Breast Cancer Drug Approval Shows How FDA Pairs a Companion Diagnostic With a Drug

The Food and Drug Administration approved Eli Lilly's imlunestrant (Inluriyo) in combination with abemaciclib (Verzenio) on Sept. 18 for adults with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer whose disease has progressed after at least one line of endocrine therapy, according to the agency's approval notice. The indication applies to tumors with ESR1 mutations "as detected by an FDA-authorized test."

In the same notice, FDA said it "also approved the Guardant360 CDx assay as a companion diagnostic device" to identify breast cancer patients with ESR1 mutations for treatment with the two drugs. The pairing of a drug and a device in one decision is how FDA handles therapies that work only in a defined group of patients.

What a companion diagnostic is

FDA's companion diagnostics page defines one as "a medical device, often an in vitro diagnostic (IVD), which provides information that is essential for the safe and effective use of a corresponding drug or biological product." The agency lists three jobs such a test can do: identify patients most likely to benefit from a therapy, identify patients at increased risk of serious side effects from it, or monitor response to treatment so it can be adjusted.

The test is regulated as a medical device, separately from the drug it accompanies. FDA's page states the stakes plainly: "If the diagnostic test is inaccurate, then the treatment decision based on that test may not be optimal."

The link runs both ways in the labeling. According to FDA's list of authorized companion diagnostics, the use of the test is stipulated in the diagnostic's instructions for use and in the labeling of the drug, "as well as in the labeling of any generic equivalents and biosimilar equivalents." The list pairs each test with its drug, biomarker and the device's PMA or 510(k) number. Some tests carry group labeling, covering a class of oncology drugs rather than one product, under a 2020 FDA guidance.

How the test shaped this approval

FDA's notice shows how the diagnostic was built into the evidence. In the Phase 3 EMBER-3 trial, which enrolled 874 adults previously treated with an aromatase inhibitor, ESR1 status "was determined by blood circulating tumor deoxyribonucleic acid (ctDNA) analysis using the Guardant360 CDx assay," limited to specific mutations in the gene's ligand-binding domain.

The agency said the combination's improvement in progression-free survival over imlunestrant alone was statistically significant in the overall population, but that imlunestrant alone did not improve progression-free survival over investigator's choice of endocrine therapy in either the overall or the ESR1-mutation-not-detected groups, "indicating that the benefit was only observed in the ESR1m population." In an exploratory analysis of 159 patients with ESR1-mutated tumors, median progression-free survival was 11.1 months with the combination and 5.5 months with imlunestrant alone, FDA said. Overall survival data were immature at the interim analysis.

That finding is what makes the test necessary: the label limits the drug to the patients the test identifies.

Planning a test and a drug together

FDA has issued guidance aimed at getting companies to plan the two products in tandem. Its 2014 final guidance on in vitro companion diagnostics was meant to help companies identify the need for a companion test earlier in drug development and plan co-development, according to the agency's page, and a 2016 draft guidance laid out principles for that co-development. In 2023 FDA announced a voluntary pilot for certain oncology drugs used with laboratory tests, intended to give more transparency about the performance characteristics that tests for oncology biomarkers should meet.