Experts say patient selection for AstraZeneca, Daiichi breast cancer drug needs improvement

Enhertu, which won U.S. approval in late 2019, is used in patients with advanced breast, gastric, and lung cancers whose tumor cells carry a protein called HER2.

Early this year, researchers found that Enhertu could also benefit certain breast cancer patients whose HER2 levels were previously thought to be too low for the drug to have a meaningful effect.

In August, the U.S. Food and Drug Administration approved Enhertu for treating HER2-low breast cancers that were inoperable or had spread to the brain or elsewhere in the body.

About 50% to 60% of breast cancer patients likely fall into the low-HER2 category, according to the National Cancer Institute. These patients formerly had limited treatment options, but Enhertu's approval for metastatic breast cancer has been changing the way doctors treat them.

The tests which most pathologists now use to look for HER2 in patients' tumors, however, were designed to measure large amounts of the protein and are imprecise in patients with low HER2, several researchers noted in presentations on Wednesday at the San Antonio Breast Cancer Symposium.

Using these so-called immunohistochemistry tests to quantify low levels of HER2 "is like weighing mice on a scale built for elephants," Dr. David Rimm of Yale University said at the meeting.

Pathologists interpret the results subjectively, and "about 50% to 60% get it right," he said.

A report in JAMA Oncology in April showed only a 26% agreement rate among 18 pathologists asked to interpret immunohistochemistry tests for low HER2 versus no HER2.

Enhertu delivers a combination of the monoclonal antibody trastuzumab and the chemotherapy drug deruxtecan.

Roughly 10% of patients taking Enhertu develop life-threatening lung disease from it, making accurate patient selection particularly important, Rimm noted.

Colorado-based Theralink Technologies Inc has a commercially available quantitative HER2 assay that appears to provide a more accurate assessment.

Theralink reported at the meeting that when it used its quantitative assay to look for HER2 in 175 patients with negative immunohistochemistry tests, 30% to 40% had "modest to moderate" HER2 levels.

Rimm's lab at Yale also has developed a quantitative assay which it has not yet commercialized.

AstraZeneca oncology executive Dr. Sunil Verma said via email that for patients classified as HER2-negative on widely available tests, "research including novel technology is still evolving to determine and interpret the clinical significance of therapeutic benefit of Enhertu."

Given how subjective current tests are, oncologists will often ask pathologists to take a second look at a patient's negative HER2 test, hoping for a different answer, Rimm said in an interview.

"Doctors faced with radiating a patient's brain would much rather be able to give that patient a drug," he said. "If we really want precision medicine and not persuasive medicine, doctors need to demand that pathologists use quantitative analytic assays.