SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the USA, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.
The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab), KADCYLA® (ado-Trastuzumab emtansine, T-DM1), ENHERTU® (Trastuzumab deruxtecan) and MARGENZA® (Margetuximab). Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2-positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a Taxane.
With advances in systemic therapies for this patient population, the incidence of brain metastases as a sanctuary site has increased. Approximately 50% of patients with HER2-positive metastatic breast cancer develop brain metastases. However, systemic HER2-targeted agents, including Tyrosine Kinase Inhibitors, as well as chemotherapy have limited antitumor activity in the brain. Local therapeutic interventions for brain metastases include neurosurgical resection and Stereotactic or Whole-Brain Radiation Therapy. There is a high unmet need for systemic treatment options to treat established brain metastases and reduce the risk for progression in the Central Nervous System (CNS).
TUKYSA® (Tucatinib) is an oral Tyrosine Kinase Inhibitor that is highly selective for the kinase domain of HER2 with minimal inhibition of Epidermal Growth Factor Receptor. In the HER2CLIMB international, randomized, double-blind, placebo-controlled trial, a combination of TUKYSA® plus HERCEPTIN® and XELODA® (Capecitabine) was compared with placebo plus HERCEPTIN® and XELODA®. TUKYSA® combination significantly improved Progression Free and Overall Survival in heavily pretreated patients, including those with brain metastases.
The HER2CLIMB-02 trial is a randomized, double-blind, placebo-controlled Phase III trial conducted to evaluate the efficacy and safety of the combination of TUKYSA® and KADCYLA® in patients with metastatic HER2-positive breast cancer, particularly those with brain metastases. This study focused on patients with brain metastases, given the limited options for managing breast cancer brain metastases. In this study, 463 patients (N=463) with unresectable locally advanced or metastatic HER2-positive breast cancer were randomly assigned in a 1:1 ratio to receive either 21-day cycles of either TUKYSA® at 300 mg orally twice a day and KADCYLA® 3.6 mg/kg IV every 3 weeks (N=228) or KADCYLA® and placebo (N=235). Both treatment groups were well balanced. The median age was 55 years, eligible patients had been previously treated with HERCEPTIN® and a Taxane in any setting, and trial entry criteria included enrollment of previously treated, stable, progressing, or untreated brain metastases not requiring immediate local therapy. Approximately 40% of all patients had baseline active or stable brain metastasis, and the researchers noted that this was the second large trial, prospectively designed to evaluate systemic therapy in patients with brain metastases. The Primary endpoint was Progression Free Survival (PFS).
At a median follow up was 24.4 months, the combination of TUKYSA® plus KADCYLA® showed a significant improvement in median PFS compared to KADCYLA® alone. The median time to disease progression or death was 9.5 months with TUKYSA® plus KADCYLA® versus 7.4 months with KADCYLA® alone, suggesting a 24% reduction in the risk of disease progression or death with the combination treatment. Among patients with brain metastasis at baseline, the median time to disease progression or death was 7.8 months with the TUKYSA® plus KADCYLA® combination versus 5.7 months with KADCYLA® alone, suggesting a 36% reduction in the risk of disease progression or death with the combination. Further, patients in the TUKYSA® plus KADCYLA® group had a higher Objective Response Rate compared to the control arm (42% versus 36.1%). Overall survival data were immature at the time of this analysis. The combination treatment group reported more treatment related adverse events which included nausea, diarrhea, fatigue and liver function abnormalities.
It was concluded that the combination of TUKYSA® and KADCYLA® demonstrated a statistically significant improvement in Progression Free Survival, compared to KADCYLA® alone, supporting its efficacy in patients with HER2-positive metastatic breast cancer. This study was prospectively designed to evaluate novel systemic therapies in patients with brain metastases, and findings from this study suggested that the combination of TUKYSA® and KADCYLA® could be a favorable treatment option, especially for patients with active or progressing brain metastases. It should be noted that this study did not directly compare the experimental regimen of TUKYSA® and KADCYLA® with other established regimens like TUKYSA® plus HERCEPTIN® and XELODA® or regimens containing ENHERTU®.
HER2CLIMB-02: randomized, double-blind phase 3 trial of tucatinib and trastuzumab emtansine for previously treated HER2-positive metastatic breast cancer. Hurvitz SA, Loi S, O’Shaughnessy J, et al. Presented at the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Session GS01-10.
