In the HER2CLIMB trial, the addition of tucatinib to trastuzumab and capecitabine significantly improved progression-free survival in patients with locally advanced, unresectable, or metastatic HER2-positive breast cancer, meeting the primary endpoint of the study, according to a press release from Seattle Genetics.<br />
In the HER2CLIMB trial, the addition of tucatinib to trastuzumab (Herceptin) and capecitabine significantly improved progression-free survival (PFS) in patients with locally advanced, unresectable, or metastatic HER2-positive breast cancer, meeting the primary endpoint of the study, according to a press release from Seattle Genetics.1
“There is significant unmet medical need following treatment with trastuzumab, pertuzumab, and T-DM1 in patients with metastatic HER2-positive breast cancer,” said Roger Dansey, MD, chief medical officer at Seattle Genetics, in a statement.
Patients enrolled in the multinational, randomized, double-blind, placebo-controlled, active comparator pivotal phase II trial (HER2CLIMB) were previously treated with trastuzumab, pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1; Kadcyla), and 47% of patients enrolled had brain metastases. Patients were randomized to tucatinib plus trastuzumab, tucatinib plus capecitabine, or tucatinib plus trastuzumab and capecitabine.
Those eligible to enroll in HER2CLIMB were males or females aged 18 years or older with progressive, HER2-positive metastatic breast cancer. Patients were required to have a target or non-target lesions as per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Other requirements included an adequate hematologic function and hepatic function, and an echocardiogram or multiple-gated acquisition scan 2 weeks prior to treatment showing that the left ventricular ejection fraction is within institutional limits. Notable exclusions were the presence of central nervous system disease, previous treatment with trastuzumab or another antibody-based treatment, previous treatment with capecitabine for metastatic disease, previous treatment with any small molecule HER2 inhibitors, and patients who are HIV positive, carry hepatitis A or B, and autoimmune hepatitis, or sclerosing cholangitis.
In the experimental arm, tucatinib was administered orally twice daily in 300 mg doses. Trastuzumab was administered intravenously as a loading dose of 8 mg/kg followed by 6 mg/kg once every 21 days and capecitabine was given orally twice per day at 1000 mg/m2on days 1 through 14 of each 21-day cycle.
The triplet combination reduced the risk of death by 46% (HR, 0.54; 95% CI, 0.42-0.71;P<.00001) compared with trastuzumab and capecitabine alone. At the interim analysis, 2 secondary endpoints, OS and PFS in the subgroup of patients with brain metastases, were also met. Overall survival was superior with the addition of tucatinib to trastuzumab and capecitabine, showing a 34% reduction in the risk of death (HR, 0.66; 95% CI, 0.50-0.88; P= .0048). In the subgroup of patients with brain metastases, the triplet combination reduced the risk of disease progression or death by 52% (HR, 0.48; 95% CI, 0.34-0.69;P<.00001).1
Based on these data, Seattle Genetics plans to submit a New Drug Application to the FDA in the first quarter of 2020.
The study also assessed the safety and tolerability of tucatinib/trastuzumab/capecitabine and found the combination to be manageable. Adverse events (AEs) seen with the addition of tucatinib included diarrhea, fatigue, vomiting, and palmar-plantar erythrodysesthesia syndrome (PPE). Reported grade 3 or higher AEs seen with the addition of tucatinib included increased aspartate aminotransferase, increased alanine aminotransferase, increased bilirubin, and diarrhea. However, antidiarrheals were not required in the trial to manage high-grade toxicity. In the triplet arm, 5.7% of patients discontinued treatment due to toxicity compared with 3.0% with trastuzumab/capecitabine alone.
In an earlier trial, the drug developer aimed to introduce a new treatment option for patients with progressive disease, by evaluating dose levels, safety, pharmacokinetics, and activity in several phases. Investigators believed the potency of the added HER2 tyrosine kinase inhibitor (TKI) would help with progression and help fill an unmet need in the space. In the phase Ib stage, tucatinib did show signals of activity. The median PFS in the triplet arm was 7.8 months compared with 7.1 months among patients receiving trastuzumab/capecitabine. Additionally, 61% of the patients getting tucatinib achieved an objective response, with a median duration of response of 11 months (range, 2.9-18.6).2These results led to the phase II confirmatory study.
The positive phase II results have led to a decision to unblind the study so that all patients can benefit from the combination.
“The addition of tucatinib to the commonly used doublet of trastuzumab and capecitabine represents a potentially significant clinical advance for patients with metastatic HER2-positive breast cancer, importantly, including those with brain metastases...,” Dansey stated in a press release.
The HER2CLIMB trial is ongoing and no longer recruiting patients. The expected completion date is September 2020. The latest data will be presented at the upcoming 2019 San Antonio Breast Cancer Symposium.
Tucatinib is currently being evaluated in other types of breast cancer, such as the phase III trial of tucatinib in combination with T-DM1 compared with T-DM1 alone in patients with unresectable locally advanced or metastatic HER2-positive breast cancer (NCT03975647), and in other diseases, such as in the multi-center, open-label, single-arm phase II MOUNTAINEER study (NCT03043313), which is looking at tucatinib in combination with trastuzumab in patients with HER2-positive,RASwild-type metastatic or unresectable colorectal cancer.