SABCS to Showcase Advances in Breast Cancer Treatments

Editor’s note: The San Antonio Breast Cancer Symposium (SABCS) will be held Dec. 10-14 at the Henry B. Gonzalez Convention Center. SABCS, the premier scientific conference focused on breast cancer and premalignant breast disease, is presented by UT Health San Antonio, the American Association for Cancer Research (AACR) and Baylor College of Medicine. It brings together breast cancer researchers and clinicians from around the world, providing an ideal format to present the latest developments in the field.   

Among several eagerly anticipated studies on this year’s program is a phase II trial of the HER2-targeted treatment tucatinib, given in combination with trastuzumab (Herceptin) and capecitabine for patients with metastatic HER2-positive breast cancer. A version of this article on the tucatinib trial is freely available on the Cancer Discovery website, where you can find further coverage of SABCS throughout the meeting. The AACR’s magazine for patients and caregivers, Cancer Today, will also cover the meeting. You can also follow @SABCSSanAntonio and #SABCS19 for the latest developments.

Tucatinib Extended Overall Survival and Progression-Free Survival in HER2-Positive Breast Cancer

Seattle Genetics recently released data suggesting that tucatinib, when combined with trastuzumab (Herceptin) 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) plus a taxane-based chemotherapy first, followed by ado-trastuzumab emtansine (T-DM1, Kadcyla) for progressive disease. Once the disease metastasizes, however, effective therapies are lacking, especially for the 30 to 50 percent 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. 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 percent 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 percent of patients who had brain metastases. Overall, tucatinib reduced the risk of death by 34 percent compared with trastuzumab plus capecitabine. Patients with brain metastases who received tucatinib had a 52 percent 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.

Additional data, such as response rates and duration of response, will be presented on December 11 at SABCS.

Kevin Kalinsky, MD, of the Herbert Irving Comprehensive Cancer Center at Columbia University Irving Medical Center and New York-Presbyterian in New York, who was not involved in the study, said 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 added, and, if so, whether it can prevent brain metastases.

Sara Hurvitz, MD, of the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, who is an investigator on the trial, said she wants to know how tucatinib compares with the TKI neratinib (Nerlynx) as an adjuvant therapy, noting that neratinib’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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