Everolimus in the treatment of subependymal giant cell astrocytomas, angiomyolipomas, and pulmonary and skin lesions associated with tuberous sclerosis complex

Figures & data

Figure 1 Computed tomography scan demonstrating acute presentation of bilateral subependymal giant cell astrocytomas with marked obstructive hydrocephalus. After emergency surgical resection, the patient with tuberous sclerosis complex was left blind and mentally retarded.

Figure 2 Renal computed tomography scan demonstrating significant angiomyolipomata burden in both kidneys of a patient with tuberous sclerosis complex.

Figure 3 Examples of tuberous sclerosis complex-associated skin lesions: (A) angiofibromas and (B) shagreen patches and ash leaf macules.

Figure 4 Chest computed tomography scan showing parenchymal destruction associated with lymphangioleiomyomatosis in a patient with tuberous sclerosis complex.

Figure 5 The mammalian target of rapamycin signaling pathway.

Note: Franz DN et al. Journal of Child Neurology. 28(5):602–607, Copyright © 2013 by Sage. Reprinted by Permission of SAGE Publications.²²
Abbreviations: 4E-BP1, 4E binding protein 1; Abl, Abelson kinase; Akt, protein kinase B; eIF-4E, eukaryotic initiation factor 4E; IGF-1R, insulin-like growth factor-1 receptor; PI3K, phosphoinositide 3-kinase; Pten, phosphatase and tensin homolog; RAS, rat sarcoma; S6K1, 40 S ribosomal S6 kinase; TSC1, tuberous sclerosis complex 1; TSC2, tuberous sclerosis complex 2.

Table 1 Common treatment modalities for SEGA, angiomyolipoma, skin lesions, and pulmonary LAM

Clinical issue	Treatment	Additional comment
SEGA^Citation30^–^Citation32,Citation36,Citation61,Citation65	• Active surveillance	• Periodic neuroimaging is recommended to monitor lesion size
	• Surgery	• Timing of surgery is debatable
	• Gamma Knife stereotactic radiosurgery	• Incomplete excision of SEGAs results in tumor recurrence
	• Pharmacotherapy with mTOR inhibitors	• Postoperative complications include limit to the efficacy of surgery
Angiomyolipoma^Citation7,Citation43,Citation60	• Arterial embolization	• Repeat embolization required
	• Partial/total nephrectomy	• Postembolization syndrome
	• Pharmacotherapy with mTOR inhibitors
Skin lesions^Citation5,Citation14	• Cryosurgery	• Variable recurrence rate
	• Curettage	• Repeat procedures needed
	• Dermabrasion
	• Chemical peeling
	• Excision
	• Laser therapy
Pulmonary LAM^Citation1,Citation45	• Bronchodilators	• Treatments are palliative only
	• Oxygen support
	• Estrogen antagonists

Abbreviations: LAM, lymphangioleiomyomatosis; mTOR, mammalian target of rapamycin; SEGA, subependymal giant cell astrocytoma.

Table 2 Pharmacokinetic properties of everolimus in various patient populations

Patient population	Tmax (h)	Cmax (ng/mL)	AUC (ng/mL · h) 0–∞	Half-life (h)
Healthy subjectsa (n = 24) 2.0 mg dose^Citation54	0.5 (0.5–2.0)	17.9 ± 5.9	122 ± 52	31.5 ± 6.4
Healthy subjectsa (n = 12) 4.0 mg dose^Citation66	0.5 (0.5–1.0)	44.2 ± 13.3	219 ± 69	32.2 ± 6.1
Refractory advanced solid tumor patients aged ≥18 years (n = 4)a 5.0 mg dose^Citation53	1 (1)	32 ± 9	238 ± 77	—
Refractory or recurrent solid tumor patients aged ≥3 years to <22 years (n = 6)b 2.1 mg/m^2 ^Citation67	1 (0.5–1.2)	21.5 (16.1–78.5)	139.8 (94.6–197.7)	18.0 (15.2–19.9)
Refractory or recurrent solid tumor patients aged ≥3 years to <22 years (n = 8)b 3.0 mg/m^2 ^Citation67	1.1 (0.6–2.3)	43.5 (18–58)	197.6 (59.6–249.4)	15.9 (13.9–22.5)

Notes:

a Values are mean ± standard deviation, except for T_max, which is median (range)

b all values are median (range).

Abbreviations: AUC, area under the concentration–time curve from zero to infinity; C_max, maximum concentration; T_max, time to reach maximum concentration.

Table 3 Efficacy and safety analyses from EXIST-1 and EXIST-2

Trial	Efficacy	Safety
EXIST-1^Citation36	Primary end point	• AEs were mostly grade 1/2 in severity
• TSC patients (n = 117) with ≥ 1 SEGA ≥ 1 cm and either serial growth of SEGA, a new lesion of ≥ 1 cm, or new or worsening hydrocephalus	• SEGA response rate: 35% vs 0% (EVE vs PBO; P < 0.0001)
	Key secondary end points	• Most common AEs were mouth ulceration (32% vs 5% EVE vs PBO), stomatitis (31% vs 21% EVE vs PBO), convulsions (23% vs 26% EVE vs PBO), and pyrexia (22% vs 15% EVE vs PBO)
	• Change from baseline to week 24 in the total number of seizures per 24 hours
• Oral 4.5 mg/m^2/day everolimus titrated to target whole blood trough level of 5–15 ng/mL	– No significant difference in seizure frequency was found in the everolimus arm relative to placebo (P = 0.20)
	• Time to progression of SEGA
	– No EVE patients progressed vs six PBO patients (15.4%) (P = 0.0002)
	• Skin lesion response rate (among patients with ≥ 1 skin lesion at baseline; n = 110)
	– 42% vs 11% (EVE vs PBO; P = 0.0004)
	Exploratory end points
	• Angiomyolipoma response rate (among patients with ≥ 1 angiomyolipoma ≥ 1 cm in longest diameter at baseline; n = 44) 53% vs 0% (EVE vs PBO)
EXIST-2^Citation60	Primary end point	• AEs were mostly grade 1/2 in severity
• TSC or sporadic lymphangioleiomyomatosis patients (n = 118) with ≥ 1 angiomyolipoma ≥3 cm in longest diameter, no requirement for angiomyolipoma-related surgery, or no angiomyolipoma-related bleeding or embolization in past 6 months	• Angiomyolipoma response rate
	– 42% vs 0% (EVE vs PBO; P < 0.0001) Key secondary end points	• Most common AEs were stomatitis (48% vs 8% EVE vs PBO), nasopharyngitis (24% vs 31% EVE vs PBO), and acne-like skin lesions (22% vs 5% EVE vs PBO)
	Key secondary end points
	• Time to progression of angiomyolipoma
	– EVE was superior to PBO (hazard ratio: 0.08; 95% CI: 0.02–0.37; P < 0.0001)
• Oral 10 mg/day EVE	• Skin lesion response rate (among patients with ≥ 1 skin lesion at baseline; n = 114): 26% vs 0% (EVE vs PBO; P = 0.0002)

Abbreviations: AE, adverse event; CI, confidence interval; EVE, everolimus; EXIST, EXamining everolimus In a Study of TSC; PBO, placebo; SEGA, subependymal giant cell astrocytoma; TSC, tuberous sclerosis complex; vs, versus.

FranzDNAgricolaKDTudorCAKruegerDAEverolimus for tumor recurrence after surgical resection for subependymal giant cell astrocytoma associated with tuberous sclerosis complexJ Child Neurol201328560260722805244

 PubMed Web of Science ®Google Scholar

BerhoumaMManagement of subependymal giant cell tumors in tuberous sclerosis complex: the neurosurgeon’s perspectiveWorld J Pediatr20106210311020490765

 PubMed Web of Science ®Google Scholar

BeaumontTLLimbrickDDSmythMDAdvances in the management of subependymal giant cell astrocytomaChilds Nerv Syst201228796396822562196

 PubMed Web of Science ®Google Scholar

FranzDNBelousovaESparaganaSEfficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trialLancet2013381986112513223158522

 PubMed Web of Science ®Google Scholar

WanXHarkavyBShenNGroharPHelmanLJRapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanismOncogene200726131932194017001314

 PubMed Web of Science ®Google Scholar

EkiciMAKumandasSPerHSurgical timing of the subependymal giant cell astrocytoma (SEGA) with the patients of tuberous sclerosis complexTurk Neurosurg201121331532421845566

 PubMed Web of Science ®Google Scholar

BisslerJJKingswoodJCRenal angiomyolipomataKidney Int200466392493415327383

 PubMed Web of Science ®Google Scholar

SooriakumaranPGibbsPCoughlinGAngiomyolipomata: challenges, solutions, and future prospects based on over 100 cases treatedBJU Int2010105110110619493268

 PubMed Web of Science ®Google Scholar

BisslerJJKingswoodJCRadzikowskaEEverolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trialLancet2013381986981782423312829

 PubMed Web of Science ®Google Scholar

SchwartzRAFernandezGKotulskaKJozwiakSTuberous sclerosis complex: advances in diagnosis, genetics, and managementJ Am Acad Dermatol200757218920217637444

 PubMed Web of Science ®Google Scholar

HofbauerGFMarcollo-PiniACorsencaAThe mTOR inhibitor rapamycin significantly improves facial angiofibroma lesions in a patient with tuberous sclerosisBr J Dermatol2008159247347518547304

 PubMed Web of Science ®Google Scholar

FranzDNBisslerJJMcCormackFXTuberous sclerosis complex: neurological, renal and pulmonary manifestationsNeuropediatrics201041519920821210335

 PubMed Web of Science ®Google Scholar

KohrmanMHEmerging treatments in the management of tuberous sclerosis complexPediatr Neurol201246526727522520346

 PubMed Web of Science ®Google Scholar

KovarikJMHartmannSFigueiredoJEffect of food on everolimus absorption: quantification in healthy subjects and a confirmatory screening in patients with renal transplantsPharmacotherapy200222215415911837553

 PubMed Web of Science ®Google Scholar

KovarikJMHartmannSFigueiredoJRouillyMPortARordorfCEffect of rifampin on apparent clearance of everolimusAnn Pharmacother200236698198512022896

 PubMed Web of Science ®Google Scholar

O’DonnellAFaivreSBurrisHA3rdPhase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumorsJ Clin Oncol200826101588159518332470

 PubMed Web of Science ®Google Scholar

FouladiMLaninghamFWuJPhase I study of everolimus in pediatric patients with refractory solid tumorsJ Clin Oncol2007253018061812

 Web of Science ®Google Scholar