Data to be presented at the San Antonio Breast Cancer Symposium (SABCS) in December 2019 will include positive topline results from the HER2CLIMB trial, a randomized, double-blind, placebo-controlled, active comparator pivotal trial evaluating tucatinib.
The trial compared tucatinib, an investigational, orally bioavailable, potent tyrosine kinase inhibitor is highly selective for the human epidermal growth factor receptor 2 (HER2), a growth factor receptor that is overexpressed in multiple cancers, including breast, colorectal and gastric cancers. HER2 mediates cell growth, differentiation and survival.
The drug is being investigated in combination with trastuzumab and capecitabine to trastuzumab and capecitabine alone in patients with locally advanced unresectable or metastatic HER2-positive breast cancer.
The investigational drug has shown activity as a single agent and in combination with both chemotherapy and other HER2 targeted agents such as trastuzumab. Furthermore, studies of tucatinib in these combinations have shown activity both systemically and in brain metastases.
HER2-positive breast cancer
Patients with HER2-positive breast cancer have tumors with high levels of a protein called HER2, which promotes the aggressive spread of cancer cells. An estimated 271,270 new cases of invasive breast cancer will be diagnosed in the United States in 2019.
Between 15 and 20% of breast cancer cases worldwide are HER2-positive. 
Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer. In patients with metastatic breast cancer, the most common site of first metastasis is in bone, followed by lung, brain, and liver.
Approximately 30 to 50% of metastatic HER2-positive breast cancer patients develop brain metastases over time.
Despite recent treatment advances, there is still a significant need for new therapies that can impact metastatic disease, especially brain metastases. There are currently no approved therapies demonstrating progression-free survival or overall survival benefit for the treatment of patients with HER2-positive metastatic breast cancer after progression on ado-trastuzumab emtansine.
Trial and trial design
The HER2CLIMB trial is a multinational randomized (2:1), double-blind, placebo-controlled, active comparator, pivotal clinical trial comparing tucatinib in combination with trastuzumab and capecitabine compared with trastuzumab and capecitabine alone in patients with locally advanced or metastatic HER2-positive breast cancer who were previously treated with trastuzumab, pertuzumab and ado-trstuzumab emtansine.
The primary endpoint was PFS per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as determined by blinded independent central review in the first 480 patients enrolled in the trial. HER2CLIMB enrolled a total of 612 patients to support the analyses of key secondary endpoints, including overall survival as well as progression-free survival in patients with brain metastases at baseline. Safety data were evaluated throughout the study.
Patients had previously received trastuzumab, pertuzumab (Perjeta®; Genentech/Roche) and the antibody-drug conjugate ado-trastuzumab emtansine (T-DM1; Kadcyla®, Genentech/Roche), and 47% of the patients enrolled in the trial had brain metastases at the time of enrollment.
The trial met the primary endpoint of progression-free survival (PFS), showing that the addition of tucatinib was superior to trastuzumab and capecitabine alone, with a 46 percent reduction in the risk of disease progression or death (hazard ratio (HR)=0.54 (95% Confidence Interval (CI): 0.42, 0.71); p<0.00001). The trial also met the two key secondary endpoints at interim analysis.
The tucatinib arm demonstrated an improvement in overall survival, with a 34 percent reduction in the risk of death (HR=0.66 (95% CI: 0.50, 0.88); p=0.0048) compared to trastuzumab and capecitabine alone. For patients with brain metastases at baseline, the tucatinib arm also demonstrated superior PFS, with a 52% reduction in the risk of disease progression or death compared to those who received trastuzumab and capecitabine alone (HR=0.48 (95% CI: 0.34, 0.69); p<0.00001).
Tucatinib in combination with trastuzumab and capecitabine was generally well tolerated with a manageable safety profile. The most frequent adverse events in the tucatinib arm included diarrhea, palmar-plantar erythrodysaesthesia syndrome (PPE), nausea, fatigue, and vomiting. Grade 3 or greater adverse events in the tucatinib arm compared to the control arm included diarrhea (12.9 vs. 8.6%), increased aspartate aminotransferase (AST) (4.5 vs. 0.5%), increased alanine aminotransferase (ALT) (5.4 vs. 0.5%) and increased bilirubin (0.7 vs. 2.5%). There was no requirement for prophylactic antidiarrheals. Adverse events leading to discontinuations were infrequent in both the tucatinib arm and the control arm (5.7 and 3.0%).
Additional results are scheduled to be presented on December 11 at the 2019 San Antonio Breast Cancer Symposium.
“There is significant unmet medical need following treatment with trastuzumab, pertuzumab and T-DM1 in patients with metastatic HER2-positive breast cancer,” noted Roger Dansey, MD, Chief Medical Officer at Seattle Genetics.
“The addition of tucatinib to the commonly used doublet of trastuzumab and capecitabine represents a potential significant clinical advance for patients with metastatic HER2-positive breast cancer, importantly, including those with brain metastases. Based on these findings, we plan to unblind the trial and offer tucatinib to patients on the control arm. We also plan to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in the first quarter of 2020, with the goal of bringing a much-needed new medicine to patients,” Dansey concluded.
A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer (HER2CLIMB) – NCT02614794
A Study of Tucatinib vs. Placebo in Combination With Ado-trastuzumab Emtansine (T-DM1) for Patients With Advanced or Metastatic HER2+ Breast Cancer – NCT03975647
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