Enhertu Approved for HER2-Low BC

The approval by the European Commission follows the positive opinion of the Committee for Medicinal Products for Human Use (CHMP)  of the EMA and is based on results from the DESTINY-Breast06 phase III trial presented at the 2024 American Society of Clinical Oncology (#ASCO24) Annual Meeting and published in The New England Journal of Medicine.(see citation)

In the DESTINY-Breast06 trial, Enhertu  demonstrated a 38% reduction in the risk of disease progression or death versus chemotherapy in patients with chemotherapy-naïve HR positive, HER2 low metastatic breast cancer (n=713; hazard ratio [HR] 0.62; 95% confidence interval [CI]: 0.52-0.75; p<0.0001) as assessed by blinded independent review (BICR). Median progression-free survival (PFS) was 13.2 months (95% CI: 11.4-15.2) in the Enhertu  arm compared to 8.1 months (95% CI: 7.0-9.0) in the chemotherapy arm.

An exploratory analysis of the HER2 ultralow population (n=152; HR 0.78; 95% CI: 0.50-1.21) showed the clinically meaningful improvement in PFS was consistent between patients with HER2 low and HER2 ultralow expression, with 13.2 months (95% CI: 9.8-17.3) in patients treated with Enhertu  compared to 8.3 months (95% CI: 5.8-15.2) in those treated with chemotherapy. Confirmed ORR was 61.8% (95% CI: 50.0-72.8) in the Enhertu arm versus 26.3% (95% CI: 16.9-37.7) in the chemotherapy arm. Median DOR was 14.3 months (95% CI: 9.2-20.7) in the Enhertu arm versus 14.1 months (95% CI: 5.9, not estimable) in the chemotherapy arm

The confirmed objective response rate (ORR) in the HER2 low population was 56.5% (95% CI: 51.2-61.7) in the  Enhertu arm versus 32.2% (95% CI: 27.4-37.3) in the chemotherapy arm. Median duration of response (DOR) was 14.1 months (95% CI: 11.8-15.9) in the Enhertu  arm versus 8.6 months (95% CI: 6.7-11.3) in the chemotherapy arm.

In the overall trial population of patients with chemotherapy-naïve HR positive, HER2 low or HER2 ultralow metastatic breast cancer (n=866), Enhertu achieved a similar 36% reduction in the risk of disease progression or death versus chemotherapy (HR 0.64; 95% CI: 0.54-0.76; p<0.0001). A median PFS of 13.2 months (95% CI: 12.0-15.2) was seen in patients treated with Enhertu compared to 8.1 months (95% CI: 7.0-9.0) in patients treated with chemotherapy. Confirmed ORR in the overall trial population was 57.3% (95% CI: 52.5-62.0) in the Enhertu  arm versus 31.2% (95% CI: 26.8-35.8) in the chemotherapy arm. Median DOR was 14.3 months (95% CI: 12.5-15.9) in the Enhertu  arm versus 8.6 months (95% CI: 6.9-11.5) in the chemotherapy arm. 

In DESTINY-Breast06, the safety profile of  Enhertu  was consistent with previous clinical trials with no new safety concerns identified. Grade 3 or grade 4 treatment-related adverse events from a pooled safety analysis of patients treated with  Enhertu  (5.4 mg/kg) across multiple tumor types in clinical studies included neutropenia (18.0%), anemia (10.5%), fatigue (7.8%), leukopenia (6.0%), thrombocytopenia (5.4%), nausea (4.9%), lymphopenia (3.9%), hypokalemia (3.8%), transaminases increased (3.5%), diarrhea (2.5%), vomiting (2.4%), decreased appetite (1.8%), pneumonia (1.3%), and ejection fraction decreased (1.0%). Grade 5 adverse reactions occurred in 1.4% of patients, including interstitial lung disease (1.1%)

DESTINY-Breast06 (NCT04494425) is a global, randomized, open-label, phase III trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) versus investigator’s choice of chemotherapy (capecitabine, paclitaxel or nab paclitaxel) in patients with HR positive, HER2 low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (defined as IHC 0 with membrane staining) advanced or metastatic breast cancer.  DESTINY-Breast06 enrolled 866 patients (n=713 for HER2 low and n=153 for HER2 ultralow) in Asia, Europe, North America, Oceania and South America.

Patients in the trial had no prior chemotherapy for advanced or metastatic disease and received at least two lines of prior endocrine therapy in the metastatic setting. Patients also were eligible if they had received one prior line of endocrine therapy combined with a CDK4/6 inhibitor in the metastatic setting and experienced disease progression within six months of starting first-line treatment or received endocrine therapy as an adjuvant treatment and experienced disease recurrence within 24 months.

HER2 IHC status was confirmed by a central lab and determined based on the most recent evaluable HER2 IHC sample prior to randomization. In tumor samples from patients screened for trial eligibility, nearly two-thirds of tumors previously assessed as IHC 0 at a local lab were re-classified as HER2low or HER2 ultralow upon central analysis of the archival tumor sample. It was also observed that approximately 85% to 90% patients with HR positive, HER2 negative metastatic breast cancer may have actionable levels of HER2 expression.

The primary endpoint of DESTINY-Breast06 is PFS in the HR positive, HER2 low patient population as measured by BICR. Key secondary endpoints include PFS by BICR in the overall trial population (HER2 low and HER2 ultralow), OS in patients in the HER2 low patient population and OS in the overall trial population. Other secondary endpoints include ORR, DOR, time to first subsequent treatment or death, time to second subsequent treatment or death and safety. Analysis of the HER2 ultralow subgroup was not powered to demonstrate statistical significance

 “ENHERTU continue s to evolve what is possible with breast cancer treatment, becoming the first HER2 directed medicine approved in the EU for patients with HR positive metastatic breast cancer with HER2 low or HER2 ultralow expression following endocrine therapy,” said Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, Inc. “The approval expands the use of ENHERTU to now include an earlier treatment setting of HER2 low metastatic breast cancer and broadens the patient population eligible for treatment to those with HER2 ultralow disease.”

"ENHERTU continues to open up new approaches to the  diagnosis and treatment of patients with metastatic breast cancer,” said Dave Fredrickson, Executive Vice President, Oncology Hematology Business Unit, AstraZeneca. “This approval underscores the importance of testing metastatic breast cancer tumors for any IHC staining to identify patients with HR positive, HER2 low or HER2 ultralow disease who may be eligible for ENHERTU once sustained responses are no longer achieved with endocrine-based therapy".

"This approval introduces a new treatment option for HR positive metastatic breast cancers that express HER2,” said Dr.Giuseppe Curigliano, Professor of Medical Oncology at the University of Milan and the Head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy and Principal Investigator of DESTINY-Breast06. “In DESTINY-Breast06, ENHERTU outperformed chemotherapy, providing progression-free survival of more than one year for patients with HR positive, HER2 low or HER2 ultralow metastatic breast cancer, demonstrating the benefit of treating these patients with ENHERTU instead of chemotherapy.”

See citation- Bardia A, Hu X, Dent R, Yonemori K, et al. Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer. N Engl J Med 2024;391:2110 DOI: 10.1056/NEJMoa24070