Adding temsirolimus (Torisel) to letrozole did not improve progression-free survival in patients with aromatase inhibitor–naive, estrogen receptor (ER)-positive advanced breast cancer, but exploratory analysis indicated the combination could benefit postmenopausal patients ≤ 65. In their Journal of Clinical Oncology report, Antonio C. Wolff, MD, of Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore, and coauthors noted the need for external confirmation of the benefit seen in the exploratory analysis.
In the phase III HORIZON study, 1,112 patients were randomized to receive first-line oral letrozole at 2.5 mg daily plus temsirolimus at 30 mg daily (5 days every 2 weeks) vs letrozole plus placebo. (The overall study was negative.) “Patients had histologically and/or cytologically confirmed ER-positive breast cancer with evidence of locally advanced or metastatic disease (stage IIIB/C or IV) and one or more measurable lesions by Response Evaluation Criteria in Solid Tumors (RECIST),” the investigators reported. The median age of patients was 63 years.
In the HORIZON exploratory analysis, patients aged ≤ 65 years receiving letrozole/temsirolimus showed improved progression-free survival over those receiving letrozole/placebo—9.0 vs 5.6 months (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.60–0.93, P = .009). Thus, the investigators performed subpopulation treatment effect pattern plot (STEPP) analyses to further examine possible interaction of age and mTOR inhibition. These analyses showed a consistent benefit in progression-free survival favoring the investigational arm for younger postmenopausal women (P = .003 for interaction). Results were consistent across time (ie, 5-, 6-, 7-, 8-, or 9-month progression-free survival).
The HORIZON trial was stopped at the second predefined interim analysis when the Independent Data Monitoring Committee concluded that the study was unlikely to reach its progression-free survival primary endpoint. The study was first reported in abstract/poster form at the 26th Annual San Antonio Breast Cancer Symposium in December 2006, and the data published in the current JCOarticle correspond to the final data lock from December 2006, with a median follow-up of 9.5 months and a range of 0 to 27.2 months. The data showed no overall improvement in progression-free survival among patients receiving letrozole/temsirolimus, although they experienced more toxicities.
The authors noted that their findings contrast with the progression-free survival benefit seen in the Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study that tested another mTOR inhibitor, everolimus (Afinitor), plus the steroidal aromatase inhibitor exemstane. They speculated that prior exposure to aromatase inhibitors “partly explains the different results observed in these two studies.” Eligibility for BOLERO-2 “required progression on a nonsteroidal [aromatase inhibitor] during or within 12 months of completing adjuvant therapy or within 1 month if in the metastatic setting,” the authors noted, whereas the HORIZON study excluded patients who had taken aromatase inhibitors within 12 months. Alternative reasons given to explain the different outcomes of the two trials included “temsirolimus itself or its dosing, route, and/or schedule of administration” and “intrinsic tumor factors associated or not with prior [aromatase inhibitor] exposure.”
Learning from Negative Studies
“The HORIZON study reminds us that we may learn as much from negative studies as from positive ones and that it is important to apply results to the clinical population shown to benefit from the intervention,” E. Claire Dees, MD, and Lisa A. Carey, MD, of Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, wrote in an editorial accompanying the article. “It is increasingly clear that ER-positive disease is heterogeneous,” they concluded, “and that endocrine resistance is a complex problem that will likely require highly translational trials to solve.” ■