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. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 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), 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. There is however no standard treatment option for this patient population following progression on KADCYLA®.
It is estimated that close to 50% of patients with HER2-positive metastatic breast cancer develop brain metastases. Systemic HER2-targeted agents, including Tyrosine Kinase Inhibitors, as well as chemotherapy have limited antitumor activity in the brain. This is therefore an area of high unmet need. Local therapeutic interventions for brain metastases include neurosurgical resection and Stereotactic or Whole-Brain Radiation Therapy.
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 a Phase 1b dose-escalation trial, TUKYSA® in combination with HERCEPTIN® and XELODA® (Capecitabine) showed encouraging antitumor activity in patients with HER2-positive metastatic breast cancer, including those with brain metastases.
HER2CLIMB is an international, randomized, double-blind, placebo-controlled trial in which the combination of TUKYSA® plus HERCEPTIN® and XELODA® was compared with placebo plus HERCEPTIN® and XELODA®. A total of 612 patients with unresectable locally advanced or metastatic HER2-positive breast cancer, who were previously treated with HERCEPTIN®, PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine) were enrolled. Patients were randomly assigned in a 2:1 ratio to receive either TUKYSA® 300 mg orally twice daily throughout the treatment period (N=410) or placebo orally twice daily (N=201), in combination with HERCEPTIN® 6 mg/kg IV once every 21 days, following an initial loading dose of 8 mg/kg, and XELODA® 1000 mg/m2 orally twice daily on days 1 to 14 of each 21-day cycle. Stratification factors included presence or absence of brain metastases, ECOG Performance Status and geographic region. The median patient age was 54 years and patient demographic as well as disease characteristics at baseline were well balanced between the two treatment groups. In the total treatment population, 47.5% had brain metastases at baseline, 48.3% in the TUKYSA® combination group and 46% in the placebo combination group. The Primary endpoint was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS), PFS among patients with brain metastases, confirmed Objective Response Rate (ORR), and safety.
In the primary analysis, at a median follow-up of 14 months, TUKYSA® added to HERCEPTIN® and XELODA®, significantly improved Overall Survival (OS) and Progression Free Survival (PFS) in patients with HER2-positive metastatic breast cancer. After the primary analysis, the protocol was amended to allow unblinding and cross-over from the placebo combination to the TUKYSA® combination. Protocol prespecified descriptive analyses of OS, PFS and safety were carried out at about 2 years from the last patient randomized. The researchers in this publication reported the final efficacy and safety outcomes after an additional 15.6 months follow up (total follow up of 29.6 months) in patients from the HER2CLIMB trial.
At a median follow up of 29.6 months, the median duration of OS was 24.7 months for the TUKYSA® combination group versus 19.2 months in the placebo combination group (HR for death=0.73; P=0.004). The estimated OS rate at 2 years was 51% in the TUKYSA® combination group and 40% in the placebo combination group. The OS benefit with the TUKYSA® combination was noted across all prespecified subgroups in the overall study population and was consistent with the primary analysis. The median duration of PFS was 7.6 months for the TUKYSA® combination group versus 4.9 months for the placebo combination group (HR for progression or death=0.57; P<0.00001), and PFS at 1 year was 29% and 14%, respectively.
Systemic treatment with TUKYSA® in combination with HERCEPTIN® and XELODA® provided consistent clinical benefit to patients with and without brain metastases. TUKYSA® combination doubled the intracranial Objective Response Rate, reduced the risk of intracranial progression or death by two-thirds in all patients with brain metastases. In this study population, the estimated 1-year intracranial PFS was 40% in the TUKYSA® group and 0% in the control group. In patients with untreated or treated and progressing (active) brain metastases, the estimated 1-year intracranial PFS was 35% in the TUKYSA® group, 0% in the control group, and in patients with treated (stable) brain metastases, was 53% in the TUKYSA® group and 0% in the control group. The TUKYSA® combination was well tolerated with a low rate of discontinuation due to toxicities. Common adverse events in the TUKYSA® group included diarrhea, Palmar-Plantar Erythrodysesthesia syndrome, nausea, vomiting and fatigue. Diarrhea and abnormal liver function tests were more common in the TUKYSA® group than in the control group.
It was concluded that with additional follow up, TUKYSA® in combination with HERCEPTIN® and XELODA® provided a clinically meaningful survival benefit, including those with brain metastases, supporting the use of this combination in patients with previously treated HER2-positive metastatic breast cancer, after progression on two HER2-targeted therapies.
Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. Curigliano G, Mueller V, Borges V, et al. Ann Oncol. 2022;33:321-329.
