Enhertu (trastuzumab deruxtecan) is a new antibody–drug conjugate that is being studied in the treatment of challenging breast cancer cases. A phase 2 clinical trial has been conducted, in which researchers studied patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer that could not be fully removed surgically or has metastasized, meaning the cancer spread around the body, after previously being treated with Kadcyla (trastuzumab emtansine). The researchers found promising results, which showed the confirmed objective response rate with Enhertu was 60.9% and median progression-free survival was 16.4 months.1
Shanu Modi, MD, Medical Oncologist, Breast Cancer, Memorial Sloan Kettering Cancer Center, New York City, and colleagues published a phase 1 study (a dose-escalation and dose-expansion study) testing the safety and activity of Enhertu in patients with advanced HER2-expressing and mutated solid tumors, specifically looking for the recommended dose for patients with a type of breast cancer called HER2-low. In this phase 1 study, treated patients who had been diagnosed with HER2-low advanced breast cancer had a confirmed objective response rate of 37.0% and the median progression-free survival was 11.1 months.2
Recently, Enhertu was approved for the treatment of adult patients with HER2-positive breast cancer that was unresectable (meaning not capable of being surgically completely removed) or metastatic (meaning the cancer spread to other parts of the body from where it originally started); these patients have received 2 or more previous anti–HER2-based treatments. In studies conducted in animal models, Enhertu combined with an anti–programmed-cell death 1 (PD-1) antibody was more effective than either treatment alone.3
Erika Hamilton, MD, Director, Breast Cancer and Gynecologic Cancer Research Program, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, and colleagues conducted a phase 1b, open-label, multicenter, 2-part study of Enhertu in combination with Opdivo in patients with HER2-expressing metastatic breast cancer or advanced urothelial cancer. They recently presented the preliminary results for the different breast cancer groups in the study.
Patients in this study were aged ≥18 years and had not received an immune checkpoint inhibitor, which is a type of drug that blocks proteins called checkpoints that are made by some types of immune system cells, such as T-cells, and some cancer cells. Patients were enrolled in the study in the United States and Europe. In part 1 of the study, called the dose-escalation study, patients received Enhertu at either 3.2 mg/kg or 5.4 mg/kg intravenously every 3 weeks and Opdivo 360 mg intravenously every 3 weeks to determine the recommended dose for expansion (RDE) or best possible dose.
In part 2, the RDE was given to 2 metastatic breast cancer groups: patients who had HER2-positive disease that progressed on previous Kadcyla or patients who had HER2-low disease that progressed on previous standard treatments. The effectiveness of the medication was judged by the primary efficacy end point and evaluated by confirmed objective response rate by independent reviewers in part 2. Some of the additional study end points included the safety, pharmacokinetics (how the drug moves in the body), duration of response (the length of time that a tumor continues to respond to treatment without the cancer growing or spreading), progression-free survival (how long a person lives without the disease worsening), and overall survival (how long patients who undergo a certain treatment regimen live compared with patients who are in a control group).
In total, 52 patients with metastatic breast cancer were enrolled. In part 1 of the study, 4 patients received Enhertu based on weight: 3.2 mg/kg (HER2-positive, N = 3; HER2-low, N = 1); and 3 patients received 5.4 mg/kg (all HER2-positive). Based on the research in part 1 of the study, in part 2 of the study, 45 patients received the recommended dose of Enhertu 5.4 mg/kg and Opdivo 360 mg (HER2-positive, N = 29; HER2-low, N = 16 [13 hormone receptor–positive]). The average follow-up time was 7.0 months and 6.9 months. All 48 patients who received this recommended dose were female, with the average duration of follow-up as 6.9 months. Patients with HER2-positive disease had an average age of 55 years and a median of 5 previous lines of metastatic or locally advanced therapy. At the time the researchers decided to begin evaluating based on data that they had accumulated (June 8, 2020), 56.3% of patients remained on treatment, with the average treatment duration of Enhertu 6.5 months and Opdivo 5.2 months. Patients with HER2-low disease had an average age of 47 years, had received an average of 4 previous lines of therapy, and half remained on treatment.
The confirmed objective response rate in the HER2-positive group was 59.4% and for the HER2-low cohort was 37.5%. Average duration of response was not reached in either group. The average progression-free survival was 8.6 months for the HER2-positive group and 6.3 months for the HER2-low group.
Safety issues, known as adverse events, occurred at different levels and rates. Remarkably, some patients reported anemia at a rate of 16.7%. The most commonly reported adverse events were nausea (54.2%), fatigue (45.8%), and alopecia or hair loss (41.7%). Five patients (10.4%, all HER2-positive disease) had treatment-related lung problems. No deaths related to the medication occurred.
The researchers concluded that in patients with HER2-expressing metastatic breast cancer, Enhertu plus Opdivo confirmed antitumor activity consistent with previous studies of Enhertu and was acceptable from a safety standpoint in this short-term analysis. Longer follow-up and additional studies are needed to determine whether adding immunotherapy to Enhertu benefits patients.
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