DASATINIB-LETROZOLE COMBINATION

SAN ANTONIO — The addition of the leukemia drug dasatinib (Sprycel, Bristol-Myers Squibb and Otsuka America) to the aromatase inhibitor (AI) letrozole as first-line treatment forHER2-negative metastatic breast cancer in postmenopausal women improved progression-free survival but not the clinical benefit rate, compared with letrozole alone, new research shows.

Results from the phase 2 study were reported here at the 36th Annual San Antonio Breast Cancer Symposium.

The preliminary findings suggest that dasatinib benefits patients on initial AI therapy by delaying the development of AI resistance, said lead investigator Devchand Paul, DO, PhD, a breast oncologist from the US Oncology and Rocky Mountain Cancer Centers in Denver.

"This preliminary exploratory study says to us that this needs to be studied further," he told Medscape Medical News.

Most studies of dasatinib in breast cancer have evaluated patients previously treated with AIs, he explained. "In our study, less than 10% of patients had received previous treatment with an AI. In those other studies, it's possible that resistance was more likely."

Dasatinib inhibits c-Scr, which is a nonreceptor tyrosine kinase involved in breast cancer invasion, proliferation, and survival.

The findings "provide a glimmer of hope for the use of dasatinib in breast cancer," said Kevin Scher, MD, from the Tower Hematology Oncology Medical Group in Beverly Hills, California, who was asked byMedscape Medical News to comment on the study.

In a recent review, Dr. Scher wrote that the future of dasatinib in breast cancer is not clear (Expert Opin Investig Drugs. 2013;22:795-801).

"Preclinical data have supported the use of dasatinib to inhibit breast cancer cell growth, modulate hormone signaling, and alter cell migration, but previous phase 1/2 trials have been disappointing and have shown only limited responses to dasatinib in breast cancer patients," he wrote in an email toMedscape Medical News. He added that the NCT00754325 trial, which evaluated the use of dasatinib in combination with the AI exemestane, found no statistical benefit for progression-free survival.

Study Findings

Dr. Paul and colleagues randomized 120 postmenopausal women (median age, 62 years) with estrogen-receptor-positive, HER2-negative disease to receive either letrozole alone (2.5 mg orally once daily; n = 63), or the same dose of letrozole plus dasatinib (100 mg orally once daily; n = 57).

Previous AI therapy for metastatic breast cancer was not allowed, but it was allowed in the adjuvant setting if it had been discontinued at least 1 year prior to study entry.

Patients in the monotherapy group who progressed had the option of crossing over to the combination group.

"Our primary objective was clinical benefit rate, which is the sum of the complete responders plus partial responders plus patients with stable disease for at least 6 months," said Dr. Paul.

Secondary outcomes included progression-free survival and changes in bone mineral density.

The study had a negative finding for its primary outcome, with no statistically significant difference in the clinical benefit rate between the combination and monotherapy groups (71% vs 66%).

"Thirty-five patients on letrozole crossed over to letrozole and dasatinib. These patients had a clinical benefit rate of 23%," he reported.

The secondary outcome of median progression-free survival was significantly better with the combination than with monotherapy (20.1 vs 9.9 months). "As this was a noncomparative parallel-group phase 2 study, the calculated hazard ratio of 0.69 is exploratory," he explained.

The combination was generally well tolerated, said Dr. Paul. Grade 2 and 3 toxicities were observed in about 10% of patients, and were well-known and expected toxicities from dasatinib, such as rash, fatigue, edema, and neutropenia. Some patients (9%) developed pleural effusion, and 26% of dasatinib patients required a dose reduction.

The study was funded by Bristol-Myers Squibb. Dr. Paul has disclosed no relevant financial relationships.

36th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S3-07. Presented December 12, 2013.