Clinical UM Guideline


Subject: Temsirolimus (Torisel®)
Guideline #:  CG-DRUG-52 Publish Date:    12/27/2017
Status: Reviewed Last Review Date:    11/02/2017


This document addresses indications for the use of Torisel (temsirolimus injection), which is an antineoplastic agent that acts as an inhibitor of mammalian target of rapamycin (mTOR) for the treatment of certain cancers including advanced renal cell carcinoma.

Clinical Indications

Medically Necessary:

Temsirolimus injection (Torisel) is considered medically necessary for any of the following conditions (I through III) when criteria are met:

  1. Advanced renal cell carcinoma for either of the following (A or B):
    1. As first-line therapy as a single agent (monotherapy) for (either 1 or 2):
      1. Relapsed metastatic disease; or
      2. Surgically unresectable stage IV renal carcinoma in individuals with a poor prognosis as manifested by having at least 3 of the following (a through f):
        1. Lactate dehydrogenase greater than 1.5 times the upper limit of normal; or
        2. Hemoglobin less than the lower limit of normal; or
        3. Corrected calcium level greater than 10mg/dL (2.5mmol/liter); or
        4. Interval of less than a year from original diagnosis to the start of systemic therapy; or
        5. Karnofsky performance status less than or equal to 70 or ECOG performance score of 2, 3, or 4; or
        6. Greater than or equal to 2 sites of metastases; 
    2. For subsequent (second-line) therapy as a single agent (monotherapy) for relapsed metastatic or for surgically unresectable stage IV disease; or
  2. Soft tissue sarcoma as single agent therapy (monotherapy) for sarcoma including, but not limited to, PEComa, recurrent angiomyolipoma, and lymphangioleiomyomatosis; or
  3. Endometrial adenocarcinoma as a single agent (monotherapy) for unresectable, recurrent or metastatic disease.

Not Medically Necessary:

Temsirolimus injection (Torisel) is considered not medically necessary when criteria are not met and for all other indications.


The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.




Injection, temsirolimus, 1 mg [Torisel]



ICD-10 Diagnosis



Malignant neoplasm of other connective and soft tissue


Malignant neoplasm of endometrium


Malignant neoplasm of renal pelvis


Malignant neoplasm of kidney, except renal pelvis


Benign neoplasm of kidney


Benign neoplasm of renal pelvis




Personal history of other malignant neoplasm of kidney

Discussion/General Information

According to a focused mTOR Taskforce convened by the National Comprehensive Cancer Network® (NCCN) to review the underlying physiology of mTOR and related cellular pathways, and to review the current research status of mTOR inhibition in solid tumors, the following is noted:

The mTOR (mammalian target of rapamycin) protein complex functions as an integration center for various intracellular signaling pathways involving cell cycle progression, proliferation and angiogenesis. These pathways are frequently dysregulated in cancer. To date, the published studies have focused on mTOR inhibition as a monotherapy, or in combination with other drugs, based on the principle that inhibition of as many targets as possible will reduce the emergence of drug resistance. To date, temsirolimus is the only mTOR inhibitor that is specifically labeled for treatment of solid tumors. Additional research is expected to further define the complicated mTOR pathways and how they may be disordered in specific malignancies…It is believed that inhibition of mTOR could reduce cell proliferation, angiogenesis, and metastases, and induce apoptosis. The emerging understanding of the complex mTOR pathways also suggests that mTOR inhibition could provide synergy with other cancer therapies (NCCN, 2007).

Torisel (temsirolimus injection, Wyeth Pharmaceuticals, Inc., a subsidiary of Pfizer, Inc., Philadelphia, PA) is an mTOR kinase inhibitor which was approved by the U.S. Food and Drug Administration (FDA) on May 30, 2007 for the treatment of advanced renal cell carcinoma for adults in the United States. Outside the U.S., temsirolimus has been approved for the treatment of relapsed or refractory mantle cell lymphoma for adults in the European Union, Australia, and other countries; (this indication is rated Class IIb, Category B [off label] by the DrugPoints® System, Truven Health Analytics MICROMEDEX Solutions® - see Definitions section for further information).
According to the latest prescribing information (PI, 2015), temsirolimus injection requires two dilutions prior to intravenous (IV) infusion. Torisel (temsirolimus) injection should be diluted only with the supplied diluent:

The recommended dose of Torisel for advanced renal cell carcinoma is 25 mg infused IV over a 30–60 minute period once a week, and treatment should continue until disease progression or unacceptable toxicity occurs…Torisel should be held for an absolute neutrophil count (ANC) < 1,000/mm,3 platelet count < 75,000/mm3 or NCI CTCAE grade 3 or greater adverse reactions. Once toxicities have resolved to grade 2 or less, Torisel may be restarted with the dose reduced by 5 mg/week to a dose no lower than 15 mg/week…The use of Torisel may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections (FDA, 2015).

Regarding adverse reactions to Torisel, the PI provides the following:

The most common (≥ 30%) adverse reactions observed with Torisel are rash, asthenia, mucositis, nausea, edema, and anorexia. The most common (≥ 30%) laboratory abnormalities observed with Torisel are anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, lymphopenia, elevated alkaline phosphatase, elevated serum creatinine, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia…The following serious adverse reactions have been associated with Torisel in clinical trials: 

Regarding use of Torisel in pediatric individuals: 

Limited data are available on the use of temsirolimus in pediatric patients. The effectiveness of temsirolimus in pediatric patients with advanced recurrent/refractory solid tumors has not been established (FDA, 2015).

According to the FDA, approval of Torisel was based on the following:

Efficacy and safety was demonstrated at a second interim analysis of a phase 3, multi-center, international, randomized, open-label study (Hudes, 2007) in previously untreated patients with advanced RCC who had 3 or more of 6 poor prognostic factors. These factors included time of diagnosis to randomization of less than one year, Karnofsky performance status of 60 or 70, hemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dL, lactate dehydrogenase > 1.5 times the upper limit of normal, and/or more than one metastatic organ site. Six hundred and twenty six patients were randomized to one of three arms: Interferon alfa (IFN-α) alone (n=207), temsirolimus 25 mg alone (n=209), or the combination of temsirolimus 15 mg and IFN-α (n=210). Patients were stratified for prior nephrectomy and geographic region. Seventy percent were less than 65 years old and 69% were male. Temsirolimus was infused intravenously over 30-60 minutes once a week either until disease progression or unacceptable toxicity. Premedication with an antihistamine (e.g., diphenhydramine) was recommended.

Study results showed that single-agent temsirolimus was associated with a statistically significant improvement in overall survival (OS) when compared to IFN-α (hazard ratio [HR] 0.73, 95% confidence interval [CI]: 0.58-0.92; p=0.008). The median OS was 10.9 months on the temsirolimus arm and 7.3 months on the IFN-α arm. Progression-free survival (PFS) was a secondary endpoint and the median PFS was 5.5 months on the temsirolimus arm (p<0.001) and 3.1 months on the IFN-α arm (HR 0.66, 95% CI: 0.53, 0.81). The combination of temsirolimus 15 mg and IFN-α did not result in a significant increase in OS when compared with IFN-α alone and was associated with an increase in multiple adverse reactions. The most common adverse reactions (incidence ≥ 30%) were rash, asthenia, mucositis, nausea, edema, and anorexia. The most common laboratory abnormalities (incidence ≥ 30%) were anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, elevated alkaline phosphatase, elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, elevated AST, and leukopenia. The most common grade 3/4 adverse reactions (incidence ≥ 5%) included asthenia, dyspnea, rash, and pain. The most common grade 3/4 laboratory abnormalities (incidence ≥ 5%) included hypertriglyceridemia, anemia, hypophosphatemia, hyperglycemia, lymphopenia, and neutropenia. Rare serious adverse reactions associated with temsirolimus included interstitial lung disease, bowel perforation, and acute renal failure (Hudes, 2007; Yang, 2010; Zbrozek, 2010).

According to the National Comprehensive Cancer Network® (NCCN) Drugs & Biologic Compendium®, the following indications for treatment with Torisel are rated Class 2A (or above) as off label uses when conditions are met:


Angiomyolipoma: A neoplasm with perivascular epithelioid cell differentiation (PEComa) often associated with tuberous sclerosis. It is characterized by a mixture of epithelioid cells, smooth muscle, vessels, and mature adipose tissue. The kidney is the most common site of involvement. Other sites of involvement include the liver, lung, lymph nodes, and retroperitoneum. The vast majority of cases follow a benign clinical course. However, cases of metastatic angiomyolipomas with sarcomatoid features have been described (NCI, 2015).

Carcinosarcoma: A malignant tumor composed of a mixture of carcinomatous and sarcomatous elements. This term describes a malignant tumor that is a mixture of carcinoma (cancer of epithelial tissue, which is skin and tissue that lines or covers the internal organs) and sarcoma (cancer of connective tissue, such as bone, cartilage, and fat).

Clear cell Adenocarcinoma: A malignant neoplasm composed of glandular epithelial clear cells. Various architectural patterns may be seen, including papillary, tubulocystic, and solid (NCI, 2015).

Complete Response (CR): The disappearance of all signs of cancer as a result of treatment; this is also called complete remission; this does not indicate the cancer has been cured.

Disease-free Survival (DFS): In cancer, this denotes the length of time after primary treatment that the individual survives without any signs or symptoms of that cancer. In a clinical trial, measuring the DFS is one way to see how well a new treatment works.

ECOG Performance Status* (Eastern Cooperative Oncology Group, also called the WHO [World Health Organization] or Zubrod score): These scales and criteria are used to assess how a person's disease is progressing, also to assess how the disease affects daily living abilities, and to determine appropriate treatment and prognosis. This table is provided by the National Cancer Institute (NCI) to define the ECOG scores used in clinical practice:




Fully active, able to carry on all pre-disease performance without restriction


Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work


Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours


Capable of only limited self-care, confined to bed or chair more than 50% of waking hours


Completely disabled; cannot carry on any self-care. Totally confined to bed or chair



*Excerpted from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program.

Endometrial Adenocarcinoma: An adenocarcinoma arising from the uterine body cavity. This is the most frequent malignant tumor affecting the uterine body, and is linked to estrogen therapy. Most individuals present with uterine bleeding and are over age 40 at the time of diagnosis. The prognosis depends on the stage of the tumor, the depth of the uterine wall invasion, and the histologic subtype. Endometrioid adenocarcinoma is the most frequently seen morphologic variant of endometrial adenocarcinoma (NCI, 2015).

Karnofsky Performance Status (KPS): A standard way of measuring the ability of individuals with cancer to perform ordinary tasks. The KPS scores range from 0 to 100. A higher score means the person is better able to carry out daily activities. The KPS may be used to determine an individual’s prognosis, to measure changes in the ability to function, or to decide if an individual could be included in a clinical trial (NCI, 2015).

Lines of therapy:
First-line therapy: The first or primary treatment for the diagnosis. This may include surgery, chemotherapy, radiation therapy or a combination of these therapies.
Second-line therapy: Treatment given when initial treatment (first-line therapy) is not effective or there is disease progression.
Third-line therapy: Treatment given when both initial (first-line therapy) and subsequent treatment (second-line therapy) are not effective or there is disease progression.

Lymphangioleiomyomatosis: A multifocal neoplasm with perivascular epithelioid cell differentiation (PEComa) affecting almost exclusively females of child-bearing age. It is characterized by the presence of smooth muscle and epithelioid cells and by the proliferation of lymphatic vessels. Sites of involvement include the lungs, mediastinum, and the retroperitoneum. It usually presents with chylous pleural effusion or ascites (NCI, 2015).

mTOR Inhibitor: Any substance that inhibits mammalian target of rapamycin (mTOR or FK506 binding protein 12-rapamycin associated protein 1 [FRAP1]), a serine/threonine protein kinase that is active in the control of cell growth, cell proliferation, and cell motility. Inhibition of mTOR can inhibit cell proliferation (NCI, 2015).

Partial Response (PR): A decrease in the size of a tumor, or in the amount of cancer in the body, resulting from treatment; this is also called partial remission.

PEComa: A soft tissue mesenchymal tumor with perivascular epithelioid cell differentiation (PEComa). Representative examples include angiomyolipoma, clear cell-sugar-tumor of the lung, and lymphangioleiomyomatosis.

Progressive Disease (PD): Cancer that is growing, spreading, or getting worse; this is also called disease progression.

Progression-free Survival (PFS): The time from random assignment in a clinical trial to disease progression.

Refractory Disease: Illness or disease that does not respond to treatment.

Relapsed Disease: The worsening of an oncologic disease after a period of improvement or remission.

Renal cell Carcinoma (RCC): A carcinoma (malignant neoplasm) arising from the renal parenchyma. RCC is a heterogeneous term comprising a group of neoplasms of renal origin. There are 4 major histologic subtypes of RCC: conventional (clear cell RCC, 75%), papillary (15%), chromophobic (5%), and collecting duct (2%). Multiple genes are involved in the molecular pathogenesis of RCC. VHL (von Hippel Lindau tumor suppressor function) is a tumor suppressor gene responsible for hereditary and sporadic variants of conventional (clear cell) RCC. In the absence of VHL, hypoxia-inducible factor alpha (HIF-alpha) accumulates, leading to production of several growth factors, including vascular endothelial growth factor and platelet-derived growth factor. An oncogene, MET has been found to be mutant in cases of hereditary papillary renal cancer (HPRC), although the incidence of c-MET mutations is low in sporadic papillary RCC. Once activated, MET mediates a number of biological effects including motility, invasion of extracellular matrix, cellular transformation, prevention of apoptosis and metastasis formation. Mutations in the fumarate hydratase (FH) gene cause hereditary leiomyomatosis and renal cancer syndrome (HLRCC) papillary renal tumors, although the incidence of FH mutations in sporadic tumors is unknown. Loss of functional FH leads to accumulation of fumarate in the cell, triggering inhibition of HPH and preventing targeted pVHL-mediated degradation of HIF-alpha. BHD mutations cause the Birt-Hogg-Dube syndrome and its associated chromophobe, hybrid oncocytic, and conventional (clear cell) RCC. The incidence of BHD mutations in sporadic renal tumors is not known. There is a strong correlation between cigarette smoking and the development of renal cell carcinoma. The clinical presentation includes: hematuria, flank pain and a palpable lumbar mass. A high percentage of renal cell carcinomas are diagnosed when an ultrasound is performed for other purposes. Radical nephrectomy is the standard intervention procedure. Renal cell carcinoma is generally considered to be resistant to radiation treatment and chemotherapy (NCI, 2015).

Serous Adenocarcinoma: A tumor type which is characterized by the presence of papillary patterns and cellular budding. Psammoma bodies may be present. Representative examples include cervical serous adenocarcinoma, endometrial serous adenocarcinoma, ovarian serous adenocarcinoma, and primary peritoneal serous adenocarcinoma (NCI, 2015).

Temsirolimus (Torisel): An antineoplastic agent that blocks a protein involved in cell division. It is an ester analog of rapamycin. Temsirolimus binds to and inhibits the mammalian target of rapamycin (mTOR), resulting in decreased expression of mRNAs necessary for cell cycle progression and arresting cells in the G1 phase of the cell cycle. mTOR is a serine/threonine kinase which plays a role in the PI3K/AKT pathway that is upregulated in some tumors (NCI, 2015).

MICROMEDEX Solutions Strength of Recommendations Scale:

Table 1. Strength Of Recommendation

Class I


The given test or treatment has been proven to be useful, and should be performed or administered.

Class IIa

Recommended, In Most Cases

The given test, or treatment is generally considered to be useful, and is indicated in most cases.

Class IIb

Recommended, In Some Cases

The given test, or treatment may be useful, and is indicated in some, but not most, cases.

Class III

Not Recommended

The given test, or treatment is not useful, and should be avoided.

Class Indeterminate

Evidence Inconclusive


MICROMEDEX Solutions Strength of Evidence Scale:

Table 2. Strength Of Evidence

Category A

Category A evidence is based on data derived from: Meta-analyses of randomized controlled trials with homogeneity with regard to the directions and degrees of results between individual studies. Multiple, well-done randomized clinical trials involving large numbers of patients.

Category B

Category B evidence is based on data derived from: Meta-analyses of randomized controlled trials with conflicting conclusions with regard to the directions and degrees of results between individual studies. Randomized controlled trials that involved small numbers of patients or had significant methodological flaws (e.g., bias, drop-out rate, flawed analysis, etc.). Nonrandomized studies (e.g., cohort studies, case-control studies, observational studies).

Category C

Category C evidence is based on data derived from: Expert opinion or consensus, case reports or case series.

No Evidence




Peer Reviewed Publications:

  1. 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(7):3663-3668.
  2. Eroglu Z, Tawbi HA, Hu J, et al. A randomized phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas. Br J Cancer. 2015; 112(10):1644-1651.
  3. Fleming GF, Filiaci VL, Marzullo B, et al. Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: a gynecologic oncology group study. Gynecol Oncol. 2014; 132(3):585-592.
  4. Hudes GR, Carducci MA, Choueiri TK, et al. Temsirolimus, Interferon Alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007; 356:2271-2281.
  5. Hutson TE, Escudier B, Esteban E, et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014; 32(8):760-767.
  6. Naing A, Kurzrock R, Burger A, et al. Phase I trial of cixutumumab combined with temsirolimus in patients with advanced cancer. Clin Cancer Res. 2011; 17(18):6052-6060.
  7. Négrier S, Gravis G, Pérol D, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomized phase 2 trial. Lancet Oncol. 2011; 12(7):673-680.
  8. Oza AM1, Elit L, Tsao MS, et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011; 29(24):3278-3285.
  9. Rini BI, Bellmunt J, Clancy J, et al. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol. 2014; 32(8):752-729.
  10. Shameem R, Lacouture M, Wu S. Incidence and risk of high-grade stomatitis with mTOR inhibitors in cancer patients. Cancer Invest. 2015; 33(3):70-77.
  11. Yang S, da Souza P, Alemao E, Purvis J. Quality of life in patients with advanced renal cell carcinoma treated with temsirolimus or interferon-a. Br J Can. 2010; 102:1456-1460.
  12. Zbrozek AS, Hudes G, Levy D, et al. Q-TWiST analysis of patients receiving temsirolimus or interferon alpha for treatment of advanced renal cell carcinoma. Pharmacoeconomics. 2010; 28(7):577-584.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Flaherty KT, Manola JB, Pins M, et al. BEST: A randomized phase II study of vascular endothelial growth factor, RAF kinase, and mammalian target of rapamycin combination targeted therapy with bevacizumab, sorafenib, and temsirolimus in advanced renal cell carcinoma--A trial of the ECOG-ACRIN Cancer Research Group (E2804). J Clin Oncol. 2015; 33(21):2384-2391.
  2. National Cancer Institute (NCI). Listing of active or planned clinical trials of Temsirolimus. Available at: Accessed on September 13, 2017.
  3. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium® (2017 electronic version). For additional information see the NCCN website: Accessed on September 13, 2017.
  4. NCCN Clinical Practice Guidelines in Oncology (NCCN). © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: Accessed on September 13, 2017.
    • Kidney cancer (V1.2018). Revised 09/07/2017.
    • Soft tissue sarcoma (V2.2017). Revised 02/08/2017.
    • Uterine neoplasm (V3.2017). Revised 07/18/2017.
  5. NCCN Task Force Report (National Comprehensive Cancer Network, Inc.): Optimizing treatment of advanced renal cell carcinoma with molecular targeted therapy. JNCCN. 2011; 9(1):S1-29.
  6. Torisel® (Temsirolimus injection) [Prescribing Information], Madison, NJ. Wyeth Pharmaceuticals, Inc. February 2015. Available at: Accessed on September 13, 2017.                                                             
  7. Temsirolimus. In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO. Updated February 27, 2016. Available at: Accessed on September 13, 2017.
Websites for Additional Information
  1. American Cancer Society. Available at: Accessed on September 13, 2017.
  2. National Cancer Institute. Cancer types. Available at: Accessed on September 13, 2017.

mTOR, Mammalian Target of Rapamycin

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.







Medical Policy & Technology Assessment Committee (MPTAC) review.



Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” References were updated.



MPTAC review.



Hematology/Oncology Subcommittee review. Updated the formatting in the Clinical Indications section. The ECOG score within the medically necessary criteria for advanced renal cell carcinoma has been clarified to 2, 3, or 4. References were updated.



MPTAC review.



Hematology/Oncology Subcommittee review. Initial document development.