By Cameron Johnston
CHICAGO -- June 6, 2008 -- Using a high dose of temsirolimus for treatment of mantle cell carcinoma may have therapeutic activity beyond what is currently seen with most other therapies, according to results of a phase 3 study presented here at the American Society of Clinical Oncology (ASCO) 44th Annual Meeting.
Mantle cell carcinoma is an uncommon and highly refractory sub-type of B-cell non-Hodgkin's lymphoma. At this time, there is no generally accepted standard of care, and relapses and recurrences are common with 5-year survival of about 25%.
Temsirolimus is a specific inhibitor of mammalian target of rapamycin kinase, which works by inhibiting the translation of several key proteins that regulate cell cycle progression and angiogenesis, explained Georg Hess, MD, Gutenburg University, Mainz, Germany, in a presentation on June 3.
Dr. Hess and colleagues compared 2 dosing regimens of temsirolimus against a wide array of other therapies that have been used to treat the condition.
In the study, patients who had already failed at least 2 therapies with either rituximab, anthracyclines, or an alkylating agent were randomised to treatment with 1 of 3 regimens: (1) temsirolimus 175 mg every 3 weeks followed by 75 mg weekly; (2) temsirolimus 175 mg every 3 weeks followed by 25 mg weekly; (3) any other single agent of the investigator's choice.
The most common investigator-assigned drugs were gemcitabine (42%) and fludarabine (26%), followed by chlorambucil, vinblastine, alemtuzumab, cladribine, cyclophosphamide, lenalidomide, and thalidomide.
The treatments were administered until disease progression, death, or unacceptable toxicity.
The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints were overall survival, objective response rates, and safety. The study enrolled 162 patients from 113 sites in 18 countries.
Patients were matched for demographic characteristics. Mean age was 68 years; two-thirds of subjects were male, which was expected with this disease; about 80% had Karnofsky performance score >80; one-fifth to one-third had had prior stem cell transplantation; 44% to 50% of patients had stage IV disease at baseline.
There was considerable variation in response rates, ranging from 22% among patients who received the higher dose of temsirolimus to 6% at the lower dose, and 2% among patients who were treated with the investigator's choice.
A partial response was seen in 11 patients at the 175/75-mg dose compared with 3% in the 175/25-mg dose. One patient treated with the investigator's choice had an objective response, and that was a complete response seen in 1 patient who was being treated with gemcitabine, according to the researchers.
At analysis, median duration of response was 7.1 months for the high-dose temsirolimus arm, 3.6 months for the low-dose arm, and could not be established for patients in the investigator's choice arm.
The difference in objective response rates was statistically significant comparing the high-dose temsirolimus arm against the investigator's choice, but there was no difference between the low-dose temsirolimus arm and the investigator's choice arm.
Median PFS was 4.8 months for patients receiving the higher dose of temsirolimus and 1.9 months for patients in the investigator's choice arm (P = .0009). There was no difference in median PFS between the lower dose of temsirolimus and the investigator's choice.
In an additional follow-up in February 2008, median overall survival was 13.6 months for patients given the higher dose of temsirolimus, 10.0 months for those given the lower dose of temsirolimus, and 9.7 months for given the investigator's choice. Although there was a 4-month prolongation of overall survival, this difference was not significant, according to the researchers.
As for safety concerns, 80% in each group experienced at least some grade 3 or 4 adverse events. Thrombocytopenia occurred more often in the temsirolimus arms compared with the investigator's choice arm, but neutropenia was more frequent in the investigator's choice patients. Despite the higher neutropenia rates in investigator's choice patients, more infections were seen in patients receiving temsirolimus. Epistaxis was also more frequent in patients receiving either dose of temsirolimus.
The improvements seen in progression-free survival and objective response rates were significant, he noted, and although there was a measurable difference in overall survival, this was not statistically significant.
This study shows that temsirolimus is effective in treating relapsed refractory mantle cell carcinoma, and that this proof of concept justifies a larger phase 3 trial, Dr. Hess concluded.
[Presentation title: Phase III Study of Patients With Relapsed, Refractory Mantle Cell Lymphoma Treated With Temsirolimus Compared With Investigator's Choice Therapy. Abstract 8513]
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