SAN ANTONIO – The oral tyrosine kinase inhibitor dasatinib appears to increase the efficacy of first-line aromatase inhibitor therapy in women with advanced breast cancer, suggests a randomized phase 2 trial presented at the San Antonio Breast Cancer Symposium.
Adding dasatinib (SPRYCEL) to letrozole (Femara) did not improve the clinical benefit rate – the trial’s primary endpoint – among the 120 postmenopausal women with hormone receptor–positive, HER2-negative locally recurrent or metastatic breast cancer.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel.
But the combination doubled patients’ median progression-free survival from 10 months to 20 months in an intent-to-treat analysis, Dr. Dev Paul of U.S. Oncology and the Rocky Mountain Cancer Centers in Denver reported in a session and a related press briefing at the meeting.
"Dasatinib may be inhibiting the emergence of resistance to aromatase inhibitor therapy," he said.
The researchers were unable to identify factors that explained why the clinical benefit rate was the same, but the progression-free survival was different for the two groups. The study was small, did not use a placebo, and permitted crossover; "all of these things could affect the results, and this is a preliminary exploratory study," Dr. Paul said.
Combining dasatinib with other aromatase inhibitors – fulvestrant or exemestane – has not improved progression-free survival benefit in women with metastatic breast cancer previously treated with a nonsteroidal aromatase inhibitor, Dr. Paul noted; thus, it may be important to give dasatinib the first time that patients are given an aromatase inhibitor. "Putative predictive biomarkers for benefit from dasatinib will be assessed in patients’ archival breast cancer tissues to help inform patient selection for future studies."
In additional findings from the trial, adding dasatinib appeared to attenuate the adverse impact of letrozole on bone health. At the end of the study, patients given the combination therapy were half as likely as their counterparts given letrozole alone to have osteopenia.
The findings on bone density suggest "an on-target effect of the Src inhibitor [dasatinib]," commented Dr. Carlos L. Arteaga, who moderated the press briefing. Dr. Arteaga is president-elect of the American Association for Cancer Research and associate director for translational/clinical research and director of the breast cancer program at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., and a codirector of SABCS.
Dr. Carlos Arteaga
Dr. Paul noted that the observations occurred in an intent-to-treat analysis that included all patients according to their initial treatment assignment.
During a discussion after the presentation, one session attendee questioned the interpretation that dasatinib was inhibiting the emergence of resistance to letrozole and pointed out that 23% of patients who had progression on letrozole monotherapy had clinical benefit after crossing over to the combination. "You could also interpret the crossover data [as saying] that [dasatinib] simply treats endocrine resistance. So my question is, have you looked at the time to total progression? Have you looked at that 23% clinical benefit in the cross-over group? Because [dasatinib] may not stop resistance, it may just treat it."
Looking at the total time to progression for sequential vs. combined therapy, it may be that the time to progression curves really don’t separate quite so much, the discussant maintained.
Dr. Paul acknowledged that this alternate interpretation was possible and said that such analyses have not yet been done.
"Src is a pleiotropic nonreceptor tyrosine kinase involved in breast cancer invasion, proliferation, and survival. Membrane estrogen receptor-alpha complexes with Src and PI3 kinase to drive breast cancer growth and endocrine therapy resistance," Dr. Paul said, giving some background to the trial. "Src also regulates osteoclast-mediated bone turnover."
Dasatinib inhibits Src tyrosine kinase and is currently approved by the Food and Drug Administration for treatment of Philadelphia chromosome–positive acute lymphoblastic leukemia and chronic myelogenous leukemia.
Women enrolled in the trial were allowed to have had prior non–aromatase inhibitor endocrine therapy for metastatic disease; prior adjuvant aromatase inhibitor therapy if completed at least 1 year before study entry; and one prior chemotherapy regimen for metastatic disease.
After stratification by disease-free interval and prior receipt of tamoxifen, patients were randomized to receive letrozole plus dasatinib or letrozole alone on 28-day cycles.
Patients on letrozole alone were allowed to cross over if they experienced progression, and 56% ultimately did so, Dr. Paul reported.
About half of the women in each treatment arm had not received any prior chemotherapy; 60% of those randomized to the combination and 49% of those randomized to letrozole alone had not received any prior endocrine therapy.
The clinical benefit rate – consisting of complete responses, partial responses, and stable disease for at least 6 months – was 71% with dasatinib plus letrozole and 66% with letrozole alone, a nonsignificant difference.