Although the addition of dasatinib to letrozole improved progression-free survival in postmenopausal women with estrogen receptor–positive, HER2-negative metastatic breast cancer compared with letrozole alone, the clinical benefit was the same for both groups.

Adding dasatinib (Sprycel; Bristol-Myers Squibb) to the aromatase inhibitor letrozole (Femara; Novartis) improved progression-free survival (PFS) in women with estrogen receptor–positive, HER2-negative metastatic breast cancer in a phase II clinical trial, according to results presented on December 12 at the 2013 San Antonio Breast Cancer Symposium in Texas.

However, the combination was no better than letrozole alone when it came to the study's primary endpoint, a “clinical benefit rate” defined as the sum of those with a complete response, partial response, or stable disease for at least 6 months.

Dasatinib is an approved treatment for chronic myelogenous leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia. Because dasatinib inhibits a variety of kinases, including the Src family of kinases, which are involved in cell proliferation, investigators are testing it against a wide variety of cancers. Preclinical data suggested that it has therapeutic potential in breast cancer.

In this trial, principal investigator Devchand Paul, DO, PhD, a breast oncologist at Rocky Mountain Cancer Centers in Denver, CO, and at US Oncology Research in The Woodlands, TX, and his colleagues enrolled 120 postmenopausal women with locally recurrent or metastatic breast cancer and randomly assigned them to either letrozole and dasatinib or letrozole alone. The results showed that 71% of the women in the dasatinib–letrozole arm met the clinical benefit rate criteria endpoint compared with 66% of those in the letrozole arm.

About 40% of the patients had received prior adjuvant endocrine therapy, with 85% treated with tamoxifen. Paul says the study was designed with the expectation that more women would have used an aromatase inhibitor as adjuvant therapy. The lack of previous exposure to an aromatase inhibitor may have made letrozole particularly effective as a treatment for metastatic disease, so the addition of dasatinib might not have made much of a difference with respect to the primary endpoint, he says.

However, there was a large difference in PFS between the two study arms: 20.1 months for the women assigned to the dasatinib–letrozole arm versus 9.9 months in the letrozole arm.

Results from previous trials testing the addition of dasatinib to exemestane (Aromasin; Pfizer), another aromatase inhibitor, and dasatinib to fulvestrant (Faslodex; AstraZeneca), an estrogen antagonist, did not show any benefit in PFS for women with metastatic breast cancer. However, those trials were conducted in women whose cancers had become resistant to aromatase inhibitor therapy. Paul says the improvement in PFS in this trial suggests that dasatinib might be effective if it were added initially to aromatase inhibitor therapy.

The crystal structure of the Abl1 kinase domain (blue) is shown in complex with dasatinib (in red).
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The crystal structure of the Abl1 kinase domain (blue) is shown in complex with dasatinib (in red).

The crystal structure of the Abl1 kinase domain (blue) is shown in complex with dasatinib (in red).
View largeDownload slide

The crystal structure of the Abl1 kinase domain (blue) is shown in complex with dasatinib (in red).

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One next step is to find markers of Src activity. “Before you invest a lot of money in a phase III trial, it would be nice to have some markers to look at so we can select out patients who aren't likely to benefit,” Paul says. Bristol-Myers Squibb is investigating several possible markers of Src activity, he adds.

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©2014 American Association for Cancer Research.
2014