FDA Advisors Recommend Galleri Multicancer Blood Test

With some trepidation, a majority of an FDA advisory committee Thursday endorsed the Galleri multicancer early detection blood test.

By 6-4 and 7-2 (with one abstention) margins, the molecular and clinical genetics panel of the Medical Services Advisory Committee voted that the test was effective and that its benefits outweigh the risks. However, many panel members who voted yes had reservations about their votes.

The panel was more decisive on the question of safety, voting unanimously (10-0) in favor of Galleri.

While most panel members agreed that as a diagnostic test Galleri was safe, effective, and demonstrated a positive benefit/risk profile, particularly for cancers for which screening tests are unavailable, they were concerned about the lack of outcome data supporting the test’s premarket approval (PMA) application, as well as the use of the term “early” in describing the purpose of the test.

“I really struggled with this one … I did change my vote twice,” said Jason Dominitz, MD, MHS, of the VA Puget Sound Health Care System in Seattle, explaining his yes vote on Galleri’s effectiveness. “Clearly, there are clinically impactful results of the test. People get a diagnosis work-up, cancers are found, but does that lead to clinically clinical benefit? I don’t see that we have evidence of clinical benefit at this time.”

“The question comes down to what do you call clinical effectiveness,” said Stanley Lipkowitz, MD, PhD, of the National Cancer Institute, who voted no. “As an oncologist, I generally look at that as outcome, and we don’t have that data.”

Because Galleri is a “transformative test,” the bar should be high for approval, Lipkowitz added.

Galleri — a qualitative, next-generation sequencing-based in vitro diagnostic test intended to detect cancer-specific methylation patterns in cell-free DNA isolated from peripheral whole blood — has been evaluated in the PATHFINDER 2 and the NHS — Galleri studies.

Data from NHS-Galleri presented at the American Society of Clinical Oncology annual meeting in May showed the study failed to meet its primary outcome of reducing the number of cancers detected at stage III or IV across a dozen tumor types for which no screening tests are currently available, although it detected more stage I and II cancers.

However, the PMA application for Galleri focused on the test performance safety results from participants with 1 year of follow-up in PATHFINDER 2, as well as data from participants in the intervention arm of the prevalent screening round (first year) of the NHS-Galleri trial.

Results from PATHFINDER 2 showed Galleri had a 12-month episode sensitivity of 35.0%, specificity of 99.85%, positive predictive value (PPV) of 77.0%, negative predictive value (NPV) of 99.07%, and cancer signal origin (CSO) prediction accuracy of 94.3%.

In NHS-Galleri, the test demonstrated a 12-month episode sensitivity of 31.6%, specificity of 99.74%, PPV of 66.2%, NPV of 98.89%, and CSO predictive accuracy 0f 91.9%.

Those high PPVs translated into a low false-positive rate that helped sway some of the panel members.

Data from the two trials also showed Galleri was most effective in detecting cancers — such as thyroid or ovarian cancer — for which there are no current screening tests.

“What really sort of drove my vote [for effectiveness] was the ability to screen for cancers that previously are not screenable,” said Danil Makarov, MD, MHS, of the NYU School of Medicine in New York City. “Detecting any of those early seems to be … a huge win and a huge benefit.”

Early detection?

While Galleri is described as a multicancer early detection test, panel members indicated they were uncomfortable with the “early” part of the term,

“Is it an early detection test?” asked Victor van Berkel, MD, PhD, of UofL Physicians in Louisville, Kentucky, who voted no on the question of effectiveness, but yes on the benefit/risk question. “It can detect things early … earlier than maybe we would find in some circumstances. But is that clinically relevant? I would say no, but I think the truest answer is I don’t know that we know the answer to that.”

“I don’t think the information we have can tell us that,” said Deborah Armstrong, MD, of Johns Hopkins Kimmel Cancer Center in Baltimore, who chaired the meeting.

She said that while had “some hesitancy,” the idea of eliminating the word “early” enabled her yes vote on each question.

On the safety question, panel members were reassured by the test’s low false positive rate, and the expectation that appropriate guidance will enable patients and physicians to understand the test’s risk and benefits and that it is designed to be used as an addition to guideline-directed cancer screening, and not as a replacement.

During the open public hearing session of the meeting, most speakers — including patients, physicians, investigators in the PATHFINDER 2 trial, and heads of health-related organizations — spoke in support of Galleri.

“We have too many folks dying from cancer,” said William Dahut, MD, chief scientific officer of the American Cancer Society. “If we are going to make an impact on those, we need to find a way to detect cancer earlier by finding better screening strategies.”

“No screening test is perfect,” Dahut said, adding that if a test is safe, “allowing a patient and physician decide whether a screening test is right for them, seems appropriate.”

However, there was some opposition. Philip Castle, PhD, MPH, director of the Division of Cancer Prevention at the National Cancer Institute, argued that the FDA should grant approval based on proven clinical benefit, not just on claims about cancer detection.

“If the FDA decides to recommend approval, despite the lack of evidence, I strongly urge it recommend product labeling that clearly articulates the lack of clinical benefit as well as potential harm, so the public can make a more informed decision about these these this test,” Castle said. “The word ‘early’ should be stricken from the use of these tests until such time as there’s rigorous evidence of clinically relevant early detection.”

While not bound by its advisors’ recommendations, the FDA usually follows their advice.