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BMS's Leukemia Drug Shows Promise in Holding Breast Cancer at Bay in HER2-Negative Patients

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Originally published Dec. 23.

A leukemia drug that inhibits a cancer-linked protein called Src has shown early promise in stopping the spread of hormone receptor-positive, HER2-negative breast cancer, researchers reported at the San Antonio Breast Cancer Symposium earlier this month.

However, due to the small size of the study, researchers believe their finding needs further confirmation. They also urged for the identification of biomarkers that can home in on molecularly-defined subsets of patients who derive the most benefit from Bristol-Myers Squibb's Sprycel (dasatinib) and letrozole.

Sprycel is an inhibitor of the Bcr-Abl and Src tyrosine kinases and is currently marketed as a treatment for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. The Src protein has been shown to spur the spread of estrogen receptor-positive breast cancer to the bone. As such, a Src inhibitor, such as Sprycel, may prove to be a future option for certain molecularly-defined HER2-negative metastatic breast cancer patients, a group that has limited treatment choices that impact their survival and improve the quality of their lives.

At SABCS, researchers presented data from a 120-patient Phase II study in which women with advanced hormone receptor-positive, HER2-negative breast cancer were randomized to receive either Sprycel plus standard anti-hormone treatment letrozole or just letrozole. In the trial, funded by BMS, researchers wanted to primarily assess the clinical benefit rate of patients on each regimen, by combining the number of patients who experienced a compete response, a partial response, and stable disease for six months or more. They also gauged toxicities and progression-free survival how long during and after treatment patients' breast cancer didn't get worse.

The addition of Sprycel to letrozole didn't significantly impact the clinical benefit rate (71 percent on Sprycel/letrozole vs. 66 percent on letrozole), but it did double progression-free survival, reported researchers led by Dev Paul of Rocky Mountain Cancer Centers in Denver, Colo., at the meeting. Patients receiving Sprycel plus letrozole had median progression-free survival of 22 months compared to 11 months for those on letrozole. Those receiving Sprycel did experience more side effects than those in the letrozole-only arm, such as rash, but Paul and his colleagues didn't identify any severe adverse reactions in the Sprycel-receiving cohort.

The size of the Phase II study was small and its design was a non-comparative, parallel group randomized trial. When patients in the letrozole-only arm progressed, they could switch to the Sprycel arm. Similarly, if patients experience adverse events to Sprycel they could not tolerate, they could switch to just letrozole. This could have impacted the study findings.

While most patients tolerated the full Sprycel dose (100 mg), 27 percent needed a dose reduction. Meanwhile, researchers crossed over 35 patients on letrozole who progressed on the single agent to receive Sprycel plus letrozole, and 23 percent had a clinical benefit rate.

"This data suggest that maybe dasatinib is inhibiting the emergence of acquired resistance to oral aromatase inhibitor therapy," Paul said at SABCS. Letrozole is an aromatase inhibitor commonly given to hormone receptor-positive breast cancer patients after surgery. He noted, however, that other studies have shown that Sprycel doesn't seem to extend progression-free survival in metastatic breast cancer patients previously treated with aromatase inhibitors, suggesting that the response to Sprycel may be most pronounced in those receiving aromatase inhibitors for the first time.

Despite the positive impact of Sprycel and letrozole on progression-free survival, Paul and colleagues noted the need for a biomarker that is associated with Src activity in breast tumors and that healthcare providers can measure to identify best responders to the regimen. Researchers are looking for biomarkers in archived breast cancer patients' tissues to help inform patient selection for future studies, Paul said at the meeting.

Paul told PGx Reporter that BMS is searching for a Src biomarker, but the firm hasn't yet identified it precisely. BMS has“narrowed it down to eight or nine [markers], and it seems to be tissue specific,” he said. “It might be all eight or nine that we need, or they may narrow it down further.”

The US Food and Drug Administration approved Sprycel first in 2006 as treatment for chronic phase CML and Philadelphia chromosome-positive ALL patients who are resistant or intolerant to previous therapy. Then in 2010, the agency again okayed the drug for chronic phase, Philadelphia chromosome-positive CML. By inhibiting proteins, such as Bcr-Abl and Src, which spur growth of cancer cells, the drug enables the bone marrow of leukemia patients to produce red and white blood cells.

BMS is studying Sprycel in a number of different cancers, and breast cancer is a main focus. In partnership with MD Anderson Cancer Center, BMS is studying Sprycel in combination with zoledronic acid in breast cancer patients with bone metastasis. The partners are also investigating if Sprycel can decrease the level of biomarkers known to drive breast cancer and prevent the spread of the disease to the unaffected breast. BMS is studying the drug in advanced triple-negative breast cancer patients and those with HER2-positive, hormone receptor-positive patients.

Sprycel garnered more than $1 billion in sales last year. The drug, which has patent exclusivity until 2020, is projected to bring in nearly $2 billion for BMS by 2018.

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