Tucatinib Impresses in Breast Cancer

Seattle Genetics recently released data suggesting that tucatinib, when combined with trastuzumab (Herceptin; Genentech) and capecitabine, may effectively treat patients with locally advanced inoperable or metastatic HER2-positive breast cancer who have received prior therapies. In a phase II trial, the drug extended overall survival (OS) and progression-free survival (PFS) compared with trastuzumab and capecitabine alone and provided a PFS benefit in patients with brain metastases.

Patients with HER2-positive breast cancer usually receive trastuzumab and pertuzumab (Perjeta; Genentech) plus a taxane-based chemotherapy first, followed by T-DM1 (ado-trastuzumab emtansine, Kadcyla; Genentech) for progressive disease. Once the disease metastasizes, however, effective therapies are lacking, especially for the 30% to 50% of patients who also develop brain lesions.

Highly selective for HER2, tucatinib is a small-molecule tyrosine kinase inhibitor (TKI). In a phase Ib trial, tucatinib plus trastuzumab and capecitabine elicited responses in 14 of 23 patients, some of whom had brain metastases, and was generally well tolerated (Lancet Oncol 2018;19:880–8). Thus, the researchers decided to compare that three-drug combination with trastuzumab plus capecitabine alone in the randomized HER2CLIMB trial.

The trial included patients with locally advanced inoperable or metastatic HER2-positive breast cancer previously treated with trastuzumab, pertuzumab, and T-DM1. In the first 480 patients enrolled, the trial met its primary endpoint of PFS, with the tucatinib-containing regimen reducing the risk of disease progression or death by 46% compared with the trastuzumab–capecitabine control arm. Among 612 enrolled patients, two key secondary endpoints were also met—OS, as well as PFS in the 47% of patients who had brain metastases. Overall, tucatinib reduced the risk of death by 34% compared with trastuzumab plus capecitabine. Patients with brain metastases who received tucatinib had a 52% reduction in disease progression or death compared with those in the control arm.

The most common side effects in the tucatinib cohort were diarrhea, hand–foot syndrome, nausea, fatigue, and vomiting. In addition, adverse events of grade 3 or greater—namely diarrhea and elevated liver enzymes—were higher with tucatinib.

“This is some of the most exciting data I've seen in a long time,” says Sara Hurvitz, MD, of the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, who is an investigator on the trial.

Kevin Kalinsky, MD, of the Herbert Irving Comprehensive Cancer Center at Columbia University Irving Medical Center and New York-Presbyterian in New York, NY, who was not involved in the study, says he is particularly intrigued by the drug's potential efficacy in patients with brain metastases. “One of the big questions is going to be whether there may be activity for patients if you use it sooner in the disease course,” Kalinsky adds, and, if so, whether it can prevent brain metastases.

Hurvitz wants to know how tucatinib compares with the TKI neratinib (Nerlynx; Puma Biotechnology) as an adjuvant therapy, noting that the latter's off-target effect on EGFR often causes severe side effects, namely diarrhea.

The researchers are now testing tucatinib in combination with T-DM1 and other agents. Seattle Genetics plans to submit tucatinib for FDA approval early next year. “I hope that we will have this drug available soon for our patients in clinical practice,” Hurvitz says.

If tucatinib is approved, “I think it will change the landscape,” Kalinsky says. “This is another targeted drug that we will have in our armamentarium.” –Catherine Caruso

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