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Temsirolimus (Torisel)

Number: 0873



Policy

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

  • Advanced (metastatic or unresectable) renal cell carcinoma; or
  • Endometrioid adenocarcinoma; or
  • Endometrial carcinosarcoma or serous or clear cell endometrial carcinoma; or
  • PEComa, recurrent angiomyolipoma, or lymphangioleiomyomatosis.

Aetna considers temsirolimus experimental and investigational for all other indications including the following (not an all-inclusive list):

  • Adenoid cystic carcinoma
  • Alzheimer's disease
  • B-cell non-Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma)
  • Bladder cancer
  • Breast cancer
  • Central nervous system tumors (e.g., ependymoma, gliomas/glioblastoma multiforme, medulloblastoma, and pontine glioma)
  • Cervical cancer
  • Cholangiocarcinoma
  • Colorectal cancer
  • Head and neck squamous cell carcinoma
  • Hepato-cellular carcinoma
  • Lung cancer (e.g., non-small cell lung cancer)
  • Melanoma
  • Neuroblastoma
  • Neuroendocrine tumors (e.g., neuroendocrine of pancreas)
  • Ovarian cancer
  • Prostate cancer
  • Sarcomas/soft-tissue sarcomas (e.g., Ewing sarcoma, leiomyosarcoma, osteosarcoma, and rhabdomyosarcoma)
  • Uterine cancer
  • Vaginal cancer
Background

Temsirolimus (Torisel) is an intravenous chemotherapeutic agent in the class mammalian target of rapamycin (mTOR) inhibitor for the treatment of renal cell carcinoma.  It was approved by the U.S. Food and Drug Administration (FDA) in May 2007 for the treatment of advanced renal cell carcinoma in adults.

Current guidelines from the National Comprehensive Cancer Network (NCCN, 2013) recommend use of temsirolimus in kidney cancer for the following indications: (i) first-line therapy as a single agent for relapsed or surgically unresectable stage IV disease (clear cell or non-clear cell); and (ii) subsequent therapy as a single agent for relapsed or surgically unresectable stage IV disease with predominant clear cell histology.

NCCN Guidelines (2014) recommend temsirolimus for endometrioid adenocarcinoma:

  • Primary treatment as a single agent  
     
    • May be considered preoperatively for intra-abdominal disease
    • With sequential radiation therapy (RT) and brachytherapy with or without surgery for extra-uterine pelvic disease
    • May be considered following palliative hysterectomy with bilateral salpingo-oophorectomy with or without RT and/or hormonal therapy for extra-abdominal or liver disease
       
  • For surgically staged patients as a single agent
     
    • With sequential pelvic RT and/or vaginal brachytherapy in patients with stage IB disease with histologic grade 3 tumors and adverse risk factors
    • With sequential pelvic RT and vaginal brachytherapy in patients with stage II disease with histologic grade 3 tumors
    • With sequential tumor-directed RT for stage IIIA disease
    • With or without sequential tumor-directed RT for stage IIIB and IIIC disease
    • With or without sequential RT for stage IIIA and IV disease
       
  • Single agent
     
    • For disseminated metastases that have progressed on hormonal therapy
    • With or without sequential palliative RT for symptomatic, grade 2 to 3, or large-volume disseminated metastases
    • May be considered for isolated metastases
    • With sequential tumor-directed RT with or without brachytherapy for local recurrence in patients with disease confined to the vagina or in pelvic, para-aortic, or common iliac lymph nodes
    • With or without sequential tumor-directed RT for microscopic upper abdominal or peritoneal recurrences
    • For local/regional recurrence in patients who have received prior external beam RT to site of recurrence

NCCN guidelines (2014) recommend temsirloimus for endometrial carcinosarcoma or serous or clear cell endometrial carcinoma as adjuvant therapy as a single agent with or without: (i) vaginal brachytherapy for stage IA disease with no myometrial invasion; or (ii) sequential tumor-directed radiation therapy for stage IA disease with myometrial invasion or stage IB-IV disease.

NCCN guidelines (2015) on soft tissue sarcoma recommend temsirolimua as single-agent therapy for the treatment of PEComa, recurrent angiomyolipoma, and lymphangioleiomyomatosis.

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:

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 % confidence interval [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 progression-free survival (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.

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 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 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.

NCCN’s Drugs & Biologics Compendium (2015) does not list central nervous system tumors as recommended indications of temsirolimus.

Cholangiocarcinoma:

UpToDate reviews on “Systemic therapy for advanced cholangiocarcinoma” (Stuart, 2015), “Treatment of localized cholangiocarcinoma: Adjuvant and neoadjuvant therapy and prognosis” (Anderson and Stuart, 2015a), and “Treatment options for locally advanced cholangiocarcinoma” (Anderson and Stuart, 2015b) do not mention temsirolimus as a therapeutic option.

Furthermore, NCCN’s Drugs & Biologics Compendium (2015) does not list cholangiocarcinoma as a recommended indication of temsirolimus.

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 (2015) 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.

NCCN’s Drugs & Biologics Compendium (2015) does not list colorectal 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.

NCCN’s Drugs & Biologics Compendium (2015) does not list melanoma as a recommended indication of temsirolimus.

Hepato-Cellular 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: (i) In phase I, to determine dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of temsirolimus in HCC patients with chronic liver disease; (ii) In phase II, to assess activity of temsirolimus in HCC, and (iii) 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 stable disease (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.

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.

NCCN’s Drugs & Biologics Compendium (2015) does not list melanoma as a recommended indication of 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.

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.

NCCN’s Drugs & Biologics Compendium (2015) does not list neuroendocrine tumors as recommended indications of temsirolimus.

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.

NCCN’s Drugs & Biologics Compendium (2015) does not list ovarian cancer as a recommended indication of temsirolimus.

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 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 % 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.

NCCN’s Drugs & Biologics Compendium (2015) does not list sarcomas/soft-tissue sarcomas as recommended indications of temsirolimus.

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.

Appendix

Continued use beyond 3 months (12 weeks) is considered medically necessary for persons with stable disease (tumor size within 25 % of baseline).  Continued use is considered not medically necessary when there is evidence of disease progression or unacceptable toxicity occurs.

CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
ICD-10 codes will become effective as of October 1, 2015:
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)
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
D49.2 Neoplasm of unspecified behavior of bone, soft tissue, and skin
J84.81 Lymphangioleiomyomatosis


The above policy is based on the following references:
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    19. Rangwala R, Chang YC, Hu J, et al. Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma
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    21. Stuart KE. Systemic therapy for advanced cholangiocarcinoma. UpToDate Inc., Waltham, MA. Last reviewed August 2015
    22. Anderson CD, Stuart KE. Treatment of localized cholangiocarcinoma: Adjuvant and neoadjuvant therapy and prognosis. UpToDate Inc., Waltham, MA. Last reviewed August 2015a
    23. Anderson CD, Stuart KE. Treatment options for locally advanced cholangiocarcinoma. UpToDate Inc., Waltham, MA. Last reviewed August 2015b
    24. Grunwald V, Keilholz U, Boehm A, et al. TEMHEAD: a single-arm multicentre phase II study of temsirolimus in platin- and cetuximab refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) of the German SCCHN Group (AIO). Ann Oncol. 2015;26(3):561-567
    25. Yeo W, Chan SL, Mo FK, et al. Phase I/II study of temsirolimus for patients with unresectable hepatocellular carcinoma (HCC)- a correlative study to explore potential biomarkers for response. BMC Cancer. 2015;15:395
    26. Knox JJ, Qin R, Strosberg JR, et al. A phase II trial of bevacizumab plus temsirolimus in patients with advanced hepatocellular carcinoma. Invest New Drugs. 2015;33(1):241-246
    27. Ushijima H, Suzuki Y, Oike T, et al. Radio-sensitization effect of an mTOR inhibitor, temsirolimus, on lung adenocarcinoma A549 cells under normoxic and hypoxic conditions. J Radiat Res. 2015;56(4):663-668
    28. National Comprehensive Cancer Network. Drugs & Biologics Compendium. Temsirolimus. 2015. NCCN: Fort Washington, PA
    29. Zhao Q, Tran H, Dimitrov DS, Cheung NK. A dual-specific anti-IGF-1/IGF-2 human monoclonal antibody alone and in combination with temsirolimus for therapy of neuroblastoma. Int J Cancer. 2015;137(9):2243-2252
    30. Hobday TJ, Qin R, Reidy-Lagunes D, et al. Multicenter phase II trial of temsirolimus and bevacizumab in pancreatic neuroendocrine tumors. J Clin Oncol. 2015;33(14):1551-1556
    31. Matsumoto K, Onda T, Yaegashi N. Pharmacotherapy for recurrent ovarian cancer: Current status and future perspectives. Jpn J Clin Oncol. 2015;45(5):408-410
    32. Wagner LM, Fouladi M, Ahmed A, et al. Phase II study of cixutumumab in combination with temsirolimus in pediatric patients and young adults with recurrent or refractory sarcoma: A report from the Children's Oncology Group. Pediatr Blood Cancer. 2015;62(3):440-444
    33. Eroglu Z, Tawbi HA, Hu J, et al. A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas. Br J Cancer. 2015;112(10):1644-1651
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