Temsirolimus (Torisel)

Number: 0873

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References


Policy

  1. Criteria for Initial Approval

    Aetna considers temsirolimus (Torisel) medically necessary for any of the following indications:

    1. Renal Cell Carcinoma - as a single agent for treatment of advanced, relapsed, or stage IV renal cell carcinoma; or
    2. Endometrial carcinoma - as a single agent for treatment of endometrial carcinoma; or
    3. Soft tissue sarcoma
      1. 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
      2. For treatment of rhabdomyosarcoma in combination with cyclophosphamide and vinorelbine.
    4. Mantle cell lymphoma - for treatment of relapsed or refractory mantle cell lymphoma

    Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

  2. 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) 
  • Hepatocellular carcinoma
  • Leiomyosarcoma
  • Lung cancer (e.g., lung adenocarcinoma, and non-small cell lung cancer)
  • Melanoma
  • 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

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

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
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
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]
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
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)
    Temsirolimus is available as Torisel (Wyeth  Pharmaceuticals, Inc.) and is an inhibitor of mammalian target of rapamycin (mTOR ). Temsirolimus binds to an intracellular protein (FKBP‐12), and the protein‐drug complex inhibits the activity of mTOR that controls cell division.  Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells.  When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked.

    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, 2021) 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 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, 2022), “Treatment of localized cholangiocarcinoma: Adjuvant and neoadjuvant therapy and prognosis” (Anderson and Stuart,2022), and “Treatment options for locally advanced, unresectable, but nonmetastatic cholangiocarcinoma” (Anderson et al., 2022) 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.

    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.

    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.

    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:
    1. In phase I, to determine dose-limiting toxicities (DLTs) and MTD of temsirolimus in HCC patients with chronic liver disease;
    2. In phase II, to assess activity of temsirolimus in HCC, and
    3. to explore potential biomarkers for response.
    Major eligibility criteria included histologically confirmed advanced HCC and adequate organ function. In Phase I part of the study, temsirolimus was given weekly in 3-weekly cycle; dose levels were 20 mg (level 1), 25 mg (level 2) and 30 mg (level 3). The MTD was used in the subsequent phase II part; the primary end-point was PFS and secondary end-points were response and OS. In addition, exploratory analysis was conducted on pre-treatment tumor tissues to determine stathmin, pS6, pMTOR or p-AKT expressions as potential biomarkers for response; OS and PFS were calculated using the Kaplan-Meier method. Re-assessment CT scans were done every 6 weeks. All adverse events were reported using CTCAE v3. The Phase I part consisted of 19 patients, 2 of 6 patients at level 3 experienced DLT; dose level 2 was determined to be the MTD. The phase II part consisted of 36 patients. Among 35 assessable patients, there were 1 PR, 20 SD, and 14 progressive disease (PD). Overall, the median PFS was 2.83 months (95 % CI: 1.63 to 5.24). The median OS was 8.89 months (95 % CI: 5.89 to 13.30). Grade greater than or equal to 3 that occurred in more than 10 % of patients included thrombocytopenia (n = 4) and hyponatremia (n = 4). Exploratory analysis revealed that disease stabilization (defined as CR + PR + SD greater than 12 weeks) in tumors having high and low pMTOR H-scores to be 70 % and 29 %, respectively (OR 5.667, 95 % CI: 1.129 to 28.454, p = 0.035). The authors concluded that in HCC patients with chronic liver disease, the MTD of temsirolimus was 25 mg weekly in a 3-week cycle. The targeted PFS end-point was not reached. However, further studies to identify appropriate patient subgroup are needed.

    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.

    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.

    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.


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