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Qiagen Enters Companion Dx Market with Approval of KRAS Test Kit for Erbitux; LDT Impact Unknown

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Originally published July 9.

A year after submitting a premarket approval application to the US Food and Drug Administration for its KRAS companion diagnostic for the colorectal cancer drug Erbitux, Qiagen has received the agency's blessing to market the test in the US.

Simultaneously with its approval of Qiagen's KRAS RGQ PCR Kit, the FDA also approved a new indication for Bristol-Myers Squibb/Eli Lilly's EGFR inhibitor Erbitux (cetuximab). The drug is now approved in combination with the chemotherapy regimen irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) as a first-line treatment in patients with metastatic colorectal cancer who have EGFR-expressing, KRAS wild-type tumors. The drug was previously available only as a treatment for patients with late-stage colorectal cancer who had stopped responding to chemotherapy.

Last week's approval of Qiagen's KRAS RGQ PCR Kit makes it the first FDA-approved companion diagnostic for Erbitux.

The KRAS test, as with all other companion diagnostics under development at Qiagen, will operate on the real-time PCR Rotor-Gene Q platform. Qiagen submitted its modular PMA for the test in August last year. The FDA approved the test along with the new Erbitux indication on July 6.

The FDA first approved Erbitux in 2004 as a treatment for late-stage colorectal cancer patients whose tumors expressed EGFR and who had stopped responding to chemo. In 2009, the agency updated the labels for Erbitux and another drug in the same class, Amgen's Vectibix, to note that "retrospective analyses of metastatic colorectal cancer trials have not shown a treatment benefit for the EGFR inhibitors in patients whose tumors had KRAS mutations in codon 12 or 13," and recommend against prescribing the treatment to advanced colorectal cancer patients with these mutations (PGx Reporter 7/22/2009).

The FDA noted in its approval announcement for the KRAS RGQ PCR Kit that Qiagen analyzed tumor samples from patients who had been enrolled in the clinical trial to support Erbitux's initial approval. In that study, median survival for Erbitux-treated patients without these mutations was 8.6 months compared to five months for those who had a mutation. Erbitux treatment did not significantly impact survival in patients with KRAS mutations, since patients with mutations receiving the drug had median survival of 4.8 months versus 4.6 months for those who were not treated with the drug.

Retrospective analysis of the 1,200-patient CRYSTAL trial, which led to the new indication for Erbitux, 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.

This data from CRYSTAL on the response of colorectal cancer patients with KRAS wild-type tumors to Erbitux was supported by retrospective analyses performed on patients' samples from the OPUS and CA225025 trials. Since the association between KRAS mutations and response to EGFR inhibitors has already been well established in multiple studies, conducting a prospective, randomized-controlled trial would be ethically problematic and difficult to recruit for researchers.

“The approval of this new Erbitux indication with the concurrent approval of a genetic test provides clear guidance on selecting patients who will optimally benefit,” Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, said in a statement announcing the approval of the test and the new drug indication. “Clinical trial data leading to the approval of this new indication supports the recommendation to treat those patients whose colorectal tumors do not have KRAS mutations and to avoid treating those with KRAS mutations.”

According to the American Cancer Society, there were 141,000 new cases of colorectal cancer in the US last year and nearly 50,000 people died from the illness. Studies have shown that approximately 60 percent of colorectal cancer patients harbor the wild-type form of the KRAS gene, and therefore may derive benefit from anti-EGFR treatment, while 40 percent have tumors with KRAS mutations and will likely not benefit.

In the absence of an FDA-approved KRAS test, physicians prescribing Erbitux have been using laboratory-developed tests to determine which colorectal cancer patients have the normal KRAS gene and therefore will derive benefit from the EGFR-inhibiting monoclonal antibody.

Qiagen said in a statement that the test's approval marked a "milestone" for the company's personalized medicine business. Testing with the KRAS RGQ PCR Kit will be offered by a number of laboratories throughout the US, including Applied Diagnostics; Boyce & Bynum Pathology Laboratories; Cellnetix Pathology & Laboratories; Clinical Molecular Oncology Laboratory at the University of Kansas Medical Center; Colorado Molecular Correlates Laboratory at the University of Colorado; Companion Dx Reference Lab; Dahl-Chase Diagnostic Services; Lab21; and the Mayo Clinic.

Although Qiagen now markets the only FDA-approved KRAS companion test kit to personalize treatment with Erbitux, the regulatory distinction won't necessarily stave off competition from LDTs. The agency has said it intends to bring LDTs under its oversight and is in the midst of crafting regulatory guidelines for such tests. However, the agency has previously noted that until such guidance is issued, FDA-approved kits will have to coexist in the marketplace with LDTs.

Recognizing this conundrum, Qiagen is wasting no time in highlighting advantages of its test over competing LDTs. According to Qiagen, its FDA-approved kit is faster than existing LDTs on the market and provides more consistent results. The Therascreen KRAS kit "has been shown to have higher sensitivity (i.e. a lower limit of detection) for KRAS mutations between 0.8 percent and 6.4 percent depending on the assay, which is critical to ensuring reliable and consistent data for treatment decisions," the company claimed in a statement.

Despite competition from LDTs, the company projected that the US market potential for the Therascreen KRAS kit will be approximately $20 million. Furthermore, Qiagen estimated that by assessing which colorectal cancer patients are genetically predisposed to respond to EGFR inhibitors, payors can save as much as $600 million each year by not giving drugs to patients who are unlikely to respond to them.

Analyst Vamil Divan from the investment banking firm Credit Suisse marked the approval for the Therascreen KRAS kit as Qiagen's formal entrance into the companion diagnostics market. "The KRAS test will likely be the first of many Qiagen tests that will obtain FDA approval in the coming years, although the long-term economic impact these tests will have on the company is still to be determined," Divan wrote in a note to investors.

Qiagen also filed a PMA for a KRAS companion test for Vectibix as a rolling submission that was completed last July. The company has projected that it will likely receive FDA approval for this test sometime this year. Qiagen also has companion diagnostic collaborations with a number of other large pharma players, including AstraZeneca, Boehringer Ingelheim, and Pfizer.

Divan estimated that Qiagen currently controls approximately 18 percent of the $20 million KRAS testing market. "While many question how well FDA-approved lab tests will be able to compete against numerous non-FDA-approved 'home brewed' LDTs, we believe that in oncology FDA-approved companion diagnostics should do well," Divan wrote in his note.

"Physicians will be making life-altering treatment decisions based on the results of the test, so we believe most will shift towards FDA-approved tests that have shown consistent results that they can rely on both so they are confident in the results and so they have some protection from a medical-legal perspective," Divan added.

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