Adding the tyrosine kinase inhibitor dasatinib to standard aromatase inhibitor therapy with letrozole doubled PFS compared with letrozole alone in women with HR-positive, HER2-negative metastatic breast cancer.
Photo Courtesy © SABCS/Todd Buchanan 2013
Devchand Paul, DO, PhD
Adding the tyrosine kinase inhibitor dasatinib to standard aromatase inhibitor therapy with letrozole doubled progression-free survival (PFS) compared with letrozole alone in women with hormone receptor-positive, HER2-negative metastatic breast cancer. The PFS endpoint was an exploratory secondary endpoint of a phase II noncomparative clinical trial presented at the 2013 San Antonio Breast Cancer Symposium.
“These findings suggest that dasatinib may inhibit the emergence of acquired resistance to aromatase inhibitor therapy,” said lead investigator Devchand Paul, DO, PhD, breast oncologist at US Oncology and Rocky Mountain Cancer Centers, Denver, Colorado.
Dasatinib is approved by the FDA for the treatment of chronic myelogenous leukemia. It blocks the activity of five tyrosine kinases, including Src, a nonreceptor tyrosine kinase that has recently been implicated in breast cancer metastases to the bone.
“Src regulates osteoclast-mediated bone turnover,” said Paul. “Several studies have shown that Src is important in enabling estrogen-receptor crosstalk with the HER2 family and other growth factor-signaling pathways, as well as other steroid hormone receptors, including the androgen receptor, leading to activation of MAP kinase and PI3 kinase pathways. Ultimately, this will affect transcription, DNA synthesis, proliferation, and breast cancer cell survival.”
Combined tamoxifen and dasatinib has previously been shown to inhibit growth of endocrine therapy-resistant breast cancers in vivo, according to Paul.
In the study, 120 postmenopausal women with locally recurrent or metastatic estrogen receptor-positive, HER2-negative breast cancer were enrolled. They were randomly assigned to letrozole 2.5 mg/day (n = 63) or letrozole 2.5 mg/day plus dasatinib 100 mg/day (n = 57). Optional crossover to dasatinib plus letrozole was permitted in women who experienced disease progression on letrozole alone. Twenty-six percent required a dasatinib dose reduction.
The median disease-free interval at baseline was 76 months and 77 months in letrozole/dasatinib and letrozole arms, respectively. Forty-two percent assigned to letrozole/dasatinib and 32% assigned to letrozole presented with stage 4 disease at initial diagnosis. Approximately 50% of patients were chemotherapy-naïve and approximately 40% received prior tamoxifen. Ten percent received prior adjuvant aromatase inhibitor therapy. Sixty percent in the letrozole/dasatinib arm and 49% in the letrozole arm were endocrine therapy-naïve.
The primary endpoint was the clinical benefit rate, defined as a composite of complete response plus partial response plus stable disease for 6 or more months. The addition of dasatinib to letrozole did not increase the clinical benefit rate compared with letrozole alone (71% vs 66%, respectively). Thirty-five women crossed over to dasatinib plus letrozole for disease progression; the clinical benefit rate in this group was 23%.
In an intent-to-treat analysis, combined therapy did improve PFS, from a median of 9.9 months to 20.1 months. “As this is a noncomparative, parallel-group, phase 2 [trial], the calculated hazard ratio of.69 is exploratory,” said Paul.
“The hope is that dasatinib may delay or postpone resistance in perhaps the adjuvant setting, where patients are getting it up front,” he said. “Maybe that’s the place to study this agent.”
The dasatinib/letrozole combination was generally well tolerated. “The grade 2 or 3 adverse events that occurred are well known and expected toxicities from dasatinib,” he said. The grade 2 or 3 toxicities that were observed in about 10% of patients were rash, fatigue, edema, neutropenia, and nausea.
About one third of patients in both arms had a baseline T score of less than -1.5 at their worst site of osteopenia upon study entry. Fewer patients in the dasatinib/letrozole arm compared with the letrozole arm had an on-study T score of less than -1.5 (14% vs 32%, respectively). About one third of patients in each arm were treated with a bisphosphonate.
Paul D, Vukelja SJ, Holmes FA, et al. Letrozole plus dasatinib improves progression-free survival (PFS) in hormone receptor-positive, HER2-negative postmenopausal metastatic breast cancer (MBC) patients receiving first-line aromatase inhibitor therapy. The 2013 San Antonio Breast Cancer Symposium, December 10—14, 2013. Abstract S3-07.