Novartis Pharmaceuticals UK Ltd

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.

Carcinoid tumours

In a randomised, double‑blind, multi-centre trial in patients with carcinoid tumours, Afinitor plus depot octreotide (Sandostatin^® LAR^®) 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.

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; hence everolimus may affect the bioavailability of co-administered substances which are CYP3A4 and/or PgP substrates.

Co-administration of everolimus and depot octreotide increased octreotide C_min 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.

Women of childbearing potential

Women of childbearing potential must use an effective method of contraception while receiving everolimus.

Pregnancy

There are no or limited amount of data from the use of everolimus in pregnant women. Studies in animals have shown reproductive toxicity effects (see section 5.3).

Everolimus is not recommended during pregnancy and in women of childbearing potential not using contraception. Women of childbearing potential must use an effective method of contraception while receiving everolimus.

a) Summary of safety profile

Two randomised, double‑blind, placebo controlled pivotal phase III studies contribute to the safety profile. The respective exposure in the phase III studies was:

The data described below reflect exposure to everolimus in a randomised phase III study for the treatment of metastatic renal cell carcinoma and in further studies in cancer patients.

·                RADIANT-3 (CRAD001C2324): everolimus plus best supportive care in patients with advanced neuroendocrine tumours of pancreatic origin. In total, 63 (30.9%) patients were exposed to everolimus 10 mg/day for ≥52 weeks. The rates of adverse reactions resulting in permanent discontinuation were 13.7% and 2.0% for the everolimus and placebo treatment groups, respectively.

·                RECORD-1 (CRAD001C2240): everolimus plus best supportive care in patients with metastatic renal cell carcinoma. In the renal cell carcinoma study (everolimus, n=274; placebo, n=137), a total, of 165 patients were exposed to everolimus 10 mg/day for ≥4 months. The median age of patients was 61 years (range 27‑85). The median duration of blinded study treatment was 141 days (range 19‑451) for patients receiving Afinitor and 60 days (range 21‑295) for those receiving placebo. The rates of adverse reactions resulting in permanent discontinuation were 7% and 0% for the Afinitor everolimus and placebo treatment groups, respectively. Most adverse reactions were grade 1 or 2 in severity.

The most frequent grade 3‑4 adverse reactions (incidence ≥2% in at least one pivotal study) were anaemia, fatigue, diarrhoea, infections, stomatitis, hyperglycaemia, thrombocytopenia, lymphopenia, neutropenia, hypophosphataemia, hypercholesterolaemia, diabetes mellituslymphocytes decreased, glucose increased, haemoglobin decreased, phosphate decreased, cholesterol increased, infections, stomatitis, fatigue, and pneumonitis. The grades follow CTCAE Version 3.0.

b) Tabulated summary of adverse reactions

Table 2 shows the incidence of adverse reactions reported for patients receiving everolimus 10 mg/day in at least one of the pivotal studies. All terms included are based on the highest frequency reported in a pivotal study. Adverse reactions in Table 2 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 2       Adverse reactions

c) Description of selected adverse reactionsInformation from further clinical studies

In clinical studies, 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.

Adverse reactions of special interest

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).

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, Pprotein kinase inhibitors, ATC code: L01XE10

....as present........

Clinical efficacy and safety

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 3 and Figure 1).

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 3            RADIANT-3 – Progression-free survival results

Figure 1          RADIANT-3 – KaplanMeier progression-free survival curves (please refer to SmPC)

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), aA 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).

.....as present.....

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.

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).

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 4.33.9 and 0.2 times the estimated clinical exposure.

Any unused product or waste material should be disposed of in accordance with local requirements.No special requirements.

Special populations

Paediatric patients (<18 years)

Afinitor is not recommended for use in children and adolescents due to lack of data on safety and efficacy.Paediatric population

The safety and efficacy of Afinitor in children aged 0 to 18 years have not been established. No data are available.

Infections

Afinitor has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoan infections, especially including infections with opportunistic pathogens (see section 4.8). Localised and systemic infections, including pneumonia, other bacterial infections, and 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 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, and institute appropriate treatment promptly and consider interruption or discontinuation of Afinitor.

Pre-existing infections should be treated appropriately and have resolved fully before starting treatment with Afinitor. If a diagnosis of invasive systemic fungal infection is made, Afinitor treatment should be promptly and permanently discontinued and the patient treated with appropriate antifungal therapy.

Blood glucose and lipids

Hyperglycaemia, hyperlipidaemia and hypertrigylceridaemia have been reported in clinical trials (see section 4.8). The majority of cases of hyperglycaemia occurred in patients who had an abnormal fasting glucose level before taking Afinitor. Monitoring of fasting serum glucose is recommended prior to the start of Afinitor therapy and periodically thereafter. When possible optimal glycaemic control should be achieved before starting a patient on Afinitor.

In clinical studies, 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.

Clinical efficacy and safety

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 renal cell carcinoma (see section 4.2 for information on paediatric use).