2016年6月3日，瑞士制药巨头诺华（Novartis）抗癌药Afinitor（everolimus，依维莫司，片剂）近日在欧盟监管方面传来喜讯。欧盟委员会批准Afinitor的新适应症，用于起源于胃肠道（gastrointestinal，GI）或肺部（lung）的不可切除性、局部晚期或转移性、进展性、分化良好型（1级或2级）非功能性神经内分泌肿瘤（neuroendocrine tumor，NET）成人患者的治疗。
这是欧盟28个成员国首个获批的用于治疗肺部非功能性神经内分泌肿瘤的药物，也是为数不多的用于治疗胃肠道非功能性神经内分泌肿瘤的药物之一。FDA已于今年2月批准Afinitor相同的适应症，目前Afinitor在美国可用于3类最常见的晚期NET的治疗。值得一提的是，在非功能性NET治疗领域，Afinitor是美国首个获批治疗晚期进展性非功能性肺部NET的药物，同时也是美国首个获批的晚期进展性非功能性胃肠道（GI）NET的口服治疗药物。
神经内分泌肿瘤（NET）是一种罕见的癌症类型，起源于遍布全身的神经内分泌细胞。NET最常见于胃肠道、肺部、胰腺。NET可被定义为功能性NET和非功能性NET。功能性NET是以激素和其他物质分泌过多引起的症状为特征。非功能性NET则是以可由肿瘤生长引起的症状为特征，例如肠胃道NET特征包括肠梗阻、疼痛及出血，肺部NET特征包括哮喘、慢性阻塞性肺病及肺炎。今年4月底，欧洲药品管理局（EMA）人用医药产品委员会（CHMP）支持批准Afinitor用于治疗该适应症，基于关键性III期RADIANT-4研究的疗效和安全性数据。临床试验结果表明，与安慰剂相比，Afinitor使该适应症的疾病进展风险显着降低52%，患者的无进展生存期（PFS）显着延长了7.1个月。
Afinitor已获全球99个国家（包括美国和欧盟）批准用于局部晚期、转移性、不可切除性、进展性、胰腺起源NET的治疗。此外，Afinitor已获全球超过120个国家批准治疗肾细胞癌，并且已在全球102个国家（包括美国和欧盟）获得批准，联合依西美坦（exemestane）用于之前已接受过内分泌治疗的HR+/HER2-乳腺癌。尽管Afinitor在众多国家收获了许多适应症，但仍面临许多激烈的竞争，如百时美的免疫检查点抑制剂Opdivo和Exelixis的Cometriq等。目前诺华仍在许多肿瘤中进行Afinitor的临床试验，以期获得更多的适应症。
Afinitor Tablets
1. Name of the medicinal product
Afinitor 2.5mg tablets
Afinitor 5mg tablets
Afinitor 10mg tablets
2. Qualitative and quantitative composition
Afinitor 2.5mg tablets:
Each tablet contains 2.5 mg everolimus.
Excipient with known effect:
Each tablet contains 74 mg lactose.
Afinitor 5mg tablets
Each tablet contains 5 mg everolimus.
Excipients with known effect:
Each tablet contains 149 mg lactose.
Afinitor 10mg tablets:
Each tablet contains 10 mg everolimus.
Excipients with known effect:
Each tablet contains 297 mg lactose.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Tablet.
Afinitor 2.5mg tablets:
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “LCL” on one side and “NVR” on the other.
Afinitor 5mg tablets:
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “5” on one side and “NVR” on the other.
Afinitor 10mg tablets:
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “UHE” on one side and “NVR” on the other.
4. Clinical particulars
4.1 Therapeutic indications
Hormone receptor-positive advanced breast cancer
Afinitor is indicated for the treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor.
Neuroendocrine tumours of pancreatic origin
Afinitor is indicated for the treatment of unresectable or metastatic, well- or moderately-differentiated neuroendocrine tumours of pancreatic origin in adults with progressive disease.
Renal cell carcinoma
Afinitor is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with VEGF-targeted therapy.
4.2 Posology and method of administration
Treatment with Afinitor should be initiated and supervised by a physician experienced in the use of anticancer therapies.
Posology
For the different dose regimens Afinitor is available as 2.5 mg, 5 mg and 10 mg tablets.
The recommended dose is 10 mg everolimus once daily. Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.
If a dose is missed, the patient should not take an additional dose, but take the next prescribed dose as usual.
Dose adjustment due to adverse reactions
Management of severe and/or intolerable suspected adverse reactions may require dose reduction and/or temporary interruption of Afinitor therapy. For adverse reactions of Grade 1, dose adjustment is usually not required. If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily.
Table 1 summarises the dose adjustment recommendations for specific adverse reactions (see also section 4.4).
Table 1 Afinitor dose adjustment recommendations
Special populations
Elderly patients (≥65 years)
No dose adjustment is required (see section 5.2).
Renal impairment
No dose adjustment is required (see section 5.2).
Hepatic impairment
? Mild hepatic impairment (Child-Pugh A) – the recommended dose is 7.5 mg daily.
? Moderate hepatic impairment (Child-Pugh B) – the recommended dose is 5 mg daily.
? Severe hepatic impairment (Child-Pugh C) – Afinitor is only recommended if the desired benefit outweighs the risk. In this case, a dose of 2.5 mg daily must not be exceeded.
Dose adjustments should be made if a patient's hepatic (Child-Pugh) status changes during treatment (see also sections 4.4 and 5.2).
Paediatric population
The safety and efficacy of Afinitor in children aged 0 to 18 years have not been established. No data are available.
Method of administration
Afinitor should be administered orally once daily at the same time every day, consistently either with or without food (see section 5.2). Afinitor tablets should be swallowed whole with a glass of water. The tablets should not be chewed or crushed.
4.3 Contraindications
 Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
 Non-infectious pneumonitis
Non-infectious pneumonitis is a class effect of rapamycin derivatives, including everolimus. Non-infectious pneumonitis (including interstitial lung disease) has been described in patients taking Afinitor (see section 4.8). Some cases were severe and on rare occasions, a fatal outcome was observed. A diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnoea, and in whom infectious, neoplastic and other non-medicinal causes have been excluded by means of appropriate investigations. Patients should be advised to report promptly any new or worsening respiratory symptoms.
Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue Afinitor therapy without dose adjustments. If symptoms are moderate (Grade 2) or severe (Grade 3) the use of corticosteroids may be indicated until clinical symptoms resolve.
Infections
Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoan infections, including infections with opportunistic pathogens (see section 4.8). Localised and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus, have been described in patients taking Afinitor. Some of these infections have been severe (e.g. leading to sepsis, respiratory or hepatic failure) and occasionally fatal.
Physicians and patients should be aware of the increased risk of infection with Afinitor. Pre-existing infections should be treated appropriately and should have resolved fully before starting treatment with Afinitor. While taking Afinitor, be vigilant for symptoms and signs of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Afinitor.
If a diagnosis of invasive systemic fungal infection is made, the Afinitor treatment should be promptly and permanently discontinued and the patient treated with appropriate antifungal therapy.
Hypersensitivity reactions
Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnoea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus (see section 4.3).
Concomitant use of angiotensin-converting enzyme (ACE) inhibitors
Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5).
Oral ulceration
Mouth ulcers, stomatitis and oral mucositis have been observed in patients treated with Afinitor (see section 4.8). In such cases topical treatments are recommended, but mouthwashes containing alcohol, peroxide, iodine and thyme derivatives should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed (see section 4.5).
Renal failure events
Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with Afinitor (see section 4.8). Renal function should be monitored particularly where patients have additional risk factors that may further impair renal function.
Laboratory tests and monitoring
Renal function
Elevations of serum creatinine, usually mild, and proteinuria have been reported (see section 4.8). Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein or serum creatinine, is recommended prior to the start of Afinitor therapy and periodically thereafter.
Blood glucose
Hyperglycaemia has been reported (see section 4.8). Monitoring of fasting serum glucose is recommended prior to the start of Afinitor therapy and periodically thereafter. More frequent monitoring is recommended when Afinitor is co-administered with other medicinal products that may induce hyperglycaemia. When possible optimal glycaemic control should be achieved before starting a patient on Afinitor.
Blood lipids
Dyslipidaemia (including hypercholesterolaemia and hypertriglyceridaemia) has been reported. Monitoring of blood cholesterol and triglycerides prior to the start of Afinitor therapy and periodically thereafter, as well as management with appropriate medical therapy, is recommended.
Haematological parameters
Decreased haemoglobin, lymphocytes, neutrophils and platelets have been reported (see section 4.8). Monitoring of complete blood count is recommended prior to the start of Afinitor therapy and periodically thereafter.
Carcinoid tumours
In a randomised, double-blind, multi-centre trial in patients with carcinoid tumours, Afinitor plus depot octreotide was compared to placebo plus depot octreotide. The study did not meet the primary efficacy endpoint (progression-free-survival [PFS]) and the overall survival (OS) interim analysis numerically favoured the placebo plus depot octreotide arm. Therefore, the safety and efficacy of Afinitor in patients with carcinoid tumours have not been established.
Interactions
Co-administration with inhibitors and inducers of CYP3A4 and/or the multidrug efflux pump P-glycoprotein (PgP) should be avoided. If co-administration of a moderate CYP3A4 and/or PgP inhibitor or inducer cannot be avoided, dose adjustments of Afinitor can be taken into consideration based on predicted AUC (see section 4.5).
Concomitant treatment with potent CYP3A4 inhibitors result in dramatically increased plasma concentrations of everolimus (see section 4.5). There are currently not sufficient data to allow dosing recommendations in this situation. Hence, concomitant treatment of Afinitor and potent inhibitors is not recommended.
Caution should be exercised when Afinitor is taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If Afinitor is taken with orally administered CYP3A4 substrates with a narrow therapeutic index (e.g. pimozide, terfenadine, astemizole, cisapride, quinidine or ergot alkaloid derivatives), the patient should be monitored for undesirable effects described in the product information of the orally administered CYP3A4 substrate (see section 4.5).
Hepatic impairment
Exposure to everolimus was increased in patients with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment (see section 5.2).
Afinitor is only recommended for use in patients with severe hepatic impairment (Child-Pugh C) if the potential benefit outweighs the risk (see sections 4.2 and 5.2).
No clinical safety or efficacy data are currently available to support dose adjustment recommendations for the management of adverse reactions in patients with hepatic impairment.
Vaccinations
The use of live vaccines should be avoided during treatment with Afinitor (see section 4.5).
Lactose
Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Wound healing complications
Impaired wound healing is a class effect of rapamycin derivatives, including everolimus. Caution should therefore be exercised with the use of Afinitor in the peri-surgical period.
4.5 Interaction with other medicinal products and other forms of interaction
 Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of PgP. Therefore, absorption and subsequent elimination of everolimus may be influenced by products that affect CYP3A4 and/or PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.
Known and theoretical interactions with selected inhibitors and inducers of CYP3A4 and PgP are listed in Table 2 below.
CYP3A4 and PgP inhibitors increasing everolimus concentrations
Substances that are inhibitors of CYP3A4 or PgP may increase everolimus blood concentrations by decreasing metabolism or the efflux of everolimus from intestinal cells.
CYP3A4 and PgP inducers decreasing everolimus concentrations
Substances that are inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by increasing metabolism or the efflux of everolimus from intestinal cells.
Table 2 Effects of other active substances on everolimus
Agents whose plasma concentration may be altered by everolimus
Based on in vitro results, the systemic concentrations obtained after oral daily doses of 10 mg make inhibition of PgP, CYP3A4 and CYP2D6 unlikely. However, inhibition of CYP3A4 and PgP in the gut cannot be excluded. An interaction study in healthy subjects demonstrated that co-administration of an oral dose of midazolam, a sensitive CYP3A substrate probe, with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). The effect is likely to be due to inhibition of intestinal CYP3A4 by everolimus. Hence everolimus may affect the bioavailability of orally co-administered CYP3A4 substrates. However, a clinically relevant effect on the exposure of systemically administered CYP3A4 substrates is not expected (see section 4.4).
Co-administration of everolimus and depot octreotide increased octreotide Cmin with a geometric mean ratio (everolimus/placebo) of 1.47. A clinically significant effect on the efficacy response to everolimus in patients with advanced neuroendocrine tumours could not be established.
Co-administration of everolimus and exemestane increased exemestane Cmin and C2h by 45% and 64%, respectively. However, the corresponding oestradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive advanced breast cancer receiving the combination. The increase in exemestane levels is unlikely to have an impact on efficacy or safety.
Concomitant use of angiotensin-converting enzyme (ACE) inhibitors
Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for angioedema (see section 4.4).
Vaccinations
The immune response to vaccination may be affected and, therefore, vaccination may be less effective during treatment with Afinitor. The use of live vaccines should be avoided during treatment with Afinitor (see section 4.4). Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG (Bacillus Calmette-Guérin), yellow fever, varicella, and TY21a typhoid vaccines.
4.6 Fertility, pregnancy and lactation
 Women of childbearing potential/Contraception in males and females
Women of childbearing potential must use a highly effective method of contraception (e.g. oral, injected, or implanted non-oestrogen-containing hormonal method of birth control, progesterone-based contraceptives, hysterectomy, tubal ligation, complete abstinence, barrier methods, intrauterine device [IUD], and/or female/male sterilisation) while receiving everolimus, and for up to 8 weeks after ending treatment. Male patients should not be prohibited from attempting to father children.
Pregnancy
There are no adequate data from the use of everolimus in pregnant women. Studies in animals have shown reproductive toxicity effects including embryotoxicity and foetotoxicity (see section 5.3). The potential risk for humans is unknown.
Everolimus is not recommended during pregnancy and in women of childbearing potential not using contraception.
Breast-feeding
It is not known whether everolimus is excreted in breast milk. However, in rats, everolimus and/or its metabolites readily pass into the milk (see section 5.3). Therefore, women taking everolimus should not breast-feed.
Fertility
The potential for everolimus to cause infertility in male and female patients is unknown, however amenorrhoea (secondary amenorrhoea and other menstrual irregularities) and associated luteinising hormone (LH)/follicle stimulating hormone (FSH) imbalance has been observed in female patients. Based on non-clinical findings, male and female fertility may be compromised by treatment with everolimus (see section 5.3).
4.7 Effects on ability to drive and use machines
 Afinitor may have a minor or moderate influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines if they experience fatigue during treatment with Afinitor.
4.8 Undesirable effects
 Summary of the safety profile
The safety profile is based on pooled data from 2,406 patients treated with Afinitor in eight clinical studies, consisting of four randomised, double-blind, placebo controlled phase III studies and four phase II studies, related to the approved indications.
The most common adverse reactions (incidence ≥1/10) from the pooled safety data were (in decreasing order): stomatitis, rash, fatigue, diarrhoea, infections, nausea, decreased appetite, anaemia, dysgeusia, pneumonitis, weight decreased, peripheral oedema, asthenia, pruritus, epistaxis, hyperglycaemia, hypercholesterolaemia, headache, and vomiting.
The most frequent Grade 3-4 adverse reactions (incidence ≥1/100 to <1/10) were stomatitis, anaemia, hyperglycaemia, fatigue, infections, pneumonitis, diarrhoea, asthenia, thrombocytopenia, neutropenia, dyspnoea, proteinuria, lymphopenia, hypophosphataemia, rash, and hypertension. The grades follow CTCAE Version 3.0.
Tabulated list of adverse reactions
Table 3 presents the frequency category of adverse reactions reported in the pooled analysis considered for the safety pooling. Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 3 Adverse reactions reported in clinical studies
Description of selected adverse reactions
In clinical studies and post-marketing spontaneous reports, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcome. Reactivation of infection is an expected event during periods of immunosuppression.
In clinical studies and post-marketing spontaneous reports, everolimus has been associated with renal failure events (including fatal outcome) and proteinuria. Monitoring of renal function is recommended (see section 4.4).
In clinical studies and post-marketing spontaneous reports, everolimus has been associated with cases of amenorrhoea (secondary amenorrhoea and other menstrual irregularities).
Elderly patients
In the safety pooling, 36% of the Afinitor-treated patients were ≥65 years of age. The number of patients with an adverse reaction leading to discontinuation of the medicinal product was higher in patients ≥65 years of age (19% vs. 12%). The most common adverse reactions leading to discontinuation were pneumonitis, stomatitis, fatigue and dyspnoea.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been given with acceptable acute tolerability. General supportive measures should be initiated in all cases of overdose.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, protein kinase inhibitors, ATC code: L01XE10
Mechanism of action
Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key serine-threonine kinase, the activity of which is known to be upregulated in a number of human cancers. Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits mTOR complex-1 (mTORC1) activity. Inhibition of the mTORC1 signalling pathway interferes with the translation and synthesis of proteins by reducing the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4EBP-1) that regulate proteins involved in the cell cycle, angiogenesis and glycolysis. S6K1is thought to phosphorylate the activation function domain 1 of the oestrogen receptor, which is responsible for ligand-independent receptor activation. Everolimus reduces levels of vascular endothelial growth factor (VEGF), which potentiates tumour angiogenic processes. Everolimus is a potent inhibitor of the growth and proliferation of tumour cells, endothelial cells, fibroblasts and blood-vessel-associated smooth muscle cells and has been shown to reduce glycolysis in solid tumours in vitro and in vivo.
Clinical efficacy and safety
Hormone receptor-positive advanced breast cancer
BOLERO-2 (study CRAD001Y2301), a randomised, double-blind, multicentre phase III study of Afinitor + exemestane versus placebo + exemestane, was conducted in postmenopausal women with oestrogen receptor-positive, HER2/neu negative advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole. Randomisation was stratified by documented sensitivity to prior hormonal therapy and by the presence of visceral metastasis. Sensitivity to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial response [PR], stable disease ≥24 weeks) from at least one prior hormonal therapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence.
The primary endpoint for the study was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors), based on the investigator's assessment (local radiology). Supportive PFS analyses were based on an independent central radiology review.
Secondary endpoints included overall survival (OS), objective response rate, clinical benefit rate, safety, change in quality of life (QoL) and time to ECOG PS (Eastern Cooperative Oncology Group performance status) deterioration.
A total of 724 patients were randomised in a 2:1 ratio to the combination everolimus (10 mg daily) + exemestane (25 mg daily) (n=485) or to the placebo + exemestane arm (25 mg daily) (n=239). The median duration of treatment was 29.5 weeks (range 1.0-123.3 weeks) for patients receiving everolimus + exemestane and 14.1 weeks (range 1.0-101.0 weeks) for the placebo + exemestane group.
The efficacy results were obtained from the final PFS analysis (see Table 4 and Figure 1). Patients in the placebo + exemestane arm did not cross over to everolimus at the time of progression.
Table 4 BOLERO-2 efficacy results
a Plus exemestane
b Objective response rate = proportion of patients with complete or partial response
c Clinical benefit rate = proportion of patients with complete or partial response or stable disease ≥24 weeks
d Not applicable
e p value is obtained from the exact Cochran-Mantel-Haenszel test using a stratified version of the Cochran-Armitage permutation test.
OS data are not mature at the time of the interim analysis and no statistically significant treatment-related difference in OS was noted [HR=0.77 (95% CI: 0.57, 1.04)].
Figure 1 BOLERO-2 Kaplan-Meier progression-free survival curves (investigator radiological review)
The estimated PFS treatment effect was supported by planned subgroup analysis of PFS per investigator assessment. For all analysed subgroups (age, sensitivity to prior hormonal therapy, number of organs involved, status of bone-only lesions at baseline and presence of visceral metastasis, and across major demographic and prognostic subgroups) a positive treatment effect was seen with everolimus + exemestane with an estimated hazard ratio versus placebo + exemestane ranging from 0.25 to 0.60.
No differences in the time to ≥5% deterioration in the global and functional domain scores of QLQ-C30 were observed in the two arms.
Advanced neuroendocrine tumours of pancreatic origin (pNET)
RADIANT-3 (study CRAD001C2324), a phase III, multicentre, randomised, double-blind study of Afinitor plus best supportive care (BSC) versus placebo plus BSC in patients with advanced pNET, demonstrated a statistically significant clinical benefit of Afinitor over placebo by a 2.4-fold prolongation of median progression-free-survival (PFS) (11.04 months versus 4.6 months), (HR 0.35; 95% CI: 0.27, 0.45; p<0.0001) (see Table 5 and Figure 2).
RADIANT-3 involved patients with well- and moderately-differentiated advanced pNET whose disease had progressed within the prior 12 months. Treatment with somatostatin analogues was allowed as part of BSC.
The primary endpoint for the study was PFS evaluated by RECIST (Response Evaluation Criteria in Solid Tumors). Following documented radiological progression, patients could be unblinded by the investigator. Those randomised to placebo were then able to receive open-label Afinitor.
Secondary endpoints included safety, objective response rate, response duration and overall survival (OS).
In total, 410 patients were randomised 1:1 to receive either Afinitor 10 mg/day (n=207) or placebo (n=203). Demographics were well balanced (median age 58 years, 55% male, 78.5% Caucasian). Fifty-eight percent of the patients in both arms received prior systemic therapy. The median duration of blinded study treatment was 37.3 weeks (range 1.1-129.9 weeks) for patients receiving everolimus and 16.1 weeks (range 0.4-146.0 weeks) for those receiving placebo.
Table 5 RADIANT-3 – Progression-free survival results
Figure 2 RADIANT-3 – KaplanMeier progression-free survival curves (investigator radiological review)
Following disease progression 172 of the 203 patients (84.7%) initially randomised to placebo crossed over to open-label Afinitor. The overall survival results show no statistically significant difference in OS (HR=0.89 [95% CI: 0.64, 1.23]).
Advanced renal cell carcinoma
RECORD-1 (study CRAD001C2240), a phase III, international, multicentre, randomised, double-blind study comparing everolimus 10 mg/day and placebo, both in conjunction with best supportive care, was conducted in patients with metastatic renal cell carcinoma whose disease had progressed on or after treatment with VEGFR-TKI (vascular endothelial growth factor receptor tyrosine kinase inhibitor) therapy (sunitinib, sorafenib, or both sunitinib and sorafenib). Prior therapy with bevacizumab and interferon-α was also permitted. Patients were stratified according to Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic score (favourable- vs. intermediate- vs. poor-risk groups) and prior anticancer therapy (1 vs. 2 prior VEGFR-TKIs).
Progression-free survival, documented using RECIST (Response Evaluation Criteria in Solid Tumours) and assessed via a blinded, independent central review, was the primary endpoint. Secondary endpoints included safety, objective tumour response rate, overall survival, disease-related symptoms, and quality of life. After documented radiological progression, patients could be unblinded by the investigator: those randomised to placebo were then able to receive open-label everolimus 10 mg/day. The Independent Data Monitoring Committee recommended termination of this trial at the time of the second interim analysis as the primary endpoint had been met.
In total, 416 patients were randomised 2:1 to receive Afinitor (n=277) or placebo (n=139). Demographics were well balanced (pooled median age [61 years; range 27-85], 78% male, 88% Caucasian, number of prior VEGFR-TKI therapies [1-74%, 2-26%]). The median duration of blinded study treatment was 141 days (range 19-451 days) for patients receiving everolimus and 60 days (range 21-295 days) for those receiving placebo.
Afinitor was superior to placebo for the primary endpoint of progression-free survival, with a statistically significant 67% reduction in the risk of progression or death (see Table 6 and Figure 3).
Table 6 RECORD-1 – Progression-free survival results
Figure 3 RECORD-1 – KaplanMeier progression-free survival curves (independent central review)
Six-month PFS rates were 36% for Afinitor therapy compared with 9% for placebo.
Confirmed objective tumour responses were observed in 5 patients (2%) receiving Afinitor, while none were observed in patients receiving placebo. Therefore, the progression-free survival advantage primarily reflects the population with disease stabilisation (corresponding to 67% of the Afinitor treatment group).
No statistically significant treatment-related difference in overall survival was noted (hazard ratio 0.87; confidence interval: 0.65-1.17; p=0.177). Crossover to open-label Afinitor following disease progression for patients allocated to placebo confounded the detection of any treatment-related difference in overall survival.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Afinitor in all subsets of the paediatric population in neuroendocrine tumours of pancreatic origin and in renal cell carcinoma (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
 Absorption
In patients with advanced solid tumours, peak everolimus concentrations (Cmax) are reached at a median time of 1 hour after daily administration of 5 and 10 mg everolimus under fasting conditions or with a light fat-free snack. Cmax is dose-proportional between 5 and 10 mg. Everolimus is a substrate and moderate inhibitor of PgP.
Food effect
In healthy subjects, high fat meals reduced systemic exposure to everolimus 10 mg (as measured by AUC) by 22% and the peak plasma concentration Cmax by 54%. Light fat meals reduced AUC by 32% and Cmax by 42%. Food, however, had no apparent effect on the post absorption phase concentration-time profile.
Distribution
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5,000 ng/ml, is 17% to 73%. Approximately 20% of the everolimus concentration in whole blood is confined to plasma in cancer patients given everolimus 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. In patients with advanced solid tumours, Vd was 191 l for the apparent central compartment and 517 l for the apparent peripheral compartment.
Biotransformation
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100 times less activity than everolimus itself. Hence, everolimus is considered to contribute the majority of the overall pharmacological activity.
Elimination
Mean oral clearance (CL/F) of everolimus after 10 mg daily dose in patients with advanced solid tumours was 24.5 l/h. The mean elimination half-life of everolimus is approximately 30 hours.
No specific excretion studies have been undertaken in cancer patients; however, data are available from the studies in transplant patients. Following the administration of a single dose of radiolabelled everolimus in conjunction with ciclosporin, 80% of the radioactivity was recovered from the faeces, while 5% was excreted in the urine. The parent substance was not detected in urine or faeces.
Steady-state pharmacokinetics
After administration of everolimus in patients with advanced solid tumours, steady-state AUC0- was dose-proportional over the range of 5 to 10 mg daily dose. Steady-state was achieved within two weeks. Cmax is dose-proportional between 5 and 10 mg. tmax occurs at 1 to 2 hours post-dose. There was a significant correlation between AUC0- and pre-dose trough concentration at steady-state.
Special populations
Hepatic impairment
The safety, tolerability and pharmacokinetics of everolimus were evaluated in two single oral dose studies of Afinitor tablets in 8 and 34 subjects with impaired hepatic function relative to subjects with normal hepatic function.
In the first study, the average AUC of everolimus in 8 subjects with moderate hepatic impairment (Child-Pugh B) was twice that found in 8 subjects with normal hepatic function.
In the second study of 34 subjects with different impaired hepatic function compared to normal subjects, there was a 1.6-fold, 3.3-fold and 3.6-fold increase in exposure (i.e. AUC0-inf) for subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively.
Simulations of multiple dose pharmacokinetics support the dosing recommendations in subjects with hepatic impairment based on their Child-Pugh status.
Based on the results of the two studies, dose adjustment is recommended for patients with hepatic impairment (see sections 4.2 and 4.4).
Renal impairment
In a population pharmacokinetic analysis of 170 patients with advanced solid tumours, no significant influence of creatinine clearance (25-178 ml/min) was detected on CL/F of everolimus. Post-transplant renal impairment (creatinine clearance range 11-107 ml/min) did not affect the pharmacokinetics of everolimus in transplant patients.
Elderly patients
In a population pharmacokinetic evaluation in cancer patients, no significant influence of age (27-85 years) on oral clearance of everolimus was detected.
Ethnicity
Oral clearance (CL/F) is similar in Japanese and Caucasian cancer patients with similar liver functions. Based on analysis of population pharmacokinetics, CL/F is on average 20% higher in black transplant patients.
5.3 Preclinical safety data
The preclinical safety profile of everolimus was assessed in mice, rats, minipigs, monkeys and rabbits. The major target organs were male and female reproductive systems (testicular tubular degeneration, reduced sperm content in epididymides and uterine atrophy) in several species; lungs (increased alveolar macrophages) in rats and mice; pancreas (degranulation and vacuolation of exocrine cells in monkeys and minipigs, respectively, and degeneration of islet cells in monkeys), and eyes (lenticular anterior suture line opacities) in rats only. Minor kidney changes were seen in the rat (exacerbation of age-related lipofuscin in tubular epithelium, increases in hydronephrosis) and mouse (exacerbation of background lesions). There was no indication of kidney toxicity in monkeys or minipigs.
Everolimus appeared to spontaneously exacerbate background diseases (chronic myocarditis in rats, coxsackie virus infection of plasma and heart in monkeys, coccidian infestation of the gastrointestinal tract in minipigs, skin lesions in mice and monkeys). These findings were generally observed at systemic exposure levels within the range of therapeutic exposure or above, with the exception of the findings in rats, which occurred below therapeutic exposure due to a high tissue distribution.
In a male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm motility, sperm head count, and plasma testosterone levels were diminished at 5 mg/kg which caused a reduction in male fertility. There was evidence of reversibility.
In animal reproductive studies female fertility was not affected. However, oral doses of everolimus in female rats at ≥0.1 mg/kg (approximately 4% of the AUC0-24h in patients receiving the 10 mg daily dose) resulted in increases in pre-implantation loss.
Everolimus crossed the placenta and was toxic to the foetus. In rats, everolimus caused embryo/ foetotoxicity at systemic exposure below the therapeutic level. This was manifested as mortality and reduced foetal weight. The incidence of skeletal variations and malformations (e.g. sternal cleft) was increased at 0.3 and 0.9 mg/kg. In rabbits, embryotoxicity was evident in an increase in late resorptions.
Genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of clastogenic or mutagenic activity. Administration of everolimus for up to 2 years did not indicate any oncogenic potential in mice and rats up to the highest doses, corresponding respectively to 3.9 and 0.2 times the estimated clinical exposure.
6. Pharmaceutical particulars
6.1 List of excipients
 Butylated hydroxytoluene (E321)
Magnesium stearate
Lactose monohydrate
Hypromellose
Crospovidone type A
Lactose anhydrous
6.2 Incompatibilities
 Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 25°C.
Store in the original package in order to protect from light and moisture.
6.5 Nature and contents of container
Aluminium/polyamide/aluminium/PVC blister containing 10 tablets.
Packs containing 10 (5mg and 10mg tablets only), 30 or 90 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8. Marketing authorisation number(s)
Afinitor 2.5mg tablets:
EU/1/09/538/009
EU/1/09/538/010
Afinitor 5mg tablets:
EU/1/09/538/001
EU/1/09/538/003
EU/1/09/538/007
Afinitor 10mg tablets:
EU/1/09/538/004
EU/1/09/538/006
EU/1/09/538/008
9. Date of first authorisation/renewal of the authorisation
Date of authorisation: 03 August 2009
Date of latest renewal: 05 August 2014
10. Date of revision of the text
16 May 2014