Tucatinib Prolongs Survival in HER2-Positive Advanced Breast Cancer, Including in Patients with CNS Metastases

In the phase 2 HER2CLIMB clinical trial, tucatinib demonstrated notable activity in patients with heavily pretreated HER2-positive metastatic breast cancer, including in those with untreated or previously treated brain metastases, according to research presented by Sara Hurvitz, MD, Director, Breast Cancer Clinical Trials Program, UCLA Health, Los Angeles, in a session on novel therapies for HER2-positive advanced breast cancer at the 37th Annual Miami Breast Cancer Conference.

According to Dr Hurvitz, treatment options in the field of HER2-positive advanced breast cancer are evolving rapidly, and tucatinib is one to watch. Although the use of HER2-directed therapies has improved survival rates in patients with HER2-positive breast cancer, approximately 50% of patients with advanced disease will eventually develop central nervous system (CNS) metastases. Recurrent CNS events negatively affect overall survival (OS) for many patients, and treatment options remain limited, representing a clear unmet medical need. In explaining the mechanism of action of tucatinib, Dr Hurvitz said, “Why not omit [epidermal growth factor receptor] inhibition and just select HER2 inhibition?”

Tucatinib has been evaluated in several phase 1b clinical trials. In one of these trials, researchers assessed the efficacy of tucatinib in combination with capecitabine and/or trastuzumab in patients with HER2-positive metastatic breast cancer. Among 23 patients who were treated with the triplet of tucatinib, capecitabine, and trastuzumab, the overall response rate (ORR) was 61%, the median progression-free survival (PFS) was 7.8 months, and the median duration of response was 10 months.

Based on these results, the US Food and Drug Administration (FDA) granted tucatinib orphan drug status for patients with HER2-positive CNS brain metastases.

“This led the company to very smartly design a clinical trial that uniquely allows patients who have active progressing, untreated, or previously treated and stable brain metastases,” Dr Hurvitz said.

In the phase 2 HER2CLIMB clinical trial, patients who were previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1) were randomized 2:1 to tucatinib plus trastuzumab plus capecitabine (N = 410) or placebo plus trastuzumab plus capecitabine (N = 202). The study’s primary end point was PFS. Approximately 50% of patients in the study had brain metastases—either previously treated stable or progressing, or new and untreated.

Approximately 60% were hormone receptor–positive and 36% had de novo metastatic breast cancer. Patients were also heavily pretreated, with a median of 3 previous lines of therapy in the metastatic setting (range, 1-14).

“The PFS in the intent-to-treat population was over 3 months improved with the addition of tucatinib, with a highly statistically significant hazard ratio of 0.54, and OS was also shown to be significantly better in the intent-to-treat population with a hazard ratio of 0.66,” Dr Hurvitz reported. “The PFS in patients with CNS disease was significantly better as well, so they hit every one of those end points.”

Data related to the actual level of activity in the CNS (the ORR) is forthcoming. “I think we’re all very eager to see those data,” she added.

In December 2019, the FDA granted breakthrough therapy designation to tucatinib in combination with trastuzumab and capecitabine for the treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have been treated with trastuzumab, pertuzumab, and T-DM1.

“I think we and many of our patients are waiting for this drug to become available,” said Dr Hurvitz. “There is an expanded access protocol available for some centers to open if you have patients who would be eligible to go on that study.”

Patients on tucatinib did experience slightly higher rates of diarrhea, but a minority (10%-12%) of those patients had grade 3 diarrhea, only slightly higher than the incidence seen in the placebo arm.

“Tucatinib is HER2-selective,” Dr Hurvitz added. “But with these tyrosine kinase inhibitors you can hit other receptors, so we have to make sure it’s well tolerated.”

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