicare payment for companion tests with FDA approval. The company has been able to negotiate a reimbursement rate of $385 per test for its FDA-approved KRAS kit, compared to the median payment level of around $200 for all lab tests that gauge KRAS mutations.

While garnering FDA approval for Qiagen's KRAS test has been two years in the making -- the firm started the PMA process for the Vectibix CDx in July 2012 -- Amgen hasn't wasted time in bolstering companion testing capabilities for the drug on different test platforms. For example, last year, Amgen signed a deal with Transgenomic to develop an IVD test to indentify NRAS and KRAS mutated patients with advanced CRC using its RAScan kits. Although the specific details of this effort are not known, healthcare providers could use Transgenomic's test to identify additional patients who might benefit from Vectibix.

Researchers from Amgen and elsewhere recently published a study comparing Vectibix and Genentech's Avastin head-to-head, and showed that not just wild-type KRAS patients, but those who are wild-type for other genes in the RAS family, also benefit from Vectibix. The 280-patient study recently published in the Journal of Clinical Oncology showed that when patients with wild-type exon 2 KRAS tumors were randomized to receive Vectibix plus modified FOLFOX6 (fluorouracil, leucovorin, oxaliplatin) or Roche/Genentech's Avastin (bevacizumab) plus modified FOLFOX6, median overall survival was 34.2 months for Vectibix-treated patients and 24.3 months for Avastin-treated patients. Researchers subsequently conducted an expanded genetic analysis on banked patient samples to identify additional RAS mutations in KRAS and NRAS exons 2, 3, and 4 using tests from Qiagen and Roche or local laboratory assays, and performed mutational analysis with bidirectional Sanger sequencing and Transgenomic's Surveyor CRC RAScan Kit. In 170 RAS wild-type patients, median overall survival was 41.3 months versus 28.9 months in the Vectibix arm versus the Avastin arm, respectively, marking a significant gain in survival for this subset.

This study adds to a growing body of data showing that the one-drug/single-gene test Rx/Dx model is unsustainable. In the near future, drugmakers will need to advance companion tests that can identify a panel of markers associated with response to their drugs. Panel-based tests also offer drugmakers the chance to capture the largest patient population for their molecularly targeted personalized cancer treatments, which are already indicated for a small slice of a broader disease market. Thinking ahead, Amgen announced earlier this year that it would work with Illumina to advance a companion diagnostic for Vectibix on the MiSeqDx, the first commercial sequencing instrument with FDA clearance. The test will identify patients' RAS mutation status.

Amgen didn't respond to questions about its plans for these other diagnostics ahead of press time. With the FDA-approved KRAS kit for Vectibix under its belt, Amgen is among a handful of companies in the pharma industry that are starting to invest in developing both FDA-cleared companion tests as well as robust lab-developed tests that can also gauge the response markers associated with their personalized drugs. In the past, limited investment by pharma in the diagnostic portion of an Rx/Dx product has led to lackluster drug sales.

Now, it seems more and more drug developers are starting to understand the importance of establishing a robust diagnostic market for personalized therapeutic products. In the absence of FDA regulations on LDTs, FDA-approved kits and lab tests will continue to exist and compete for samples in the market place. And as a result, many hospital and academic labs may choose not to adopt an FDA-approved kit if they're already running an LDT to gauge the same analyte – as was the problem when Roche launched Zelboraf with a companion BRAF testing kit. In recent years, drugmakers such Novartis, Pfizer, and Amgen, have invested in research involving LDTs, to ensure that a variety of standardized, companion testing options are available and that the diagnostic component won't hinder broad uptake of their drug.

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