Tag Archive for: everolimus


Article of the week: Pneumonitis should not prevent continued mTOR inhibitor use

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by prominent members of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Mammalian target of rapamycin (mTOR) inhibitor-associated non-infectious pneumonitis in patients with renal cell cancer: predictors, management, and outcomes

Bradley J. Atkinson, Diana H. Cauley, Chaan Ng*, Randall E. Millikan, Lianchun Xiao, Paul Corn, Eric Jonasch and Nizar M. Tannir

Departments of Pharmacy Clinical Programs, *Diagnostic Radiology, †Genitourinary Medical Oncology and ‡Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA

B.J.A. and D.H.C. are co-first authors
Supported in part by a Cancer Center Support Grant (CA016672) from the National Institutes of Health.


• To characterise the incidence, onset, management, predictors, and clinical impact of mammalian target of rapamycin (mTOR) inhibitor-associated non-infectious pneumonitis (NIP) on patients with metastatic renal cell carcinoma (mRCC).


• Retrospective review of 310 patients with mRCC who received temsirolimus and/or everolimus between June 2007 and October 2010.

• Clinical correlations were made with serial radiological imaging.

• Fisher’s exact, Wilcoxon rank-sum, and logistic regression analyses were used to evaluate the association of NIP with demographic or clinical factors.

• Log-rank and Cox proportional hazards regression analyses were used for the time-to-event analysis.


• NIP occurred in 6% of temsirolimus-treated and 23% of everolimus-treated patients. Symptoms included cough, dyspnoea, and fever (median of two and three symptoms per patient, respectively).

• The median National Cancer Institute Common Toxicity Criteria for Adverse Events pneumonitis grade was 2 for both groups.

• Older age and everolimus treatment were predictive of NIP.

• Patients who developed NIP had a significantly longer time on treatment (median 4.1 vs 2 months) and overall survival (OS) (median 15.4 vs 7.4 months).

• NIP was a predictor of improved OS by multivariate analysis.


• There was an increased incidence of NIP in everolimus-treated patients.

• Improved OS in patients who developed NIP is an intriguing finding and should be further investigated. Given the incidence, morbidity, and outcomes seen in patients on everolimus who develop NIP, management should include proactive monitoring and treatment of NIP with the goal of preserving mTOR inhibitor therapy.


Editorial: mTOR-related non-infectious pneumonitis: a potential biomarker of clinical benefit?

The study by Atkinson et al. [1] published in the present issue of the BJUI is the largest study to date to address the role of non-infectious pneumonitis (NIP) as a predictive biomarker in patients with RCC who are treated with mammalian target of rapamycin (mTOR) inhibitors. It is also the first article to correlate mTOR-related NIP with improved overall survival (OS). Until now, only radiological response as measured by RECIST and progression-free survival (PFS) had been correlated to the onset of NIP in two small retrospective studies [2, 3], but the results obtained in those studies were contradictory and, therefore, this correlation remains controversial.

While the predictive relationship between NIP and OS needs to be further investigated in well-designed prospective clinical trials, the implications of such a relationship may be significant because no predictive biomarkers for mTOR inhibitors have been validated to date. In the era of targeted therapies, the detection of biomarkers of treatment efficacy is crucial to differentiate the subpopulations of patients who are most likely to benefit from treatment. Several biomarkers, such as the development of arterial hypertension and hypothyroidism, have been correlated with improved outcomes in patients with advanced RCC treated with vascular endothelial growth factor pathway inhibitors [1]; however, there are currently very limited data regarding the potential predictors of the clinical efficacy of mTOR inhibitors. A recent study by Lee et al. [4] showed that greater increases in serum cholesterol levels from baseline in patients with advanced RCC treated with temsirolimus were significantly associated with longer PFS and OS. Interestingly, temsirolimus-related hypertriglyceridemia and hyperglycaemia were not associated with improved clinical outcomes. Although NIP or hypercholesterolaemia must still be validated prospectively to ascertain whether they are true surrogate biomarkers of pharmacodynamic effect or just confounding epiphenomena, these promising findings may be the first steps in the identification of predictive biomarkers in mTOR inhibitor therapy.

Other important aspects addressed by Atkinson et al. [1] are the uncertainty of the pathogenesis of mTOR-related NIP and the lack of clinical predictive factors. Older age and treatment with everolimus were the only significant predictive factors of onset of NIP in their multivariate analysis. Similarly, a retrospective study by Dabydeen et al. [2] showed a statistically nonsignificant higher incidence of NIP in patients with RCC treated with everolimus compared to those treated with temsirolimus. Interestingly, in a randomized phase II study testing three different dose levels of temsirolimus (25,75 and 250 mg/week) in patients with advanced RCC, none of the six patients diagnosed with NIP were in the highest dose group of 250 mg/week [5], suggesting that mTOR-related NIP might have a non-dose-dependent pathogenesis. Similarly, a meta-analysis of 2233 patients affected by different tumours including RCC treated with an mTOR inhibitor failed to show any relationship between median treatment duration and incidence of NIP [6]. Finally, underlying respiratory conditions before treatment, such as the presence of lung metastases [6], chronic obstructive pulmonary disease or smoking habit [2], were not shown to be predictive factors of development of mTOR-related NIP. Another study by White et al. [3] showed that the development of pneumonitis in patients with RCC treated with everolimus was not associated with more impaired baseline pulmonary function tests, indicating that pulmonary function tests may not help identify patients with an increased risk of pneumonitis nor predict its severity. At present, there are therefore very few pretreatment clinical predictive factors to help clinicians identify patients at higher risk of developing mTOR-related NIP.

In conclusion, given the potential value of NIP as a predictive biomarker of survival in patients with RCC treated with mTOR inhibitors, Atkinson et al. [1] suggest that efforts should be made to avoid dose reductions and treatment discontinuation whenever possible. However, predictive factors of the severity of lung toxicity are needed to identify those patients at risk of developing life-threatening NIP as the maintenance of dose intensity may be crucial for maximizing clinical benefit.

Alejo Rodriguez-Vida, Noan-Minh Chau and Simon Chowdhury
Department of Medical Oncology, Guy’s Hospital, London, UK


  1. Atkinson BJ, Pharm D, Cauley DH et al. mTOR inhibitor-associated non-infectious pneumonitis in patients with renal cell cancer: management, predictors, and outcomesBJU Int 2014; 113: 376–382
  2. Dabydeen DA, Jagannathan JP, Ramaiya N et al. Pneumonitis associated with mTOR inhibitors therapy in patients with metastatic renal cell carcinoma: incidence, radiographic findings and correlation with clinical outcomeEur J Cancer 2012; 48:1519–1524
  3. White DA, Camus P, Endo M et al. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinomaAm J Respir Crit Care Med 2010; 182: 396–403
  4. Lee CK, Marschner IC, Simes RJ et al. Increase in cholesterol predicts survival advantage in renal cell carcinoma patients treated with temsirolimusClin Cancer Res 2012; 18: 3188–3196
  5. Atkins MB, Hidalgo M, Stadler WM et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinomaJ Clin Oncol 2004; 22: 909–918
  6. Iacovelli R, Palazzo A, Mezi S, Morano F, Naso G, Cortesi E. Incidence and risk of pulmonary toxicity in patients treated with mTOR inhibitors for malignancy. A meta-analysis of published trialsActa Oncol 2012; 51: 873–879


Potentially Fatal Lingual Angioedema in Everolimus Treated Metastatic Renal Cell Carcinoma

We describe a case of an acute onset of severe everolimus-induced lingual angioedema in a 70 year-old man, who received everolimus 10 mg in the treatment of mRCC.

Authors: Martijn van Dorp1, Sevilay Altintas1, Johan Feyen2, Luc Vanuytrecht3

1Department of Medical Oncology, University Hospital Antwerp, Antwerp, Belgium.
2Department of Orthopaedic Surgery, AZ St Dimpna, Geel, Belgium.
3Department of Head and Neck Surgery, AZ St Dimpna, Geel, Belgium.

Corresponding Author: Martijn van Dorp, University Hospital Antwerp, Wilrijkstraat 10, 2650 Edegem, Antwerp, Belgium. Tel: +3238214973. Fax: +3238214102. E-mail: [email protected]


Everolimus is commonly used as a second line therapeutic option in the treatment of metastatic renal cell carcinoma (mRCC). Angioedema is a well described adverse event of everolimus treatment in the transplant area, where it is used as an immunosuppressant. However this is an extremely rare adverse event when everolimus is used in the treatment of mRCC.
We describe a case of an acute onset of severe everolimus-induced lingual angioedema in a 70 year-old man, who received everolimus 10 mg in the treatment of mRCC. Complete resolution occurred when everolimus was withdrawn. After re-administration of a reduced dose no recurrence was observed during a follow-up period of 11 months. During and after the onset of lingual angioedema, we opted not to terminate the administration of an angiotensin-converting enzyme (ACE) inhibitor, showing that everolimus was synergistic for the occurrence of this event.
We concluded that the occurrence of lingual angioedema in this particular case was an adverse event associated with everolimus treatment. In the literature, as in our case, a strong association between the co-administration of an ACE inhibitor and an inhibitor of the mammalian target of rapamycin (mTOR) is described.


Targeted therapy is now the standard treatment for metastatic renal cell carcinoma (mRCC). In recent years, there have been a series of phase III randomized trials showing benefit of targeted therapy, i.e. the small molecule multitargeted tyrosine kinase inhibitors sunitinib [1], sorafenib [2] and pazopanib [3], the vascular endothelial growth factor inhibitor bevacizumab [4] and the mammalian target of rapamycin (mTOR) inhibitors everolimus [5] and temsirolimus [6].
Everolimus demonstrated a significant improvement in progression free survival of 4.9 months versus 1.9 months for placebo in the phase III RECORD-1 study [5]. Upcoming are a phase II RECORD-2 study [7], everolimus and bevacizumab versus interferon alfa and bevacizumab in first-line, and a phase II RECORD-3 study [8], everolimus as first-line therapy followed by second-line sunitinib versus sunitinib as first-line followed by second-line everolimus. Usage of everolimus is an important contributor in the treatment of mRCC. Other tumor types in which mTOR inhibitors are explored include breast cancer, GIST, gastric carcinoma, hepatocellular carcinoma and B-cell lymphoma. [9]
The most common grade 3 or 4 adverse events for mTOR inhibitors are hyperlipidaemia, hyperglycaemia, stomatitis, non-infectious pneumonitis and myelosuppression. [5, 6] In this case we report a potentially fatal [10] but rare toxicity: lingual angioedema.


We present a 70-year old white male who underwent a nephrectomy for a pT1bN0M0 renal cell carcinoma of the clear cell type, who developed diffuse skin, bone, lung and lymph node metastases 14 years later. After radiotherapy to a single bone metastasis in the tibia, he initially started on sorafenib 400 mg bid. One and a half years later the patient progressed and at that time he opted to participate into the RAD001 expanded access trail. He received oral everolimus 10 mg qd.
114 days after initiation of this therapy, he experienced a progressive swelling and a burning sensation of the tongue at 3:00 am. Within an hour he presented to the emergency department with a vast, swollen and oedematous tongue, as a result of which he wasn’t able to close his mouth (Figure 1).


Figure 1. Lingual angioedema five hours after presentation



He was unable to speak and had  stridorous breathing. Physical examination revealed diffuse bilateral swelling and redness of the base of the mouth, the soft palate and the tongue. He did not have hives, pruritus, nor were there signs of peripheral edema. The patient did not have a history of allergic reactions and these symptoms occurred for the first time in his life. His concurrent medications included quinapril 5 mg qd, indapamide 2.5 mg qd and atorvastatine 20 mg qd.
At the time of presentation, total and differential leukocyte counts, thrombocyte counts, liver enzymes and coagulation factors were within the normal range. However, there was a marked rise in the fibrin degradation products and iron deficiency anaemia.
Indirect laryngoscopy revealed diffuse nasopharyngeal, oropharyngeal and laryngeal swelling without critical airway obstruction. Chest X-ray showed no significant abnormalities. He was diagnosed with lingual angioedema.
Everolimus was discontinued and intravenous treatment with methylprednisolone 125 mg, ranitidine 50 mg, promethazine 25 mg and cetirizine 10 mg was started and improved the patients’ symptoms. The dosages of his other medications, including quinapril, were not altered. Although the progression of the swelling was clearly brought to a halt five hours after administration of medication, there was no decrease noted in the volume of the tongue. Therefore intravenous hydrocortisone 250 mg in combination with ranitidine 50 mg was administrated and a CT scan was performed. The CT scan (Figure 2) revealed narrowing of the naso- and oropharynx, a dilated soft palate and an unmistakable voluminous tongue.


Figure 2. Computed tomography showing nearly complete obstruction of the oropharynx and obvious swelling of the tongue
He remained hospitalised for four more days in which time he received a declining dose of methylprednisolone, starting at 40 mg qd. His tongue returned to normal 18 hours after commencement. He was discharged with methylprednisolone 16mg qd for three more days.
Everolimus was re-administered nine days after the initial event at a reduced dose of 5 mg per day. More than 11 months after reinitiation, there has been no recurrence.


To our knowledge this is the second reported case of lingual angioedema as a result of using a mTOR inhibitor in the treatment of mRCC. Mackenzie and Wood [11] described a 61-year old man treated with everolimus 10 mg qd in second line and who developed lingual angioedema after 21 days of treatment. Interestingly this patients’ concurrent medication also contained an angiotensin-converting enzyme (ACE) inhibitor, ramipril 10mg qd.  Everolimus was initially stopped, but resumed one week later with no recurrence of the noticed side-effect.
In transplant medicine, there is longstanding clinical experience with mTOR inhibitors, where sirolimus and everolimus have been used as immunosuppressants. Everolimus is administrated at a dosage of 3 mg qd, as part of triple therapy, together with a calcineurin inhibitor and prednisone. Calcineurin inhibitors (like cyclosporine and tacrolimus) and everolimus are both metabolized by the CYP3A4 isoenzyme system, and their concomitant administration increases everolimus exposure by 2- to 3-fold. [12]
The largest series reports on 309 german kidney transplant recipients who had received mTOR inhibitors as immunosuppressants. Nine patients developed angioedema after a mean period of 123 days under combined therapy of an mTOR- and an ACE inhibitor. Six of these nine patients ceased the administration of the ACE inhibitor, no recurrence took place. In the three patients who continued to take the ACE inhibitor, angioedema recurred. All patients continued their mTOR inhibitor after the onset of the angioedema. In seven patients the everolimus or sirolimus levels were measured at the time of the event and six of them had increased plasma concentration levels. After replacement of the ACE inhibitor by an angiotensin receptor blocker (ARB) no recurrence was noticed. [13]
Stallone et al [14] were in 2004 the first to report the development of lingual angioedema in five kidney transplant recipients, one month after initiating the combination everolimus and an ACE inhibitor. Interestingly, in these five patients both drugs were administered at high dosages. The sirolimus dosage was decreased and the ACE inhibitor was stopped, but later reintroduced without recurrence of the assumed side effect. The authors hypothesized a dosage dependent synergistic effect when combining both drugs.
No reports of temsirolimus associated with lingual angioedema were found. Of note, temsirolimus is not used in the transplant population and is a newer agent.
Angioedema is a well-known side effect of ACE inhibitors. The OCTAVE trial reported the occurrence of ACE inhibitor induced angioedema in 0,68% out of >12,000 patients. [15] 99% of all cases present within the first year of therapy, of which a clear majority present within the first 8 weeks. [15, 16] Our patient had taken quinapril, in a low dose, for 2 years and 9 months without any adverse clinical events.
The concomitant administration of everolimus and inhibitors or inducers of the CYP3A4 enzyme system may affect everolimus blood levels. Concomitant administration of typical CYP3A4 inhibitors (ketoconazole [17] and erythromycin [18]) has been shown to significantly increase everolimus maximum concentration and everolimus area under the curve.
ACE inhibitors are also metabolized by the CYP3A4 enzyme system. CYP3A4 interaction could be an important part in linking the occurrence of angioedema to the concomitant administration of everolimus and an ACE inhibitor.
Furthermore, the incidence of angioedema is greater in the transplant setting. This might be because of the additional CYP3A4 interactions induced by the administration of calcineurin inhibitors.


In recent years different types of cancer are being treated by targeted therapy, given the relatively favorable side effects in comparison to chemotherapy. An impressive advance, especially in renal cell cancer, is made in increasing overall survival and disease free survival due to the specialized form of inhibiting tumor proliferation and differentiation.
In an area where targeted therapy is being examined and experimented on all types of cancer, one must never forget to think about possible drug interactions and side effects.
We describe the occurrence of lingual angioedema due to everolimus treatment. As in our patient, literature revealed a strong association with concomitant administration of ACE inhibitors. We demonstrated that interrupting everolimus therapy, while continuing the ACE inhibitor, led to a resolution of lingual angioedema. Furthermore we showed that a rechallenge with a reduced dose of everolimus within two weeks after the initial event was safe and the patient could be treated for a further 11 months.
Dosage of everolimus and drug interaction most probably play an important role in the pathogenesis of lingual angioedema.


1. Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal cell carcinoma. N Engl J Med 2007; 356:115-124.
2. Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356:125-134.
3. Sternberg Co, Davis ID, Mardiak J et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trail. J Clin Oncol 2010; 8:1061-1068.
4. Escudier B, Pluzanska A, Koralewski P et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007; 370:2103-2111.
5. Motzer RJ, Escudier B, Oudard S et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2010; 372:449-456.
6. Hudes G, Carducci M, Tomczak P et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356:2271-2281.
7. NCT00719264: A randomized, open-label, multi-center phase II study to compare bevacizumab plus RAD001 versus interferon alfa-2a plus bevacizumab for the first-line treatment of patients with metastatic clear cell carcinoma of the kidney. Available at: https://www.clinicaltrials.gov. Last accessed Dec 22, 2009.
8. NCT00903175: Efficacy and safety comparison of RAD001 versus sunitinib in the first-line and second-line treatment of patients with metastatic renal cell carcinoma. Available at: https://www.clinicaltrials.gov. Last accessed Jun 23, 2009.
9. Chan H, Grossman AB, Bukowski RM. Everolimus in the treatment of renal cell carcinoma and neuroendocirne tumors. Adv Ther 2010; 278:495-511.
10. Ulmer JL, Garvey MJ. Fatal angioedema associated with lisinopril. Ann Pharmacother 1992; 26:1245-6.
11. M. Mackenzie, L. A. Wood. Lingual angioedema associated with everolimus. Acta Oncologica 2010; 49:107-109.
12. Schaffer SA, Ross HJ. Everolimus: efficacy and safety in cardiac transplantation. Expert Opin Drug Saf 2010; 9:843-854.
13. Duerr M, Glander P, Iekmann F et al. Increased incidence of angioedema with ACE inhibitors in combination with mTOR inhibitors in kidney transplant recipients. Clin J Am Soc Nephrol 2010; 5:703-708.
14. Stallone G, Infante B, Di Paolo S et al. Sirolimus and angiotensin-converting enzyme inhibitors together induce tongue oedema in renal transplant recipients. Nephrol Dial Transplant 2004; 19:2906-2908.
15. Kostis JB, Kim HJ, Rusnak J et al. Incidence and characteristics of angioedema associated with enalapril. Arch Intern Med 2005; 165:1637-1642.
16. Schuster C, Reinhart WH, Hartmann K et al. Angioedema induced by ACE inhibitors and angiotensin II-receptor antagonists: analysis of 98 cases. Schweiz Med Wochenschr 1999; 129:362.
17. Kovarik JM, Beyer D, Bizot MN et al. Blood concentrations of everolimus are markedly increased by ketoconazole. J Clin Pharmacol 2005; 45:514-158.
18. Kovarik JM, Beyer D, Bizot MN et al. Effect of multiple-dose erythromycin on everolimus pharmacokinetics. Eur J Clin Pharmacol 2005; 61:35-38.

The authors have declared no conflicts of interest.


Date added to bjui.org: 20/10/2011

DOI: 10.1002/BJUIw-2011-069-web


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