Summary Basis of Decision for Afinitor

Renal cell carcinoma is an adenocarcinoma of the kidney that originates in the renal cortex and accounts for 85-90% of all kidney tumours. Chemotherapy and radiation therapy demonstrate little efficacy in advanced disease, and the five-year survival rate is low, ranging from 5-10%.

Renal cell carcinoma is linked to different environmental factors and in some cases is due to genetic predispositions (familial forms). The strongest environmental factor remains cigarette smoking. Loss of function of the tumour-suppressor gene product Von Hippel Lindau (VHL) is the most common familial form of the disease. The increased expression of VEGF in patients with VHL syndrome has led to the supposition that angiogenesis is a key factor in RCC. This resulted in the development and market authorization of the anti-neoplastic agents sorafenib and sunitinib that block angiogenesis by inhibiting the function of the VEGF receptor (VEGFr).

Despite recent progress in treating RCC, most patients progress at some point after treatment with the VEGFr TKI therapies sorafenib and sunitinib. Everolimus is a signal transduction inhibitor targeting mTOR, or more specifically, mTORC1, a key serine-threonine kinase that plays a central role in the regulation of cell growth, proliferation and survival. Consistent with the central regulatory role of mTORC1, its inhibition by everolimus has been shown to reduce cell proliferation, glycolysis and angiogenesis in solid tumours in vivo, both through direct anti-tumour cell activity and inhibition of the tumour stromal compartment.

3.3.1 Human Pharmacology

Everolimus has been approved as an immunosuppressive drug for use in the transplant setting in many countries in Europe and elsewhere (but not in Canada or the United States of America) under the name Certican^®.

Clinical studies supporting the oncological indication were used in the evaluation of Afinitor^*; however, studies in support of the transplant indication were also considered.

3.3.2 Pharmacodynamics

The proposed 10 mg dose for the treatment of patients with RCC was determined in part from pre-clinical modelling studies, clinical pharmacology reports, and from published literature results. The maximum tolerated dose (MTD) was derived from kidney transplant patients receiving a 5 mg/day-dose together with Neoral^® (cyclosporine A). Cyclosporine A increases everolimus exposure by 2- to 3-fold therefore it was proposed that a 10 to 15 mg dose in an oncological setting would be equivalent (in the absence of a CYP3A4 inhibitor). The dose-limiting toxicity for this study was thrombocytopaenia (three out of seven patients receiving 10 mg everolimus plus Neoral^®). Results from the Phase I studies suggested that a daily dose of ≥10 mg everolimus is required to achieve inhibition of the phosphorylation of S6K1, 4E-BP1, and eIF-4G in the majority of patients.

In quiescent cells, mTOR activity is reduced and the eukaryotic initiation factor 4G (eIF-4G) protein is bound by 4E-BP1 (in its non-phosphorylated state). In cancer cells, active signalling through mTOR induces the phosphorylation of 4E-BP1, which results in the release of eIF-4G, in turn initiating CAP-dependent translation resulting in protein synthesis. In addition to its classic role in the phosphorylation of S6-kinase, mTOR has also been implicated in the direct phosphorylation of eIF-4G.

A study was conducted in adult patients with advanced solid cancers that were refractory or unsuitable for existing standard therapies. Patients who participated in the study had to be able and willing to undergo comparative tumour biopsy. One of the primary objectives of the study was to assess changes in the molecular markers within the tumours known to be most directly influenced by mTOR. Analysis of these markers was used as a means to determine the ability of Afinitor^* to inhibit mTOR and its downstream effectors. The results of this study demonstrated a change in the phosphorylation status of S6, eIF-4G, 4E-BP1, and AKT in tumour and skin biopsies before and after Afinitor^* treatment with the indicated doses and scheduling of the drug. In addition, the 10 mg dose was marginally better at inhibiting eIF-4G phosphorylation within the tumour; however, the 5 mg dose was nearly as effective as the 10 mg dose, therefore a dose reduction may still have a beneficial effect.

3.3.3 Pharmacokinetics

Absorption

In patients with advanced solid tumours, peak plasma everolimus concentrations (C_max) were reached 1 to 2 hours following oral administration of a 5 to 70 mg dose under fasting conditions or with a light fat-free snack. The C_max was dose-proportional between 5 and 10 mg in daily and weekly regimens. At doses of ≥20 mg/week, the increase in C_max was less than dose-proportional; however, the area under the concentration time curve (AUC) showed dose-proportionality within the 5 to 70 mg dose range.

The bioavailability of everolimus is estimated to be 11% determined as the amount of remaining radioactivity of the administered radio-labelled everolimus measured at C_max. Steady-state was achieved within two weeks with the daily dosing regimen. There was a significant correlation between AUC_0-τ (the area under the curve in a dosing interval) and pre-dose trough concentration at steady-state on the daily regimen.

In healthy subjects taking 1 mg everolimus tablets, a high-fat meal reduced C_max and AUC by 60% and 16% respectively. No data are currently available with Afinitor^* 5 and 10 mg tablets, which have a quantitatively different formulation from the 1 mg everolimus tablets used in this study.

Distribution

The blood-to-plasma ratio of everolimus, which is concentration dependent within the range of 5 to 5,000 ng/mL was 17% to 73%. The amount of everolimus confined to the plasma was approximately 20% at blood concentrations observed in cancer patients given Afinitor^* 10 mg/day. Plasma protein binding was approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.

Metabolism

Everolimus is metabolized in the liver and is a substrate of CYP3A4 and p-glycoprotein (PgP). The major metabolites of everolimus in the blood are hydroxylation derivatives with the exception of one metabolite that was modified by the addition of a phosphatidylcholine group. All identified metabolites were >100-times less potent than everolimus in a mixed lymphocyte reaction suggesting that the parent compound is the major biologically active compound.

Excretion

Following the administration of a single dose of radio-labelled everolimus in conjunction with cyclosporine, only 5% of the total radioactivity was detected in urine whereas 80% was detected in the faeces over 10 days. The results confirm non-clinical findings and suggest that the major route of excretion is by the liver. No parent compound could be detected in either the faeces or urine.

Special Populations

The PK evaluations of everolimus in healthy subjects versus (vs.) those with moderately impaired hepatic function (Child-Pugh Class B) further demonstrate the important role of the liver in clearance of the drug. The apparent clearance of everolimus was reduced by half in individuals with moderate hepatic impairment compared with healthy, demographically-matched subjects. Dose reductions to 5 mg would be warranted in this population. No studies of patients with severe hepatic impairment (Child-Pugh Class C) have been performed. Treatment of this population should be avoided pending such investigations.

3.3.4 Clinical Efficacy

The efficacy for Afinitor^* was primarily assessed in the pivotal study RECORD-1, a Phase III, prospective, randomized, double-blind, multicentre, placebo-controlled, parallel-group study. RECORD-1 was designed to evaluate the efficacy and safety of Afinitor^* in patients with mRCC who failed initial treatment with either of the VEGFr TKIs sunitinib and/or sorafenib. Afinitor^* fulfills an unmet medical need for these patients as no other treatment options have proven effective for this population. RECORD-1 is the only Phase III study that has addressed the efficacy of Afinitor^* in patients with mRCC.

Patients who met the study criteria were randomized 2:1 to receive 10 mg/day Afinitor^* (n = 277) or a matching placebo (n = 139). Prior to randomization, patients were stratified according to Memorial Sloan Kettering Cancer Centre (MSKCC) prognostic score class of good, intermediate or poor, as well as by treatment with either one or two of the VEGFr TKI therapies.

The primary objective of the study was to compare progression-free survival (PFS) in patients who received Afinitor^* plus best supportive care (BSC) vs. patients who received placebo plus BSC. Secondary objectives included an assessment of benefits in overall survival (OS), objective response rates (ORR), and patient reported outcomes (disease related symptoms and quality of life [QoL]).

The study design permitted immediate cross-over from the placebo group to the treatment group upon detection of progressive disease (PD) as determined by the investigator (who became un-blinded upon progression). The primary analysis of radiological assessments was based on the Response Evaluation Criteria in Solid Tumours (RECIST) and was conducted by an independent (central) review committee (IRC) who remained blinded. RECIST is a set of criteria used to measure tumour response using X-ray, computed tomography (CT), and magnetic resonance imaging (MRI).

The results of the primary PFS data were robust. The most up-to-date analyses provided by the sponsor demonstrated that patients who were administered Afinitor^* had a median PFS of 4.9 months compared to 1.9 months for those who received placebo [hazard ratio (HR): 0.33, 95% confidence interval (CI): 0.25 to 0.43, p < 0.0001].

An independent data monitoring committee (IDMC) recommended stopping the study at the second interim analysis because the pre-specified PFS endpoint had been met. Despite the PFS results, no benefit in OS was demonstrated. This may have occurred, in part, because the study protocol allowed patients in the placebo group with PD to cross-over immediately to the treatment group, which when combined with very early progression, resulted in confounding of the OS results. By the October 15^th, 2007 cut-off, 79 of 98 individuals in the placebo group who had PD had accepted Afinitor^* treatment. Of these 79 patients, 60 had PD within the first 8 weeks of randomization.

The Oncology Division (OD), Health Canada, felt that immediate cross-over at progression might not have been necessary despite ethical and feasibility considerations. This study was conducted to assess a second-/third-line therapy and no other treatments were available. The placebo group was therefore not necessarily disadvantaged as the effectiveness of Afinitor^* had not been established at enrolment of this first and only Phase III study.

No statistically significant differences between the Afinitor^* and placebo groups were observed in any of the pre-specified secondary efficacy endpoints. Only five patients (1.8%) in the Afinitor^* group experienced a partial response as measured by RECIST criteria. Also, patients who received Afinitor^* did not exhibit an improved QoL compared to patients who received placebo.

The superiority of Afinitor^* was demonstrated in the time to definitive deterioration of Karnofsky performance status (KPS) score relative to placebo. The KPS scale classifies patients according to their functional impairment. The time to deterioration was prolonged for patients receiving Afinitor^* therapy (HR: 0.66, 95% CI: 0.49 to 0.90); however, the KPS was not included as a pre-planned secondary efficacy endpoint by the sponsor. In addition, some potential for bias exists in these results as the investigator may not have been truly blinded due to the presence of rash and other adverse events (AEs) which were more commonly presented in the Afinitor^* group. This may have influenced the objectivity of the assessment. Despite this potential bias, the evidence shows a modest improvement in performance status in the Afinitor^* group.

Overall, the results of the pivotal study demonstrated a PFS benefit for patients receiving Afinitor^* over placebo. No statistically significant differences in response rates or quality of life were demonstrated between the Afinitor^* and placebo arms. Crossover to open-label Afinitor^* following disease progression for patients allocated to placebo may have confounded the ability to detect treatment-related differences in overall survival. Despite the failure to show a statistically significant improvement in OS, Afinitor^* is likely to provide a clinically meaningful benefit to patients whose disease has progressed after initial treatment with sunitinib and/or sorafenib. A gain of 3 months in PFS together with a compelling hazard ratio (0.33), could likely result in an OS gain for this mRCC patient population.

3.3.5 Clinical Safety

The clinical safety of Afinitor^* was primarily assessed in the pivotal study RECORD-1 that is described in section 3.3.4 Clinical Efficacy.

The most up-to-date safety information provided by the sponsor (in the 90-day safety update report) reported that 13.9% of patients in the Afinitor^* group discontinued due to an AE.

Mucositis (including stomatitis and aphthous stomatitis) was the most common treatment-emergent AE associated with Afinitor^*. In general, these cases were manageable with minimal treatment and in some cases dose interruptions. Rarely was discontinuation from study medication required.

Other notable AEs that occurred more frequently in Afinitor^*-treated patients included cardiovascular disorders (tachycardia and congestive heart failure, >1% of patients), respiratory disorders (pleural effusion, 7% of patients), and gastrointestinal disorders (abdominal pain, dry mouth, and haemorrhoids). Rash and similar events were very common and occurred in 35% of patients; however, no discontinuations resulted from these AEs.

Pneumonitis and Infections

Pneumonitis and infections were the most clinically significant treatment-emergent AEs (TEAEs), even though these were not the most commonly experienced AEs. Two deaths resulting from underlying infections were suspected to be related to Afinitor^*. At the October 15^th, 2007 cut-off, one Afinitor^*-related death was the result of overwhelming candidal sepsis, complicated by acute respiratory failure. A second death which resulted from sepsis (on Day 112) was reported at the February 25^th, 2008 cut-off date. A third patient died from an event attributed to underlying renal cancer; however, the individual also had Grade 3 pneumonitis that was suspected to be caused by Afinitor^*. This event may have contributed to the fatality.

Both pneumonitis and infections must be carefully monitored during the course of treatment with Afinitor^*. A Serious Warnings and Precautions box has been included in the Product Monograph highlighting pneumonitis and infections as potentially serious side effects of Afinitor^*.

Thrombocytopaenia and Anaemia

Afinitor^* was initially developed as an immunosuppressive drug for use in the transplant setting. During development, it was determined that a daily 5 mg dose of Afinitor^* when taken with cyclosporine A produced the same systemic exposure to the drug as a daily 10 mg dose of Afinitor^* taken alone; however, a 10 mg dose taken with cyclosporine A was associated with three severe cases of thrombocytopaenia in seven patients (dose-limiting toxicity).

For the current NDS, thrombocytopaenia occurred more frequently in patients receiving Afinitor^* in both the pivotal and supportive studies. Based on the totality of the data, 10 mg is the near-maximum tolerated dose and thrombocytopaenia is a class effect of mTOR inhibitor drugs. As thrombocytopaenia is an important AE associated with Afinitor^*, platelet counts need to be monitored closely throughout the course of treatment.

Anaemia was also common throughout the pivotal and supportive studies and in the pivotal study at least two-thirds of the cases were suspected to be directly related to Afinitor^* treatment. Haemoglobin levels should be routinely measured and blood transfusions will be required for a subset of the patient population.

Hyperlipidaemia and Hyperglycaemia

Afinitor^* has been shown to increase both circulating lipids (cholesterol and triglycerides) and glucose concentrations. Baseline measurements should be performed as high initial lipid and glucose concentrations were often found to be associated with exacerbation of these levels. Type 2 new-onset diabetes occurred with the use of Afinitor^*, although rarely. Hyperlipidaemia can be managed with diet, statins, and fibrates as necessary. Dietary changes can usually alleviate hyperglycaemia with or without additional therapy such as metformin and possibly insulin.

Renal Considerations

Although renal failure was uncommon, the frequency increased in the 90-day safety update in the Afinitor^* group indicating that it could become more prevalent with chronic use. Ten percent of the patients in the Afinitor^* group experienced notable increases in serum creatinine (usually Grade 1 or 2). No increases were reported in the placebo group. Serum creatinine levels should be monitored throughout treatment.

No studies have been carried out in patients with impaired renal function. However, given that the drug is primarily metabolized by the liver, no exclusions with this population are listed.

Hepatic Considerations

Afinitor^* is primarily metabolized by the liver and is a primary substrate for CYP3A4. No studies have been performed in patients with severe hepatic impairment (Child-Pugh Class C) and treatment is not recommended for this patient population. Furthermore, strong CYP3A4 inhibitors should not be taken with this medication. A dose reduction to 5 mg/day or every second day is recommended for patients that require co-medication with moderate CYP3A4 inhibitors. By contrast, although a decrease in Afinitor^* systemic exposure is expected with CYP3A4 inducers, no recommendations have been made to increase the Afinitor^* dose as no formal studies have been carried out in this setting.

Summary

Overall, the safety features of Afinitor^* appear acceptable for the indicated population. Afinitor^* has important safety issues highlighting the need for this oral medication to be prescribed by a qualified healthcare professional who is experienced in the use of anti-neoplastic therapy. The two most clinically relevant adverse drug reactions (ADRs) are pneumonitis (interstitial lung disease) and infections. Fatalities have occurred during the pivotal study with this medication due to these ADRs.

Careful monitoring of the symptoms mentioned above and appropriate use of co-medications, dose interruptions, and reductions should make the AEs manageable for the majority of patients taking this drug. Severe AEs may result in discontinuations; however, the effects are usually reversible. A few drug-related deaths have occurred in the clinical studies.

3.3.6 Additional Issues

A risk management plan (RMP) was submitted with this NDS which focuses primarily on subjects excluded from the pivotal study and potential risks to these patients if treated with Afinitor^*. Hepatitis B reactivation has occurred with Afinitor^* in clinical experience with the drug. Patients with active hepatitis were excluded from the pivotal study and may be more susceptible to serious illness if treated with Afinitor^*.

As well, the sponsor will be requested to provide to Health Canada the final per-protocol OS analysis of the RECORD-1 study which was to be conducted two years after randomization of the last patient as a post-marketing commitment.