CHMP Recommends Enhertu

Daiichi Sankyo  and AstraZeneca’s   Enhertu (trastuzumab deruxtecan) has been recommended for approval in the European Union (EU) as a monotherapy for the treatment of adult patients with unresectable or metastatic hormone receptor (HR) positive, HER2 low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (IHC 0 with membrane staining) breast cancer who have received at least one endocrine therapy in the metastatic setting and who are not considered suitable for endocrine therapy as the next line of treatment.  The Committee for Medicinal Products for Human Use (CHMP) of the EMA based its positive opinion 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 (vide infra, see above).. The recommendation will now be reviewed by the European Commission, which has the authority to grant marketing authorizations for medicines in the EU 

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. There were 13 CRs and 237 PRs seen in the Enhertu arm, compared to zero CRs and 134 PRs in the chemotherapy arm. Median DOR was 14.3 months in the Enhertu arm versus 8.6 months in the chemotherapy arm.

In DESTINY-Breast06, the safety profile of Enhertu awas consistent with previous breast cancer clinical trials with no new safety concerns identified. The most common grade 3 or higher treatment related treatment emergent adverse events (TEAEs) occurring in 5% or more of patients treated with Enhertu were neutropenia (20.7%), leukopenia (6.9%) and anemia (5.8%). Interstitial lung disease (ILD) or pneumonitis occurred in 11.3% of patients treated with Enhertu. The majority of ILD or pneumonitis events were low grade (grade 1 [n=7; 1.6%] or grade 2 [n=36; 8.3%]). There were three grade 3 ILD events (0.7%), zero grade 4 events and three grade 5 events (0.7%) as determined by an independent adjudication committee.

" Enhertu  is the first HER2 directed treatment and antibody drug conjugate to show a progression free survival of more than one year in patients with HER2 low or HER2 ultralow metastatic breast cancer following endocrine therapy,” said Ken Takeshita, Global Head, R&D, Daiichi Sankyo. “The CHMP recommendation is encouraging and supports our goal of further developing and advancing the way breast cancer is classified and treated.”

"Endocrine therapy is typically used in the initial treatment of HR positive metastatic breast cancer but as the disease progresses the benefit of continued endocrine therapy is limited and subsequent standard of care chemotherapy is associated with poor outcomes,” said Dr.  Susan Galbraith, Executive Vice President, Oncology Hematology R&D, AstraZeneca. “Enhertu  has the potential to be the first HER2 directed treatment for patients in the EU with HR positive, HER2 low or HER2 ultralow metastatic breast cancer directly following endocrine therapy, which would mark an important shift in how patients in this setting are treated.”

 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