Torisel Approved For the Treatment of Relapsed or Refractory Mantle Cell Lymphoma

Pfizer Healthcare Ireland are pleased to announce the approval of Torisel for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL). The recent approval was based on results of a phase III clinical study that showed patients with relapsed and/or refractory MCL treated with Torisel experienced a statistically significant improvement in median progression-free survival, compared with standard single agent chemotherapy.

Mantle cell lymphoma is a rare subset of non-Hodgkin’s lymphoma that is characterised by diffuse lymph node involvement, advanced stage of cancer at diagnosis, bone marrow involvement, and lymphoma cancer cells in the blood. It accounts for approximately 6% of non-Hodgkin’s lymphoma cases and has the lowest five-year survival of any type of lymphoma. More than half of patients with MCL will respond to initial treatment, but the responses are typically short, and patients have an average survival of less than three years from diagnosis. Many chemotherapy agents have shown activity against MCL but have not improved overall average survival rates beyond three years.
Temsirolimus (Torisel) is a dihydroester of rapamycin that inhibits mTOR (mammalian target of rapamycin) kinase, an important regulator of cell proliferation, cell growth and cell survival. Inhibition of mTOR also results in reduced levels of vascular endothelial growth factor (VEGF) and other growth factors involved in angiogenesis. On a molecular level, mantle cell lymphoma is characterised by an overexpression of cyclin D1 mRNA, the translation of which is thought to be regulated by the mTOR (mammalian target of rapamycin) kinase pathway. It is on the basis of this hypothesis that Torisel was originally evaluated in patients with MCL.
Study Design
The purpose of this randomised, multicenter, open-label, phase III study was to evaluate temsirolimus therapy in comparison with standard single-agent therapy in relapsed or refractory MCL. To explore a dose-response relationship, two different dose regimens of temsirolimus were chosen, and each was compared with prospectively approved investigator’s choice therapy. The composition of the competitor arm was chosen to reflect daily practice and, therefore, allowed clinically relevant comparison of the experimental arms with established treatment options.
A total of 162 patients with relapsed or refractory MCL were randomly assigned to receive either:
• temsirolimus 175mg weekly for 3 weeks followed by 75mg weekly (175/75mg)
• temsirolimus 175mg weekly for 3 weeks followed by 25mg weekly (175/25mg)
• investigator’s choice therapy from prospectively approved options
The primary end point was progression-free survival by independent assessment.
Treatment With Torisel Improves Progression-Free Survival
The key results from the study were as follows:
• Median progression-free survival was 4.8 months, 3.4 months, and 1.9 months for the temsirolimus 175/75mg, temsirolimus 175/25mg, and investigator’s choice groups, respectively.
• Patients treated with temsirolimus 175/75mg had significantly longer PFS than those treated with investigator’s choice therapy (p=0.0009; hazard ratio = 0.44).
• Patients treated with temsirolimus 175/25mg showed a trend toward longer PFS (p=0.0618; hazard ratio = 0.65).
• The objective response rate was significantly higher in the 175/75mg group (22%) compared with the investigator’s choice group (2%; p=0.0019).
• Median overall survival for the temsirolimus 175/75mg group and the investigator’s choice group was 12.8 months and 9.7 months, respectively (p=0.3519).
• The most frequent grade 3 or 4 adverse events in the temsirolimus groups were thrombocytopenia, anaemia, neutropenia, and asthenia.
Conclusion
With current treatment approaches, MCL remains an incurable disease, and refractoriness to available therapy options is frequently observed late in its course. Therefore, new treatment approaches are needed. This study is the only randomised phase III study of a single agent in relapsed or refractory MCL. It demonstrated the value of mTOR inhibition in MCL and showed that temsirolimus 175mg-75mg conferred a statistically significant improvement in progression-free survival and objective response rate in comparison with standard chemotherapeutic single agents.
“Relapsed and refractory mantle cell lymphoma is a difficult-to-treat disease, and the ability of Torisel to improve progression-free survival makes it an important new therapeutic option for patients living with this condition,” said Georg Hess, M.D., Johannes Gutenberg-Universitat, Mainz, Germany, an investigator in the Torisel phase III clinical program.
Reference: 1- Hess et al. Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009. Aug 10; 27(23):3822-9.
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