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Oral temsirolimus combined with letrozole failed to improve PFS
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The addition of oral temsirolimus to letrozole as a first-line treatment did not improve PFS in patients with aromatase inhibitor-naive metastatic breast cancer, according to results from a phase 3 study.
Tamoxifen is widely considered the primary treatment option for patients with ER-positive metastatic breast cancer. Still, most patients have disease progression. Aromatase inhibitors temporarily improve clinical outcomes and significantly block estrogen biosynthesis. The mTOR inhibitor temsirolimus (Toricel, Wyeth Pharmaceuticals) showed clinical activity in heavily pretreated metastatic breast cancer, according to background information in the study.
For this randomized, double blind study, researchers examined the efficacy and safety of adding oral temsirolimus to letrozole in postmenopausal, aromatase inhibitor-naive women with ER-positive and/or PR-positive locally advanced breast cancer.
Antonio C. Wolff, MD, professor of oncology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, and colleagues randomly assigned patients to 2.5 mg of letrozole once daily plus 30 mg of oral temsirolimus for 5 days every 2 weeks (n=550) or letrozole plus placebo (n=553).
Median patient age was 63 years, and median follow-up was 9.5 months.
At the second predefined interim analysis, the Independent Data Monitoring Committee found the study was unlikely to reach its primary PFS endpoint and recommended the study’s termination in March 2006. The results reported correspond to the December 2006 data lock.
The median PFS for patients in the letrozole/temsirolimus arm was 8.9 months compared with 9 months for patients in the placebo arm (P=.25).
Data from an exploratory analysis showed patients the letrozole/temsirolimus regimen conferred longer PFS among patients aged 65 years or younger (9 months vs. 5.6 months; P=.009).
Patients in the letrozole plus temsirolimus arm experienced more grade 3 and 4 toxicities than patients in the placebo arm (37% vs. 24%).
“Despite single-agent activity when given intravenously in patients with advanced breast cancer, oral temsirolimus failed to improve PFS when added to letrozole in [aromatase inhibitor]-naive postmenopausal patients as first-line therapy for advanced ER-positive breast cancer,” Wolff and colleagues concluded.
Previous research indicated a PFS benefit when everolimus was added to exemestane in patients with advanced breast cancer who experienced disease progression after nonsteroidal aromatase inhibitors. Researchers speculated that prior exposure to aromatase inhibitors may explain the contrasting results between the current investigation and prior studies.
In an accompanying editorial, E. Claire Dees, MD, of the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill, said researchers learn as much from negative studies as positive ones.
“At this point, the cumulative experience suggests that targeting mTOR should be limited to populations with acquired [aromatase inhibitor] resistance and should use everolimus, not others in the class,” Dees wrote.
Disclosure: The researchers report consulting and employment relationships with, stock ownership in, and funding/honoraria from Eli Lilly, Genentech, GlaxoSmithKline, Novartis, Pfizer, Roche and Wyeth Research.
Perspective
Back to TopAdam M. Brufsky, MD, PhD, FACP
This is very interesting and suggests that the type of mTOR inhibitor used in trials of this type may be important. There is preclinical data to support this conclusion.
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