Management of everolimus-associated adverse events in patients with tuberous sclerosis complex: a practical guide

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder [1]. Prevalence rates vary, but estimates typically fall in the range of 6.8 to 12.4 per 100,000 people [2]. TSC is caused by mutations in TSC1 on chromosome 9 or TSC2 on chromosome 16; however, two-thirds of cases result from de novo mutations [3]. Mutations in TSC1 or TSC2 result in inappropriate mTORC1 signalling within cells, and this is thought to be responsible for many of the features of TSC [4].

TSC is a highly variable condition in both the type and severity of its manifestations. A history of seizures has been reported in up to 85% of patients, often beginning in the first few years of life (>80% of patients) [5‐7], with intellectual disability found in ~45% of cases [8]. The condition is also commonly associated with the development of benign tumours in organs such as the kidneys, brain, heart and skin [9, 10]. Renal angiomyolipomas (AMLs) are among the most common features of TSC [9, 10], affecting around ~70% of patients [11, 12]. They manifest as benign tumours composed of abnormal blood vessels and cells, with either adipocyte-like or smooth muscle-like phenotypes [9], and commonly occur in both kidneys [9]. Around 20% of patients with TSC develop subependymal giant astrocytoma (SEGA), a benign glioneuronal brain tumour [13], and ~10% of women with TSC develop symptomatic lymphangioleiomyomatosis (LAM), a condition characterised by cystic destruction of the lung, pneumothorax and chylous pleural effusion [1]. This comorbid organ dysfunction and associated disease burden [10] requires careful management. The care of people with TSC can therefore be complex and requires a multidisciplinary approach [14].

Normalisation of defective mTORC1 signalling may be an effective approach to managing patients with TSC. Several mTORC1 inhibitors are in clinical use for many conditions and have the potential as therapeutic agents in TSC. Clinical trials have demonstrated the efficacy of some of these agents in the treatment of TSC. The mTOR inhibitor sirolimus has shown efficacy in clinical trials investigating the treatment of patients with AML and LAM [15‐18], while another mTOR inhibitor, everolimus, is indicated for the treatment of adult patients with renal AML associated with TSC who are at risk of complications (based on factors such as tumour size or presence of aneurysm, or presence of multiple or bilateral tumours), but who do not require immediate surgery; and of patients with SEGA who require therapeutic intervention, but who are not amenable to surgery [19]. Three randomised, placebo-controlled phase III trials have demonstrated the efficacy and safety of everolimus in these patients [20‐22].

EXIST-1 assessed the efficacy and tolerability of everolimus 4.5 mg/m²/day compared with placebo in 117 patients with a SEGA of ≥1 cm in diameter, and showed that response rate (reduction in the total volume of all target SEGA of 50% or more relative to baseline, in the absence of worsening of non-target SEGA, new lesions of 1 cm or greater in diameter, and new or worsening hydrocephalus) was greater in everolimus- than placebo-treated patients (35% versus 0%; p < 0.0001) [21]. At a median follow-up of 9.7 months, 97% of patients in the everolimus group were undergoing treatment; furthermore, no everolimus-treated patients discontinued due to disease progression. In an open-label extension phase of EXIST-1, responses persisted in 94% of responders, and only 8% of all patients had SEGA progression at a median follow-up of 28.3 months [23]. EXIST-2 compared oral everolimus 10 mg/day with placebo in 118 adults with TSC and at least one AML of ≥3 cm in diameter [20]. In this study, 42% of everolimus- and 0% of placebo-treated patients (p < 0.0001) had a confirmed AML response (reduction in AML volume [sum of volumes of all target AMLs identified at baseline] of ≥50% or more relative to baseline and absence of AML progression), with a median time to response of 2.9 months in the everolimus group [20]. Long-term follow up (median 28.9 months) showed an increase in response rate to 54%, with 97% of patients experiencing a reduction in tumour volume [24]. The final four-year analysis of 112 patients, including those who had crossed over from placebo, showed an overall response rate of 58% after a median duration of everolimus exposure of 204.1 weeks [19]. Recent data from the phase III EXIST-3 showed that adjunctive everolimus in patients receiving one to three antiepileptic drugs significantly reduced the rate of seizures in TSC patients refractory to treatment (29.3% and 39.6% reduction in seizure rate for 3–7 ng/mL and 9–15 ng/mL trough concentrations vs a 14.9% reduction with placebo), and increased the response rate (defined as ≥50% reduction; 28.2% and 40%, vs 15.1% for placebo) [22].

There are a number of important challenges relating to everolimus use for the treatment of TSC. In particular, although everolimus is indicated for TSC-related AML and SEGA, the majority of experience with the drug comes from oncological indications. Furthermore, there is no clear and defined management pathway for TSC and patients may be seen by any number of different specialists depending on their presentation. In addition, many healthcare professionals who treat TSC are unfamiliar with everolimus and are unsure about prescribing it to their patients. AEs may be of particular concern; however, their successful management will increase the number of patients who can tolerate everolimus long-term and, therefore, help to optimise treatment benefit, which will help ensure sustained efficacy and adherence.

The aim of this article is to provide practical guidance to nephrologists and other specialists such as paediatricians, neurologists and geneticists who treat patients with TSC, including providing advice on what to consider at a patient’s first consultation and the key investigations to perform. Guidance will also be provided on the management of AEs, including lessons from everolimus use in oncological indications, as well as recommendations for patient education.

Patients with TSC require special considerations prior to the initiation of everolimus treatment (Fig. 1). Before treatment is given, a full blood count and liver and kidney function tests should be performed. Serum electrolytes and creatinine should be measured, and urine protein estimated by dipstick analysis and protein:creatinine ratio. Baseline lipids should be measured; if fasting lipids cannot be ascertained then random cholesterol is an acceptable substitute. If lipids are significantly elevated then improved lipid control should ideally be obtained before starting everolimus (e.g. through dietary modifications or statins).

Fasting blood glucose should also be measured, but in the absence of this a random glucose and glycated haemoglobin test can be performed. If these tests are abnormal, optimal glycaemic control should be achieved before starting everolimus whenever possible.

Because mTOR inhibitors have immunosuppressive properties, a thorough medical history relating to infection should also be obtained (e.g. history of pneumonia, recurrent otitis media, sinusitis, fungal infections, hepatitis, HIV, tuberculosis) [34]. A hepatitis screen may be warranted due to the potential risk of virus reactivation.

Patients with respiratory symptoms or radiological evidence suggestive of LAM should have a computed tomography scan, lung function tests, transfer factor of the lung for carbon monoxide and arterial oxygen saturation before everolimus administration.

Patients should be provided with information and advice on how their treatment may impact their daily life. It may be beneficial to pre-emptively prescribe or recommend items such as non-alcoholic mouthwashes and soft toothbrushes before the occurrence of AEs such as stomatitis. Another important consideration before prescribing treatment is to take an inventory of current medications patients are receiving; information on drug–drug interactions is presented later in this article.

Live vaccines should be avoided or completed before initiating everolimus owing to its immunosuppressive properties. Treatment with everolimus should be delayed or temporarily discontinued in patients undergoing surgery because the drug can delay wound healing [34]. Finally, as everolimus tablets contain lactose, patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose–galactose malabsorption should not take the drug [19].

Understandably, clinicians have concerns regarding the use of mTOR inhibitors in children, specifically regarding their effect on growth and gonadal function over the long-term. There are few studies that have evaluated the use of mTOR inhibitors in children with TSC [35, 36], however 5-year data from a phase II study show that growth parameters such as height, height velocity and weight in children were comparable before and after starting treatment [36]. Furthermore, paediatric kidney transplant studies with mTOR inhibitor-treated patients suggest no effect on longitudinal growth as well as comparable ages of sexual maturation and reproductive hormone levels when compared with kidney transplant patients who did not receive mTOR inhibitors [37‐40]. Some studies of sirolimus have suggested the occurrence of testosterone suppression in adolescents [41] and adults [42‐44], however most of these studies had small numbers of patients and used a higher dose regimen compared to recent studies.

Standard recommendation currently advises against concomitant use of everolimus on ketogenic diets in children with epilepsy, which is due to additive toxicity with hyperlipidaemia. Although data are limited regarding this side effect, the authors would recommend that clinicians use their discretion while prescribing mTOR inhibitors in such cases.

Common AEs associated with the use of everolimus in TSC are stomatitis, nasopharyngitis, acne-like skin lesions, headache, cough and hypercholesterolaemia. Other AEs occurring in ≥10% of patients in the EXIST-1 and -2 trials are shown in Table 1 [20, 21]; the Common Terminology Criteria for Adverse Events (CTCAE) are shown in Table 2 [45].

The management of AEs may require dose reduction or temporary cessation of therapy (Table 3) [19]. As a general rule, this should be considered with all grade 2–3 AEs thought to be everolimus treatment-related; adjustments are usually not required for grade 1 AEs. When a dose reduction is needed, it is recommended that the new dose should be around 50% lower than that previously administered. For dose reduction below the lowest available strength, alternate day dosing should be considered. If the AE is persistent or recurrent, the dose should be interrupted for 3–14 days (or until the AE is resolved to grade ≤1), with everolimus then restarted at a lower dose. Dose interruption/reduction can help to ameliorate AEs while allowing for continued therapeutic benefit, as evidenced in EXIST-2 in which 71% of patients had a dose interruption/reduction and around a third were maintained on doses less than the initial 10 mg/day [24].

Many patients with TSC have learning difficulties and may not be reliably able to report any toxicities, or the toxicities may manifest in atypical ways such as altered behaviour, e.g. pain can manifest as increased aggression, withdrawal or sleep disturbance. Family members and other carers are often attuned to such changes, and any concerns they raise must be taken seriously.

Based on lessons from clinical trials in TSC-related conditions and oncology indications, and from our own clinical experience, we have provided the following guide as a reference for nephrologists and other specialists who may encounter specific AEs in their patients. AEs of note have been listed, along with a summary of their presentation, practical advice for physicians and important information that should be communicated to patients to aid in their management.

Non-infectious pneumonitis is a class effect of rapamycin analogues, such as everolimus and temsirolimus. A diagnosis of non-infectious pneumonitis should be considered in patients with TSC presenting with new or worsening signs, or with non-specific respiratory symptoms such as cough or dyspnoea, the development of a pleural effusion, or radiological changes (ground-glass opacities and focal consolidation, predominantly in the lower lobes). Pneumonitis grading is shown in Table 2.

Recommendations for dose modification in everolimus-treated patients experiencing non-infectious pneumonitis are provided in Table 3. Differentiating non-infectious pneumonitis from infection is a key issue for investigations. Pneumocystis jiroveci pneumonia and Legionella should be ruled out.

Treatment interruption, dose reductions and treatment with corticosteroids (e.g. in adults, 3–7 days of 30–60 mg prednisolone followed by steroid tapering) and antibiotics are the common management strategies for non-infectious pneumonitis. It is important to try and exclude an infectious aetiology before the use of corticosteroids. Early proactive management is a must, and dose reduction should be considered as early as grade 1. Patients who develop radiological changes suggestive of non-infectious pneumonitis and those have few or no symptoms may continue everolimus without dose adjustments.

Patients should be advised to report promptly any new or worsening respiratory symptoms, and it is recommended that patients keep a diary to monitor these effects [19]. In addition, patients may consider taking warm baths/showers, or using a vaporiser to help thin out secretions; and avoiding allergens, such as smoke and pollen, if pneumonitis is present [46].

While the rates of infections were no higher with everolimus than placebo in the EXIST-1 and -2 studies (around 70% in both groups in both trials) [20, 21], everolimus has immunosuppressive properties and patients may be susceptible to bacterial, fungal, viral or protozoal infections, including opportunistic pathogens and reactivation of previous infections (see Table 1 for a list of described infections). Hence, in normal clinical practice some increase in infection rates may be expected, even in patients not taking other concurrent immunosuppressants. Any pre-existing infections should be treated appropriately and resolved before commencing therapy. Guidelines for hepatitis B screening, prophylaxis and reactivation management have been developed [34].

If a diagnosis of infection is made, appropriate treatment must be given promptly. Everolimus interruption/discontinuation should also be considered in this scenario, particularly when associated with fever. In cases of invasive systemic fungal infection, everolimus should be discontinued and appropriate antifungal therapy initiated [34]. Patients being treated with everolimus should be warned about the risk of infection and educated on the need to seek medical help if they develop suggestive symptoms and if they develop cuts or wounds because these are at an elevated risk of becoming infected. Furthermore, to reduce the risk of infection, patients should wash their hands frequently keep food preparation areas clean, and avoid cleaning up after pets.

Stomatitis is an inflammation of the mucous membranes in the oral cavity, inner surface of the lips or the tongue, and is associated with erythema, oedema, a burning sensation and occasionally bleeding. It can impair a patient’s ability to eat, swallow and talk, and can cause significant pain. Stomatitis is one of the most common AEs in patients treated with mTOR inhibitors, although the effect is typically transient. It usually occurs within 1 month of treatment initiation.

The early and active management of stomatitis is essential. When starting everolimus, patients should be issued with suitable oral care products (e.g. sucralfate suspension, bioadherent oral rinse gels, raspberry mucilage). For example, sucralfate suspension can be applied 3–4 times day with a cotton wool bud to the ulcer or patients can rinse and spit. The sucralfate suspension can also be swallowed if the patient has a lesion in the pharynx. The steroid triamcinolone acetonide can be used for ulcers on or inside the lip, or in the front of the mouth [34]. For those who do not respond to these medications, or those who require greater pain control, a topical analgesic (e.g. benzocaine with or without a steroid) may be required. Some clinicians recommend a ‘magic mouthwash’ for which several formulations are available, but which typically contains a topical anaesthetic, a steroid, an antibiotic, an anti-fungal and an antacid – it should however be noted that concomitant anti-fungals are not recommended with everolimus treatment [19]. Direct application of clobetasol, a high potency steroid, has been associated with rapid symptomatic improvement in mTOR-treated patients with aphthous ulceration [47].

All patients with stomatitis should receive recommendations regarding good oral care. This may include consistent regular brushing with a soft toothbrush that is changed on a regular basis, frequent rinsing with bland rinses (e.g. sterile water, saline or sodium bicarbonate), and avoidance of strong-flavoured toothpastes and those containing lauryl sulphate; instead, children’s toothpastes may be favoured. Mouthwashes containing alcohol should be avoided. Patients should also avoid acidic, spicy, hard or crunchy foods, those that are too hot in temperature, and alcohol. Care should be taken when eating and drinking; it may be advisable to eat 5–6 smaller meals per day and drink through a straw. Physicians should also consider vitamin B and zinc supplementation prior to everolimus initiation; while the data supporting the evidence of this in ameliorating mouth ulcers are mixed [48‐51], there are likely patients who are both deficient and predisposed to this side effect of mTOR inhibition and who would therefore benefit.

Rash in everolimus-treated patients is usually macular or papular, and may also contain pustules and eczematous changes. It is most commonly found on the face, upper trunk and scalp, and may be associated with pruritus. Topical treatments are typically the first choice for managing rash, such as those products containing benzoyl peroxide and an antibiotic, or topical steroids, such as alcometasone or mometasone.

Oral antibiotics (e.g. minocycline or doxycycline) may also be necessary. In patients with pruritus, topical emollients or antihistamines may be advisable. Retinoids should be avoided as they may disrupt skin integrity and potentially increase risk of infection. Physicians should advise patients to consider the following advice: wear loose, comfortable clothing; use mild soaps without perfume and take short, lukewarm showers; when washing and drying, pat the area instead of rubbing with a towel or washcloth; avoid tanning booths; use a moisturiser frequently; and use sunscreen (at least SPF 15) [52].

The metabolic events that often occur with everolimus treatment – namely hypercholesterolaemia, hyperglycaemia, hypophosphataemia, hypertriglyceridaemia, elevated lactate dehydrogenase and hyperuricaemia – are shown in Table 2 [19]. Abnormal laboratory values can usually be managed routinely without treatment interruption. Intervention is recommended at grade 3 severity, with the nature of the intervention dependent on the specific metabolic abnormality. It is important to bear in mind that hypercholesterolaemia can increase the risk of cardiovascular events and that hypertriglyceridaemia at levels of ≥1,000 mg/dL can cause life-threatening pancreatitis.

With regard to practical management, fasting blood glucose and lipid profiles should be assessed before starting everolimus and then monitored periodically (e.g. every 6–8 weeks) during treatment. Patients with diabetes require careful monitoring – and potential modification – of their antihyperglycaemic medications. In particular, metformin should be avoided in diabetic patients with renal impairment (creatinine clearance <30 mL/min/1.73 m²) and in patients with lactic acidosis [53]. Statins and fibrates are recommended for lowering total cholesterol and triglycerides, respectively, along with lifestyle and nutritional changes. Consideration should be given to the use of lipid regulating drugs since some may not be licensed for use in children.

Bone marrow suppression is a common toxicity associated with mTOR inhibitors. Grade 1 effects do not require any interruption of treatment. Thrombocytopenia requires intervention at grade 2 and neutropenia at grade 3. Thrombocytopenia and neutropenia are rarely associated with clinically significant bleeding or infection, and hence do not typically necessitate platelet transfusion or growth factor support [54]. Microcytosis and hypochromia have also been reported in patients with TSC treated with mTOR inhibitors; generally these effects are self-limiting [18].

In cases of grade 3 toxicity, interruption of treatment with everolimus is required, with a lowering of the dose upon resumption. Everolimus should be discontinued in any cases of life-threatening toxicity.

Renal tubular abnormalities have been observed in patients treated with sirolimus [54], and hence physicians should be vigilant when initiating everolimus, particularly in patients with TSC with significant renal involvement. Renal function should be assessed before starting everolimus treatment and periodically thereafter (Fig. 1), which should include assessment of urinary protein (e.g. urine protein:creatinine ratio). Although AEs such as proteinuria or an increased degree of proteinuria may be common, they are generally intermittent and should not trigger treatment cessation. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers can be used to ameliorate microalbuminuria or proteinuria when necessary. Cessation of everolimus should be considered if there is progressively increasing proteinuria to >1 g/day, especially if >3 g/day or if associated with peripheral oedema. Similarly if GFR progressively declines to <30 mL/min, cessation should be considered, although this may be due to the underlying pathophysiology of TSC rather than everolimus.