A recent Phase II study investigating the efficacy of patritumab deruxtecan (HER3-DXd) in patients with metastatic breast cancer (MBC) has produced promising results. HER3-DXd is an antibody-drug conjugate (ADC) composed of a fully human anti-HER3 IgG1 monoclonal antibody and a topoisomerase 1 inhibitor. This study, conducted in three parts, aims to evaluate the effectiveness of HER3-DXd across subsets of MBC and identify the patient population likely to derive the greatest benefit. The research was presented at the 2023 ASCO Annual Meeting (Abstract 1004).
In Part A of the study, conducted through September 6, 2022, HER2-negative MBC patients with measurable disease were enrolled. They had received 0-2 prior chemotherapy regimens and prior endocrine therapy with CDK4/6 inhibitors for HR-positive breast cancer or 1-3 prior chemotherapy regimens for triple-negative breast cancer (TNBC). Patients with previous treatment using anti-HER3 agents and ADCs with exatecan derivatives were excluded.
Biomarker expression in pre-treatment tissue samples was analyzed for its association with progression-free survival (PFS) at 6 months. Primary endpoints were overall response rate (ORR) and PFS at 6 months, with secondary endpoints including safety/tolerability, duration of response (DOR), and clinical benefit rate (CBR).
In the analysis, 60 patients were treated, predominantly female with a median age of 57.5 years. TNBC accounted for 32 percent, while 48 percent had HR-positive status. Liver and lung metastases were observed in 48 percent and 32 percent of patients, respectively. Varying levels of HER3 membrane expression were found. The treatment duration had a median of 5.2 months, with 21 patients remaining on treatment. All patients experienced treatment-emergent adverse events, with 93 percent experiencing treatment-related adverse events (TRAEs). Common TRAEs included nausea, fatigue, diarrhea, vomiting, alopecia, and anemia. Serious adverse events were reported in 12 percent of patients, with four treatment-related cases. HER3-DXd demonstrated an acceptable safety profile.
The ORR was 35 percent with a CBR of 48 percent. Patients with >=75 percent HER3 expression had an ORR of 33 percent and a CBR of 50 percent, while those with HER3 expression levels of 25-74 percent had an ORR of 46 percent and a CBR of 54 percent. Efficacy assessment was limited for patients with HER3 expression below 25 percent. The median DOR was 10.0 months. Progression-free survival at 6 months (PFS: 6 months) was 60 percent for all patients, 50 percent for those with >=75 percent HER3 expression, and 70 percent for patients with HER3 expression levels of 25-74 percent.
Oncology Times caught up with Erika P. Hamilton, MD, for additional insights into the study. She is Director of Breast Cancer and Gynecologic Cancer Research for Sarah Cannon Research Institute (SCRI), and cares for patients facing breast and gynecologic cancer at the SCRI drug development unit at Tennessee Oncology.
Oncology Times: What is the mechanism of action of HER3-DXd in patients with mBC?
Hamilton: "HER3-DXd is an ADC comprised of three subunits-a target-finding antibody, a linker, and a chemotherapy-based payload. Patritumab deruxtecan is structurally similar to the approved agent trastuzumab deruxtecan. It has the same linker and exatecan-based payload, but instead of targeting HER-2, it targets HER-3."
Oncology Times: What were the most notable findings from the study and how do they compare to previous research in this area?
Hamilton: "The first notable aspect of patritumab deruxtecan is that it is active across multiple breast cancer subtypes. This study disclosure focused on both TNBC, as well as hormonally driven breast cancer (HR+), but HER2-positive breast cancer will also be examined in Part Z of the study.
"The ORR was 47.5 percent among HR+ and 18.2 percent among the more challenging subtype TNBC. Most notably, the expression of HER-3 did not appear important for response. ORR was 33 percent for HER-3 >75 percent, 46.2 percent for HER-3 expression 25-74 percent, and 50 percent for HER-3 expression <25 percent. This means that it is unlikely we will need to even test for HER-3 to determine who is appropriate for the therapy. The other encouraging finding was that for those patients who responded, DOR of at least 6 months occurred for nearly 48 percent of patients."
Oncology Times: What are the implications of this study for future research and clinical practice in the treatment of metastatic breast cancer?
Hamilton: "This adds to the growing body of literature from ADCs in breast cancer. Three such therapies currently FDA-approved include: 1) T-DM1 with activity in HER-2 positive breast cancer; 2) TDXd with activity in both HER-2 positive and HER-2 low breast cancer, and 3) sacituzumab govitecan, a TROP-2 targeting ADC with activity in HR+ and TNBC. Patritumab deruxtecan is the first ADC to target a new protein HER-3 and encouragingly is showing activity across all three types of breast cancer-TNBC, HR+, and HER2+.
"The side effect profile was as expected with the three most common being nausea, fatigue, and diarrhea. Reassuringly, we saw that only 15 percent of patients needed a dose reduction, and 43 percent of patients had disease control and remained on therapy for more than 6 months. Further studies are needed to help determine where patritumab deruxtecan fits in our armamentarium for breast cancer treatment."
Dibash Kumar Das is a contributing writer.