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First HER2-low metastatic breast cancer Phase III results for AstraZeneca and Daiichi Sankyo’s ENHERTU offer potential to redefine how the disease is classified and treated
Positive high-level results from the pivotal DESTINY-Breast04 Phase III trial showed ENHERTU® (fam-trastuzumab deruxtecan-nxki) demonstrated a statistically significant and clinically meaningful improvement in both progression-free survival (PFS) and overall survival (OS) in patients with HER2-low unresectable and/or metastatic breast cancer regardless of hormone receptor (HR ) status versus physician’s choice of chemotherapy.
ENHERTU is a HER2-directed antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo.
All patients in the trial received a HER2 test, and the results were centrally confirmed. HER2-low status was defined as an immunohistochemistry (IHC) score of 1+ or IHC 2+ with a negative in-situ hybridization (ISH) score.
Up to 55% of all patients with breast cancer have tumors with an HER2 IHC score of 1+, or 2+ in combination with a negative ISH test, a level of HER2 expression not currently eligible for HER2-targeted therapy.1,2 HER2-low expression occurs in both HR-positive and HR-negative disease.3
HER2 testing is well established to determine an appropriate treatment strategy in metastatic breast cancer. Targeting the lower range of HER2 expression may offer another approach to delay disease progression and extend survival in patients with metastatic breast cancer.4 Currently, chemotherapy remains the only treatment option both for patients with HR-positive tumors following progression on endocrine (hormone) therapy, and for those who are HR-negative.5
DESTINY-Breast04 met its primary endpoint, where ENHERTU demonstrated superior PFS in previously treated patients with HR-positive HER2-low metastatic breast cancer compared to the standard-of-care chemotherapy. The trial met the key secondary endpoint of PFS in patients with HER2 -low metastatic breast cancer regardless of HR status (HR-positive or HR-negative). The trial also met the key secondary endpoints of OS in patients with HR-positive disease and in patients regardless of HR status at interim analysis.
The safety profile of ENHERTU was consistent with previous clinical trials, with no new safety concerns identified. Overall interstitial lung disease (ILD) rates were consistent with that observed in late-line HER2-positive breast cancer trials of ENHERTU, with a lower rate of Grade 5 ILD observed as determined by an independent adjudication committee.
Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca said: “Today’s historic news from DESTINY-Breast04 could reshape how breast cancer is classified and treated. A HER2-directed therapy has never-before shown a benefit in patients with HER2-low metastatic breast cancer. These results for ENHERTU are a huge step forward and could potentially expand our ability to target the full spectrum of HER2 expression, validating the need to change the way we categorize and treat breast cancer.”
Ken Takeshita, Global Head, R&D, Daiichi Sankyo said: “ENHERTU continues to redefine the treatment of HER2-targetable cancers. DESTINY-Breast04 is the first ever Phase III trial of a HER2-directed therapy in patients with HER2-low metastatic breast cancer to show statistically significant and clinically meaningful benefit in progression-free and overall survival to standard treatment. We look forward compared to sharing the detailed findings of DESTINY-Breast04 with the medical community and initiating discussions with regulatory agencies globally with the goal of bringing ENHERTU to patients with metastatic breast cancer previously considered to be HER2-negative.”
The data will be presented at a forthcoming medical meeting and shared with global health authorities.
ENHERTU (5.4mg/kg) is approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY- Breast01 trial.
ENHERTU is being further assessed in a comprehensive clinical development program evaluating efficacy and safety across multiple HER2-targetable cancers, including breast, gastric, lung and colorectal cancers.
Important Safety Information
Indications
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:
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Unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.
This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
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Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.
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WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY
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Contraindications
None.
Warnings and Precautions
Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤ 28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (eg, ≥0.5 mg/kg/day prednisolone or equivalent ). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (eg, ≥1 mg/kg/day prednisolone or equiva lent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.
Metastatic Breast Cancer
In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).
Locally Advanced or Metastatic Gastric Cancer
In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2‑positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21.0).
Neutropenia
Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3ºC or a sustained temperature of ≥38ºC for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level.
Metastatic Breast Cancer
In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4mg/kg, a decrease in neutrophil count was reported in 62% of …
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