|Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors; ATC code: L01X E09|
Mechanism of actionTemsirolimus is a selective inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein/temsirolimus complex binds and inhibits the activity of mTOR that controls cell division. In vitro, at high concentrations (10-20 μM), temsirolimus can bind and inhibit mTOR in the absence of FKBP-12. Biphasic dose response of cell growth inhibition was observed. High concentrations resulted in complete cell growth inhibition in vitro, whereas inhibition mediated by FKBP-12/temsirolimus complex alone resulted in approximately 50% decrease in cell proliferation. Inhibition of mTOR activity results in a G1 growth delay at nanomolar concentrations and growth arrest at micromolar concentrations in treated tumour cells resulting from selective disruption of translation of cell cycle regulatory proteins, such as D-type cyclins, c-myc, and ornithine decarboxylase. When mTOR activity is inhibited, its ability to phosphorylate, and thereby control the activity of protein translation factors (4E-BP1 and S6K, both downstream of mTOR in the P13 kinase/AKT pathway) that control cell division, is blocked. In addition to regulating cell cycle proteins, mTOR can regulate translation of the hypoxia-inducible factors, HIF-1 and HIF-2 alpha. These transcription factors regulate the ability of tumours to adapt to hypoxic microenvironments and to produce the angiogenic factor vascular endothelial growth factor (VEGF). The anti-tumour effect of temsirolimus, therefore, may also in part stem from its ability to depress levels of HIF and VEGF in the tumour or tumour microenvironment, thereby impairing vessel development.
Clinical efficacy and safety
Renal cell carcinomaThe safety and efficacy of Torisel in the treatment of advanced renal cell carcinoma were studied in the following two randomised clinical trials:
RCC Clinical Trial 1RCC Clinical Trial 1 was a phase 3, multi-centre, three-arm, randomised, open-label study in previously untreated patients with advanced renal cell carcinoma and with 3 or more of 6 pre-selected prognostic risk factors (less than one year from time of initial renal cell carcinoma diagnosis to randomisation, Karnofsky performance status of 60 or 70, haemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dl, lactate dehydrogenase>1.5 times the upper limit of normal, more than one metastatic organ site). The primary study endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), clinical benefit rate, time to treatment failure (TTF), and quality adjusted survival measurement. Patients were stratified for prior nephrectomy status within three geographic regions and were randomly assigned (1:1:1) to receive IFN-α alone (n = 207), temsirolimus alone (25 mg weekly; n = 209), or the combination of IFN-α and temsirolimus (n = 210). In RCC Clinical Trial 1, temsirolimus 25 mg was associated with a statistically significant advantage over IFN-α in the primary endpoint of OS at the 2nd pre-specified interim analysis (n = 446 events, p = 0.0078). The temsirolimus arm showed a 49% increase in median OS compared with the IFN-α arm. Temsirolimus also was associated with statistically significant advantages over IFN-α in the secondary endpoints of PFS, TTF, and clinical benefit rate.The combination of temsirolimus 15 mg and IFN-α did not result in a significant increase in overall survival when compared with IFN-α alone at either the interim analysis (median 8.4 vs. 7.3 months, hazard ratio = 0.96, p = 0.6965) or final analysis (median 8.4 vs. 7.3 months, hazard ratio = 0.93, p = 0.4902). Treatment with the combination of temsirolimus and IFN-α resulted in a statistically significant increase in the incidence of certain grade 3-4 adverse events (weight loss, anaemia, neutropaenia, thrombocytopaenia and mucosal inflammation) when compared with the adverse events observed in the IFN-α or temsirolimus -alone arms.
CI = confidence interval; NA = not applicable.a Based on log-rank test stratified by prior nephrectomy and region.b Based on Cox proportional hazard model stratified by prior nephrectomy and region (95% CI are descriptive only).c Based on Cochran-Mantel-Hansel test stratified by prior nephrectomy and region.In RCC Clinical Trial 1, 31% of patients treated with temsirolimus were 65 or older. In patients younger than 65, median overall survival was 12 months (95% CI 9.9, 14.2) with a hazard ratio of 0.67 (95% CI 0.52, 0.87) compared with those treated with IFN-α. In patients 65 or older, median overall survival was 8.6 months (95% CI 6.4, 11.5) with a hazard ratio of 1.15 (95% CI 0.78, 1.68) compared with those treated with IFN-α.
|Summary of efficacy results in temsirolimus RCC clinical trial 1 |
|Parameter ||temsirolimus n = 209
||IFN-αn = 207
||P-valuea||Hazard ratio(95% CI)b|
|Pre-specified interim analysis |
|Median overall survival,
Months (95% CI)
||10.9 (8.6, 12.7)
||7.3 (6.1, 8.8)
||0.73 (0.58, 0.92)
|Final analysis |
|Median overall survival,
Months (95% CI)
||10.9 (8.6, 12.7)
||7.3 (6.1, 8.8)
||0.78 (0.63, 0.97)
|Median progression-free survival by independent assessment Months (95% CI)
||5.6 (3.9, 7.2)
||3.2 (2.2, 4.0)
||0.74 (0.60, 0.91)
|Median progression-free survival by investigator assessment Months (95% CI)
||3.8 (3.6, 5.2)
||1.9 (1.9, 2.2)
||0.74 (0.60, 0.90)
|Overall response rate by independent assessment % (95% CI)
||9.1 (5.2, 13.0)
||5.3 (2.3, 8.4)
RCC Clinical Trial 2RCC Clinical Trial 2 was a randomised, double-blind, multi-centre, outpatient trial to evaluate the efficacy, safety, and pharmacokinetics of three dose levels of temsirolimus when administered to previously treated patients with advanced renal cell carcinoma. The primary efficacy endpoint was ORR, and OS was also evaluated. One hundred eleven (111) patients were randomly assigned in a 1:1:1 ratio to receive 25 mg, 75 mg, or 250 mg temsirolimus intravenous weekly. In the 25 mg arm (n = 36), all patients had metastatic disease; 4 (11%) had no prior chemo- or immunotherapy; 17 (47%) had one prior treatment, and 15 (42%) had 2 or more prior treatments for renal cell carcinoma. Twenty-seven (27, 75%) had undergone a nephrectomy. Twenty-four (24, 67%) were Eastern Cooperative Oncology Group (ECOG) performance status (PS) = 1, and 12 (33%) were ECOG PS = 0. For patients treated weekly with 25 mg temsirolimus OS was 13.8 months (95% CI: 9.0, 18.7 months); ORR was 5.6% (95% CI: 0.7, 18.7%).
Mantle cell lymphomaThe safety and efficacy of intravenous temsirolimus for the treatment of relapsed and/or refractory mantle cell lymphoma were studied in the following phase 3 clinical study.
MCL Clinical TrialMCL Clinical Trial is a controlled, randomised, open-label, multicenter, outpatient study comparing 2 different dosing regimens of temsirolimus with an investigator's choice of therapy in patients with relapsed and/or refractory mantle cell lymphoma. Subjects with mantle cell lymphoma (that was confirmed by histology, immunophenotype, and cyclin D1 analysis) who had received 2 to 7 prior therapies that included anthracyclines and alkylating agents, and rituximab (and could include haematopoietic stem cell transplant) and whose disease was relapsed and/or refractory were eligible for the study. Subjects were randomly assigned in a 1:1:1 ratio to receive temsirolimus intravenous 175 mg (3 successive weekly doses) followed by 75 mg weekly (n = 54), temsirolimus intravenous 175 mg (3 successive weekly doses) followed by 25 mg weekly (n=54), or the investigator's choice of single-agent treatment (as specified in the protocol; n = 54). Investigator's choice therapies included: gemcitabine (intravenous : 22 [41.5%]), fludarabine (intravenous : 12 [22.6%] or oral: 2 [3.8%]), chlorambucil (oral: 3 [5.7%]), cladribine (intravenous: 3 [5.7%]), etoposide (intravenous: 3 [5.7%]), cyclophosphamide (oral: 2 [3.8%]), thalidomide (oral: 2 [3.8%]), vinblastine (intravenous: 2 [3.8%]), alemtuzumab (intravenous: 1 [1.9%]), and lenalidomide (oral: 1 [1.9%]). The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent radiologist and oncology review. Secondary efficacy endpoints included overall survival (OS) and objective response rate (ORR).The results for the MCL Clinical Trial are summarized in the following table. Temsirolimus 175/75 (temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly) led to an improvement in PFS compared with investigator's choice in patients with relapsed and/or refractory mantle cell lymphoma that was statistically significant (hazard ratio = 0.44; p-value = 0.0009). Median PFS of the temsirolimus 175/75 mg group (4.8 months) was prolonged by 2.9 months compared to the investigator's choice group (1.9 months). Overall survival was similar. Temsirolimus also was associated with statistically significant advantages over investigator's choice in the secondary endpoint of overall response rate (ORR). The evaluations of PFS and ORR were based on blinded independent radiologic assessment of tumour response using the International Workshop Criteria.
a Compared with INV CHOICE based on Cox proportional hazard model. b Disease assessment is based on radiographic review by independent radiologists and review of clinical data by independent oncologists.c Compared with INV CHOICE based on log-rank test.d Compared with INV CHOICE alone based on Fisher's exact test.Abbreviations: CI = confidence interval; NA = not applicable.The temsirolimus 175 mg (3 successive weekly doses) followed by 25 mg weekly treatment arm did not result in a significant increase in PFS when compared with investigator's choice (median 3.4 vs. 1.9 months, hazard ratio = 0.65, CI = 0.39, 1.10, p = 0.0618).In the MCL Clinical Trial, there was no difference in efficacy in patients with respect to age, sex, race, geographic region, or baseline disease characteristics.
|Summary of efficacy results in temsirolimus MCL clinical trial|
|Parameter||Temsirolimus Concentrate for Injection175/75 mg
n = 54
||Investigator's Choicen = 54
||P-value||Hazard Ratio (97.5% CI)a|
|Median progression-free survivalbMonths (97.5% CI)
||4.8 (3.1, 8.1)
||1.9 (1.6, 2.5)
||0.0009c||0.44 (0.25, 0.78)
|Objective response rateb% (95% CI)
||22.2 (11.1, 33.3)
||1.9 (0.0, 5.4)
|Overall survivalMonths (95% CI)||12.8 (8.6, 22.3)
||10.3 (5.8, 15.8)
||0.2970c||0.78 (0.49, 1.24)
|One-year survival rate% (97.5% CI)
||0.47 (0.31, 0.61)
||0.46 (0.30, 0.60)
|| || |
Paediatric populationIn a phase 1/2 safety and exploratory efficacy study, 71 patients (59 patients, aged from 1 to 17 years, and 12 patients, aged from 18 to 21 years) received temsirolimus as a 60-minute intravenous infusion once weekly in three-week cycles. In part 1, 14 patients aged from 1 to 17 years with advanced recurrent/refractory solid tumours received temsirolimus at doses ranging from 10 mg/m2 to 150 mg/m2. In part 2, 45 patients aged from 1 to 17 years with recurrent/relapsed rhabdomyosarcoma, neuroblastoma, or high grade glioma were administered temsirolimus at a weekly dose of 75 mg/m2. Adverse events were generally similar to those observed in adults (see section 4.8).Temsirolimus was found to be ineffective in paediatric patients with neuroblastoma, rhabdomyosarcoma, and high-grade glioma (n = 52). For subjects with neuroblastoma, the objective response rate was 5.3% (95% CI: 0.1%, 26.0%). After 12 weeks of treatment, no response was observed in subjects with rhabdomyosarcoma or high-grade glioma. None of the 3 cohorts met the criterion for advancing to the second stage of the Simon 2-stage design.The European Medicines Agency has waived the obligation to submit the results of studies with Torisel in all subsets of the paediatric population in MCL (see section 4.2 on paediatric use).