Temsirolimus: a safety and efficacy review
Ronald M. Bukowski
Cleveland Clinic Taussig Cancer Center, Cleveland, OH, USA
Introduction: The vascular endothelial growth factor (VEGF) pathway and the mammalian Target of Rapamycin (mTOR) represent the most frequently exploited targets in renal cell carcinoma (RCC). Temsirolimus is an inhibitor of mTOR, and is a unique ester derivative of sirolimus, a macrocyclic lactone, with improved pharmaceutical properties, including stability and solubility. Temsirolimus binds to the cytoplasmic protein FKBP-12, and the complex binds and inhibits mTOR.
Areas covered: This review summarizes the clinical findings and safety of tem- sirolimus in RCC patients.
Expert opinion: A Phase III clinical trial has demonstrated that temsirolimus has statistically significant advantages over treatment with IFN-a in RCC patients with poor prognosis, in terms of OS (overall survival), PFS (progres- sion-free survival), and tumor response. Median OS was improved 49% compared to IFN-a, and median PFS was approximately doubled. It is now considered the standard for RCC patients with poor prognostic features. The possibility that this agent is useful in metastatic non-clear cell carcinoma patients has also been suggested by a subset analysis of the pivotal Phase III trial. Studies in untreated favorable and intermediate risk clear cell and refractory mRCC patients are required.
Keywords: carcinoma, cell, renal, temsirolimus
Expert Opin. Drug Saf. (2012) 11(5):861-879
1. Introduction
During the last 10 years the molecular mechanisms involved in renal cell carcinoma (RCC) pathogenesis have been investigated, with subsequent identification of a variety of therapeutic targets. Inhibition of the vascular endothelial growth factor (VEGF) pathway, either by blockade (i.e., bevacizumab) or inhibition of the tyro- sine kinase activity with small molecules (i.e., sunitinib, sorafenib, and pazopanib) of the VEGF receptor have emerged as the primary therapeutic approaches for most patients with metastatic RCC [1,2]. The mammalian Target of Rapamycin (mTOR) represents the second molecular target for which small molecule inhibitors (i.e., temsirolimus (Box 1) and everolimus) have demonstrated a significant clinical activity in this malignancy [3,4]. These approaches have improved patient outcomes, and are associated with relatively good tolerability. They have revolutionized the treatment of advanced RCC, a malignancy, which was formerly considered resistant to most forms of treatment.
Renal cell carcinoma is a highly vascularized malignancy and therefore was considered a target for antiangiogenesis-based approaches. The most common histologic subtype of RCC is clear-cell carcinoma (approximately 85% of cases), and is associated with inactivation of the von-Hippel-Lindau (VHL) tumor- suppressor gene [5]. von-Hippel-Lindau-deficient cells are characterized by an up regulation of hypoxia-inducible factor (HIF) and a corresponding increase in VEGF and various other growth and angiogenic factors [6]. Because mTOR may be activated in clear-cell RCC [7], the possibility that the PI3K/Akt/mTOR
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Box 1. Drug summary.
Drug name Temsirolimus
Phase Launched
Indication Advanced Renal Cell Carcinoma
Pharmacology description mTOR (mammalian target of rapamycin) inhibitor
Route of administration Injectable, oral Chemical structure [15]
OH
O OH
O
H
O
N O
O O O O
HO
O
OH
O
O O
Pivotal Trials Phase III Global Study in Advanced Renal Cell Carcinoma (ARCC)
Pharmaprojects copyright to Citeline Drug Intelligence (an Informa business). Readers are referred to Pipeline (http://informa-pipeline.citeline.com) and
Citeline (http://informa.citeline.com).
pathway represented a potential therapeutic target in RCC was considered. Pantuck et al. examined expression of compo- nents of the mTOR pathway in samples from 375 patients who underwent nephrectomy for sporadic RCC, demonstrat- ing particularly high mTOR activation among clear-cell, high-grade, and other poor-prognosis tumors [7].
mTOR is a highly conserved serine/threonine kinase that regulates cell growth and metabolism in response to environ- mental factors [8]. It activates downstream of the phosphati- dylinositol 3-kinase (PI3-K)/AKT pathway and executes its biologic functions as two distinct complexes, mTORC1 and mTORC2. mTORC1 is inhibited by rapamycin and the other rapalogues (including temsirolimus). mTORC2 may be insen- sitive to rapamycin, and in contrast to mTORC1, is resistant to inhibition by rapalogues. As noted previously, the mTOR pathway may be of particular relevance in RCC, and HIF protein expression may be dependent on mTOR. Toschi et al. [9] have reported mTOR activation enhances the expres- sion HIF-1a and HIF-2a in RCC cells at a translational level. Additionally, treatment of mice with RCC xenografts with
temsirolimus produces impaired expression of HIF-1a in both hypoxic and normoxic conditions. This suggests a possible mechanism of action for mTOR inhibitors in RCC [9].
2. Temsirolimus: structure, function, and pharmacokinetics
2.1 Drug history
Rapamycin (sirolimus, Wyeth) was the first mTOR inhibitor studied. Rapamycin was primarily derived from Streptomyces hygroscopicus and was initially developed as an antifungal agent [10]. It is a macrocyclic lactone that inhibits activation of T cells, and causes G1 arrest in tumor cells in vitro [8]. It binds to a cytosolic receptor, FK506-binding protein (FKBP-12), and the resulting complex inhibits kinase activity [11].
Rapamycin was introduced into clinics as an immunosup- pressive agent used in patients undergoing allogeneic trans- plantations [12], and has also been used for prevention of coronary artery re-stenosis following percutaneous coronary interventions. In the late 1990s, following studies with
temsirolimus, other rapalogues such as everolimus were inves- tigated for their anticancer potential in preclinical and clinical settings [13].
Despite initial evidence from in vitro and in vivo studies demonstrating cytostatic activity against cancer cells, the vari- ous rapalogues were not studied extensively as an antineoplas- tic agents until the late 1990s [10]. In preclinical studies, inhibition of the AKT/mTOR pathway by rapamycin was shown to reverse tumor-associated angiogenesis [14]. It is now recognized that the major anticancer effects associated with rapamycin derivatives such as temsirolimus may be impairment of angiogenesis. Additionally, unlike other tar- geted agents used in the treatment of RCC, the rapalogues have clear bidirectional activity against both tumor and endothelial cells.
2.2 Structure/Function
Sirolimus (Rapamune™, Wyeth) was initially found on Easter Island (RapaNui), and possesses fungicidal, immunosuppres- sive, and antiproliferative properties [13]. Temsirolimus is a water-soluble ester derivative of sirolimus with improved pharmaceutical properties including stability and solubility making it suitable for intravenous (i.v.) administration. In vitro, it appears similar to rapamycin with respect to potency and inhibition of mTOR signaling [16]. Like rapamycin, tem- sirolimus binds the cytoplasmic protein FKBP-12, and the complex binds to mTOR adjacent to its kinase domain. The rapamycin–FKBP12 complex only interacts with unbound mTOR or mTOR in the mTORC1 complex. The clinical activity of the rapalogues is primarily mediated by the inhibition of mTORC1 [16]. Rapamycin-resistant cells are also resistant to temsirolimus, suggesting similar mechanisms of action [17].
The TOR protein family is functionally pleiotropic, and regulates a variety of cellular processes such as initiation of mRNA transcription and protein translation (Figure 1). It may facilitate organization of the actin cytoskeleton, mem- brane trafficking, protein degradation, PKC signaling, and ribosome biogenesis [18,19]. Thus, mTOR regulates multiple signal transduction pathways and the coupling of growth stimuli to the cell-cycle [10]. The inhibition of mTOR by the sirolimus FKBP-12 complex results in the inhibition of p70 S6 kinase and 4E-binding protein-1 functions. This is followed by a decrease in cyclin D1 levels, increase in p27 levels, and cell-cycle arrest [20]. Apoptosis has been noted in selected preclinical models [21], and antiangiogenic effects related to decreased HIF-1a induced secretion of VEGF [22].
2.3 Pharmacokinetics
Temsirolimus was developed for i.v. administration, and the principal metabolite in humans is sirolimus [23]. In view of this, pharmacokinetic (PK) exposure to temsirolimus is consi- dered generally a composite of both compounds [24]. The mean steady-state volume of distribution of temsirolimus is high, suggesting extensive tissue penetration. After i.v. injection,
temsirolimus is rapidly cleared and converted in the liver by cytochrome CYP 450 3A4/5 into sirolimus, which then becomes more prevalent. The half-life decreases with increasing dose, and excretion occurs predominantly in the feces, with renal elimination of drug and metabolites accounting for only 4.6% of the administered dose [25]. Administration of 25 mg temsiroli- mus to RCC patients produces a mean whole blood maximum concentration (Cmax) of 595 ng ml-1 and mean area under the curve (AUC) of 1580 ng h ml-1 [26]. This is followed by rapid appearance of sirolimus, with Cmax values 10 — 20% compared to those of temsirolimus [26]. Because sirolimus has a longer half-life, the sirolimus/temsirolimus AUC ratio produced a 2.8-fold higher exposure to sirolimus compared to temsirolimus. The rapalogues are metabolized by the liver and are extensively excreted in the feces [27]; therefore, renal impairment does not affect their pharmacokinetics.
Temsirolimus and sirolimus are metabolized by cyto- chrome CYP3A4 [28], and five metabolites have been detected [27]. Because this is the most abundant CYP isozyme in humans [29], drug interaction potential does exist. In vitro, the CYP3A4 inhibitor ketoconazole decreased the concentra- tion of temsirolimus metabolites by 10 — 20% [28]. In patients, administration of ketoconazole (400 mg po) with 5 mg i.v. temsirolimus had no effect on Cmax; however, mean AUC increased 3.1-fold and the combined AUCs of temsirolimus plus sirolimus increased 2.3-fold when compared to temsiro- limus alone [30]. This combination was well tolerated. The authors recommend that for patients receiving 25 mg i.v. of temsirolimus, concomitant administration of a strong CYP3A4 inhibitor should be avoided, if possible. If required, dose reduction of temsirolimus to 12.5 mg i.v. is suggested.
2.4 Pharmacodynamics
Pharmacodynamic biomarkers in peripheral blood mononu- clear cells (PBMC) and tumor tissue have been investigated. Peralba et al. [31] measured phospho70s6 (p70s6) kinase activity in PBMC from nine patients with renal cell cancer receiving a single dose of 25, 75, or 250 mg of I.V. temsiroli- mus (three patients each). Eight of nine patients had evidence of p70s6 kinase inhibition unrelated to dose. Interestingly, the degree of inhibition appeared to be associated with time to disease progression. The authors suggest this may be a pharmacodynamic marker of temsirolimus activity.
Other potential biomarkers are also being explored in patients with RCC. CAIX expression or pathology risk group do not correlate with response to temsirolimus [32]. Preliminary analyses suggested tumors expressing low levels of upstream mTOR activity modulators, for example, phospho-AKT or a down-stream target of activation such as phospho-S6 ribosomal protein, may be less likely to respond to temsirolimus [32]. High p70s6 kinase expression was associated with clinical benefit, longer progression-free intervals, and longer survival in patients receiving temsirolimus.
Subgroup analyses of these biomarkers in the pivotal Phase III trial have previously been reported [33]. In the
Temsirolimus: Mechanisms of action [8, 19, 20]
Nutients, energy,
Growth factors/receptors
stress, & O2
PI3 Kinase
AKT
TEMSR FKBP-12
mTOR
X
p70S6K
Protein translation
4E-BP1
Figure 1. The mechanisms of action for temsirolimus and an mTOR inhibitor are illustrated. Signaling through the PI3 kinase and Akt pathway is shown, with the downstream effects of mTOR inhibition on cell growth/metabolism and angiogenesis [8,18,19].
416 patients treated with either temsirolimus or IFN-a, avail- able tumor specimens were investigated utilizing immunohis- tochemical staining for tumor PTEN and HIF-1a (available in 51 and 60%, respectively). Seventy-one per cent of tumors stained positively for PTEN and 62% demonstrated absence of HIF-1a. No correlation of efficacy with either PTEN or HIF-1a levels was found. Improvement of median overall survival (OS) or progression-free survival (PFS) occurred regardless of baseline levels, and did not predict the clinical efficacy of temsirolimus.
Armstrong et al. [34] assessed serum LDH as a potential pretreatment predictive biomarker in patients treated with tem- sirolimus in the ARCC (Advanced Renal Cell Carcinoma) trial. A retrospective analysis of 140 patients with elevated LDH demonstrated survival was significantly improved with temsiro- limus therapy compared to interferon (6.9 vs. 4.2 months, p < 0.002). By contrast, no improvement in median OS in 264 patients (11.7 vs. 10.4 months, p = 0.514) with normal LDH levels receiving temsirolimus treatment compared with interferon was found. Adjusting for known prognostic factors, the HR for death was 2.01 for patients with LDH > upper limit of normal (ULN) vs. £ ULN (p < 0.0001). The authors suggested serum LDH may be a potential predictive biomarker for the survival benefit conferred by mTOR inhibition in patients with poor-risk RCC. Confirmation of these findings is required.
Lipid elevation is a frequent metabolic effect associated
with administration of various rapamycin analogues, and has been investigated as a predictive biomarker. In a Phase II trial
of temsirolimus in glioblastoma patients, individuals deve- loping grade ‡ 2 hyperlipidemia (elevated cholesterol and/or triglycerides), had a higher likelihood of radiographic improvement (71%) compared to patients with < grade 2 elevations [35]. Recently, a retrospective analysis of the Phase III ARCC data examined serial measurements of cho- lesterol, triglycerides, and glucose from patients randomized to IFN-a or temsirolimus [36]. Changes in these biomarkers from baseline were correlated with median OS and PFS. The authors found temsirolimus therapy was associated with significant increases in cholesterol (1.02 mmol/L; p < 0.0001) and improved OS and PFS (OS: HR 0.76, p = 0.02; PFS: HR 0.70; p = 0.001) compared to IFN-a. The effects of temsirolimus on triglyceride or glucose levels, however, did not correlate with the survival benefit. A provocative finding was that increases in serum cholesterol during treatment were associated with improved clinical out- comes across the study, and independent of the treatment arm. This raises the question of whether the increases in cholesterol represent a mechanism-based toxicity or an epiphenomenon [37]. The exact mechanisms responsible for the induction of hypercholesterolemia are unknown. Lee and colleagues [36] suggest attenuation of sterol regulatory ele- ment binding protein (SREBP) activity may underlie the hypercholesterolemia associated with temsirolimus. SREBP-1 and -2 are transcriptional regulators of fatty acid and choles- terol biosynthesis. It is also possible that low density lipopro- tein (LDL) receptor gene expression that is dependent upon TORC1 and sensitive to rapamycin also contributes to the
induction of hypercholesterolemia [38]. These findings must be validated prospectively by other investigators. If the increase in serum cholesterol is validated as a predictive biomarker of temsirolimus efficacy, it could then be utilized to identify patients who would not benefit from therapy.
3. Clinical data
3.1 Phase I trials
Phase I trials with temsirolimus were initially performed in heavily pretreated solid tumor patients. The report by Raymond et al. [25], included 24 patients, and administered temsirolimus once weekly as a 30-min i.v. infusion (pretreat- ment with i.v. antihistamine was permitted). Dose levels of
7.5 -- 220 mg/m2 were utilized. The maximum tolerated dose (MTD) was not reached and 1/6 RCC patients in the trial had a confirmed partial response. In a second report by Hidalgo et al. [39], 63 patients were treated, and temsirolimus was administered as an i.v. infusion over 30 min on days 1 -- 5 of each 2-week cycle. Dose levels of 0.75 -- 24 mg/m2/d were employed. The MTD in heavily pretreated patients was 15 mg/m2. Dose-limiting toxicity included grade 3 hepatic enzyme elevations, vomiting, diarrhea, and asthenia. In this trial, one confirmed and three unconfirmed PRs were reported in 16 RCC patients. For Phase II studies, a flat dose was adopted as there was a lack of variability in comparison with body surface area (BSA)-normalized doses.
3.2 Phase II trials
The responses in RCC patients provided the clinical rationale for Phase II evaluation of temsirolimus in RCC [26]. In a Phase II trial in advanced refractory RCC, 111 patients were randomized to receive either 25 , 75 , or 250 mg of temsiro- limus once weekly as a 30-min infusion. The eligible patients had extensive metastatic disease and prior therapy (28% with ‡ 3 previous immunotherapy or chemotherapy regi- mens). The objective ORR was 7% (CR 1, PR 7) with a 26% minor response rate. The median time to progression (TTP) and OS data for the various patient groups are summa- rized in Table 1. An exploratory analysis based on previously described prognostic factors [40] was undertaken. These had been described in treatment-na¨ıve patients, and were incor- rectly utilized in this heavily pretreated and refractory RCC group. For the intermediate- and poor-prognosis populations, the median OS of the temsirolimus-treated patients was
1.6 -- 1.7-fold longer than those in an IFN-a historical group.
This advantage was not seen in good-prognosis patients. This may have been related to the small number of patients in this category. Temsirolimus was generally well tolerated, with no differences between the various dose levels noted. Hyperglyce- mia (17%) and hypophosphatemia (13%) were the most frequent grade 3 or 4 adverse events. This report was in part responsible for the design of the Phase III trial comparing temsirolimus alone, combined with IFN-a or IFN-a alone as first-line treatment for poor-prognosis RCC [3]. The choice
of poor-prognosis RCC patients was based on the results of the previously mentioned exploratory analysis [26] as well as the perception that study duration would be shortened by focusing on this group.
Prior to initiation of the Phase III trial, a Phase I/II trial with the combination of temsirolimus and IFN-a was conducted [41]. Patients were treated with i.v. temsirolimus (5, 10, 15, 20, or 25 mg) administered once a week combined with subcutaneous IFN-a (6 or 9 million U) three times per week. An expanded cohort received the recommended dose to provide additional safety and efficacy information. Seventy-one RCC patients were treated at one of six dose levels. The doses recommended for the Phase III trial were temsiroli- mus 15 mg and IFN-a 6 million U. Dose-limiting toxicities (DLT) included stomatitis, fatigue, and nausea/vomiting, at the higher dose levels. The most frequent ‡ grade 3 toxicities noted included leukopenia, hypophosphatemia, asthenia, anemia, and hypertriglyceridemia.
3.3 Phase III Trial in Advanced Renal Cell Carcinoma (ARCC)
The temsirolimus Global Phase III Trial in ARCC was
submitted to the FDA for special protocol assessment in 2002, and agreement was reached on the acceptability of treatment-na¨ıve patients, the use of IFN-a as a suitable comparator, and OS as the primary end point [42]. IFN-a was considered an appropriate comparator even though it did not have regulatory approval in the US for therapy of metastatic RCC, as it was historically the most commonly used therapeutic agent for mRCC, and additionally had been demonstrated to improve survival [43].
The study was an international, multi-center, open label, Phase III trial, and enrolled 626 treatment-na¨ıve patients with advanced RCC and a poor prognosis [3]. Patients with a poor prognosis were defined as having at least three of the six poor prognostic factors (Figure 2). These reflect the five factors identified by Motzer et al. [40], with the addition of multiple sites of metastases [44]. Additionally, all histologic subtypes of RCC were eligible, including clear and non- clear cell variants. Patients were randomized on a 1:1:1 basis to one of the three arms (Figure 3). Patients were stratified by nephrectomy status and region (1----USA; 2 Western
Europe, Australia, and Canada; and 3----other). Accrual opened in June 2003, and was completed in 22 months (April 2005). The primary end point was OS in the intent-to-treat (ITT) population and secondary end points included the PFS, ORR, and response duration. The PFS and ORR end points were determined utilizing blinded central review. Of importance was the primary end point of OS in this trial, in contrast to the recent Phase III studies with other targeted agents that utilized PFS. This may reflect the time during which this study was designed, as well as the necessity to dem- onstrate significant OS improvement for regulatory approval. Comparisons planned were between the temsirolimus and the IFN-a or the combination arm. This design permitted
Table 1. Phase II Trial Temsirolimus Dose Levels Efficacy Results [26].
Dose Level Temsirolimus 25 mg Temsirolimus 75 mg Temsirolimus 250 mg All Patients
Number of Patients 36 38 37 111
Median OS* Months (95% CI) 13.8 (9.0, 18.7) 11.0 (8.6, 18.6) 17.5 (12.0, 24.6) 15.0 mos
Median PFSz Months (95% CI) 6.3 (3.6, 7.8) 6.7 (3.5, 8.5) 5.2 (3.7, 7.4) 5.8 mos
ORR§ % (95% CI) 5.6 (0.7, 18.7) 7.9 (1.7, 21.4) 8.1 (1.7, 21.9) 7.2%
Clinical benefit rate{ % (95% CI) 52.8 (35.5, 69.6) 55.3 (38.3, 71.4) 43.2 (27.1, 60.5) 50.5%
*Overall survival; time from randomization to death.
zProgression-free survival; time from randomization to disease progression or death, censored at the last tumor evaluation date.
§Complete response plus partial response.
{Complete response, partial response, or stable disease for > 24 weeks.
Prognostic Factors in Phase III trial IFN-a versus Temsirolimus
MSKCC poor prognostic factors [40]
1) Karnofsky PS 70%*
2) Hemoglobin < LLN*
3) DFI < 1 year from time initial diagnosis*
4) Corrected serum Ca++ > 10 mg/dL*
5) Lactate dehydrogenase > 1.5 x ULN*
Additional poor prognostic factors [44]
1) Number of metastatic sites (1 vs 2)*.
2) Prior radiation therapy
In pivotal Phase III temsirolimus trial in advanced RCC, poor risk patient characterized by presence of 3 of the poor prognostic
factors* illustrated
Figure 2. The prognostic factors utilized to define a poor-risk patient with metastatic renal cell carcinoma in the Phase III temsirolimus pivotal trial are illustrated.
DFI: Disease-free interval; LLN: Lower limit normal; MSKCC: Memorial Sloan Kettering Cancer Center; PS: Performance status; ULN: Upper limit normal.
*: Poor prognostic factors
isolation of treatment effects related to each individual agent, as well as the combination. Treatment was given weekly in 28-day cycles and was continued until disease progression or toxicity required discontinuation. Patients receiving temsiroli- mus were premedicated with an antihistamine, and patients receiving IFN-a with acetaminophen.
The results are summarized in Table 2. A statistically signifi- cant longer median OS for the temsirolimus monotherapy arm compared to IFN-a monotherapy (medians, 10.9 vs 7.3 months; HR, 0.73; p = 0.0078) was found. Additionally, a significantly longer median PFS time for the temsirolimus group (median,
5.5 vs 3.1 months; HR, 0.66; unadjusted p = 0.001) was also found. The combination of temsirolimus and IFN-a produced increased toxicity and no significant improvement in OS when compared to IFN-a alone. The results of the subgroup analyses of OS stratified by nephrectomy status and region were consistent with the results in the overall ITT population. The analyses of OS and PFS by age, sex, and race were also consistent with the results for the overall ITT population.
The secondary end points of ORR and response duration were also of interest. Independent review demonstrated the ORR was 8.6% in the temsirolimus versus 4.8% in the IFN-a arm (p =. 12). All of the responses were partial. Median response duration was 11.1 months for temsirolimus, compared to 7.4 months for IFN-a-treated individuals.
In summary, temsirolimus therapy was associated with sig- nificantly longer median OS and PFS compared to IFN-a monotherapy. In the US, the FDA approved temsirolimus for treatment of patients with advanced/metastatic RCC [45], whereas in Europe, the European Medicines Agency (EMA) approved temsirolimus for treatment of RCC patients having three or more poor prognostic features [46]. The approved dose is 25 mg i.v. once weekly.
Several exploratory analyses were performed to investigate the effects of underlying histology and prognostic groups utilizing the MSKCC criteria [47,48]. In this Phase III trial, approximately 80% of patients had clear-cell carcinoma and 20% had other histology, the majority of which were papillary.
Temsirolimus IFN-a: Phase III Trial in Metastatic RCC [3]
Clinical results
Treatment arm IFN- (n = 207)
Arm 1 TEMSR (n = 209)
Arm 2 TEMSR + IFN- (n = 210)
Arm 3
Median OS 7.3 mos 10.9 mos 8.4 mos
Comparisons Arms 2:1 Arms 3:1
Stratified log rank p 0.0069 0.6912
Figure 3. A schematic diagram of the Global trial in Advanced Renal Cell Carcinoma (ARCC) is illustrated and includes the eligibility criteria, three treatment arms, and effects on median overall survival [3].
*Modified MSKCC Risk Status.
zStratification: nephrectomy status; region.
CR: Complete response; DFI: Disease-free interval; KPS: Karnofsky performance status; LLN: Lower limit of normal; MSKCC: Memorial Sloan Kettering Cancer Center; OS: Overall survival; PR: Partial response; SD: Stable disease; ULN: Upper limit of normal.
Table 2. Phase III Trial IFN-a versus Temsirolimus Primary and Secondary End points (ITT Analysis) [3,45].
End point IFN-a Temsirolimus
1◦ Median Overall Survival Months (95% CI) 7.3 (6.1 — 8.8) 10.9 (8.6 — 12.7)
Secondary Median PFS* Months (95% CI) 3.1 (2.2 — 3.8) 5.5 (3.9 — 7.0)
Median TTFz Months (95% CI) 1.9 (1.7 — 1.9) 3.7 (3.4 — 3.9)
ORR* (CR + PR) Number (%) 10 (4.8) 18 (8.6)
Clinical Benefit Rate* Number (%) 32 (15.5) 67 (32.1)
*Independent assessment.
zInvestigator assessment.
Clinical Benefit: CR + PR + SD > 24 weeks; CR: Complete Response; ORR: Objective Response Rate; PR: Partial Response; PFS: Progression-Free Survival; TTF: Time to Treatment Failure.
These were abstracted from case records and independent pathology review was not conducted. Temsirolimus-treated patients with either clear or non-clear cell histology demon- strated comparable median OS or PFS improvement. By contrast, IFN-a-treated patients with non-clear cell histology
had shorter median OS and PFS than those with clear- cell tumors. The authors suggested temsirolimus appeared efficacious for both clear and non-clear cell RCC.
A second issue of potential interest relates to the efficacy of temsirolimus in good and intermediate treatment-na¨ıve
RCC patients. Because hybrid prognostic criteria were uti- lized in this Phase III trial, approximately 25% of the patients accrued were in the intermediate prognostic category. Table 3 summarizes the data for the various sub- groups for the ITT population dependent upon the number of poor prognostic factors present, as well as for the poor and intermediate prognostic groups. In poor-risk patients, improved median OS was associated with temsirolimus ther- apy. In the 25% of patients having an intermediate risk, this was not seen. These results may reflect the small number of patients in the intermediate group, but also raise the issue of whether the beneficial effects of temsirolimus are confined to poor-risk patients.
4. Safety evaluation
4.1 Clinical trials
In the Phase III trial temsirolimus monotherapy was associ- ated with a lower frequency of constitutional adverse events such as asthenia and pyrexia.
Overall, the incidence of grade 3 and 4 adverse reactions and serious adverse events were similar when compared to IFN-a (Table 4). The frequency of adverse reactions was the lowest in the temsirolimus arm, and a higher frequency of dose reduc- tions and/or delays was seen in IFN-a-treated patients (Table 5). Selected adverse events reported in temsirolimus-treated patients are summarized in Table 4. The most common non- laboratory adverse reactions associated with temsirolimus were asthenia (51%), rash (47%), and mucositis (41%), and the most frequent ‡ grade 3 or 4 events were asthenia (11%), dyspnea (9%), and rash (5%). A variety of laboratory abnor- malities (Table 4) were also reported in temsirolimus-treated patients, and including anemia (94%), hyperglycemia (89%), hyperlipidemia (87%), and hypertriglyceridemia (83%). The most common grade 3/4 laboratory abnormalities in the temsirolimus patients were hypertriglyceridemia (44%), anemia (20%), hypophosphatemia (18%), and hyperglycemia (16%). The incidence of ‡ grade 3 laboratory abnormalities was slightly higher in the temsirolimus arm (78%) compared to patients receiving IFN-a (72%).
Temsirolimus shares a variety of specific side effects with other sirolimus derivatives, consistent with a class effect. These include a variety of metabolic, gastrointestinal, hematologic, respiratory, renal, and dermatologic toxicities.
4.2 Metabolic toxicity
In contrast to tyrosine kinase inhibitors, metabolic abnorm- ities are among the most common adverse events seen during temsirolimus administration. Current data suggest the Akt/mTOR pathway may have a crucial role in regulation of the glucose and lipid metabolic pathways as well as regula- tion of the cell cycle. Under conditions of excess energy intake, insulin receptor engagement results in Akt/mTOR- mediated lipogenesis and promotion of glucose uptake, glycolysis, and cholesterol synthesis [36,49,50]. Hyperglycemia,
hypercholesterolemia, and hyperlipidemia were common in patients receiving temsirolimus. It should be noted that preex- isting laboratory abnormalities were present in a significant proportion of these patients with baseline levels of glucose ele- vated in 42% (grade 1/2 hyperglycemia) and cholesterol and/ or triglyceride levels in 35% (grade 1/2 elevation). At baseline ‡ grade 3, elevations of glucose, cholesterol, or trigly- cerides in patients receiving temsirolimus monotherapy were present in 16, 2, and 44%, respectively [51]. Management of these metabolic abnormalities may require administration of hypoglycemic or lipid-lowering agents, and/or dose modifica- tion of temsirolimus. This will depend upon the specific patient, presence of previous diabetes, and clinical circum- stances. Additionally, an increase in the dose of insulin and/ or oral hypoglycemic agent therapy may be required. It is rec- ommended that serum glucose, cholesterol, and triglycerides should be tested before and during treatment with temsiroli- mus. As was previously noted, increases of serum cholesterol in the temsirolimus-treated patients were associated with improved survival [36]. More temsirolimus patients received statins compared to the IFN-a group (11.0 vs. 1.0%, p < 0.0001), however, statin therapy did not decrease the efficacy of therapy (OS or PFS).
Other metabolic abnormalities associated with temsiroli-
mus [3,27] include hypophosphatemia (49%) and hypokalemia (21%). Grade 3 or greater hypophosphatemia or hypokalemia were seen in 18 and 5% of patients, respectively. Hypokale- mia (‡ Grade 3) occurred more frequently in patients receiv- ing temsirolimus (5%) than IFN-a (0%), but an increase in cardiac arrhythmias was not seen [51].
4.3 Hematologic toxicity
Most drug-related hematologic abnormalities were grade 1 or 2 events (Table 4). Anemia was the predominant ‡ grade 3 hematologic AE, and was similar in temsirolimus (20%) or IFN-a (22%) treated patients. Neutropenia and thrombo- cytopenia were reported in 19 and 40% of temsirolimus- treated patients, but were ‡ grade 3 in only 5 and 1%, respectively. Temsirolimus should be held for an abso- lute neutrophil count < 1000/mm3 and/or platelet count
< 75,000/mm3, and may be restarted after resolution to £ grade 2 following a dose reduction of 5 mg/week (no lower than 15 mg/week) [27].
4.4 Respiratory/pulmonary toxicity
The association between rapalogue administration and pul- monary toxicity was first reported in renal transplant patients [52], and subsequently has been well recognized. Drug-related pneumonitis has been reported in 2 -- 36% of patients receiving temsirolimus [26,51,53]. Pulmonary toxicity was noted in the Phase II temsirolimus randomized trial in RCC patients [26]. Six of 111 (5.4%) patients were reported to have developed nonspecific pneumonitis (five----75 mg; one----25 mg). Four of these patients were re-treated, and two experienced recurrent pneumonitis.
Table 3. Phase III Trial IFN-a versus Temsirolimus [3,48] Overall Survival by Prognostic Factors (ITT Analysis).
Variable IFN Temsirolimus
N OS* (CI)‡ N OS (CI) HR P
ITT Population 207 7.3 (6.1 -- 8.8) 209 10.9 (8.6 -- 12.7) 0.78 0.0252
Subgroups by Protocol-defined Poor Prognostic Factors:
‡ 3 196 6.9 (5.6 -- 8.3) 196 10.9 (8.6 -- 12.9) 0.73 0.0020
< 3 11 NA (20.6 -- NA) 13 10.2 (6.9 -- 15.4) 4.93 0.0052
Subgroups by MSKCC risk factors:
Poor Risk [41] 156 6.0 (4.3 -- 7.1) 145 10.2 (7.6 -- 11.7) 0.70 0.0014
Intermediate Risk [41] 51 17.7 (11.3 -- 24.2) 64 13.0 (9.9 -- 15.4) 1.17 0.2441
*Median Overall Survival in months.
z95% Confidence Interval.
HR: Hazard ratio; ITT: Intent to treat; N: Number patients; P: P-value.
Table 4. Selected Adverse Events and Laboratory Abnormalities (%) All Grades and Grade 3/4 Phase III
Global ARCC Trial [3,27].
Treatment Group IFN-a Temsirolimus
Number of Patients 200 208
Adverse Event Grade All Gr 3/4 All Gr 3/4
Adverse Events (%)
Asthenia
64
26
51
11
Nausea 41 5 37 2
Rash 7 0 47 5
Dyspnea 24 6 28 9
Cough 15 0 26 1
Diarrhea 20 2 27 1
Pyrexia 50 4 24 1
Vomiting 29 3 19 2
Mucositis 10 0 41 3
Laboratory Abnormalities (%)
Anemia 90 22 94 20
Hyperlipidemia 72 35 83 44
Hyperglycemia 64 3 89 16
Hypercholesterolemia 48 1 87 2
Creatinine Increase 49 1 57 3
Thrombocytopenia 26 0 40 1
Neutropenia 29 10 19 5
In the Phase III trial [3,27] cough and dyspnea were reported in 26 and 28% of patients, respectively. The dyspnea was charac- terized as ‡ grade 3 in 9%. The investigators identified 2% of patients (4/208) as having temsirolimus-related pneumonitis. A retrospective, independent, blinded radiographic review of chest computed tomography (CT) images of patients in the Phase III pivotal trial was conducted to further characterize the temsirolimus-related pneumonitis in this trial [54]. Three hundred and sixteen of 416 eligible patients randomized to either temsirolimus or IFN-a were evaluable for review. Twenty-nine per cent (52/178) of temsirolimus and 6% (8/138) of IFN-a-treated patients were found to have radiologic
evidence of drug-related pneumonitis. The time to onset was significantly shorter on the temsirolimus arm than on the interferon arm (log-rank p < 0.001). The estimated cumulative probability of pneumonitis at 8 and 16 weeks of therapy was 21 and 31%, respectively, for patients receiving temsirolimus, and 6 and 8%, respectively, for those treated with IFN-a. In 60% of patients (31/52), the onset was during the first 8 weeks of temsirolimus administration. Respiratory symptoms tempo- rally related to the radiographic diagnosis of drug-related pneu- monitis were reported in 16/52 patients. The radiographic abnormalities consistent with this diagnosis included ground glass opacities and/or consolidation, involving multiple lobes. The findings in temsirolimus-related pneumonitis were acute and inflammatory in nature, without evidence of long-term scar- ring and fibrosis. The pathophysiology of this pneumonitis and the associated risk factors are unclear. In patients with only radiographic changes of pneumonitis without clinical symptoms (grade 1), temsirolimus may be continued, but patients should be closely monitored [27,55,56]. If symptoms and concurrent radiographic changes are present (grade 2), temsiro- limus should be held while diagnostic evaluation such as cultures, pulmonary function tests, and bronchoscopy are performed. Empiric therapy such as corticosteroids and/or antibiotics can be considered depending upon the patient. Treatment resumption and dose reduction can be considered depending upon the patient’s clinical course, response to empiric therapy, and overall risk/benefit assessment. In patients developing grade 3 pneumonitis, temsirolimus should be discontinued.
4.5 Renal toxicity
The renal adverse events reported in the Phase III study included elevation of serum creatinine in 57% of patients receiving temsirolimus compared to 49% of IFN-a-treated patients [3,27]. In the former group, 7/208 (3%) had ‡ grade 3 creatinine elevation. Adverse events characterized as renal failure were noted in three patients. The frequency of protein- uria is uncertain.
Table 5. Summary Grade 3/4 Adverse Events and Dose Modifications (%) Global ARCC Trial [3,27].
Treatment Group IFN-a Temsirolimus
Number of Patients 203 209
AE: any Grade 3/4 85 69*
Dose Reduction 40 23
> 2 Dose Delays 42 24
It should be noted that abnormal renal function is common in patients with advanced cancer, and has been reported in over 50% of such individuals [57]. It is possible that advanced RCC patients are at higher risk to develop nephrotoxicity, as most have had a previous nephrectomy, and also represent an elderly population. Gupta et al. [58] reviewed the toxicity of 51 patients receiving various targeted agents, 37% had renal insufficiency, defined as a creatinine clearance £ 60 ml/min, prior to initiation of treatment. Twenty-four patients received an mTOR inhibitor and 13/23 (57%) developed proteinuria. The authors suggest an increase in cutaneous rashes and fre- quency of dose interruptions in patients with impaired renal function.
The mechanisms responsible for renal insufficiency follow-
ing temsirolimus administration are not well characterized. Izzedine et al. [59] have described a single case of a patient with RCC receiving temsirolimus, who developed grade 3 proteinuria and edema, and a subsequent renal biopsy dem- onstrated focal segmental glomerulosclerosis. The authors suggest this may have been related to the mTOR inhibitor, as sirolimus may induce proteinuria related to ischemic glo- merulopathy and/or focal segmental glomerulosclerosis [60]. Acute renal failure following infusion of temsirolimus has also been reported [61]. These represent anecdotal reports, however, and the mechanisms responsible for the observed increases in serum creatinine remain unclear. Patients receiv- ing temsirolimus should have their renal function monitored. In the Phase III trial, this was performed every 2 weeks [3].
4.6 Hepatic toxicity
Elevations of alkaline phosphatase and aspartate amino- transferase (AST) were common during temsirolimus adminis- tration. Eligibility criteria allowed patients with a total bilirubin £ 1.5 ULN, and/or an AST £ 3 ULN (£ 5 ULN in patients with hepatic metastases) to be treated; there- fore, mild hepatic function abnormalities may have been pres- ent at baseline [3]. During temsirolimus therapy, elevations of total bilirubin, AST, or alkaline phosphatase were reported in 8, 38, and 68 of patients, respectively. Grade 3/4 elevations of hepatic functions were uncommon, and were reported in < 1 -- 2% of individuals. Hepatic toxicity was limited, how- ever, in other reports; patients with moderate or severe hepatic impairment had higher rates of adverse events [3,27]. Temsiroli- mus is contraindicated in patients with total bilirubin > 1.5 ULN, and if utilized in the setting of mildly impaired hepatic
function, dose adjustment based on AST and bilirubin levels is suggested. For bilirubin > 1 — 1.5 ULN, or AST > ULN with a normal bilirubin, the starting temsirolimus dose level recommended is 15 mg i.v. weekly [27]. In patients receiving temsirolimus, hepatic function should be checked at baseline and every 2 — 4 weeks [27].
4.7 Gastrointestinal toxicity
Gastrointestinal toxicity [3,27] in patients receiving temsiroli- mus is generally mild. The most common adverse event is mucositis, which included aphthous stomatitis, glossitis, mouth ulceration, mucositis, and stomatitis in 41% of patients (‡ grade 3 in 3%). Nausea (37%) and vomiting (19%) were also reported, but are generally £ grade 2. Anorexia (32%), diarrhea (27%), and abdominal pain (21%) were also noted, with ‡ grade 3 toxicity uncommon. Management of these adverse events is generally symptomatic.
4.8 Cutaneous toxicity
The dermatologic toxicity associated with temsirolimus was first noted during the Phase I trials [25,39]. Rashes and/or pru- ritus were reported in 29% of patients. These AEs included reversible maculopapular rashes (40 — 50%) during the first few weeks of treatment, and grade 1 — 2 acne-like erythema- tous rashes (37%) on the face and trunk. In one patient, a clinical picture consistent with erythema nodosum was seen [39]. In the Phase III trial ARCC trial, 47% of patients receiving temsirolimus developed rashes that included eczema, exfoliative dermatitis, plus maculopapular, pustular, and vesiculobullous rashes [3,27]. Acne was reported in 10%. These were generally grade 1/2 skin disorders, with 5% reported as ‡ grade 3. Finally, pruritus was noted in 19% of patients, and various nail disorders/changes in 14%.
A recent report [62] analyzing the skin rashes associated
with temsirolimus in 779 patients concluded the risk of developing a rash was significant and independent of tumor type. The overall frequency was reported as 45.8% with severe rashes in 3.3% of patients. Management suggestions included use of topical moisturizers for low-grade rashes and antihistamines for pruritus. Hot water and soaps that produce skin drying should be avoided. Dose interruptions and/or modification may be required for severe (grade 3 or higher) rashes.
4.9 Infectious Adverse Events
The administration of mTOR inhibitors may be associated with immunosuppression; therefore, the development of secondary or opportunistic infections in patients receiving these agents are a possibility. In the Phase III ARCC trial, infections were reported in 20 and 10% of temsirolimus and IFN-a-treated patients, respectively [3,27]. These included development of bronchitis, cellulitis, abscesses, and herpetic infections. The majority of infections in the temsirolimus- treated individuals were £ grade 2 adverse events, with only 6/42 (14%) described as ‡ grade 3. Other types of localized
infections including urinary tract infections (15%) and phar- yngitis (12%) were also reported. Opportunistic infections were not reported with i.v. temsirolimus. It is uncertain whether this represents the effect of the weekly schedule and lack of immunosuppression. Sibaud et al. [63] recently reported seven patients with solid tumors who developed paronychia with/without pyogenic granuloma. Three of seven patients were receiving temsirolimus (monotherapy 2,
bevacizumab 1). A second report [64], in which the combina-
tion of temsirolimus, temozolomide, and cranial irradiation was utilized, noted 3/12 patients with ‡ grade 4 fungal or viral infections. In this setting, it is uncertain whether the combination contributed to the frequency of infections.
Activation of mTOR signaling may play an essential role in regulation of hepatitis B virus (HBV) replication [65]. Recent findings suggest inhibition of mTOR signaling may potentially lead to HBV reactivation. This has been recog- nized in patients receiving chemotherapy [66,67]; however, the frequency of HBV reactivation in patients receiving temsirolimus is unknown.
The possibility that vaccination may be less effective while receiving temsirolimus has been suggested, and avoid- ance of live vaccinations or close contact with individuals who have received them has been recommended [27]. The data demonstrating this risk is limited. In a prospective study in solid-organ transplant patients receiving mTOR inhibitors, a decreased response after vaccination with pan- demic influenza H1N1 vaccine has been described [68]. mTOR inhibitor administration was independently associa- ted with lower seroprotection and titers after pandemic vaccination. The effects of mTOR inhibition on dendritic cell and CD-8 T-lymphocyte functions are, however, complex and diverse [69,70]. It has also been suggested that mTOR inhibitors may function as vaccine adjuvants against bacterial infections or cancer [71].
4.10 Hypersensitivity reactions
In the Phase III trial, patients receiving temsirolimus were pre- medicated with 25 — 50 mg of i.v. diphenhydramine or an H1 blocker approximately 30 min before each weekly infusion. This was utilized prophylactically to prevent allergic reac- tions [3,27]. Hypersensitivity reactions occurred in 9% of patients [27,72], and were generally mild to moderate in severity. These reactions may occur despite premedication, and may include flushing, chest pain, dyspnea, hypotension, apnea, or anaphylaxis. Hypersensitivity reactions typically develop during the first infusion, but may also occur with subsequent treat- ments. When a hypersensitivity reaction develops [27,72], the temsirolimus infusion should be stopped, the patient observed closely, and appropriate supportive measures initiated. Treat- ment can be resumed at a slower rate, if appropriate, and an H1-receptor antagonist (e.g., diphenhydramine), and/or an H2-receptor antagonist (e.g., i.v. famotidine or ranitidine) administered if not previously utilized. One fatal hypersensitiv- ity reaction has been noted in the post-marketing setting [72];
however, the overall frequency of this adverse event is unknown. The etiology of these reactions is uncertain.
4.11 Cardiovascular toxicity
In contrast to tyrosine kinase inhibitors such as sunitinib or pazopanib, cardiac events including hypertension were infrequent. Hypertension was reported in 7% of patients receiving temsirolimus [27]. Venous (VTE) and arterial (ATE) thromboembolic events are common complications in cancer patient population [73,74]. Risk factors include age older than 65 years, previous VTE events, and surgery. The role of temsirolimus in modifying the risk of VTE is uncer- tain. In the Phase III ARCC trial, these events were uncom- mon, and VTEs (including deep vein thrombosis and pulmonary embolus) occurred in five patients (2%) and thrombophlebitis in 1% [27].
4.12 Miscellaneous adverse events
A series of adverse reactions including gastrointestinal perfora- tions, abnormal wound healing, and bleeding has been associ- ated with administration of various targeted agents [55]. In patients receiving temsirolimus alone or in combination regi- mens, these have also been recognized. In the Phase III trial [3], two cases of bowel perforation were reported, one in the tem- sirolimus arm and one in a patient receiving temsirolimus plus IFN-a. In a Phase I trial in Japan [75], 1/10 patients with solid tumors receiving 15 mg/m2 of temsirolimus devel- oped a GI perforation. In a second report [76], 28 patients received a standard regimen of 5-flourouracil (5-FU) and leu- covorin (LV) with temsirolimus escalated from 15 to 75 mg/ m2. Two patients in the 45 mg/m2 cohort developed bowel perforations, one with coexisting mucositis, and the second with neutropenic sepsis. Seven cases of bowel perforation that included four deaths have been reported across the tem- sirolimus safety database [42]. As bowel perforations may be fatal if unrecognized and treated inappropriately, it was rec- ommended that patients receiving temsirolimus should be closely monitored for signs and symptoms associated with this complication, particularly in those experiencing severe mucositis. Treatment of this complication includes bowel rest, antibiotics, and surgical evaluation.
Abnormal or delayed wound healing represents an AE
associated with agents such as bevacizumab [77]. In organ transplant patients this effect associated with mTOR inhibi- tor administration has also been noted [55]. In the Phase III Global ARCC trial, three patients (< 1%) with RCC were reported as having impaired wound healing [27]. In view of this, caution is recommended when administering temsiroli- mus in the perioperative period. The optimal duration of therapy interruption in the pre- and postsurgical setting is uncertain.
Hemorrhagic complications in patients receiving targeted agents are also commonly recognized [55]. In patients with RCC receiving temsirolimus monotherapy, the frequency of grade 1/2 epistaxis was 12%, compared to 4% in the
IFN-a cohort [3,27]. This in part may be related to the development of thrombocytopenia, life-threatening hemor- rhagic events, however, are rare. Patients with untreated CNS metastases may be at an increased risk of developing intracerebral bleeding [27].
4.13 Drug interactions
Because sirolimus and temsirolimus are substrates for cyto- chrome P450 3A4 (CYP3A4), administration of inhibitors or inducers of CYP3A4/5 activity can alter their metabo- lism [24]. In a PK assessment in healthy volunteers, administra- tion of 5 mg temsirolimus and 400 mg oral ketoconazole, a potent cytochrome P450 3A4 inhibitor, had no significant effects on temsirolimus Cmax or AUC, but increased mean plasma sirolimus Cmax 2.2-fold and AUC 3.2-fold compared to temsirolimus alone [30]. If alternative treatment is not pos- sible, a dose reduction of temsirolimus to 12.5 mg should be considered [27]. Likewise, strong CYP3A4 inducers such as dexamethasone, phenytoin, carbamazepine, rifampin, or phe- nobarbital should be avoided. Pharmacokinetic studies in which temsirolimus and rifampin were administered together,
frequency and relationship to drug are not clear in many instances. These reports have included pleural effusions, pericardial effusions requiring intervention, convulsions, rhabdomyolysis, Stevens-Johnson Syndrome, and reflex sympathetic dystrophy.
Temsirolimus extravasations associated with local swelling, pain, warmth, and erythema have also been noted.
6. Treatment of specialized populations
Temsirolimus’ safety has been assessed in a variety of patient groups; however, efficacy is not well defined in the majority of these settings.
6.1 Pediatric patients
The DLT, maximum-tolerated dose (MTD), and pharma- cokinetics of weekly i.v. temsirolimus were assessed in patients with recurrent or refractory solid tumors between
1 and 21 years old [80]. Temsirolimus was administered
i.v. weekly at four different dose levels: 10, 25, 75, or
150 mg/m2. Dose-limiting toxicity (grade 3 anorexia)
demonstrated no effects on the temsirolimus C
max
and AUC,
occurred in one patient at 150 mg/m2, and the MTD was
but decreased sirolimus Cmax and AUC by 65 and 56%,
respectively [27]. If patients must receive a strong CYP3A4 inducer, an increase in the temsirolimus starting dose level (up to 50 mg/week) should be considered.
4.14 Quality of life data
EuroQol-5D utility score (EQ-5D index) and the EQ-5D visual analogue scale (EQ-VAS) were utilized to assess patient-reported outcomes in the ARCC Phase III trial [78]. An analysis [79] was recently reported of patients who had EQ-5D data recorded at baseline, week 12, and the last visit, comparing patients receiving either temsirolimus or IFN-a. The last-visit data and a repeated-measures mixed-effect (RMME) model were employed to assess differences between the temsirolimus and IFN-a patients. Only 270/416 patients (65%) were evaluable for QOL analysis: 155 receiving temsir- olimus and 115 IFN-a. In both the last visit and RMME analyses, temsirolimus was associated with superior EQ-5D index scores and EQ-VAS scores when compared to IFN-a. This report extended the findings from a Q-TWIST analy- sis [79], which suggested that the patients receiving temsirolimus had significantly longer quality-adjusted survival (1.4 months; approximately a 25% improvement) when compared with IFN-a-treated patients. The improvement in QOL compared to IFN-a, along with the OS and PFS improvement associated with temsirolimus therapy are consistent, and demonstrate the clinical benefit associated with temsirolimus therapy in a
predominantly poor-risk group of mRCC patients.
5. Postmarketing evaluation
During the post-approval use of temsirolimus, a group of adverse reactions have been reported voluntarily [27]. The
not reached. Thirteen patients were evaluable for response,
with one CR seen in a neuroblastoma patient. The most common treatment-related AEs were anemia, leukopenia, and thrombocytopenia (53% each); neutropenia (47%), anorexia, and hyperlipidemia (42% each). Nine of 19 patients experienced ‡ grade 3 AEs. The pharmacokinetics of temsirolimus and sirolimus in this population were reported as comparable to respective values in adults receiv- ing similar doses. Phase I trials utilizing temsirolimus with either perifosine in neuroblastoma [81] or an insulin growth factor-receptor antibody (cixutumumab) in refractory Ewing’s sarcoma patients [82] have been reported. In the latter report the toxicity of the combination included pre- dominantly grade 1/2 thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%). The MTD dose level of temsirolimus was 25 mg i.v. weekly and interestingly 2/20 heavily pretreated patients with refractory disease had PRs.
6.2 Renal failure/hemodialysis
The renal toxicity of temsirolimus has been discussed previ- ously, and no dosage adjustments are recommended in patients with renal impairment [27]. Lunardi et al. [83] have investigated the pharmacokinetics of temsirolimus and siroli- mus in patients with mRCC not on dialysis, and those receiv- ing hemodialysis. A single i.v. dose of 25 mg was administered to 13 patients (two receiving hemodialysis). No significant differences in the pharmacokinetic parameters of temsiroli- mus and sirolimus were reported, and in the hemodialysis mRCC patients, plasma drug concentrations assessed imme- diately before hemodialysis were similar to those assayed 1 h after the treatment.
6.3 Elderly patients
In the Phase III ARCC trial in poor-risk mRCC patients, 31% were ‡ 65 years old [3,48]. The effects of temsirolimus compared to IFN-a on OS was greater among patients under 65 years of age (HR 0.67, 95% CI 0.52 -- 0.87) than among
older patients (HR 1.15, 95% CI 0.78 -- 1.68). For patients £ 65 years old, the median OS was longer with temsirolimus (12 months) compared to IFN-a (6.9 months). In contrast, in the patients 65 or older, there was no appreci- able difference (8.6 vs 8.3 months). Interestingly, the side effect profile of temsirolimus was better than IFN-a among elderly patients. No or little influence of age on the frequency of grade 3/4 toxicities related to temsirolimus was noted. In patients over 65 or < 65 years of age, asthenia was reported in 14 and 10%, dyspnea 10 and 8%, anemia 19 and 20%,
neutropenia 2 and 3%, and hyperglycemia 13 and 10%, respectively. Further exploration of temsirolimus in the elderly mRCC patient group should be considered in view of the clinical benefit associated with this agent.
6.4 CNS tumors
A variety of clinical trials with temsirolimus have been con- ducted in patients with primary brain tumors, and with CNS metastases. An Eastern Cooperative Group trial in small-cell lung cancer [84] included 11/87 patients with previ- ously treated CNS metastases. The patients were randomized to receive either 25 or 250 mg of temsirolimus i.v. weekly after induction chemotherapy was completed. The median PFS for this group was 2.3 months, and no differences in toxicity were reported for patients with/without CNS lesions. Several studies in patients with glioblastoma multiforme (GBM) have been reported. Chang et al. [85] treated 43 indi- viduals with weekly temsirolimus utilizing a dose of 250 mg (170 mg in patients receiving enzyme inducing anti- epileptic drugs). The toxicity profile was described as low, and two patients had partial responses. A second trial in 65 GBM patients [35] also reported temsirolimus was well tol- erated at a dose of 250 mg i.v. weekly, with no CNS toxicity. In patients receiving p450 inducing anti-epileptic drugs, grade 3 hematologic toxicity was less common (3%) than in patients not receiving such agents (20%). Likewise, plasma Cmax for temsirolimus and sirolimus was decreased 73 and 47%, respectively. Despite the potential risk of CNS hemor- rhage with temsirolimus noted previously, patients with treated CNS tumors (primary or metastatic) appear to tolerate temsirolimus without untoward toxicity. Data for temsiroli- mus administration to mRCC patients with CNS metastases is not available; however, the observations in patients with small-cell lung cancer or primary CNS tumors are applicable.
6.5 Treatment-naı¨ve favorable/intermediate risk mRCC patients
The clinical activity and OS improvement observed in the Phase III
ARCC trial in predominantly poor-risk mRCC patients strongly sug- gests the probability of similar efficacy in other prognostic groups [48].
In this study [3], a subset of intermediate risk patients was entered, and a post-hoc analysis did not demonstrate OS improvement compared to IFN-a. This group only contained 115 patients (temsirolimus 64;
IFN-a----51), possibly contributing to the lack of improvement. A Phase II randomized trial is underway, which compares the mTOR inhibitor everolimus to sunitinib in treatment-na¨ıve clear- cell carcinoma patients. This study will address some of the issues with mTOR monotherapy [85] in untreated patients.
6.6 Treatment refractory mRCC patients
It is now clear that intrinsic and acquired resistance to antian- giogenic agents such as the VEGF pathway inhibitors are major clinical issues [86]. The majority of mRCC patients receiving a TKI as initial therapy develop refractory disease. The efficacy of the oral mTOR inhibitor everolimus was investigated in sunitinib and/or sorafenib refractory mRCC patients with metastatic clear-cell carcinoma [4]. In a blinded placebo controlled trial, everolimus was superior to a placebo and improved the PFS (4.0 vs 1.8 months; HR 0.30, 95% CI
0.22 -- 0.40, p < 0.0001).
Four retrospective analyses have examined the toxicity and efficacy of temsirolimus in mRCC patients receiving second- line therapy who were considered refractory to frontline ther- apy with a TKI or anti-VEGF therapy [87-90]. A total of 142 patients receiving second-line temsirolimus were included in these reports. Time to progression or PFS ranged from
2.5 to 3.9 months and median OS from 8.2 to 11.2 months. The authors reported no new adverse events, and toxicity was described generally as manageable.
Two prospective trials will provide some interesting informa- tion on the efficacy of this agent in refractory mRCC patients. In a Phase III randomized trial [91], temsirolimus is being compared to sorafenib as second-line therapy (INTORSECT Trial) for sunitinib refractory mRCC patients (Figure 4). The primary end point is PFS, and over 500 patients have been accrued. The preliminary results of this trial have recently been made available by Pfizer [92]. The PFS in patients receiving temsirioli- mus was increased compared to those receiving sorafenib; how- ever, the difference was not significant. By contrast, OS for sorfenib-treated patients was significantly longer than in the temsirolimus arm. The actual data are not yet available; however, the preliminary report is of interest and suggests temsirolimus has no role in the therapy of TKI refractory patients.
A second Phase II trial [93] is investigating the novel approach of alternating sunitinib with temsirolimus, with a primary end point of TTP.
6.7 Temsirolimus combinations
Another approach is to utilize temsirolimus in combination with other agents in mRCC. The ARCC trial addressed the issue of a cytokine (IFN-a) combination [3]. The efficacy was not enhanced and toxicity was increased. Combining tar- geted agents in mRCC is another method to potentially enhance efficacy; however, this has been problematic in view of the increase in toxicity [94]. Combinations have investigated
Phase III Trial: Temsirolimus versus Sorafenibas Second Line Therapy in Metastatic RCC [91, 92]
Estimated enrollment: N = 508
Figure 4. The study schematic for the Phase III randomized trial (NCT00474786) comparing temsirolimus to sorafenib in sunitinib refractory RCC is illustrated [91,92].
*NCT00474786: clinicaltrials.gov identifier.
†MSKCC: Memorial Sloan Kettering Cancer Center.
utilizing either horizontal or vertical inhibition [94] of targets in RCC. Horizontal blockade utilizes two different agents targeting kinases in separate signaling pathways, whereas vertical blockade targets molecules within the same pathway. A group of recent Phase I trials investigating temsirolimus combinations have been reported [95-101]. A Phase I study utiliz- ing bevacizumab [95] represents an example of horizontal block- ade, and the results suggested full doses of both agents were possible. This combination was then examined in a random- ized Phase II [102] and an ongoing Phase III trial [103]. Negrier and colleagues [102] assessed the progression-free rate at 48 weeks for bevacizumab and temsirolimus compared to sunitinib and bevacizumab plus IFN-a. One hundred and seventy-one patients were randomized, with 88 receiving the combination of temsirolimus and bevacizumab. The PFS at 48 weeks was 29.5% (95% CI 20.0 -- 39.1), compared to 35.7% (95% CI
21.2 -- 50.2) or 61% (95% CI 46 -- 75.9%) for the groups receiving sunitinib or bevacizumab plus IFN-a, respectively. The median PFS for these groups were 8.2, 8.2, and
16.8 months, respectively. Patients tolerated the temsirolimus combination poorly, with ‡ grade 3 adverse events reported in 77%. The investigators concluded the toxicity was unexpect- edly high, the efficacy was limited, and study results did not support the use of this combination in first-line therapy for mRCC patients. Additional evaluation of this regimen is ongo- ing in a Phase III trial comparing bevacizumab plus temsiroli- mus to the IFN-a plus bevacizumab combination [103]. Over 750 patients have been randomized in this trial, and the primary end point is PFS. Finally, a cooperative group Phase II randomized trial (BEST trial) is ongoing, and utilizes temsirolimus combined with either bevacizumab or sorafenib as two of four treatment arms [104]. This trial includes patients
who are treatment-na¨ıve or cytokine refractory, and utilizes PFS (investigator determined) as the primary end point. These reports demonstrate the difficulties encountered in developing combination approaches, as formidable toxicity may be encountered, and unless robust improvement in the efficacy end points is seen, cost and the adverse events profiles are clearly a major issue.
7. Comparisons with other agents
Temsirolimus has been investigated adequately in treatment- na¨ıve poor-risk RCC patients, and is superior to the cytokine IFN-a. Comparisons with other targeted agents have not been reported, likewise, adequate studies in the favorable and intermediate RCC patient population have not been conducted. The ongoing clinical trial comparing temsiroli- mus with sorafenib will provide data on efficacy and toxicity in refractory patients [91]. In the absence of direct clinical comparisons, various methods for indirect comparison have been utilized for the various mRCC treatment options [105]. The absence of another randomized trial investigating thera- peutic outcomes in poor-risk patients prevents comparative indirect analyses [105,106]. Mills et al. [105] conclude in their analysis that temsirolimus provided significant improvement of PFS in patients with poor prognosis (HR 0.69, 95% CI 0.57 -- 0.85).
8. Conclusions
Temsirolimus is a highly specific potent inhibitor of the mTOR, a central regulator of signaling pathways involved in cell growth, proliferation, and response to hypoxia. It
forms a complex with the intracellular protein FKBP-12, that inhibits mTOR and causes suppression of tumor growth and inhibition of angiogenesis. The clinical develop- ment of temsirolimus involved a standard sequence of Phase I, II, and III trials, ultimately demonstrating a signifi- cant improvement in median OS in patients with metastatic RCC with three or more poor-risk features. In these clinical studies in poor-risk RCC, the AE profile of temsirolimus was primarily metabolic in nature, with limited impact on QOL when contrasted with the side effects seen with the oral multikinase inhibitors. This agent is now considered a standard of care for patients with mRCC and poor-risk features, with ongoing investigation in other populations such as refractory mRCC patients.
9. Expert opinion
The data and studies with temsirolimus demonstrate this mTOR inhibitor that was developed for i.v. use is a useful therapeutic agent in mRCC. The pharmacologic and pharma- codynamics effects of this drug represent the combined effects of both sirolimus and temsirolimus. Pharmacologically, tem- sirolimus appears distinct from everolimus, the other mTOR inhibitor approved for the therapy of mRCC, clini- cally, however, the two agents have never been compared. The i.v. route for administration of temsirolimus may provide some advantages in terms of patient compliance and accep- tance, as well as drug delivery. Except for bevacizumab, it remains the only i.v. targeted agent available, and interest- ingly, the only targeted agent that has produced a statistically significant improvement in OS in mRCC patients.
The pivotal ARCC study investigating temsirolimus in patients with mRCC included predominantly individuals with ‡ three poor-risk features. Based on these findings, it is now considered standard therapy for this patient group. Com- parative studies with other agents such as sunitinib, pazopa- nib, or bevacizumab plus IFN-a regimen have not been conducted in poor-risk patients; however, the data in this patient subset is minimal with these agents, and temsirolimus remains the therapy of choice.
Temsirolimus treatment produces clinically relevant and statistically significant advantages when compared to IFN-a in mRCC patients with a poor prognosis. The significant improvement is OS is unique among the available targeted agents utilized in RCC. Median OS was improved 49% com- pared to IFN-a, and median PFS was approximately doubled from 1.9 months with IFN to 3.8 months with temsirolimus (HR 0.74; 95% CI 0.60 -- 0.90). ORR was higher in patients receiving temsirolimus, but the improvement did not reach statistical significance.
Temsirolimus has a favorable adverse event profile, and is associated with a lower frequency of grade 3 or 4 adverse events compared to IFN-a monotherapy. In view of its side effect profile, administration of temsirolimus, even to patients
with advanced RCC and poor performance status is possible with acceptable risk benefit. The AE profile of temsirolimus appears different than the first and second generation TKIs such as sunitinib and pazopanib, with metabolic and pulmo- nary toxicity effects seen with this rapalogue. Data from the INTORSECT trial [92] will provide a direct comparison of the adverse event profile of a TKI and temsirolimus, and address the issue in a randomized Phase III trial setting.
Subset analyses of patients with non-clear cell carcinoma or with their primary renal tumor in place (no nephrectomy), suggest temsirolimus is more effective than IFN-a in these subgroups. Based on these observations, temsirolimus is an important treatment alternative for patients with metastatic non-clear cell RCC. The clinical effects of temsirolimus in other mRCC clear-cell carcinoma patient subgroups such as the favorable/intermediate MSKCC risk group, refractory mRCC patients, and as potential adjuvant therapy after nephrectomy in high-risk patients remain unclear. In the future, additional clinical trials should be conducted to fur- ther define its efficacy as monotherapy in treatment- na¨ıve patients with clear-cell carcinoma. A series of studies combining temsirolimus with either bevsacizumab or sorafe- nib will be available in the near future, but these may well produce problematic findings given the difficulty in develop- ing combinations of targeted agents in mRCC. In refractory mRCC, comparative studies with active agents such as sorafe- nib or everolimus are necessary. The preliminary results from the recently completed INTORSECT trial, in which temsiro- limus and sorafenib were compared in sunitinib refractory mRCC patients [92], suggest temsirolimus is not effective for TKI refractory disease. Importantly, it still remains unclear whether temsirolimus is equivalent to the oral mTOR inhib- itor everolimus in the refractory setting.
These findings and studies with temsirolimus clearly dem-
onstrate the importance of well-designed comparative trials to assess therapy for various mRCC patient populations. The recent investigations of this drug have been almost entirely designed and conducted by various pharmaceutical companies, and have defined its clinical characteristics and benefit for a limited group of poor prognosis mRCC patients. Clearly, additional data and studies are needed, especially as this agent is the only targeted drug associated with a statisti- cally significant survival improvement, albeit in a very limited and selected patient subgroup. In this setting, the lack of cooperative group studies in the US to help define standards of care for the mRCC patient population remains a significant issue.
Declaration of interest
RM Bukowski has received honoraria from Pfizer, Novartis, GSK, BMS, Argos, and Genentech; speaker’s bureau from Novartis, Pfizer, and GSK; and consultancy fees from Pfizer, Novartis, GSK, BMS, and Argos.
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Affiliation
Ronald M. Bukowski MD Emeritus Staff Physician,
Cleveland Clinic Taussig Cancer Center, Cleveland, OH 44195, USA
E-mail: [email protected]