Temsirolimus (Torisel)
Number: 0873
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
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Criteria for Initial Approval
Aetna considers temsirolimus (Torisel) medically necessary for any of the following indications:
- Renal Cell Carcinoma - as a single agent for treatment of advanced, relapsed, or stage IV renal cell carcinoma; or
- Endometrial carcinoma - as a single agent for subsequent treatment of recurrent endometrial carcinoma; or
- Soft tissue sarcoma
- For treatment of any of the following subtypes of soft tissue sarcoma as single agent therapy: locally advanced unresectable or metastatic perivascular epithelioid cell tumor (PEComa), recurrent angiomyolipoma, or recurrent lymphangioleiomyomatosis; or
- For treatment of rhabdomyosarcoma in combination with cyclophosphamide and vinorelbine.
- Mantle cell lymphoma - for treatment of relapsed or refractory mantle cell lymphoma
- Uterine sarcoma - as a single agent for subsequent treatment of advanced, recurrent/metastatic or inoperable PEComa.
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
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Continuation of Therapy
Aetna considers continuation of temsirolimus (Torisel) therapy for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.
Dosage and Administration
Advanced Renal Cell Carcinoma
The recommended dose is 25 mg administered as an intravenous infusion over a 30‐60 minute period once a week. Treat until disease progression or unacceptable toxicity.
Source: Wyeth, 2018
Experimental and Investigational
Aetna considers temsirolimus (Torisel) experimental and investigational for all other indications including the following (not an all-inclusive list):
- Acute lymphoblastic leukemia
- Adenoid cystic carcinoma
- Alzheimer's disease
- B-cell non-Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma, and follicular lymphoma)
- Bladder cancer
- Breast cancer
- Central nervous system tumors (e.g., ependymoma, gliomas/glioblastoma multiforme, lymphoma, medulloblastoma, and pontine glioma)
- Cervical cancer
- Cholangiocarcinoma
- Colorectal cancer
- COVID-19 therapy
- Desmoplastic small round cell tumor
- Fallopian tube serous carcinoma
- Ewing sarcoma
- Head and neck squamous cell carcinoma (nasopharyngeal carcinoma, and oropharyngeal squamous cell carcinoma)
- Hepatoblastoma
- Hepatocellular carcinoma
- Leiomyosarcoma
- Lung cancer (e.g., lung adenocarcinoma, and non-small cell lung cancer)
- Melanoma
- Multiple myeloma
- Myelodysplastic syndromes
- Neuroblastoma
- Neuroendocrine tumors (e.g., neuroendocrine of pancreas)
- Osteosarcoma
- Ovarian cancer
- Pancreatic cancer
- Parkinson's disease
- Prostate cancer
- Retinoblastoma
- Salivary gland muco-epidermoid carcinoma
- Thyroid cancer
- Vaginal cancer
Aetna considers temsirolimus (Torisel) for the endovascular treatment of atherosclerotic lesions of below-the-knee arteries (e.g., popliteal and tibial/peroneal arteries) experimental and investigational.
| Code | Code Description |
|---|---|
Other CPT codes related to the CPB: |
|
| 96409 | Chemotherapy administration; intravenous, push technique, single or initial substance/drug |
| 96413 - 96417 | Chemotherapy administration; intravenous infusion technique |
HCPCS codes covered if selection criteria are met: |
|
| J9330 | Injection, temsirolimus, 1 mg (Torisel) |
Other HCPCS codes related to the CPB: |
|
| J9070 | Cyclophosphamide, 100 mg |
| J9390 | Injection, vinorelbine tartrate, 10 mg |
ICD-10 codes covered if selection criteria are met: |
|
| C49.8 - C49.9 | Malignant neoplasm of connective and soft tissue |
| C53.0 – C54.0, C54.2 – C55 | Malignant neoplasm of uterus |
| C54.1 | Malignant neoplasm of endometrium |
| C64.1 - C65.9 | Malignant neoplasm of kidney and renal pelvis |
| C83.10 - C83.19 | Mantle cell lymphoma |
| D49.2 | Neoplasm of unspecified behavior of bone, soft tissue, and skin |
| J84.81 | Lymphangioleiomyomatosis |
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive): |
|
| C10.0 – C10.9 | Malignant neoplasm of oropharynx |
| C11.0 - C11.9 | Malignant neoplasm of nasopharynx |
| C22.2 | Hepatoblastoma |
| C25.0 - C25.9 | Malignant neoplasm of pancreas |
| C57.00 – C57.02 | Malignant neoplasm of fallopian tube |
| C69.20 - C69.22 | Malignant neoplasm of retina |
| C07 | Malignant neoplasm of parotid gland |
| C73 | Malignant neoplasm of thyroid gland |
| C08.0 – C08.9 | Malignant neoplasm of other and unspecified major salivary glands |
| C83.30 - C83.39 | Diffuse large B-cell lymphoma [primary CNS lymphoma] |
| C83.80 - C83.89 | Other non-follicular lymphoma [primary CNS lymphoma] |
| C85.80 - C85.89 | Other specified types of non-Hodgkin lymphoma [primary CNS lymphoma] |
| C90.00 – C90.02 | Multiple myeloma |
| C91.0 - C91.02 | Acute lymphoblastic leukemia (ALL) |
| D09.3 | Carcinoma in situ of thyroid and other endocrine glands |
| D46.0 - D46.9 | Myelodysplastic syndromes |
| D48.1 | Malignant neoplasm of specified parts of peritoneum [Desmoplastic small round cell tumor] |
| G20 | Parkinson’s disease |
| I70.291 – I70.299 | Other atherosclerosis of native arteries of extremities [atherosclerotic lesions of below-the-knee arteries] |
| U07.1 | COVID-19 |
Background
U.S. Food and Drug Administration (FDA)-Approved Indications
- Advanced renal cell carcinoma (RCC)
Compendial Uses
- Relapsed or stage IV renal cell carcinoma
- Endometrial carcinoma
- Soft tissue sarcoma subtypes:
- Perivascular epithelioid cell tumors (PEComa)
- Rhabdomyosarcoma
- Angiomyolipoma
- Lymphangioleiomyomatosis
- Mantle cell lymphoma (MCL)
- Uterine sarcoma
Temsirolimus (Torisel) is contraindicated in patients with bilirubin > 1.5 x ULN (Wyeth, 2018).
Per the prescribing information, temsirolimus (Torisel) carries the following warnings and precautions:
- Hypersensitivity/infusion reactions (including some life-threatening and rare fatal reactions)
- Hepatic impairment
- Hyperglycemia and hyperlipidemia
- Infections may result from immunosuppression.
- Symptoms or radiographic changes of interstitial lung disease (ILD)
- Bowel perforation may occur.
- Renal failure, sometimes fatal, has occurred.
- Use cautiously in the perioperative period due to abnormal would healing
- Proteinuria and nephrotic syndrome may occur
- Live vaccinations and close contact with those who received live vaccines should be avoided
- Embryo-fetal toxicity
- Elderly patients may be more prone to the adverse events of diarrhea, edema and pneumonia.
The most common adverse reactions (occurrence ≥ 30%) include rash, asthenia, mucositis, nausea, edema, and anorexia. The most common laboratory abnormalities (occurrence ≥ 30%) include anemia, hyperglycemia, hyper lipidemia, hypertriglyceridemia, elevated alkaline phosphatase, elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia (Wyeth, 2018).
Acute Lymphoblastic Leukemia
In a phase I clinical trial, Rheingold and colleagues (2017) noted that the phosphatidylinositol 3-kinase (PI3K)/mTOR signaling pathway is commonly dysregulated in acute lymphoblastic leukemia (ALL). These researchers studied the use of temsirolimus in combination with UKALL R3 re-induction chemotherapy in children and adolescents with second or greater relapse of ALL. The initial temsirolimus dose level (DL1) was 10 mg/m2 weekly × 3 doses. Subsequent patient cohorts received temsirolimus 7.5 mg/m2 weekly × 3 doses (DL0) or, secondary to toxicity, 7.5 mg/m2 weekly × 2 doses (DL-1). A total of 16 patients were enrolled, 15 were evaluable for toxicity; DLT occurred at all 3 dose levels and included hyper-triglyceridemia, mucositis, ulceration, hypertension with reversible posterior leukoencephalopathy, elevated gamma-glutamyltransferase or alkaline phosphatase and sepsis. The addition of temsirolimus to UKALL R3 re-induction therapy resulted in excessive toxicity and was not tolerable in children with relapsed ALL. However, this regimen induced remission in 7 of 15 patients; 3 patients had minimal residual disease levels of less than 0.01 %. The authors concluded that inhibition of PI3K signaling was detected in patients treated at all dose levels of temsirolimus, but inhibition at an early time-point did not appear to correlate with clinical responses at the end of re-induction therapy. These preliminary findings need to be further investigated in phase II/III clinical trials.
Tasian et al (2022) stated that PI3K/mTOR signaling is commonly dysregulated in ALL. The TACL2014-001 phase-I clinical trial of temsirolimus in combination with cyclophosphamide and etoposide was carried out in children and adolescents with relapsed/refractory ALL. Temsirolimus was administered intravenously (IV) on days 1 and 8 with cyclophosphamide 440 mg/m2 and etoposide 100 mg/m2 IV daily days 1 to 5. The starting dose of temsirolimus was 7.5 mg/m2 (DL1) with escalation to 10 mg/m2 (DL2), 15 mg/m2 (DL3), and 25 mg/m2 (DL4). PI3K/mTOR pathway inhibition was measured by phosphor flow cytometry analysis of peripheral blood specimens from treated patients. A total of 16 heavily pre-treated patients were enrolled with 15 evaluable for toxicity. One DLT of grade-IV pleural and pericardial effusions occurred in a patient treated at DL3. Additional DLTs were not observed in the DL3 expansion or DL4 cohort. Grade-III/IV non-hematologic toxicities occurring in 3 or more patients included febrile neutropenia, elevated alanine aminotransferase, hypokalemia, mucositis, and tumor lysis syndrome and occurred across all DLs. Complete responses were observed at all DLs with a 47 % overall response rate (ORR) and 27 % CR rate. Pharmacodynamic correlative studies demonstrated dose-dependent inhibition of PI3K/mTOR pathway phosphoproteins in all studied patients. Temsirolimus at doses up to 25 mg/m2 with cyclophosphamide and etoposide had an acceptable safety profile in children with relapsed/refractory ALL. Responses were observed across all DLs. Pharmacodynamic mTOR target inhibition was achieved and appeared to correlate with temsirolimus dose. The authors concluded that future testing of next-generation PI3K/mTOR pathway inhibitors with chemotherapy may be needed to increase response rates in children with relapsed/refractory ALL.
Adenoid Cystic Carcinoma
Liu et al (2014) stated that temsirolimus acts as an mTOR-dependent autophagic inhibitor. In order to clarify its effects and mechanisms on human salivary adenoid cystic carcinoma (ACC), these researchers examined whether temsirolimus induced autophagy as the mTOR inhibitor in ACC, both in-vitro and in-vivo. In this study, MTT assay showed that the inhibition effect of temsirolimus assumed an obvious dose-response relationship on ACC-M cells, and the 50 % inhibitory concentration (IC(50)) approached 20 μmol/L; numerous autophagosomes were observed by the transmission electron microscopy in temsirolimus treatment groups; notably, expression of LC3 and Beclin1 was significantly up-regulated by temsirolimus. More importantly, the xenograft model provided further evidence of temsirolimus-induced autophagy in-vivo by inhibiting mTOR activation as well as up-regulation the expression of Beclin1. The authors concluded that these results suggested that temsirolimus could act as an mTOR inhibitor to induce autophagy in ACC both in-vitro and in-vivo.
Alzheimer's Disease
Jiang et al (2014) stated that accumulation of amyloid-β peptides (Aβ) within brain is a major pathogenic hallmark of Alzheimer's disease (AD). Emerging evidence suggested that autophagy, an important intra-cellular catabolic process, is involved in Aβ clearance. These researchers examined if temsirolimus would promote autophagic clearance of Aβ and thus provide protective effects in cellular and animal models of AD. HEK293 cells expressing the Swedish mutant of APP695 (HEK293-APP695) were treated with vehicle or 100 nM temsirolimus for 24 hours in the presence or absence of 3-methyladenine (5 mM) or Atg5-siRNA, and intra-cellular Aβ levels as well as autophagy biomarkers were measured. Meanwhile, APP/PS1 mice received intra-peritoneal injection of temsirolimus (20 mg/kg) every 2 days for 60 days, and brain Aβ burden, autophagy biomarkers, cellular apoptosis in hippocampus, and spatial cognitive functions were assessed. The results showed that temsirolimus enhanced Aβ clearance in HEK293-APP695 cells and in brain of APP/PS1 mice in an autophagy-dependent manner. Meanwhile, temsirolimus attenuated cellular apoptosis in hippocampus of APP/PS1 mice, which was accompanied by an improvement in spatial learning and memory abilities. The authors concluded that the findings of this study provided the first evidence that temsirolimus promotes autophagic Aβ clearance and exerts protective effects in cellular and animal models of AD, suggesting that temsirolimus administration may represent a new therapeutic strategy for AD treatment.
B-Cell Non-Hodgkin Lymphoma
A published 2009 multicenter, open-label, phase III study evaluated two dose regimens of temsirolimus in comparison with investigator's choice single-agent therapy in relapsed or refractory mantle cell lymphoma (MCL) in 162 patients. Patients were randomly assigned (1:1:1) to receive one of two temsirolimus regimens: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigator's choice therapy from prospectively approved options. The primary end point was progression-free survival (PFS) by independent assessment. Hess et al. found that the median PFS was 4.8, 3.4, and 1.9 months for the temsirolimus 175/75-mg, 175/25-mg, and investigator's choice groups, respectively. Patients treated with temsirolimus 175/75-mg had significantly longer PFS than those treated with investigator's choice therapy (p = .0009); those treated with temsirolimus 175/25-mg showed a trend toward longer PFS (p = .0618). Objective response rate was significantly higher in the 175/75-mg group (22%) compared with the investigator's choice group (2%; p = .0019). Median overall survival for the temsirolimus 175/75-mg group and the investigator's choice group was 12.8 months and 9.7 months, respectively (p = .3519). The most frequent grade 3 or 4 adverse events in the temsirolimus groups were thrombocytopenia, anemia, neutropenia, and asthenia. Hess and colleagues concluded that temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly significantly improved PFS and objective response rate compared with investigator's choice therapy in patients with relapsed or refractory MCL.
Fenske et al (2015) conducted a single-arm, phase II clinical trial of combined temsirolimus and bortezomib in patients with relapsed and refractory B-cell non-Hodgkin lymphoma (NHL) using a dosing scheme that was previously tested in multiple myeloma. The patients received bortezomib and temsirolimus weekly on days 1, 8, 15, and 22 of a 35-day cycle. Of 39 patients who received treatment, 3 achieved a complete response (CR) (7.7 %; 95 % CI: 1.6 % to 21 %), and 9 had a partial response (PR) (23 %; 95 % CI: 11 % to 39 %). Thus, the overall response rate (ORR; 12 of 39 patients) was 31 % (95 % CI: 17 % to 48 %), and the median PFS was 4.7 months (95 % CI: 2.1 to 7.8 months; 2 months for patients with diffuse large B-cell lymphoma [n = 18], 7.5 months for those with mantle cell lymphoma [n = 7], and 16.5 months for those with follicular lymphoma [n = 9]). Two extensively treated patients with diffuse large B-cell lymphoma achieved a CR. There were no unexpected toxicities from the combination. The authors concluded that the current results demonstrated that the combination of an mTOR inhibitor and a proteasome inhibitor is safe and has activity in patients with heavily pretreated B-cell NHL. They stated that further studies with this combination are needed in specific subtypes of NHL.
An UpToDate review on "Treatment of relapsed or refractory mantle cell lymphoma" (Freedman and Friedberg, 2023) state that temsirolimus has shown modest response rates and is used in Europe.
In a phase-I clinical trial, Pirosa et al (2022) examined the safety, tolerability, and preliminary activity of inotuzumab ozogamicin in combination with temsirolimus in patients with relapsed/refractory CD22 positive B-cell NHL. A total of 19 patients received at least 1 dose of both study drugs. DLTs consisted of thrombocytopenia, hypertriglyceridemia, oral mucositis, clinical deterioration, and the inability to receive at least 3 doses of temsirolimus during cycle 1. The most common grade-3 or higher treatment-related AEs were thrombocytopenia (n = 8), neutropenia (n = 5), and 2 patients each hyperphosphatemia, lymphopenia, and hypertriglyceridemia. The recommended phase-II dose was inotuzumab ozogamicin 0.8 mg/m2 on day 1 in combination with temsirolimus 10 mg on days 8, 15, and 22 every 28 days. Among 18 patients evaluable, 7 (39 %) with follicular lymphoma had a PR. The authors concluded that this drug combination was not possible within a therapeutically useful range of doses due to toxicities. Moreover, anti-tumor activity was observed in heavily pre-treated patients.
Major et al (2022) noted that the PI3K/Akt/mTOR (PAM) axis is constitutively activated in multiple lymphoma subtypes and is a promising therapeutic target. The mTOR inhibitor temsirolimus (TEM) and the immunomodulatory agent lenalidomide (LEN) have overlapping effects within the PAM axis with synergistic potential. In a multi-center, phase-I/II clinical trial, these researchers examined combination therapy with TEM/LEN in patients with relapsed and refractory lymphomas. Primary endpoints of the phase-II trial were CR and ORR. There were 18 patients in the phase-I dose-finding study, and TEM 25 mg weekly and LEN 20 mg on day 1 through day 21 every 28 days was established as the recommended phase-II dose. An additional 93 patients were enrolled in the phase-II component with 3 cohorts: diffuse large B-cell lymphoma (DLBCL, n = 39), follicular lymphoma (FL, n = 15), and an exploratory cohort of other lymphoma histologies with classical Hodgkin lymphoma (cHL) comprising the majority (n = 39 total, n = 20 with cHL). Patients were heavily pre-treated with a median of 4 (range of 1 to 14) prior therapies and 1/3 with relapse following autologous stem cell transplantation (ASCT); patients with cHL had a median of 6 prior therapies. The FL cohort was closed prematurely due to slow accrual; ORR were 26 % (13 % CR) and 64 % (18 % CR) for the DLBCL and exploratory cohorts, respectively. ORR for cHL patients in the exploratory cohort, most of whom had relapsed after both brentuximab vedotin and ASCT, was 80 % (35 % CR); 8 cHL patients (40 %) proceeded to allogeneic transplantation after TEM/LEN therapy. Grade-3 or higher hematologic AEs were common; and 3 grade-5 AEs occurred. The authors concluded that combination therapy with TEM/LEN was feasible and showed encouraging activity in heavily pre-treated lymphomas, especially in relapsed/refractory cHL.
Bladder Cancer
Pulido and colleagues (2018) noted that bladder cancer is the 7th cause of death from cancer in men and 10th in women. Metastatic patients have a poor prognosis with a median OS of 14 months. Until recently, vinflunine was the only 2nd-line chemotherapy available for patients who relapse. Deregulation of the PI3K/AKT/mTOR pathway was observed in more than 40 % of bladder tumors and suggested the use of mTOR as a target for the treatment of urothelial cancers. This trial assessed the efficacy of temsirolimus in a homogenous cohort of patients with recurrent or metastatic bladder cancer following 1st-line chemotherapy. Efficacy was measured in terms of non-progression at 2 months according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Based on a 2-stage optimal Simon's design, 15 non-progressions out of 51 evaluable patients were required to claim efficacy. Patients were treated at a weekly dose of 25 mg IV until progression, unacceptable toxicities or withdrawal. Among the 54 patients enrolled in the study between November 2009 and July 2014, 45 were assessable for the primary efficacy end-point. A total of 22 (48.9 %) non-progressions were observed at 2 months with 3 PRs and 19 SD. Remarkably, 4 patients were treated for more than 30 weeks. A total of 50 patients experienced at least a related grade1/2 (94 %) and 28 patients (52.8 %) a related grade 3/4 AE; 11 patients had to stop treatment for toxicity. This led to recruitment being halted by an independent data monitoring committee with regard to the risk-benefit balance and the fact that the primary objective was already met. The authors concluded that while the positivity of this trial indicated a potential benefit of temsirolimus for a subset of bladder cancer patients who are refractory to 1st-line platinum-based chemotherapy, the risk of AEs associated with the use of this mTOR inhibitor would need to be considered when such an option is envisaged in this frail population of patients. It also remains to identify patients who will benefit the most from this targeted therapy.
Breast Cancer
Qiao and colleagues (2014) performed a meta-analysis of randomized controlled trials (RCT) in breast cancer patients undergoing chemotherapy using steroid (exemestane) or non-steroid (letrozole) aromatase inhibitors with or without mTOR inhibitors (everolimus). The ORR, PFS, clinical benefit rate (CBR) with 95 % CI, and the major toxicities/adverse effects were analyzed. Data were extracted from 12 studies that meet the selection criteria. Among these, 6 studies that enrolled 3,693 women received treatment of everolimus plus exemestane, or placebo with exemestane. The results showed that everolimus plus exemestane significantly increased the ORR relative risk (relative risk [RR] = 9.18, 95 % CI: 5.21 to 16.15), PFS hazard ratio (HR = 0.44, 95 % CI: 0.41 to 0.48), and clinical benefit rate (RR = 1.92, 95 % CI: 1.69 to 2.17) compared to placebo control, while the risks of stomatitis, rash, hyperglycemia, diarrhea, fatigue, anorexia and pneumonitis also increased. Three studies that enrolled 715 women who received everolimus as neoadjuvant therapy were analyzed. Compared to chemotherapy with placebo, chemotherapy plus everolimus did not increase the ORR (RR = 0.90, 95 % CI: 0.77 to 1.05). Meanwhile, 2 other studies that enrolled 2,104 women examined the effectiveness of temsirolimus (or placebo control) plus letrozole. The results indicated that emsirolimus plus letrozole did not increase the ORR and CBR (p > 0.05). The authors concluded that these data suggested that the combined mTOR inhibitor (everolimus) plus endocrine therapy (exemestane) is superior to endocrine therapy alone. As a neoadjuvant, everolimus did not increase the ORR, while temsirolimus plus letrozole treatment has limited effect on the ORR and the CBR of breast cancer patients.
Central Nervous System Tumors
Piha-Paul et al (2014) noted that pre-clinical findings suggested that combination treatment with bevacizumab and temsirolimus could be effective against malignant pediatric central nervous system (CNS) tumors. A total of 6 pediatric patients were treated as part of a phase I trial with intravenous temsirolimus 25 mg on days 1, 8, 15, and bevacizumab at 5, 10, or 15 mg/kg on day 1 of each 21-day cycle until disease progression or patient withdrawal. The median patient age was 6 years (range of 3 to 14 years). The primary diagnoses were glioblastoma multiforme (n = 2), medulloblastoma (n = 2), pontine glioma (n = 1) and ependymoma (n = 1). All patients had disease refractory to standard-of-care (2 to 3 prior systemic therapies). Grade 3 toxicities possibly related to drugs used occurred in 2 patients: anorexia, nausea, and weight loss in 1, and thrombocytopenia and alanine aminotransferase elevation in another. One patient with glioblastoma multiforme achieved a PR (51 % regression) and 2 patients (with medulloblastoma and pontine glioma) had stable disease (SD) for 4 months or more (20 and 47 weeks, respectively). One other patient (with glioblastoma multiforme) showed 18 % tumor regression (duration of 12 weeks). The authors concluded that the combination of bevacizumab with temsirolimus was well-tolerated and resulted in SD of at least 4 months/PR in 3 out of 6 pediatric patients with chemo-refractory CNS tumors.
Wen et al (2014) stated that inhibition of epidermal growth factor receptor (EGFR) and the mTOR may have synergistic anti-tumor effects in high-grade glioma patients. These investigators conducted a phase I/II study of the EGFR inhibitor erlotinib (150 mg/day) and the mTOR inhibitor temsirolimus. Patients initially received temsirolimus 50 mg weekly, and the dose adjusted based on toxicities. In the phase II component, the primary end-point was 6-month PFS (PFS6) among glioblastoma patients. A total of 22 patients enrolled in phase I, 47 in phase II; 12 phase I patients treated at the maximum tolerated dose (MTD) were included in the phase II cohort for analysis. The MTD was 15 mg temsirolimus weekly with erlotinib 150 mg daily. Dose-limiting toxicities were rash and mucositis. Among 42 evaluable glioblastoma patients, 12 (29 %) achieved SD, but there were no responses, and PFS6 was 13 %. Among 16 anaplastic glioma patients, 1 (6 %) achieved CR, 1 (6 %) PR, and 2 (12.5 %) SD, with PFS6 of 8 %. Tumor levels of both drugs were low, and post-treatment tissue in 3 patients showed no reduction in the mTOR target phosphorylated (phospho-)S6(S235/236) but possible compensatory increase in phospho-Akt(S473). Presence of EGFR variant III, phospho-EGFR, and EGFR amplification did not correlate with survival, but patients with elevated phospho-extracellular signal-regulated kinase or reduced phosphatase and tensin homolog protein expression had decreased PFS at 4 months. The authors concluded that because of increased toxicity, the MTD of temsirolimus in combination with erlotinib proved lower than expected. Insufficient tumor drug levels and redundant signaling pathways may partly explain the minimal anti-tumor activity noted.
Schiff and associates (2018) conducted a phase 1/2 study of sorafenib and temsirolimus in patients with recurrent glioblastoma. Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with less than or equal to 2 prior chemotherapy regimens were eligible. The end-point of the phase 1 study was the MTD, using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)-naive patients and patients who progressed after prior VEGFi. The MTD was sorafenib at a dose of 200 mg twice-daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (PFS at 6 months [PFS6]) in the VEGFi-naive group (17.1 %); this finding met the pre-study threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8 %), and this did not meet the pre-study threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival (OS) for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event (AE) of grade greater than or equal to 3 was observed in 75.5 % of the VEGFi-naive patients and in 73.9 % of the prior VEGFi patients. The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade greater than or equal to 3; significant dose reductions that were needed in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy.
Kaley and colleagues (2020) stated that malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and thus a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well-tolerated as single agents; but with limited activity pre-clinical data demonstrated synergistic anti-tumor effects from combined treatment. Therefore, these researchers initiated a phase-I clinical trial of combined therapy in recurrent MGs to determine safety and a recommended phase-II dose. Adults with recurrent MG, Karnofsky Performance Status (KPS) of greater than or equal to 60 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3 + 3 design from 15 mg to 170 mg administered once-weekly. Perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly (single agent MTD) until dose level 7 when the load increased to 900 mg. These investigators treated 35 patients with glioblastoma (n = 17) or other MGs (n = 18; including 9 anaplastic astrocytoma, 9 anaplastic oligodendroglioma, 1 anaplastic oligoastrocytoma, and 2 low-grade astrocytomas with radiographic transformation to MG). They observed 5 DLTs: 1 at dose level 3 (50 mg temsirolimus), then 2 at dose level 7 expansion (170 mg temsirolimus), and then 2 more at dose level 6 expansion (170 mg temsirolimus). DLTs included thrombocytopenia (n = 3), intra-cerebral hemorrhage (n = 1) and lung infection (n = 1). The authors concluded that this phase-I clinical trial declared an MTD of combined temsirolimus with perifosine, and responses were anecdotally observed, especially at the higher dose levels. However, the large gap between temsirolimus doses (115 mg weekly as the MTD and 170 mg weekly as the next higher level) did not allow interrogation of intermediate levels between that may be as efficacious but more tolerable. Lack of pharmacokinetic analyses also limited the authors’ ability to draw any conclusions on the efficacy of the regimen. Thus, these researchers are conducting a subsequent pilot study combining temsirolimus at 140 mg weekly with perifosine that also mandates pneumocystis (jiroveci) pneumonia prophylaxis based on the results reported here.
Cholangiocarcinoma
UpToDate reviews on “Systemic therapy for advanced cholangiocarcinoma” (Stuart, 2023), “Treatment of localized cholangiocarcinoma: Adjuvant and neoadjuvant therapy and prognosis” (Anderson and Stuart, 2023), and “Treatment options for locally advanced, unresectable, but nonmetastatic cholangiocarcinoma” (Anderson et al. 2023) do not mention temsirolimus as a therapeutic option.
Colorectal Cancer
Kaneko and associates (2014) stated that temsirolimus (TEM) has shown activity against a wide range of cancers in pre-clinical models, but its efficacy against colorectal cancer (CRC) has not been fully explored. These researchers evaluated the anti-tumor effect of TEM in CRC cell lines (CaR-1, HT-29, Colon26) in-vitro and in-vivo. In-vitro, cell growth inhibition was assessed using a MTS assay. Apoptosis induction and cell cycle effects were measured using flow cytometry. Modulation of mTOR signaling was measured using immunoblotting. Anti-tumor activity as a single agent was evaluated in a mouse subcutaneous tumor model of CRC. The effects of adding chloroquine, an autophagy inhibitor, to TEM were evaluated in-vitro and in-vivo. In-vitro, TEM was effective in inhibiting the growth of 2 CRC cell lines with highly activated AKT, possibly through the induction of G1 cell cycle arrest via a reduction in cyclin D1 expression, whereas TEM reduced HIF-1α and VEGF in all 3 cell lines. In a mouse subcutaneous tumor model, TEM inhibited the growth of tumors in all cell lines, not only through direct growth inhibition but also via an anti-angiogenic effect. These investigators also explored the effects of adding chloroquine, an autophagy inhibitor, to TEM. Chloroquine significantly potentiated the anti-tumor activity of TEM in-vitro and in-vivo. Moreover, the combination therapy triggered enhanced apoptosis, which corresponded to an increased Bax/Bcl-2 ratio. The authors concluded that based on these data, they proposed TEM with or without chloroquine as a new treatment option for CRC.
He et al (2016) stated that the mTOR is commonly activated in colon cancer; mTOR complex 1 (mTORC1) is a major down-stream target of the PI3K/ATK pathway and activates protein synthesis by phosphorylating key regulators of messenger RNA translation and ribosome synthesis. Rapamycin analogs everolimus and temsirolimus are non-ATP-competitive mTORC1 inhibitors, and suppress proliferation and tumor angiogenesis and invasion. These researchers showed that apoptosis plays a key role in their anti-tumor activities in colon cancer cells and xenografts through the DR5, FADD and caspase-8 axis, and is strongly enhanced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and 5-fluorouracil. The induction of DR5 by rapalogs is mediated by the ER stress regulator and transcription factor CHOP, but not the tumor suppressor p53, on rapid and sustained inhibition of 4E-BP1 phosphorylation, and attenuated by eIF4E expression. ATP-competitive mTOR/PI3K inhibitors also promote DR5 induction and FADD-dependent apoptosis in colon cancer cells. The authors concluded that these results established that activation of ER stress and the death receptor pathway as a novel anti-cancer mechanism of mTOR inhibitors.
Okamoto et al (2022) noted that banoxantrone is a topoisomerase II inhibitor that is selectively activated in hypoxia. Although it has exhibited anti-tumor activity against several types of cancers in pre-clinical models, its effectiveness against CRC remains unclear. These researchers examined the anti-tumor effects of 1,4-bis[2-(dimethylamino)ethylamino]-5,8-dihydroxyanthracene-9,10-dione (AQ4), an activated metabolite of banoxantrone, in CRC cell lines (HT-29, CaR-1) using in-vitro experiments under normoxic and hypoxic conditions. The inhibition of cell growth was evaluated using a proliferation assay. The induction of apoptosis and changes in the cell cycle were measured using flow cytometry. Signaling pathways involved in apoptosis and hypoxia were analyzed. The anti-tumor activity of temsirolimus, and the combined effects of temsirolimus and AQ4 were also examined. Regardless of the oxygen condition, a single drug treatment with AQ4 or temsirolimus inhibited proliferation and induced apoptosis in both cell lines, accompanied by a reduction in the phosphorylation of S6. AQ4 induced G2/M cell cycle arrest, whereas temsirolimus induced G0/G1 arrest. Moreover, the combined treatment markedly reduced the proportion of cells in the S phase and enhanced apoptosis, as evidenced by an increased Bax/Bcl-2 ratio. The hypoxia-induced activation of the HIF-1α pathway was suppressed by AQ4 and temsirolimus. The authors concluded that based on the co-operative anti-tumor activity of AQ4 and temsirolimus in-vitro, the combination of banoxantrone and temsirolimus has potential as a therapeutic option for CRC in pre-clinical and clinical settings.
COVID-19 Therapy
Aneva et al (2021) noted that infection by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) provokes acute inflammation due to extensive replication of the virus in the epithelial cells of the upper and lower respiratory system. The mTOR is known for its regulatory functions in protein synthesis and angiogenesis cascades. The structure of mTOR consists of 2 distinct complexes (mTORC1 and mTORC2) with diverse functions at different levels of the signaling pathway. By activating mRNA translation, the mTORC1 plays a key role in regulating protein synthesis and cellular growth. On the other hand, the functions of mTORC2 are mainly associated with cell proliferation and survival. By using an appropriate inhibitor at the right time, mTOR modulation could provide immunosuppressive opportunities as anti-rejection regimens in organ transplantation as well as in the treatment of autoimmune diseases and solid tumors. The mTOR has an important role in the inflammatory process, too. Inhibitors of mTOR might indeed be promising agents in the treatment of viral infections. They have further been successfully used in patients with severe influenza A/H1N1 pneumonia and acute respiratory failure. The authors concluded that the officially accepted mTOR inhibitors that have undergone clinical testing are sirolimus, everolimus, temsirolimus, and tacrolimus; therefore, further studies on mTOR inhibitors for SARS-CoV-2 infection or COVID-19 therapy are well merited.
Desmoplastic Small Round Cell Tumor
Tarek and co-workers (2018) stated that desmoplastic small round cell tumor (DSRCT) is a rare mesenchymal tumor that typically presents with multiple abdominal masses. Initial treatment is multi-modal in nature. Patients with relapsed DSRCT have a poor prognosis, and there are no standard therapies. These investigators reported their experience with 5 patients treated with vinorelbine, cyclophosphamide, and temsirolimus (VCT). Median number of VCT courses delivered was 7 (range of 4 to 14 courses), and PR was observed in all patients. Median time to progression or relapse was 8.5 months (range of 7 to 16 months). Neutropenia and mucositis were most common toxicities (n = 4 each). Moreover, they stated that further study is needed to determine if this regimen can be utilized in newly diagnosed patients, and additional pre-clinical study is needed to determine the mechanism of action for this combination in DSRCT. The authors noted that one drawback of this report was that they were unable to determine if the observed responses were due to a synergistic effect derived from this drug combination versus single agent activity.
The National Comprehensive Cancer Network’s clinical practice guideline on “Soft tissue sarcoma” (Version 2.2021) does not mention temsirolimus (Torisel) in the treatment of metastatic desmoplastic small round cell tumor. Furthermore, the National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2021) does not list desmoplastic small round cell tumor as a recommended indication of temsirolimus.
Endovascular Treatment of Atherosclerotic Lesions of Below-the-Knee Arteries
Cawich et al (2022) stated that current endovascular treatments of below the knee (BTK) popliteal or tibial/peroneal arteries including investigational drug-coated balloons have limited long-term effectiveness. In a prospective, comparative, double-blinded, dose-escalation, multi-center, phase-II clinical trial, these researchers examined the feasibility of adventitial deposition of temsirolimus to reduce neointimal hyperplasia and clinically relevant target lesion failure (CR-TLF) 6 months following BTK arterial re-vascularization. This study enrolled 61 patients with Rutherford 3 to 5 symptoms undergoing endovascular re-vascularization of 1 or higher angiographically significant BTK lesions. Peri-vascular infusion following completion of arterial re-vascularization was randomized into control (saline) versus low-dose (0.1 mg/ml) temsirolimus groups for the first 30 patients. In the 2nd part of the study, patients were randomized to control versus high-dose (0.4 mg/ml) temsirolimus groups. Primary and secondary effectiveness endpoints were target lesion (TL) transverse-view vessel area loss percentage (TVAL%) and CR-TLF at 6 months, respectively. CR-TLF was defined as a composite of ischemia-driven major amputation of the target limb, clinically driven target lesion re-vascularization (CD-TLR), and clinically relevant TL occlusion. The primary safety endpoint was freedom from major adverse limb events or peri-operative death (MALE+POD) at 30 days. There was no discernable difference in effect between temsirolimus doses; thus, the low- and high-dose cohorts were pooled for the analyses. The principal analysis on the per protocol (PP) group of 53 patients revealed superior primary effectiveness of the treatment arm, with reduction in TVAL% of 13.9 % absolute (37.3 % relative) and the rate of CR-TLF reduced by 27.1 % absolute (51.3 % relative), at 6 months. Subgroup analysis of all Trans-Atlantic Inter-Society Consensus (TASC) B to D lesions (n = 36) revealed TVAL% reduction of 22.3 % absolute (48.3 % relative) and the rate of CR-TLF reduced by 39.2 % absolute (56.6 % relative). Freedom from 30-day MALE+POD was 100 % in all groups. The authors concluded that this hypothesis-generating trial suggested that adventitial infusion of temsirolimus in BTK arteries improved TVAL% and CR-TLF with no adverse safety signals through 6 months. These researchers stated that sub-adventitial temsirolimus offers the potential to improve the results of BTK interventions in this challenging patient population, supporting the move to a phase-III clinical trial.
Fallopian Tube Serous Carcinoma
The National Comprehensive Cancer Network’s clinical practice guideline on “Ovarian cancer/fallopian tube cancer/primary peritoneal cancer” (Version 1.2021) does not mention temsirolimus as a therapeutic option. Furthermore, National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2021) does not list fallopian tube serous carcinoma / ovarian cancer as a recommended indication of temsirolimus.
Head and Neck Squamous Cell Carcinoma
Nguyen et al (2012) noted that head and neck squamous cell carcinomas (HNSCC) represent 6 % of all cancers diagnosed each year in the United States, affecting approximately 43,000 new patients and resulting in approximately 12,000 deaths. Currently, 3 main rapalogs exist for the treatment of cancer: CCI-779 (temsirolimus), RAD001 (everolimus), and AP235373 (deforolimus). Clinicians managing HNSCC need to be aware of the 3 rapalogs. Extensive evidence has shown rapamycin-analogs to be effective agents in the treatment of a number of solid tumors. While extensive pre-clinical data suggested that HNSCC would be an appropriate tumor type to benefit from inhibition of the mTOR pathway, limited clinical data is yet available to support this. Numerous phase II trials evaluating mTOR inhibitors for use in HNSCC are currently recruiting patients.
Grunwald et al (2015) stated that HNSCC is a common disease, which has a poor prognosis after failure of therapy. Activation of the PI3K-AKT-mTOR axis is commonly detected in recurrent or metastatic HNSCC, and provided the rationale for the clinical phase II trial in pre-treated HNSCC. The primary end-point was the PFS rate (PFR) at 12 weeks. A total of 40 eligible patients have been recruited after failure of platinum chemotherapy and cetuximab. A pre-planned futility analysis was successfully passed after greater than or equal to 1 success was detected in 20 patients. Secondary objectives consisted of PFS, disease control rate (DCR), OS, safety and tolerability, and predictive biomarkers for KRAS, BRAF, PIK3CA mutations, and HPV status. Archived tumor tissue was analyzed for DNA sequence. A total of 40 patients were eligible. The PFR at 12 weeks was 40 % (95 % CI: 25.0 to 54.6). The median PFS and OS were 56 days (95 % CI: 36 to 113 days) and 152 days (76 to 256 days), respectively. In 33 assessable patients, disease stabilization occurred in 57.6 %, with tumor shrinkage in 13 patients (39.4 %). Overall, the treatment was well-tolerated. Fatigue (47.5 %), anemia (25.0 %), nausea (20.0 %), and pneumonia (20.0 %) were the most common adverse events. Neither PIK3CA mutations, nor HPV status were predictive for success with temsirolimus treatment. No mutations were found for KRAS or BRAF. The authors concluded that tumor shrinkage and efficacy parameter indicated that inhibition of the PI3K-AKT-mTOR axis was a putative novel treatment paradigm for SCCHN. These investigators could not identify parameters predictive for treatment success of temsirolimus, which underscored the need for refinement of the molecular analysis in future studies.
Hepatoblastoma
Thompson et al (2023) noted that survival for children with metastatic hepatoblastoma (HB) remains suboptimal. These investigators reported the response rate and outcome of 2 courses of vincristine/irinotecan/temsirolimus (VIT) in children with high-risk (HR) metastatic HB. Patients with newly diagnosed HB received HR-window chemotherapy if they had metastatic disease or a serum alpha-fetoprotein (AFP) level of less than 100 ng/ml. Participants received vincristine (days 1 and 8), irinotecan (days 1 to 5), and temsirolimus (days 1 and 8). Cycles were repeated every 21 days. Responders had either a 30 % decrease using RECIST criteria, or a 90 % (greater than 1 log10 decline) AFP decline after 2 cycles. Responders received 2 additional cycles of VIT inter-mixed with 6 cycles of cisplatin/doxorubicin/5-fluorouracil/vincristine (C5VD). Non-responders received 6 cycles of C5VD alone. A total of 36 eligible patients enrolled in this trial. The median age at enrollment was 27 months (range of 7 to 170); 17 (47 %) of 36 patients were responders (RECIST and AFP = 3, RECIST only = 4, AFP only = 10). The median AFP at diagnosis was 222,648 ng/ml and the median AFP following 2 VIT cycles was 19,262 ng/ml; and 3-year EFS was 47 % (95 % CI: 30 % to 62 %), while OS was 67 % (95 % CI: 49 % to 80 %). The authors concluded that VIT did not achieve the study effectiveness endpoint. Temsirolimus did not improve the response rate observed in patients treated with vincristine and irinotecan (VI) alone as part of the initial treatment regimen examined in this study. Furthermore, AFP response may be a more sensitive predictor of disease response than RECIST in HB.
Hepatocellular Carcinoma
Yeo et al (2015) stated that the oncogenic PI3K/Akt/mTOR pathway is frequently activated in hepato-cellular carcinoma (HCC). Data on the mTOR inhibitor, temsirolimus, is limited in HCC patients with concomitant chronic liver disease. The objectives of this study were:- In phase I, to determine dose-limiting toxicities (DLTs) and MTD of temsirolimus in HCC patients with chronic liver disease;
- In phase II, to assess activity of temsirolimus in HCC, and
- to explore potential biomarkers for response.
Knox et al (2015) noted that there is strong rationale to combine temsirolimus (TEM) with bevacizumab (BEV) for patients with advanced HCC. These researchers performed a modified 2-stage Simon phase II trial with plans to advance to stage 2 if more than 2 patients had confirmed PR or more than 18 patients were progression free at 6 months out of 25 in stage 1. Toxicity, PFS and OS were secondary end-points. Eligible patients had advanced HCC, Child Pugh A liver status and no prior systemic therapy involving the VEGF or m-TOR targeted agents. Patients were treated with temsirolimus 25 mg I.V. on Days 1, 8, 15, and 22 of a 28-day cycle and bevacizumab 10 mg/kg I.V. on Days 1 and 15 of the cycle. A total of 28 eligible patients were enrolled, 26 evaluable receiving a median of 6.5 cycles (range of 1 to 18). Drug related toxicities were common including cytopenia, fatigue, mucositis, diarrhea and mild bleeds. Dose reductions or discontinuation of TEM were common. Accrual closed for presumed futility after interim analysis of the first 25 evaluable patients showed only 1 PR and 16/25 were progression-free at 6 months. However, the final data update in March 2013 demonstrated 4 confirmed PRs, a 5th unconfirmed PR and 16 /26 progression-free at 6 months. Median PFS and OS were 7 and 14 months, respectively. The authors concluded that this first-line HCC trial evaluating the BEV/TEM doublet reported an ORR of 19 % and OS of 14 months, which is favorable but requires further study at a more optimized dose and schedule.
Kelly et al (2021) stated that the mTOR pathway is up-regulated in nearly 50 % of HCC and is associated with poor prognosis . In pre-clinical models of HCC, the combination of mTOR pathway inhibition with the multi-kinase inhibitor sorafenib improves treatment effectiveness. A prior phase-I clinical trial of temsirolimus combined with sorafenib demonstrated acceptable safety at the recommended phase-II dose. In a single-arm, multi-center phase-II clinical trial, these researchers examined the effects of combined temsirolimus (10 mg intravenously weekly) and sorafenib (200 mg b.i.d) in the treatment of advanced HCC. The primary endpoint was time to progression (TTP) with efficacy target of median TTP of at least 6 months; secondary endpoints included OS, objective response rate, safety, and alpha-fetoprotein (AFP) tumor marker response; tumor next-generation sequencing (NGS) was carried out as an exploratory endpoint. A total of 29 patients were enrolled, including 48 % with hepatitis C virus infection and 28 % with hepatitis B virus; 86 % had Barcelona clinic liver cancer stage C disease. Among 28 patients evaluable for effectiveness, the median TTP was 3.7 (95 % CI: 2.2 to 5.3) months, with 14 % of patients achieving TTP of at least 6 months. The median OS was 8.8 (95 % CI: 6.8 to 14.8) months. There were no CR or PR; 75 % of patients had SD as best response. AFP decline by at least 50 % was associated with prolonged TTP and OS. Serious AEs occurred in 21 %; the most common treatment-related AEs of CTCAE grade-3 or higher were hypophosphatemia (36 %), thrombocytopenia (14 %), and rash (11 %). There were no grade-5 events attributed to sorafenib or temsirolimus. Tumor NGS was carried out in a subgroup of 24 patients with adequate tumor samples. Tumor mTOR pathway mutations were identified in 42 %; there was no association between tumor mutation profile and OS or TTP. The authors concluded that the combination of temsirolimus and sorafenib demonstrated acceptable safety but did not achieve the target threshold for effectiveness in this phase-II clinical trial. Tumor NGS including the presence of mTOR pathway mutations was not associated with therapeutic response in an exploratory subgroup analysis. These researchers stated that this regimen of temsirolimus combined with sorafenib did not demonstrate sufficient effectiveness to warrant further investigation in the expanding landscape of therapeutic options for advanced HCC.
Lung Cancer
The targeted therapies dabrafenib and neratinib are being tested separately in subsets of patients with BRAF- and HER2-mutant non-small cell lung cancer (NSCLC). While dabrafenib showed some promise, the preliminary results for neratinib with or without temsirolimus were insufficient to determine whether patients may benefit (No authors listed, 2014).Ushijima et al (2015) noted that the mTOR correlates with cell survival under hypoxia and regulates hypoxia-inducible factor-1α (HIF-1α), a key protein in hypoxia-related events. However, the role of mTOR in radio-resistance has not been fully investigated. Therefore, the effect of mTOR on the radio-resistance of cancer cells under hypoxia was evaluated using the mTOR inhibitor temsirolimus. Clonogenic survival was examined in the A549 human lung adenocarcinoma cell line under normoxia or hypoxia, with or without temsirolimus. An oxygen enhancement ratio (OER) was calculated using the D(10) values, the doses giving 10 % survival. Western blotting was performed to investigate the effect of temsirolimus on mTOR and the HIF-1α pathway under normoxia and hypoxia. A549 cells showed a radio-resistance of 5.1 and 14.2 Gy, as indicated by D(10) values under normoxia and hypoxia, respectively; the OER was 2.8. The cell survival rates under hypoxia and with temsirolimus remarkably decreased compared with those under normoxia. The D(10) values of the cells under normoxia and hypoxia were 4.8 and 5.4 Gy, respectively (OER = 1.1). mTOR expression was suppressed by temsirolimus under both normoxia and hypoxia. HIF-1α expression decreased under hypoxia in the presence of temsirolimus. The authors concluded that these results suggested that temsirolimus can overcome the radio-resistance induced by hypoxia. They stated that when the fact that mTOR acts up-stream of HIF-1α is considered, these findings suggested that the restoration of radiation sensitivity by temsirolimus under hypoxia may be associated with the suppression of the HIF-1α pathway. Temsirolimus could therefore be used as a hypoxic cell radio-sensitizer.
Melanoma
Velho (2012) stated that melanoma is one of the most aggressive cancers, and it is estimated that 76,250 men and women will be diagnosed with melanoma of the skin in the USA in 2012. Over the last few decades many drugs have been developed but only in 2011 have new drugs demonstrated an impact on survival in metastatic melanoma. A systematic search of literature was conducted, and studies providing data on the effectiveness of current and/or future drugs used in the treatment of metastatic melanoma were selected for review. This review discussed the advantages and limitations of these agents, evaluating past, current and future clinical trials designed to overcome such limitations. The authors noted that “To date, there are 4 drugs approved by the Food and Drug Administration for melanoma (dacarbazine, interleukin-2, ipilimumab and vemurafenib). Despite efforts to develop new drugs, few of them have demonstrated any clinical benefits. Approved in 1975, dacarbazine remains the gold standard in chemotherapy, although ipilimumab and vemurafenib have raised many hopes in the last few years. Combining dacarbazine or other chemotherapy agents with new pharmacological agents may be a new way to achieve better clinical responses in patients with metastatic melanoma”. The authors concluded that advances in the molecular knowledge of melanoma have led to major improvements in the treatment of patients with metastatic melanoma, providing new targets and insights. However, heterogeneity among study populations, different approaches to treatment and the different melanoma types and localizations included in the trials made their comparison difficult; new studies focusing on drugs developed in recent decades are needed.
Vazakidou et al (2015) stated that the mTOR promotes cancer cell proliferation and survival, transduces pro-angiogenic signals and regulates immune cell differentiation and function. These researchers hypothesized that temsirolimus, an mTOR inhibitor, would curtail experimental mesothelioma progression in-vivo by limiting tumor cell growth, abrogating tumor angiogenesis and modulating immune/inflammatory tumor milieu. These investigators produced flank and pleural syngeneic murine mesotheliomas by delivering AE17 and AB1 murine mesothelioma cells into the right flank or the pleural space of C57BL/6 and BALB/c mice, respectively. Animals were given 5 times/week intra-peritoneal injections of 20 mg/kg temsirolimus or vehicle and were sacrificed on day 26 (flank) or on day 15 (pleural) post-tumor cell propagation. Temsirolimus limited mesothelioma growth in-vivo by stimulating tumor cell apoptosis, inhibiting tumor angiogenesis, enhancing tumor lymphocyte abundance and blocking pro-tumor myeloid cell recruitment. Pleural fluid accumulation was significantly mitigated in AE17 but not in AB1 mesotheliomas. In-vitro, temsirolimus hindered mesothelioma cell growth, NF-kappaB activation and macrophage migration. The authors concluded that temsirolimus apart from inducing tumor cell apoptosis, targets tumor angiogenesis and influences inflammatory tumor microenvironment to halt experimental mesothelioma growth in-vivo.
Multiple Myeloma
Sun et al (2023) stated that multiple myeloma (MM) is an incurable, malignant B-cell disorder characterized by frequent relapses and a poor prognosis. The phosphatidylinositol-3-kinase (PI3K) pathway plays a key role in many critical cellular processes, including cell proliferation and survival. Activated PI3K/AKT (protein kinases B)/mTOR (mammalian target of rapamycin) signaling has been identified in MM primary patient samples and cell lines. These researchers examined the effectiveness of PI3K and mTOR inhibitors in various MM cell lines representing 3 different prognostic subtypes. Whereas MM cell lines were rather resistant to PI3K inhibition, treatment with the mTOR inhibitor temsirolimus decreases the phosphorylation of key molecules in the PI3K pathway in MM cell lines, leading to G0/G1 cell cycle arrest; thus, reducing proliferation. Moreover, the effectiveness of temsirolimus was enhanced by combining the treatment with the mitogen-activated protein kinase (MEK) inhibitor trametinib. The authors concluded that these findings provided a scientific rationale for the simultaneous inhibition of mTOR and MEK as a novel approach for the treatment of MM.
Myelodysplastic Syndromes
Wermke and colleagues (2016) noted that the mTOR pathway integrates various pro-proliferative and anti-apoptotic stimuli and is involved in regulatory T-cell (TREG) development. As these processes contribute to the pathogenesis of myelodysplastic syndromes (MDS), these investigators hypothesized that mTOR modulation with temsirolimus (TEM) might show activity in MDS. This prospective multi-center trial enrolled lower and higher risk MDS patients, provided that they were transfusion-dependent/neutropenic or relapsed/refractory to 5-azacitidine, respectively. All patients received TEM at a weekly dose of 25-mg. Of the 9 lower- and 11 higher-risk patients included, only 4 (20 %) reached the response assessment after 4 months of treatment and showed SD without hematological improvement. The remaining patients discontinued TEM prematurely due to AEs. Median OS was not reached in the lower-risk group and 296 days in the higher-risk group. These researchers observed a significant decline of bone marrow (BM) vascularization (p = 0.006) but were unable to demonstrate a significant impact of TEM on the balance between TREG and pro-inflammatory T-helper-cell subsets within the peripheral blood or BM. The authors concluded that mTOR-modulation with TEM at a dose of 25 mg/week was accompanied by considerable toxicity and had no beneficial effects in elderly MDS patients.
Nasopharyngeal Carcinoma
Huang et al (2022) noted that radio-resistance is a leading cause of nasopharyngeal carcinoma (NPC) treatment failure and identification of sensitizing therapeutic targets is an unmet need to enhance clinical management. Given that the mTOR signaling confers resistance to cancer therapy, these investigators examined if mTOR contributes to radio-resistance in NPC and pharmacological inhibition of mTOR could overcome radio-resistance. They found that mTOR mRNA and protein levels, and phosphorylation of its down-stream effector were increased in radio-resistant NPC compared with parental cells. mTOR inhibitor temsirolimus inhibited proliferation and induced apoptosis in a panel of NPC cell lines. More importantly, temsirolimus acted synergistically with radiation and was effective against radio-resistant cells. Using radio-resistant xenograft mouse model, these researchers validated the effectiveness of temsirolimus in preventing tumor formation and inhibiting tumor growth. Temsirolimus overcame radio-resistance in NPC by inhibiting mTOR signaling. The authors concluded that these findings provided the pre-clinical evidence that the combination of radiation and mTOR inhibitor may be a therapeutic strategy in NPC; these results might accelerate the initiation of clinical trials on radio-resistant NPC patients using temsirolimus.
Neuroblastoma
Zhao et al (2015) noted that the insulin-like growth factors (IGFs), IGF-1 and IGF-2, have been implicated in the growth, survival and metastasis of a broad range of malignancies including pediatric tumors. They bind to the IGF receptor type 1 (IGF-1R) and the insulin receptor (IR) which are over-expressed in many types of solid malignancies. Activation of the IR by IGF-2 results in increased survival of tumor cells. These researchers have previously identified a novel human monoclonal antibody, m708.5, which binds with high (pM) affinity to both human IGF-1 and IGF-2, and potently inhibits phosphorylation of the IGF-1R and the IR in tumor cells. m708.5 exhibited strong anti-tumor activity as a single agent against most cell lines derived from neuroblastoma, Ewing family of tumor, rhabdomyosarcoma and osteosarcoma. When tested in neuroblastoma cell lines, it showed strong synergy with temsirolimus and synergy with chemotherapeutic agents in-vitro. In xenograft models, the combination of m708.5 and temsirolimus significantly inhibited neuroblastoma growth and prolonged mouse survival. Taken together, these results support the clinical development of m708.5 for pediatric solid tumors with potential for synergy with chemotherapy and mTOR inhibitors.
Kling et al (2021) stated that neuroblastoma (NB) patients with MYCN amplification or over-expression respond poorly to current therapies and exhibit extremely poor clinical outcomes. PI3K-mTOR signaling-driven deregulation of protein synthesis is very common in NB and various other cancers that promote MYCN stabilization. Furthermore, both the MYCN and mTOR signaling axes could directly regulate a common translation pathway that results in increased protein synthesis and cell proliferation. However, a strategy of combined targeting MYCN and mTOR signaling in NB remains unexplored. These investigators examined the therapeutic potential of targeting dysregulated protein synthesis pathways by inhibiting the MYCN and mTOR pathways together in NB. Using small molecule/pharmacologic approaches, these researchers examined the effects of combined inhibition of MYCN transcription and mTOR signaling on NB cell growth/survival and associated molecular mechanism(s) in NB cell lines. They used 2 well-established BET (bromodomain extra-terminal) protein inhibitors (JQ1, OTX-015), and a clinically relevant mTOR inhibitor, temsirolimus, to target MYCN transcription and mTOR signaling, respectively. The single agent and combined effectiveness of these inhibitors on NB cell growth, apoptosis, cell cycle and neuro-spheres were evaluated using MTT, Annexin-V, propidium-iodide staining and sphere assays, respectively. Effects of inhibitors on global protein synthesis were quantified using a fluorescence-based (FamAzide)-based protein synthesis assay. In addition, these investigators examined the specificities of these inhibitors in targeting the associated pathways/molecules using Western blot analyses. Co-treatment of JQ1 or OTX-015 with temsirolimus synergistically suppressed NB cell growth/survival by inducing G1 cell cycle arrest and apoptosis with greatest effectiveness in MYCN-amplified NB cells. Mechanistically, the co-treatment of JQ1 or OTX-015 with temsirolimus significantly down-regulated the expression levels of phosphorylated 4EBP1/p70-S6K/eIF4E (mTOR components) and BRD4 (BET protein)/MYCN proteins. Furthermore, this combination significantly inhibited global protein synthesis, compared to single agents. These results also demonstrated that both JQ1 and temsirolimus chemo-sensitized NB cells when tested in combination with cisplatin chemotherapy. The authors concluded that the findings of this study showed synergistic effectiveness of JQ1 or OTX-015 and temsirolimus against MYCN-driven NB, by dual-inhibition of MYCN (targeting transcription) and mTOR (targeting translation). Moreover, these researchers stated that additional pre-clinical evaluation is needed to determine the clinical utility of targeted therapy for high-risk NB patients.
Neuroendocrine Tumors
Chan and Kulke (2014) stated that neuroendocrine tumors (NETs) are a heterogeneous group of malignancies characterized by variable but most often indolent biologic behavior. Well-differentiated NETs can be broadly classified as either carcinoid or pancreatic NET. Although they have similar characteristics on routine histologic evaluation, the 2 tumor subtypes have different biology and respond differently to treatment, with most therapeutic agents demonstrating higher response rates in pancreatic NETs compared with carcinoid. Until recently, systemic treatment options for patients with advanced NETs were limited. However, improvements in the understanding of signaling pathways involved in the pathogenesis, growth, and spread of NETs have translated into an expansion of treatment options. Aberrant signaling through the mTOR pathway has been implicated in neuroendocrine tumorigenesis. Additionally, altered expression of mTOR pathway components has been observed in NETs and has been associated with clinical outcomes. Targeting the mTOR pathway has emerged as an effective treatment strategy in the management of advanced NETs. In a randomized, placebo-controlled study of patients with advanced pancreatic NET, treatment with the mTOR inhibitor everolimus was associated with improved PFS. Largely based upon these data, everolimus has been approved in the United States and Europe for the treatment of patients with advanced pancreatic NET. The activity of everolimus remains under investigation in patients with carcinoid tumors. In a randomized study of patients with advanced carcinoid tumors associated with carcinoid syndrome, the addition of everolimus to octreotide was associated with improved PFS compared with octreotide. However, the results did not meet the pre-specified level of statistical significance based on central review of radiographic imaging. Results from a randomized study examining the efficacy of everolimus in patients with non-functional gastro-intestinal and lung NETs are awaited. In addition, further investigation is needed to determine whether primary tumor site or other clinical and molecular factors can impact response to mTOR inhibition. Although everolimus can slow tumor progression, significant tumor reduction is rarely obtained. Targeting multiple signaling pathways is a treatment strategy that may provide better tumor control and overcome resistance mechanisms involved with targeting a single pathway. Results of ongoing and future studies will provide important information regarding the added benefit of combining mTOR inhibitors with other targeted agents, such as VEGF pathway inhibitors, and cytotoxic chemotherapy in the treatment of advanced NETs.
Hobday et al (2015) stated that there are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mTOR inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved PFS. Pre-clinical studies have suggested enhanced anti-tumor effects with combined mTOR and VEGF pathway-targeted therapy. These investigators conducted a clinical trial to evaluate combination therapy against these targets in PNETs. They conducted a 2-stage, single-arm, phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once-weekly and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Co-primary end-points were tumor response rate and 6-month PFS. A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41 % (23 of 56 patients); PFS at 6 months was 79 % (44 of 56). Median PFS was 13.2 months (95 % CI: 11.2 to 16.6). Median OS was 34 months (95 % CI: 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21 %), fatigue (16 %), lymphopenia (14 %), and hyperglycemia (14 %). The authors concluded that the combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multi-center phase II clinical trial, with RR of 41 %, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79 % in a population of patients with disease progression by RECIST criteria within 7 months of study entry. The authors concluded that on the basis of this phase II clinical trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is needed.
Oropharyngeal Squamous Cell Carcinoma
Kondo and colleagues (2021) noted that despite reports of a link between human papillomavirus (HPV) infection and mechanistic target of rapamycin (mTOR) signaling activation, the role of the mTOR pathway, especially raptor and rictor, in HPV-related head and neck cancer is still unclear. These researchers examined the role of the mTOR pathway in HPV-related oropharyngeal squamous cell carcinoma (OPSCC). This trial entailed 2 strategies. The 1st was to examine the activity of mTOR and mTOR-related complexes in high-risk HPV-positive (UM-SCC47 and CaSki) and HPV-negative (SCC-4 and SAS) cancer cell lines. The 2nd was to elucidate mTOR complex expression in 80 oropharyngeal cancer tissues and to examine the relationship between mTOR complex expression and survival in patients with OPSCC. The UM-SCC47 and CaSki cell lines showed high gene and protein expression of raptor. They also exhibited G1/S and G2/M phase cell cycle arrest following 24-hour incubation with 6 μM temsirolimus, and temsirolimus administration inhibited their growth. HPV-related OPSCC samples showed high gene and protein expression of raptor and rictor compared with HPV-unrelated OPSCC. Furthermore, HPV-related OPSCC patients with high raptor and rictor expression tended to have a worse prognosis than those with low or medium expression. The authors concluded that the findings of this study suggested that raptor and rictor had important roles in HPV-related OPSCC and that temsirolimus is a potential therapeutic agent for patients with HPV-related OPSCC. This was the 1st report to show the over-expression of raptor and rictor in HPV-related OPSCC.Other Solid Tumors
Piatek (2014) determined the MTD of the combination of weekly temsirolimus and every other week vinorelbine in patients with advanced or refractory solid tumors. Patients were treated with I.V. temsirolimus on days 1, 8, 15, and 22 and I.V. vinorelbine on days 1 and 15. Cycles were repeated every 28 days. A total of 19 patients were enrolled in the study. Tumor types included lung (n = 5), prostate (n = 2), neuroendocrine of pancreas (n = 1), bladder (n = 2), uterus (n = 3), cervix (n = 4), and vagina (n = 2). All patients had received prior chemotherapy. Four patients were enrolled to dose level I, 9 to dose level II, and 6 to dose level III. Six patients were non-evaluable and replaced; 57 total cycles were administered. There was 1 DLT at level II (grade 3 anorexia/dehydration) and 2 at level III (grade 3 hypokalemia; grade 4 neutropenia). Two patients died at dose level III; 1 was study-related with grade 4 neutropenia. Grade 3/4 toxicities observed during the first cycle included neutropenia (n = 2), anemia (n = 1), anorexia (n = 1), dehydration (n = 1), hyperglycemia (n = 1), hypertriglyceridemia (n = 1), and hypokalemia (n = 1). Best response included 2 patients (prostate cancer and NSCLC) with PR and 8 patients with SD with median duration of best response of 3.2 months. The authors concluded that temsirolimus 25 mg given days 1, 8, 15, and 22 in combination with vinorelbine 20 mg/m(2) given days 1 and 15 every 4 weeks was found to be the MTD. This dose combination is considered feasible in phase II trials.
Rangwala and colleagues (2014) stated that the combination of TEM and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in pre-clinical models. This phase 1 dose-escalation study evaluated the MTD, safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well-tolerated, and grade 3 or 4 toxicity was limited to anorexia (7 %), fatigue (7 %), and nausea (7 %). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice-daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67 %) patients in the dose escalation and 14/19 (74 %) patients with melanoma achieved SD. The median PFS in 13 melanoma patients treated with HCQ 1,200 mg/day in combination with TEM was 3.5 months. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1,200 mg daily HCQ. The authors concluded that the findings of this study indicated that TEM and HCQ is safe and tolerable, modulated autophagy in patients, and had significant anti-tumor activity. They stated that further studies combining mTOR and autophagy inhibitors in cancer patients are needed.
Ovarian Cancer
Matsumoto et al (2015) noted that several “lines of therapy” that utilize cytotoxic agents and are driven by platinum-free intervals are the current standard of care for patients with recurrent ovarian cancer. For patients with platinum-resistant disease, single-agent chemotherapy (pegylated liposomal doxorubicin, topotecan, gemcitabine or weekly paclitaxel) is the standard of care. For patients with platinum-sensitive disease, combination chemotherapy (carboplatin plus paclitaxel, pegylated liposomal doxorubicin or gemcitabine) is the standard of care. In addition, anti-angiogenic therapy using bevacizumab is an established option. Future directions could include “lines of therapy” with biologic agents driven by specific biologic targets. Data from anti-angiogenic agents (trebananib, pazopanib and cediranib), anti-folate drugs (farletuzumab and vintafolide), poly(ADP-ribose) polymerase inhibitors (olaparib and veliparib), mTOR inhibitors (everolimus and temsirolimus) and immune-editing agents (nivolumab) had been summarized in this review.
In a phase-II clinical trial, Farley et al (2022) estimated the 12-month PFS for carboplatin/paclitaxel + temsirolimus in women with newly diagnosed clear cell ovarian cancer (CCOC), compared to historical controls in this patient population. Patients with stage III or IV CCOC were treated with paclitaxel 175 mg/m2 on Day 1, carboplatin AUC 6 on Day 1, and temsirolimus (CCI-779) 25 mg IV on Days 1 and 8 every 3 weeks for cycles 1 to 6 or disease progression, followed by consolidation therapy with temsirolimus 25 mg on Days 1, 8, and 15 every 3 weeks cycles 7 to 17 or until disease progression. A total of 90 patients were enrolled in this trial: 45 in the U.S. and Korea (US/Korea) and 45 in Japan; 22 % received 6 cycles or less of therapy while 28 % completed all 17 cycles of chemotherapy. Median PFS (OS) was 11 (23) months for U.S./Korea and 12 (26) months for Japan. In the U.S., none of sub-optimally debulked patients had PFS of greater than 12 months, and 49 % of optimal patients did, compared to 25 % and 59 %, respectively, in Japan. Most common grade 3-4 AEs were neutropenia, leukopenia, anemia, thrombocytopenia, hypertension, hypertriglyceridemia, and oral mucositis. The authors concluded that the carboplatin/paclitaxel + temsirolimus regimen was well-tolerated. In optimally debulked patients, 54 % had a PFS of greater than 12 months. This regimen did not statistically significantly increase PFS at 12 months compared to historical controls. No statistically significant differences in PFS or OS were observed between U.S./Korea versus Japan, or Asians versus non-Asians.
Pancreatic Cancer
Hajatdoost and colleagues (2018) stated that pancreatic cancer is one of the most fatal cancers. Cytotoxic chemotherapy remains the mainstream treatment for unresectable pancreatic cancer. In a systematic review, these researchers compared the OS and PFS outcomes obtained from recent phase-II and phase-III clinical trials of pancreatic cancer chemotherapy. A total of 32 studies were included and compared based on chemotherapy agents or combinations used. Additionally, outcomes of 1st-line versus 2nd-line chemotherapy in pancreatic cancer were compared. In studies that examined the treatments in adjuvant settings, the highest OS reported was for S-1 in patients, who received prior surgical resection (46.5 months). In neoadjuvant settings, the combination of gemcitabine, docetaxel, and capecitabine prior to the surgical resection had promising outcomes (OS of 32.5 months). In non-adjuvant settings, the highest OS reported was for the combination of temsirolimus plus bevacizumab (34.0 months). Among studies that examined 2nd-line treatment, the highest OS reported was for the combination of gemcitabine plus cisplatin (35.5 months), then temsirolimus plus bevacizumab (34.0 months). The authors concluded that there is a need to develop further strategies besides chemotherapy to improve the outcomes in pancreatic cancer treatment. They stated that future studies should consider surgical interventions, combination chemotherapy, and individualized 2nd-line treatment based on the prior chemotherapy.
Karavasilis and associates (2018) determined the MTD and DLTs of a novel gemcitabine (G) and temsirolimus (T) combination (phase-I) and estimated the 6-month PFS in patients treated with the T + G combination (phase-II). Eligible patients with histologically confirmed inoperable or metastatic pancreatic carcinoma (MPC) were entered into the trial; G was given bi-weekly and T weekly in a 4-week cycle. The 1st dose level was set at G 800 mg/m2 and T 10 mg; G was escalated in increments of 200 mg/m2 and T in increments of 5 mg until DLT was reached, and the recommended dose was used for the phase-II part. A total of 30 patients were enrolled in the phase-I component at the pre-planned 6 dose levels; 1 bilirubin DLT of grade-III occurred at the 1st dose level. The MTD was established as the approved doses of both drugs. A total of 55 patients were entered into the phase-II component. Median relative dose intensities administered in the 1st cycle were 0.75 for T and 0.99 for G. Grade 3 to 4 hematological toxicities were recorded in 87.3 % of patients. The most common non-hematological AEs were metabolic disorders (81.8 %) followed by gastro-intestinal (GI) disorders (63.6 %). Median PFS was 2.69 months (95 % CI: 1.74 to 4.95) and median OS was 4.95 months (95 % CI: 3.54 to 6.85), while the 6-month PFS rate was 30.9 %. The authors concluded that combination of G and T was feasible in patients with locally advanced or MPC with manageable side effects, but lacked clinical efficacy.
Parkinson's Disease
Siracusa and colleagues (2018) stated that Parkinson's disease (PD) is a disorder caused by degeneration of dopaminergic neurons. At the moment, there is no cure. Recent studies have shown that autophagy may have a protective function against the advance of a number of neurodegenerative diseases. Temsirolimus is an analogue of rapamycin that induces autophagy by inhibiting mTOR complex 1. In the present study, these researchers examined the neuroprotective effects of temsirolimus (5 mg/kg intraperitoneal) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced (MPTP) neurotoxicity in in-vivo model of PD. At the end of the experiment, brain tissues were processed for histological, immunohistochemical, Western blot, and immunofluorescent analysis. Treatment with temsirolimus significantly ameliorated behavioral deficits, increased the expression of specific markers of PD such as tyrosine hydroxylase, dopamine transporter, as well as decreased the up-regulation of α-synuclein in the substantia nigra after MPTP induction. Furthermore, Western blot and immunohistochemistry analysis showed that temsirolimus administration significantly increased autophagy process. In fact, treatment with temsirolimus maintained high Beclin-1, p62, and microtubule-associated protein 1A/1B-light chain 3 expression and inhibited the p70S6K expression. In addition, these investigators showed that temsirolimus also exhibited anti-inflammatory properties as indexed by the significant inhibition of the expression of mitogen-activated protein kinases such as p-JNK, p-p38, and p-ERK, and the restored levels of neurotrophic factor expression such as BDNF and NT-3. On the basis of this evidence, these researchers demonstrated that temsirolimus was able to modulate both the autophagic process and the neuroinflammatory pathway involved in PD, actions which may underlie its neuroprotective effect.
Primary CNS Lymphoma
In a phase II clinical trial, Korfel and colleagues (2016) examined the effectiveness of temsirolimus in patients with relapsed or refractory primary CNS lymphoma (PCNSL). Immunocompetent adults with histologically confirmed PCNSL after experiencing high-dose methotrexate-based chemotherapy failure who were not eligible for or had experienced high-dose chemotherapy with autologous stem-cell transplant (ASCT) failure were included. The first cohort (n = 6) received 25 mg temsirolimus intravenously once-weekly. All consecutive patients received 75 mg intravenously once-weekly. A total of 37 eligible patients (median age of 70 years) were included whose median time since their last treatment was 3.9 months (range of 0.1 to 14.6 months); CR was seen in 5 patients (13.5 %), CR unconfirmed in 3 (8%), and PR in 12 (32.4 %) for an ORR of 54 %. Median PFS was 2.1 months (95 % CI: 1.1 to 3.0 months). The most frequent Common Toxicity Criteria greater than or equal to 3° AE was hyperglycemia in 11 (29.7 %) patients, thrombocytopenia in 8 (21.6 %), infection in 7 (19 %), anemia in 4 (10.8 %), and rash in 3 (8.1 %); 14 blood/CSF pairs were collected in 9 patients (10 pairs in 5patients in the 25-mg cohort and 4 pairs in 4 patients in the 75-mg cohort). The mean maximum blood concentration was 292 ng/ml for temsirolimus and 37.2 ng/ml for its metabolite sirolimus in the 25-mg cohort and 484 ng/ml and 91.1 ng/ml, respectively, in the 75-mg cohort. Temsirolimus CSF concentration was 2 ng/ml in 1 patient in the 75-mg cohort; in all others, no drug was found in their CSF. The authors concluded that single-agent temsirolimus at a weekly dose of 75 mg was found to be active in relapsed/refractory patients with PCNSL; however, responses were usually short-lived.
These investigators stated that frequent administration of steroids before response assessment had to be considered a confounding factor for response evaluation due to their lymphotoxic effect, which may persist for several weeks after discontinuation. Only in 7 of 20 responders not taking steroids for at least 3 months before 1st response assessment could the therapeutic effect be attributed solely to temsirolimus. Another drawback was the preferential inclusion of elderly patients whose initial treatment was frequently not according to the current standards used in younger patients. Generalization of these findings to unselected patients with PCNSL should thus be viewed with caution. The authors noted that although most responses were short-lived, some patients achieved long-term control. They stated that further evaluation in combination with other drugs appeared reasonable.
Prostate Cancer
McHugh and colleagues (2020) noted that despite frequent PTEN (phosphatase and tensin homologue) loss and Akt/mammalian target of rapamycin (mTOR) signaling in prostate cancer (PCa), the disease is insensitive to single-agent mTOR inhibition. Insulin-like growth factor-1 receptor inhibition might mitigate the feedback inhibition by Torc1 inhibitors, suppressing down-stream Akt activation and, thus, potentiating the anti-tumor activity of mTOR inhibition. In a phase-I clinical trial, patients with metastatic castration-resistant PCa received 6 mg/kg cixutumumab and 25 mg temsirolimus intravenously each week. The primary objective was safety and tolerability. Temsirolimus was decreased if greater than or equal to 2 DLTs were observed in 6 patients. The correlative analyses included measurement of circulating tumor cells, [18F]-fluoro-2-deoxyglucose positron emission tomography (18FD-PET), 16β-[18F]-fluoro-α-dihydrotestosterone PET, and tumor biopsy. A total of 16 patients were enrolled across 3 cohorts (1, -1, -2). Two DLTs (grade 3 oral mucositis) were observed in cohort 1 (temsirolimus, 25 mg), and 1 DLT (grade 3 lipase) in cohort -1 (temsirolimus, 20 mg). The most common AEs included hyperglycemia (100 %; 31 % grade-3), oral mucositis (63 %; 19 % grade-3), and diarrhea (44 %; 0 grade-3). Low-grade pneumonitis occurred in 7 of 11 patients (44 %; 0 grade-3), prompting the opening of a 3-weekly cohort (temsirolimus, 20 mg/kg), without pneumonitis events. No patient had a greater than 50 % decline in prostate-specific antigen (PSA) from baseline. The best radiographic response was SD, with median study duration of 22 weeks (range of 7 to 63 weeks). The authors concluded that despite a strong scientific rationale for the combination, temsirolimus plus cixutumumab demonstrated limited anti-tumor activity and a greater than expected incidence of toxicity, including low-grade pneumonitis and hyperglycemia. Thus, this phase-I clinical trial was stopped in favor of alternative androgen receptor/phosphatidylinositol 3-kinase-directed combinatorial therapies.
Retinoblastoma
Chen and colleagues (2019) noted that targeting the mammalian target of rapamycin (mTOR) is a promising strategy for cancer therapy. Temsirolimus is a potent mTOR inhibitor. These investigators were the first to provide pre-clinical evidence that temsirolimus is an attractive candidate for retinoblastoma treatment as a dual inhibitor of retinoblastoma and angiogenesis. They showed that temsirolimus selectively inhibited growth, survival and migration of retinoblastoma cells while sparing normal retinal and fibroblast cells, with IC50 value that was within the clinically achievable range. Temsirolimus potently inhibited retinal angiogenesis via targeting biological functions of retinal endothelial cells. The authors’ mechanism analysis demonstrated that temsirolimus inhibited retinoblastoma and angiogenesis via suppressing mTOR signaling and secretion of pro-angiogenic cytokines. In line with in-vitro data, these researchers further demonstrated the inhibitory effects of temsirolimus on retinoblastoma and angiogenesis in in-vivo xenograft mouse model. The authors concluded that these findings provided a pre-clinical rationale to examine temsirolimus as a strategy to treat retinoblastoma and highlighted the therapeutic value of targeting mTOR in retinoblastoma.
Sarcomas / Soft-Tissue Sarcomas
Wagner et al (2015) stated that the combined inhibition of insulin-growth factor type 1 receptor (IGF-1R) and the mTOR has shown activity in pre-clinical models of pediatric sarcoma and in adult sarcoma patients. These researchers evaluated the activity of the anti-IGF-1R antibody cixutumumab with the mTOR inhibitor temsirolimus in patients with relapsed or refractory Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, and other soft tissue sarcoma, using the recommended dosages from a pediatric phase I trial. Cixutumumab 6 mg/kg and temsirolimus 8 mg/m(2) were administered intravenously once-weekly in 4-week cycles to patients less than 30 years. Temsirolimus was escalated to 10 mg/m(2) for subsequent cycles in patients who did not experience unacceptable first-cycle toxicity. A 2-stage design was used to identify a response rate less than 10 or greater than 35 % for each tumor-specific cohort. Tumor tissue was analyzed by immunohistochemistry for potential biomarkers of response. A total of 43 evaluable patients received a median of 2 cycles (range of 1 to 7). No objective responses were observed, and 16 % of patients were progression-free at 12 weeks. Dose-limiting toxicity was observed in 15 (16 %) of 92 cycles. The most common toxicities were mucositis, electrolyte disturbances, and myelosuppression. The majority of patients receiving a second cycle were not eligible for temsirolimus escalation due to first-cycle toxicity. The lack of objective responses precluded correlation with tissue biomarkers. The authors concluded that despite encouraging pre-clinical data, the combination of cixutumumab and temsirolimus did not result in objective responses in this phase II trial of pediatric and young adults with recurrent or refractory sarcoma.
Eroglu et al (2015) stated that the MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in-vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib versus selumetinib plus temsirolimus was conducted. A total of 71 adults with advanced STS who received less than or equal to 2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid (by mouth, twice-daily) and allowed to cross-over upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg I.V. weekly, with primary end-point of progression-free survival (PFS). There was no difference in PFS between the 2 arms for the overall cohort (median of 1.9 versus 2.1 months); an improved median PFS was observed in the combination arm (n = 11) over single agent (n = 10) in the pre-specified leiomyosarcoma stratum (median of 3.7 versus 1.8 months; p = 0.01). Four-month PFS rate was 50 % (95 % confidence interval [CI]: 0.19 to 0.81) with the combination versus 0 % with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29 %), lymphopenia (26 %), neutropenia and anemia (20 % each). The authors concluded that while single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.
In a phase-II clinical trial, Mascarenhas and colleagues (2019) examined bevacizumab or temsirolimus for additional investigation in rhabdomyosarcoma (RMS) when administered in combination with cytotoxic chemotherapy to patients with RMS in 1st relapse with unfavorable prognosis. Patients were randomly assigned to receive bevacizumab on day 1 or temsirolimus on days 1, 8, and 15 of each 21-day treatment cycle, together with vinorelbine on days 1 and 8, and cyclophosphamide on day 1 for a maximum of 12 cycles. Local tumor control with surgery and/or RT was permitted after 6 weeks of treatment. The primary end-point was event-free survival (EFS); radiographic response was evaluated at 6 weeks. The study had a phase-II selection that was designed to detect a 15 % difference between the 2 regimens (α = .2; 1-β = 0.8; 2-sided test). A total of 87 of 100 planned patients were enrolled when the trial was closed after the 2nd interim analysis after 46 events occurred in 68 patients with sufficient follow-up. The O'Brien Fleming boundary at this analysis corresponded to a 2-sided p value of 0.058 with an observed 2-sided p value of 0.003 favoring temsirolimus. The 6-month EFS for the bevacizumab arm was 54.6 % (95 % CI: 39.8 % to 69.3 %) and 69.1 % (95 % CI: 55.1 % to 83 %) for the temsirolimus arm. Objective response rates were 28 % (95 % CI: 13.7 % to 41.3 %) and 47 % (95 % CI: 31.5 % to 63.2 %) for the bevacizumab and temsirolimus arms, respectively (p = 0.12), and 28 % of patients on bevacizumab and 11 % on temsirolimus had progressive disease at 6 weeks. The authors concluded that patients who received temsirolimus had a superior EFS compared with bevacizumab; thus, temsirolimus has been selected for additional investigation in newly diagnosed patients with intermediate-risk RMS.
Salivary Gland Muco-Epidermoid Carcinoma
Andrade and colleagues (2021) stated that advanced salivary gland muco-epidermoid carcinoma (MEC) is a relentless cancer that exhibits resistance to conventional chemotherapy. As such, treatment for patients with advanced MEC is usually radical surgery and radiotherapy (RT). Facial disfigurement and poor quality of life (QOL) are frequent treatment challenges, and many patients succumb to loco-regional recurrence and/or metastasis. These researchers know that cancer stem-like cells (CSC) drive MEC tumorigenesis. They tested the hypothesis that MEC CSC are sensitive to therapeutic inhibition of mTOR. These investigators reported a correlation between the long-term clinical outcomes of 17 MEC patients and the intra-tumoral expression of p-mTOR (p = 0.00294) and p-S6K1 (p = 0.00357). In-vitro, these researchers observed that MEC CSC exhibited constitutive activation of the mTOR signaling pathway (i.e., mTOR, AKT, and S6K1), unveiling a potential strategy for targeted ablation of these cells. Using a panel of inhibitors of the mTOR pathway, i.e., rapamycin and temsirolimus (mTOR inhibitors), buparlisib and LY294002 (AKT inhibitors), and PF4708671 (S6K1 inhibitor), these investigators observed consistently dose-dependent decrease in the fraction of CSC, as well as inhibition of secondary sphere formation and self-renewal in 3 human MEC cell lines (UM-HMC-1,-3A,-3B). Notably, therapeutic inhibition of mTOR with rapamycin or temsirolimus induced preferential apoptosis of CSC, when compared to bulk tumor cells. In contrast, conventional chemotherapeutic drugs (cisplatin, paclitaxel) induced preferential apoptosis of bulk tumor cells and accumulation of CSC. In-vivo, therapeutic inhibition of mTOR with temsirolimus caused ablation of CSC and down-regulation of Bmi-1 expression (major inducer of stem cell self-renewal) in MEC xenografts. Transplantation of MEC cells genetically silenced for mTOR into immunodeficient mice corroborated the results obtained with temsirolimus. The authors concluded that these findings showed that mTOR signaling is needed for CSC survival, and unveiled the therapeutic potential of targeting the mTOR pathway for elimination of highly tumorigenic CSC in salivary gland MEC.
Thyroid Cancer
In a single-institution, phase II clinical trial, Sherman and colleagues (2017) stated that patients with recurrent and/or metastatic, radioactive iodine-refractory thyroid carcinoma have limited therapeutic options. Sorafenib, an oral kinase inhibitor, is approved by the FDA for the treatment of radioactive iodine-refractory thyroid carcinoma, although it demonstrated low response rates (12.2 %) as a single-agent in the 1st-line setting. The objective of the current study was to examine if adding the mammalian target of rapamycin inhibitor temsirolimus to sorafenib could improve on these results. A total of 36 patients with metastatic, radioactive iodine-refractory thyroid carcinoma of follicular origin received treatment with the combination of oral sorafenib (200 mg twice-daily) and intravenous temsirolimus (25 mg weekly). The receipt of prior systemic treatment with cytotoxic chemotherapy and targeted therapy, including sorafenib, was permitted. The primary end-point was the radiographic response rate. The best response was a PF in 8 patients (22 %), SD in 21 (58 %), and PD in 1 (3 %); 6 patients were not evaluable for a response. Patients who had received any prior systemic treatment had a response rate of 10 % compared with 38 % of those who had not received prior systemic treatment; 1 of 2 patients with anaplastic thyroid cancer had an objective response. The PFS rate at 1 year was 30.5 %. The most common grade 3 and 4 toxicities associated with sorafenib and temsirolimus included hyperglycemia, fatigue, anemia, and oral mucositis. The authors concluded that sorafenib and temsirolimus appeared to be an active combination in patients with radioactive iodine-refractory thyroid carcinoma, especially in patients who received no prior treatment compared with historic data from single-agent sorafenib. Activity was also observed in patients who previously received sorafenib. These investigators stated that this regimen warrants further investigation.
References
The above policy is based on the following references:
- Anderson CD, Stuart KE. Treatment of localized cholangiocarcinoma: Adjuvant and neoadjuvant therapy and prognosis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2023.
- Anderson CD, Stuart KE, Palta M. Treatment options for locally advanced, unresectable, but nonmetastatic cholangiocarcinoma. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2023.
- Andrade NP, Warner KA, Zhang Z, et al. Survival of salivary gland cancer stem cells requires mTOR signaling. Cell Death Dis. 2021;12(1):108.
- Aneva IY, Habtemariam S, Banach M, et al. Can we use mTOR inhibitors for COVID-19 therapy? Comb Chem High Throughput Screen. 2022;25(11):1805-1808.
- Benson C, Vitfell-Rasmussen J, Maruzzo M, et al. A retrospective study of patients with malignant PEComa receiving treatment with sirolimus or temsirolimus: The Royal Marsden Hospital experience. Anticancer Res 2014;34:3663-3668.
- Cawich I, Armstrong EJ, George JC, et al. Temsirolimus adventitial delivery to improve angiographic outcomes below the knee. J Endovasc Ther. 2022 Nov 1 [Online ahead of print].
- Chan J, Kulke M. Targeting the mTOR signaling pathway in neuroendocrine tumors. Curr Treat Options Oncol. 2014;15(3):365-379.
- Chang HW, Wu MJ, Lin ZM, et al. Therapeutic effect of repurposed temsirolimus in lung adenocarcinoma model. Front Pharmacol. 2018;9:778.
- Chen Z, Yang H, Li Z, et al. Temsirolimus as a dual inhibitor of retinoblastoma and angiogenesis via targeting mTOR signalling. Biochem Biophys Res Commun. 2019;516(3):726-732.
- Clinical Pharmacology. Tampa, FL: Gold Standard/Elsevier; updated periodically.
- Dunn LA, Fury MG, Xiao H, et al. A phase II study of temsirolimus added to low-dose weekly carboplatin and paclitaxel for patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Ann Oncol. 2017;28(10):2533-2538.
- Eroglu Z, Tawbi HA, Hu J, et al. A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas. Br J Cancer. 2015;112(10):1644-1651.
- Farley JH, Brady WE, O'Malley D, et al. A phase II evaluation of temsirolimus with carboplatin and paclitaxel followed by temsirolimus consolidation in clear cell ovarian cancer: An NRG oncology trial. Gynecol Oncol. 2022;167(3):423-428.
- Fenske TS, Shah NM, Kim KM, et al. A phase 2 study of weekly temsirolimus and bortezomib for relapsed or refractory B-cell non-Hodgkin lymphoma: A Wisconsin Oncology Network study. Cancer. 2015;121(19):3465-3471.
- Freedman AS, Friedberg JW. Treatment of relapsed or refractory mantle cell lymphoma. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2023.
- Grunwald V, Keilholz U, Boehm A, et al. TEMHEAD: a single-arm multicentre phase II study of temsirolimus in platin- and cetuximab refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) of the German SCCHN Group (AIO). Ann Oncol. 2015;26(3):561-567.
- Hajatdoost L, Sedaghat K, Walker EJ, et al. Chemotherapy in pancreatic cancer: A systematic review. Medicina (Kaunas). 2018;54(3).
- He K, Zheng X, Li M, et al. mTOR inhibitors induce apoptosis in colon cancer cells via CHOP-dependent DR5 induction on 4E-BP1 dephosphorylation. Oncogene. 2016;35(2):148-157.
- Heo JH, Park C, Ghosh S, et al. A network meta-analysis of efficacy and safety of first-line and second-line therapies for the management of metastatic renal cell carcinoma. J Clin Pharm Ther. 2021;46(1):35-49.
- Hess G, Herbrecht R, Romaguerra J, 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;27:3822-29.
- Hobday TJ, Qin R, Reidy-Lagunes D, et al. Multicenter phase II trial of temsirolimus and bevacizumab in pancreatic neuroendocrine tumors. J Clin Oncol. 2015;33(14):1551-1556.
- Huang S, Du K, Liu Z, Li J. Inhibition of mTOR by temsirolimus overcomes radio-resistance in nasopharyngeal carcinoma. Clin Exp Pharmacol Physiol. 2022;49(7):703-709.
- Hudes G, et al. Temsirolimus, Interferon Alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271-2281.
- Jiang T, Yu JT, Zhu XC, et al. Temsirolimus promotes autophagic clearance of amyloid-β and provides protective effects in cellular and animal models of Alzheimer's disease. Pharmacol Res. 2014;81:54-63.
- Kaley TJ, Panageas KS, Pentsova EI, et al. Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma. Ann Clin Transl Neurol 2020; 7(4):429-436.
- Kaneko M, Nozawa H, Hiyoshi M, et al. Temsirolimus and chloroquine cooperatively exhibit a potent antitumor effect against colorectal cancer cells. J Cancer Res Clin Oncol. 2014;140(5):769-781.
- Karavasilis V, Samantas E, Koliou GA, et al. Gemcitabine combined with the mTOR inhibitor temsirolimus in patients with locally advanced or metastatic pancreatic cancer. A Hellenic Cooperative Oncology Group Phase I/II Study. Target Oncol. 2018;13(6):715-724.
- Kelley RK, Joseph NM, Nimeiri HS, et al. Phase II trial of the combination of temsirolimus and sorafenib in advanced hepatocellular carcinoma with tumor mutation profiling. Liver Cancer. 2021;10(6):561-571.
- Kling MJ, Griggs CN, McIntyre EM, et al. Synergistic efficacy of inhibiting MYCN and mTOR signaling against neuroblastoma. BMC Cancer. 2021;21(1):1061.
- Knox JJ, Qin R, Strosberg JR, et al. A phase II trial of bevacizumab plus temsirolimus in patients with advanced hepatocellular carcinoma. Invest New Drugs. 2015;33(1):241-246.
- Kondo S, Hirakawa H, Ikegami T, et al. Raptor and rictor expression in patients with human papillomavirus-related oropharyngeal squamous cell carcinoma. BMC Cancer. 2021;21(1):87.
- Korfel A, Schlegel U, Herrlinger U, et al. Phase II trial of temsirolimus for relapsed/refractory primary CNS lymphoma. J Clin Oncol. 2016;34(15):1757-1763.
- Liu W, Huang S, Chen Z, et al. Temsirolimus, the mTOR inhibitor, induces autophagy in adenoid cystic carcinoma: In vitro and in vivo. Pathol Res Pract. 2014;210(11):764-769.
- Major A, Kline J, Karrison TG, et al. Phase I/II clinical trial of temsirolimus and lenalidomide in patients with relapsed and refractory lymphomas. Haematologica. 2022;107(7):1608-1618.
- Mascarenhas L, Chi Y-Y, Hingorani P, et al. Randomized phase II trial of bevacizumab or temsirolimus in combination with chemotherapy for first relapse rhabdomyosarcoma: A report From the Children's Oncology Group. J Clin Oncol. 2019;37(31):2866-2874.
- Matsumoto K, Onda T, Yaegashi N. Pharmacotherapy for recurrent ovarian cancer: Current status and future perspectives. Jpn J Clin Oncol. 2015;45(5):408-410.
- McHugh DJ, Chudow J, DeNunzio M, et al. A phase I trial of IGF-1R inhibitor cixutumumab and mTOR inhibitor temsirolimus in metastatic castration-resistant prostate cancer. Clin Genitourin Cancer. 2020; 18(3):171-178.e2.
- National Cancer Institute. Torisel, Cancer Topics. Bethesda, MD: NCI; updated October 28, 2011. Available at: www.cancer.gov/cancertopics/druginfo/temsirolimus. Accessed March 11, 2013.
- National Comprehensive Cancer Network (NCCN). Kidney cancer. NCCN Clinical Practice Guidelines in Oncology, Version 1.2024. Plymouth Meeting, PA: NCCN; June 2023.
- National Comprehensive Cancer Network (NCCN). Ovarian cancer including fallopian tube cancer and primary peritoneal cancer. NCCN Clinical Practice Guidelines, Version 2.2023. Plymouth Meeting, PA: NCCN; June 2023.
- National Comprehensive Cancer Network (NCCN). Soft tissue sarcoma. NCCN Clinical Practice Guidelines in Oncology, Version 2.2023. Plymouth Meeting, PA: NCCN; April 2023.
- National Comprehensive Cancer Network (NCCN). Temsirolimus. NCCN Drugs & Biologics Compendium. Plymouth Meeting, PA: NCCN; May 2023.
- National Comprehensive Cancer Network (NCCN). Uterine neoplasms. NCCN Clinical Practice Guidelines in Oncology, Version 2.2023. Plymouth Meeting, PA: NCCN; April 2023.
- Nguyen SA, Walker D, Gillespie MB, et al. mTOR inhibitors and its role in the treatment of head and neck squamous cell carcinoma. Curr Treat Options Oncol. 2012;13(1):71-81.
- No authors listed. Expanding targeted therapies for NSCLC. Cancer Discov. 2014;4(12):OF1
- Okamoto K, Nozawa H, Sonoda H, et al. Combinatory anti-tumor activities of 1,4-bis[2-(dimethylamino)ethylamino]-5,8-dihydroxyanthracene-9,10-dione (AQ4) and temsirolimus against colorectal cancer cells. J Cancer Res Clin Oncol. 2022 Oct 11 [Online ahead of print].
- Piatek CI, Raja GL, Ji L, et al. Phase I clinical trial of temsirolimus and vinorelbine in advanced solid tumors. Cancer Chemother Pharmacol. 2014;74(6):1227-1234. Autophagy. 2014;10(8):1391-1402.
- Piha-Paul SA, Shin SJ, Vats T, et al. Pediatric patients with refractory central nervous system tumors: Experiences of a clinical trial combining bevacizumab and temsirolimus. Anticancer Res. 2014;34(4):1939-1945.
- Pirosa MC, Zhang L, Hitz F, et al. A phase I trial of inotuzumab ozogamicin in combination with temsirolimus in patients with relapsed or refractory CD22-positive B-cell non-Hodgkin lymphomas. Leuk Lymphoma. 2022;63(1):117-123.
- Pulido M, Roubaud G, Cazeau AL, et al. Safety and efficacy of temsirolimus as second line treatment for patients with recurrent bladder cancer. BMC Cancer. 2018;18(1):194.
- Qiao L, Liang Y, Mira RR, et al. Mammalian target of rapamycin (mTOR) inhibitors and combined chemotherapy in breast cancer: A meta-analysis of randomized controlled trials. Int J Clin Exp Med. 2014;7(10):3333-3343.
- Rangwala R, Chang YC, Hu J, et al. Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma
- Rheingold SR, Tasian SK, Whitlock JA, et al. A phase 1 trial of temsirolimus and intensive re-induction chemotherapy for 2nd or greater relapse of acute lymphoblastic leukaemia: a Children's Oncology Group study (ADVL1114). Br J Haematol. 2017;177(3):467-474.
- Schiff D, Jaeckle KA, Anderson SK, et al. Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572. Cancer. 2018;124(7):1455-1463.
- Sherman EJ, Dunn LA, Ho AL, et al. Phase 2 study evaluating the combination of sorafenib and temsirolimus in the treatment of radioactive iodine-refractory thyroid cancer. Cancer. 2017;123(21):4114-4121.
- Siracusa R, Paterniti I, Cordaro M, et al. Neuroprotective effects of temsirolimus in animal models of Parkinson's disease. Mol Neurobiol. 2018;55(3):2403-2419.
- Stuart KE. Systemic therapy for advanced cholangiocarcinoma. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed June 2023.
- Sun K, Jin L, Karolova J, et al. Combination treatment targeting mTOR and MAPK pathways has synergistic activity in multiple myeloma. Cancers (Basel). 2023;15(8):2373.
- Tarek N, Hayes-Jordan A, Salvador L, et al. Recurrent desmoplastic small round cell tumor responding to an mTOR inhibitor containing regimen. Pediatr Blood Cancer. 2018;65(1).
- Tasian SK, Silverman LB, Whitlock JA, et al. Temsirolimus combined with cyclophosphamide and etoposide for pediatric patients with relapsed/refractory acute lymphoblastic leukemia: A Therapeutic Advances in Childhood Leukemia Consortium trial (TACL 2014-001). Haematologica. 2022;107(10):2295-2303.
- Thompson PA, Malogolowkin MH, Furman WL, et al. Vincristine/irinotecan/temsirolimus upfront window treatment of high-risk hepatoblastoma: A report from the Children's Oncology Group AHEP0731 Study Committee. Pediatr Blood Cancer. 2023;70(7):e30365.
- Torisel. Drug Facts and Comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health, Inc; updated periodically.
- Ushijima H, Suzuki Y, Oike T, et al. Radio-sensitization effect of an mTOR inhibitor, temsirolimus, on lung adenocarcinoma A549 cells under normoxic and hypoxic conditions. J Radiat Res. 2015;56(4):663-668.
- Vazakidou ME, Magkouta S, Moschos C, et al. Temsirolimus targets multiple hallmarks of cancer to impede mesothelioma growth in vivo. Respirology. 2015;20(8):1263-1271.
- Velho TR. Metastatic melanoma - a review of current and future drugs. Drugs Context. 2012;2012:212242.
- Wagner LM, Fouladi M, Ahmed A, et al. Phase II study of cixutumumab in combination with temsirolimus in pediatric patients and young adults with recurrent or refractory sarcoma: A report from the Children's Oncology Group. Pediatr Blood Cancer. 2015;62(3):440-444.
- Wen PY, Chang SM, Lamborn KR, et al. Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02. Neuro Oncol. 2014;16(4):567-578.
- Wermke M, Schuster C, Nolte F, et al. Mammalian-target of rapamycin inhibition with temsirolimus in myelodysplastic syndromes (MDS) patients is associated with considerable toxicity: Results of the temsirolimus pilot trial by the German MDS Study Group (D-MDS). Br J Haematol. 2016;175(5):917-924.
- Wyeth Pharmaceuticals, Inc. Torisel Kit (temsirolimus) injection, for intravenous use. Prescribing Information. Philadelphia, PA: Wyeth; revised March 2018.
- Yeo W, Chan SL, Mo FK, et al. Phase I/II study of temsirolimus for patients with unresectable hepatocellular carcinoma (HCC)- a correlative study to explore potential biomarkers for response. BMC Cancer. 2015;15:395.
- Zhao Q, Tran H, Dimitrov DS, Cheung NK. A dual-specific anti-IGF-1/IGF-2 human monoclonal antibody alone and in combination with temsirolimus for therapy of neuroblastoma. Int J Cancer. 2015;137(9):2243-2252.
