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An FDA panel on Thursday endorsed a blood-based test for colorectal cancer (CRC) screening in adults 45 years and older at average risk for the disease, putting aside concerns over the test's low sensitivity for precancerous lesions.

In a series of three votes on Guardant Health's Shield test, the voted 8-1 in support of the test's safety, 6-3 in support of its effectiveness, and 7-2 in support of the test's benefit-risk profile.

Despite the positive votes, the panel as a whole still had concerns about Shield's ability to detect early-stage CRC and advanced adenomas, and many advocated for strong labeling emphasizing this issue.

"It's a good colon cancer screening test, but for later-stage colon cancer," said Karla Ballman, PhD, of the Mayo Clinic College of Medicine and Science in Rochester, Minnesota, who cast her votes in support of the test. "It's not as good in stage I, and definitely not good for advanced adenoma."

"In the labeling it should clearly indicate that this is not to detect adenomas and is not designed as a preventative strategy," said Sean Spencer, MD, PhD, of the Stanford School of Medicine in California.

Shield was evaluated in the pivotal ECLIPSE trial -- a multisite, prospective, non-randomized, observational study designed to evaluate the clinical performance of the test in patients 45 to 84 years of age who were of average risk for CRC.

Results from the study showed that the cell-free DNA blood-based test had a sensitivity of 83.1% for CRC and a specificity of 89.6% for advanced neoplasia. ECLIPSE investigators also found that sensitivity increased with stage -- 55% for stage I CRC and 100% for stage II-IV CRC. However, Shield's sensitivity for detecting advanced adenomas was only 13.2%.

Charity Morgan, PhD, of the University of Alabama at Birmingham, reasoned that the proposed indication for Shield is for the detection of CRC only.

"If the indication had said something about advanced adenomas I would have changed my vote," said Morgan, who voted in support on all three questions. "I was on the fence about the effectiveness because of the limited sensitivity for stage I [CRC]. I think that if the labeling is very clear that this test is strongest for detecting stages II, III, and IV, that would turn my vote from a weak yes to a strong yes."

During an earlier discussion, Stephen Hewitt, MD, PhD, of the National Cancer Institute in Bethesda, Maryland, suggested that the test "undermines the concept of cancer prevention."

"It has nice performance as a cancer detection assay, particularly in stage II, stage III, stage IV," he said. "And yes, there is a blind spot in colonoscopy, especially at stage I or stage II diagnosis, but [Shield] is not necessarily beating colonoscopy at stage I, and the failure to be able to remove lesions that have a propensity to move forward is concerning."

Hewitt voted against Shield on all three questions and said he specifically voted against the safety question "because it puts patients at risk of the development of cancer" based on the available data.

An Unmet Need

The Shield test is an in vitro diagnostic blood test intended to detect CRC-derived alterations in cell-free DNA. In addition to its intended use for average risk adults ages 45 years and older, Guardant's proposed indications for use also say the test "is not a replacement for diagnostic colonoscopy or surveillance colonoscopy in high-risk individuals" and that if patients have an "abnormal signal detected" they may have CRC or advanced adenoma and should be referred to colonoscopy.

Speaking for Guardant, Peter Liang, MD, MPH, of NYU Grossman School of Medicine in New York City, noted that most recent data suggest only about 58% of U.S. adults between the ages of 45 and 75 are up to date with screening, below the National Colorectal Cancer Roundtable screening target of 80%, and the test therefore addresses an unmet need.

"Patients and providers need additional CRC screening options that are convenient, noninvasive, and accurate," Liang said.

"Our goal is to increase colon cancer screening," said committee member Mark Gilger, MD, of the University of the Incarnate Word in San Antonio, during an earlier discussion on Shield's risks and benefits. "You offer the patient a test. The test preference is colonoscopy because not only can you see it, you can remove it if you see something there. That makes great sense. The problem is -- not everyone wants a colonoscopy."

"That's an issue," he added. "I think the blood test simply offers you an alternative, and if that's positive, I think the patient is going to be very inspired to have a colonoscopy. That makes sense to me."

During an open public hearing session a number of physicians, representatives of CRC advocacy organizations, and patients enthusiastically supported the idea of a blood-based test as a way to increase CRC screening and detection.

Candace Henley of the Blue Hat Foundation, a CRC organization serving minority and medically underserved communities, noted that African Americans, in particular, face significantly lower screening rates than the general population.

"Blood-based screening is not just an alternative, it is an imperative step towards equity in healthcare," she said.

Picking up on the topic of access to colonoscopy, panelist Vikesh Singh, MD, MSc, of Johns Hopkins University in Baltimore, wondered how many patients with a positive result on non-invasive tests end up getting a follow-on colonoscopy.

If patients lack access to colonoscopy, "then the test is just a test, right?" he asked. "There's no confirmation -- there's nothing actually done to reduce the incidence of colorectal cancer ... or treat it at a stage in which it can be treated more effectively."

Victoria Raymond, senior director of medical affairs at Guardant Health, told Singh he raised a "critical point about the benefits and limitations of these non-invasive screening tests, and it is exactly true that when a patient decides to pursue one of these colonoscopy alternatives it is critical that they understand that an abnormal signal by any of these tests requires a diagnostic follow-on colonoscopy."

"It is one of the reasons it will be part of our education materials, and is also part of our indication for use," she added.

While the FDA is not required to follow the recommendations of its advisory committees, it typically does.

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