FDA Clears Guardant360 CDx as Companion Diagnostic for Imlunestrant in ESR1-Mutated Breast Cancer

The FDA has approved the Guardant360 CDx as a companion diagnostic that can be leveraged to identify patients with ESR1-mutated advanced breast cancer who are candidates to receive imlunestrant (Inluriyo), which was also recently approved on September 25, 2025.1,2

This decision signifies the second approved indication for the test by the regulatory agency in breast cancer, and the sixth indication total, according to a news release issued by Guardant Health, Inc.

Earlier this month, imlunestrant was cleared by the regulatory agency for use in adult patients with estrogen receptor (ER)–positive, HER2-negative advanced or metastatic breast cancer harboring ESR1 mutations whose disease progressed after 1 or more previous lines of endocrine therapy.2 The decision was supported by data from the phase 3 EMBER-3 trial (NCT04975308) in which single-agent imlunestrant (n = 138) led to a median progression-free survival (PFS) of 5.5 months (95% CI, 3.9-7.4) vs 3.8 months (95% CI, 3.7-5.5) with fulvestrant (Faslodex) or exemestane (Aromasin; n = 118), translating to a 38% reduction in the risk of disease progression or death (HR, 0.62; 95% CI, 0.46-0.82; P = .0008).3

“This FDA approval provides another treatment for breast cancer patients with ESR1 mutations for their specific type of cancer along with expanded access to comprehensive genomic profiling with a simple blood draw,” Helmy Eltoukhy, chairman and co–chief executive officer of Guardant Health, stated in the release.1 “Precision testing plays a critical role in helping physicians identify the correct treatment, providing patients and their doctors with the comprehensive genomic profiling needed to see if they are eligible to receive the right treatment and improving outcomes.”

What Are the Current Indications of the Guardant360 CDx?

The first FDA-approved comprehensive liquid biopsy, Guardant360 CDx requires 2 tubes of blood and yields actionable results in 5 days.4 The test is also broadly covered by commercial insurers and Medicare. The test has several indications in lung cancer, serving as a companion diagnostic for:

• Osimertinib (Tagrisso) with regard to EGFR exon 19 deletions, L858R, and T790M
• Amivantamab-vmjw (Rybrevant) with regard to EGFR exon 20 insertions
• Fam-trastuzumab deruxtecan-nxki (Enhertu) with regard to ERBB2/HER2 activating mutations
• Sotorasib (Lumakras) with regard to KRAS G12C mutations

Its other indication in breast cancer is for elacestrant (Orserdu) with regard to ESR1 missense mutations between codons 310 and 547.

Patients are eligible to receive imlunestrant if ESR1 E380, V422del, S463, L469, L536, Y537, and D538 mutations are detected by Guardant360 CDx.1

What Else Was Learned About Imlunestrant in the EMBER-3 Trial?

The randomized, open-label, active-controlled, multicenter phase 3 trial enrolled patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer who previously received an aromatase inhibitor (AI) by itself or paired with a CDK4/6 inhibitor.3 They were required to have experienced disease progression within 1 year of completion of neoadjuvant or adjuvant AI therapy without systemic treatment for recurrent disease or longer than 1 year following neoadjuvant or adjuvant endocrine treatment or de novo metastatic disease and had progressed on only 1 line of AI therapy. If they were eligible to receive a PARP inhibitor, they were excluded.

Participants were randomized 1:1:1 to receive imlunestrant at a once-daily dose of 400 mg; or investigator’s choice of endocrine therapy in the form of fulvestrant at 500 mg on days 1, 15, and 29 and once monthly thereafter or exemestane at 25 mg once daily; or another investigational combination regimen. They were stratified based on prior exposure to CDK4/6 inhibition (yes vs no), presence of visceral metastases (yes vs no), and region (East Aisa vs North America/Western Europe vs others).

The primary end point was PFS by investigator assessment and RECIST 1.1 criteria and other efficacy measures comprised overall survival, PFS by blinded independent review committee assessment, and objective response rate (ORR).

Additional efficacy data showed that imlunestrant (n = 138) elicited an ORR of 14.3% (95% CI, 7.8%-20.8%), which comprised a complete response (CR) rate of 0.9% and a partial response (PR) rate of 13.4%; fulvestrant or exemestane (n = 118) induced an ORR of 7.7% (95% CI, 2.2%-13.2%), which was comprised entirely of PRs.

The safety of imlunestrant was examined in 651 patients enrolled in the trial. The median duration of exposure to the drug was 5.6 months (range, 0.2-28.6). Serious toxicities were observed in 10% of patients. Adverse effects (AEs) led to dose reductions or interruptions for 2.4% and 10% of patients, respectively; they led to treatment discontinuation for 4.6% of patients.

Among those who received imlunestrant (n = 327), the most common AEs experienced by at least 10% of patients included musculoskeletal pain (all grade, 30%; grade 3/4, 3.7%), fatigue (23%; 0.3%), diarrhea (22%; 0.6%), nausea (17%; 0.3%), constipation (10%; 0%), and abdominal pain (10%; 0.3%). The most common laboratory abnormalities that worsened from baseline in those who received the agent on the trial included decreased hemoglobin (all grade, 30%; grade 3/4, 1.2%), decreased neutrophil count (26%; 4%), decreased calcium (26%; 0%), increased aspartate aminotransferase level (25%; 1.9%), increased alanine aminotransferase level (21%; 1.3%), increased triglycerides (21%; 0%), decreased platelet count (16%; 1.8%), and increased cholesterol (10%; 0%).

References

1. FDA approves Guardant360 CDx as companion diagnostic for Eli Lilly and Company’s Inluriyo (imlunestrant) for treatment of ESR1-mutated advanced breast cancer. News release. Guardant Health, Inc. September 29, 2025. Accessed September 29, 2025. https://investors.guardanthealth.com/press-releases/press-releases/2025/FDA-Approves-Guardant360-CDx-as-Companion-Diagnostic-for-Eli-Lilly-and-Companys-Inluriyo-imlunestrant-for-Treatment-of-ESR1-mutated-Advanced-Breast-Cancer/default.aspx
2. US FDA approves Inluriyo (imlunestrant) for adults with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer. News release. Eli Lilly and Company. September 25, 2025. Accessed September 29, 2025. https://investor.lilly.com/news-releases/news-release-details/us-fda-approves-inluriyo-imlunestrant-adults-er-her2-esr1
3. Inluriyo. Prescribing information. Lilly; September 2025. Accessed September 29, 2025. https://pi.lilly.com/us/inluriyo-uspi.pdf
4. FDA-approved Guardant 360 CDx. Guardant website. Accessed September 29, 2025. https://www.guardantcomplete.com/hcp/solutions/guardant360-cdx