Summary Basis of Decision for Inlyta ™

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.

Product type:


Axitinib, 1 mg and 5 mg, Tablet, Oral

Pfizer Canada Inc.

Submission control no: 144404

Date issued: 2012-11-06


Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.

Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.

The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).

For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.

Other Policies and Guidance

Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.

1 Product and submission information

Brand name:



Pfizer Canada Inc.

Medicinal ingredient:


International non-proprietary Name:



mg and 5 mg

Dosage form:


Route of administration:


Drug identification number(DIN):

  • 02389630 - 1 mg
  • 02389649 - 5 mg

Therapeutic Classification:

Kinase inhibitor, Anti-tumour agent

Non-medicinal ingredients:

Microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate and Opadry® II Red. The Opadry® II Red film coating contains lactose monohydrate, HPMC 2910/Hypromellose 15cP, titanium dioxide, triacetin (glycerol triacetate), and red iron oxide.

Submission type and control no:

New Drug Submission, Control Number: 144404

Date of Submission:


Date of authorization:

2 Notice of decision

On July 12, 2012, Health Canada issued a Notice of Compliance to Pfizer Products Inc., for the drug product Inlyta.

Inlyta contains the medicinal ingredient axitinib which is a kinase inhibitor and an anti-tumour agent.

Inlyta is indicated for the treatment of patients with metastatic renal cell carcinoma (RCC) of clear cell histology after failure of prior systemic therapy with either a cytokine or the vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI), sunitinib. Inlyta should not be administered to children under 18. Axitinib inhibits tyrosine kinase VEGFR-1, VEGFR-2, and VEGFR-3. These receptors are implicated in the pathologic angiogenesis, tumour growth, and metastatic progression of cancer.

The market authorization was based on quality, non-clinical, and clinical information submitted. The clinical efficacy and safety of Inlyta were evaluated primarily in one pivotal, multicentre, randomized, open-label, Phase III study in 723 patients with metastatic RCC whose disease had progressed following failure of one prior systemic first-line therapy consisting of sunitinib-, bevacizumab-, temsirolimus-, or cytokine-containing regimens. Patients were randomized to receive Inlyta or sorafenib. Of the 723 patients enrolled in this study, most patients had received 1 prior sunitinib-based therapy or 1 prior cytokine-based therapy (interleukin-2 or interferon-alpha). The primary endpoint was progression-free survival (PFS) as assessed by using an independent central review committee consisting of blinded radiologists.

There was a statistically significant advantage for Inlyta over sorafenib for the primary endpoint of PFS. The overall median PFS increased by 2 months in patients treated with Inlyta as compared to those treated with sorafenib (6.7 months - Inlyta versus 4.7 months - sorafenib). The difference in median PFS for patients previously treated with a cytokine was 5.6 months whereas the difference in patients previously treated with sunitinib was 1.4 months. The secondary endpoints of overall survival and quality of life were not significantly different in patients treated with Inlyta compared to those treated with sorafenib. Clinically significant adverse events associated with Inlyta included: hypertension and hypertensive crisis; arterial thromboembolism, including deaths; venous thromboembolism, including deaths; haemorrhage, including gastrointestinal, cerebral and respiratory tract; gastrointestinal perforation, including death and gastrointestinal fistulas; and reversible posterior leukoencephalopathy syndrome.

Inlyta (1 mg and 5 mg, axitinib) is presented as tablets. The recommended starting dose for Inlyta is 5 mg taken orally twice per day. Inlyta may be taken with or without food and should be swallowed whole with a glass of water. Dose increase or reduction is recommended based on individual safety and tolerability. Inlyta should be prescribed by a qualified healthcare professional who is experienced in the use of anti-neoplastic therapy. Dosing guidelines are available in the Product Monograph.

Inlyta is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Inlyta has not been studied in patients with severe hepatic impairment. Inlyta should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Inlyta are described in the Product Monograph.

Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Inlyta is favourable for the treatment of patients with metastatic RCC of clear cell histology after failure of prior systemic therapy with either a cytokine or the VEGFR-TKI, sunitinib.

3 Scientific and Regulatory Basis for Decision

3.1 Quality Basis for Decision

3.1.1 Drug Substance (Medicinal Ingredient)

General Information

Axitinib, the medicinal ingredient of Inlyta, is an oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. VEGFRs are implicated in pathologic angiogenesis, tumour growth, and metastatic progression of cancer.

Manufacturing Process and Process Controls

Axitinib is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:

  • The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
  • The drug substance specifications are found to be satisfactory. Impurity limits meet International Conference on Harmonisation (ICH) requirements.
  • The processing steps have been evaluated and the appropriate ranges for process parameters have been established.

The structure of axitinib has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH-established limits and/or were qualified from toxicological studies and therefore are considered to be acceptable.

Control of Drug Substance

Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of axitinib.

The drug substance packaging is considered acceptable.


Based on the long-term, real-time, and accelerated stability data submitted, the proposed shelf-life and storage conditions for the drug substance were supported and are considered to be satisfactory.

3.1.2 Drug Product

Description and Composition

Inlyta tablets are supplied as follows:

  • 1 mg tablet: red, film-coated, oval tablets debossed with "Pfizer" on one side and "1 XNB" on the other and containing 1 mg of axitinib.
  • 5 mg tablet: red, film-coated, triangular tablets debossed with "Pfizer" on one side and "5 XNB" on the other and containing 5 mg of axitinib.

Both tablets contain the following excipients: microcrystalline cellulose; lactose monohydrate; croscarmellose sodium; magnesium stearate; and Opadry II red. The Opadry II red film-coating contains lactose monohydrate; HPMC 2910/Hypromellose 15cP; titanium dioxide; triacetin (glycerol triacetate); and red iron oxide.

Inlyta tablets are packaged in a high density polyethylene (HDPE) bottle closure system with desiccant, or a unit dose aluminium foil/aluminium foil blister system.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of axitinib with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.

Pharmaceutical Development

Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.

Manufacturing Process and Process Controls

The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.

Control of Drug Product

Inlyta tablets are tested to verify that their identity, appearance, content uniformity, assay, dissolution, water content, hardness, disintegration, and levels of microbiological impurities, degradation products and drug-related impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits for individual and total degradation products are within acceptable limits.

The validation process is considered to be complete. Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.


Based on the real-time, long-term, and accelerated stability data submitted, the proposed shelf-life of 36 months is considered acceptable when Inlyta tablets, packaged in HDPE bottles with desiccant or aluminium foil/aluminium foil blisters, are stored at 25°C (excursions permitted to 15-30°C).

The compatibility of the drug product with the container closure systems was demonstrated through stability studies. The container closure systems met all validation test acceptance criteria.

3.1.3 Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production of Inlyta are considered suitable for the activities and products manufactured.

3.1.4 Adventitious Agents and Safety Evaluation

The lactose monohydrate used in the formulation is a milk derivative manufactured from mild sourced from healthy animals in the same condition as milk collected for human consumption, and no other ruminant materials, with the exception of calf rennet, are used in the manufacture. All other components used in the formulation are of vegetable or synthetic origin.

3.1.5 Conclusion

The Chemistry and Manufacturing information submitted for Inlyta has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.

3.2 Non-Clinical Basis for Decision

3.2.1 Pharmacodynamics

Axitinib is a selective inhibitor of VEGFR-1, 2 and 3. In the cell-based assays, axitinib inhibited the autophosphorylation of the VEGFRs at picomolar concentrations compared to weaker inhibitory activity (approximately 100-fold less potent) against the platelet-derived growth factor receptors (PDGFRs) alpha and beta and the cytokine receptor, KIT in broad kinase panels and cellular kinase pathway-based enzymatic assays where axitinib was most selective for VEGFR tyrosine kinases followed by PDGFRs. The two circulating human metabolites of axitinib, a sulfoxide and N-glucuronide, were inactive against VEGFRs, PDGFRs, KIT (cell-based assays), and other kinases (in biochemical assays). Axitinib blocked VEGF-stimulated endothelial cell (EC) survival, tubule formation, and induced EC apoptosis. Axitinib inhibited the phosphorylation of VEGF/VEGFR mediated endothelial nitric oxide synthase (eNOS) and Akt (a protein kinase that plays a key role in multiple cellular processes).

In vivo, axitinib treatment inhibited the phosphorylation of vascular VEGFR-2, decreased tumour vascular endothelial cell fenestration, microvessel density, and induced regression of existing vessels in the tumour. Axitinib exhibited single agent anti-tumour and anti-metastasis activity against human xenograft and mouse syngeneic models. Axitinib demonstrated efficacy in tumours that were resistant to bevacizumab treatment in a human colon carcinoma xenograft model.

The safety pharmacology studies suggest that exposure to axitinib may lead to decreases and increases in heart rate. Non-clinical results demonstrated elevated blood pressure and, to a lesser extent, decreased heart rate after repeat axitinib dosing. The axitinib-related increase in gastric emptying observed in the rat is of uncertain significance to humans. Axitinib had no effects on respiration.

3.2.2 Pharmacokinetics


Overall, the animal studies indicated that radiolabelled axitinib was rapidly absorbed. Absorption and first pass clearance in the mouse, rat, dog, and monkey translated to absolute oral bioavailability values of 16%, 31%, 59%, and 3%, respectively.


After intravenous (IV) administration, axitinib had a moderate to large volume of distribution. The volume at steady state (Vss) was 1.67, 1.17, and 0.80 L/kg in the mouse, dog, and monkey, respectively.

The unbound fraction of axitinib in plasma was 3.0%, 1.9%, 2.0%, and 0.5% in the mouse, rat, dog, and human, respectively.

At 1 hour following the oral administration of radiolabelled axitinib in mice, the highest amounts of radioactivity were present in the gall bladder, uveal tract, liver, and stomach mucosa. The lowest concentrations were in the spinal cord and brain. Moderate to low radioactivity was observed in all other tissues. Overall, the results indicated that radiolabelled axitinib was well distributed into tissues with the exception of the central nervous system (CNS) tissues protected by the blood brain barrier. From 4 to 48 hours, there was a rapid decline of radioactivity from blood and most tissues. Results also suggested that axitinib-derived radioactivity was very low, or not detectable, beyond 48 hours in most tissues and organs, with the exception of the pigmented uveal tract and small amounts in the liver and gall bladder.


In vitro and in vivo data indicate that axitinib is primarily metabolized by the liver.

Axitinib was predominantly metabolized by the cytochrome P450 (CYP) enzyme 3A4/5. Axitinib also forms glucuronides in human microsomes via uridine diphosphate-dependent glucuronosyl transferase (UGT) catalyzed by isoforms UGT1A1 and UGT1A4. In circulation, the major products in the mouse were parent drug, a sulfoxide metabolite, and an N-glucuronide, conjugate; in the dog, only the sulfoxide metabolite was detected. Pharmacological tests indicated these metabolites were essentially inactive when compared to axitinib.

When axitinib was evaluated for CYP inhibition in vitro, results suggest the potential for clinical interactions with substrates of CYP2C8 and CYP1A2. In vitro studies indicated that axitinib does not inhibit CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or UGT1A1. Axitinib did not induce activities of CYP1A2 and CYP3A4 in human hepatocytes.

Axitinib is a substrate for the efflux transporters P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2) and can inhibit P-gp in vitro.


The excretion of unchanged axitinib in mouse and dog urine was negligible. In faeces, the excretion of unchanged axitinib was <5% of the dose. The mouse and dog mass balance studies showed that axitinib was eliminated as metabolites mainly in the faeces and much less in the urine by 48 to 72 hours.

3.2.3 Toxicology

Single-Dose Toxicity

Axitinib was well-tolerated following single-dose administration in the mouse and dog at dosages up to 2,000 mg/kg. The maximum tolerated doses (MTD) for acute oral administration of axitinib in the mouse and dog are considered to be ≥2,000 mg/kg.

Repeat-Dose Toxicity

Axitinib tolerability in the repeat-dose studies showed an inverse correlation to dose and the duration of dosing. Clinical signs related to repeat-dosing of axitinib at high doses included thin appearance; hypoactivity; rough hair coat; and hunched posture in the mouse or dog; and were indicative of the poor clinical condition of the animals. Signs consistent with gastrointestinal toxicity were observed in the dog and included an increased frequency of abnormal faeces (discoloured, mucoid, liquid, or non-formed) and hyperemic oral mucosa with ulcerations that was sometimes accompanied by dehydration or excessive salivation.

In mouse and dog repeat-dose toxicity studies of up to 39 weeks in duration, there were four primary target organ systems. The gastrointestinal (faecal abnormalities; inflammation, ulceration, and necrosis of the tongue or oral mucosa; haemorrhage and inflammation in the stomach and intestines; fibrinoid necrosis of vessels in the stomach or intestines; hyperplasia of intestinal mucosa), haematopoietic (decreased reticulocyte counts or reticulocytosis; increases in mean corpuscular volume and mean corpuscular haemoglobin; erythroid bone marrow hypocellularity), musculoskeletal (thickening of the growth plate; incisor tooth odontopathy), and/or reproductive (bilateral atrophy or degeneration of the testes; decreased number of germinal cells; decrease or absence of corpora lutea; uterine atrophy) systems were the primary organ systems affected by axitinib administration, where the axitinib effect on vascular beds was also reflected. Reversibility of axitinib-related changes that were observed following 13 and 39 weeks of dosing was indicated by the notable decrease to absence of effect after a 4- and 8-week treatment-free recovery period, respectively.

The no-observed-adverse-effect-levels (NOAELs) for axitinib were <10 mg/kg/day in mice following 26 weeks of once daily oral administration; and 1 and 6 mg/kg/day, in male and female dogs, respectively, following 39 weeks of once daily oral administration.


Axitinib was tested using a series of genetic toxicology assays consisting of in vitro bacterial reverse mutation (Ames), human lymphocyte chromosome aberration, and in vivo mouse bone marrow micronucleus assays. Axitinib was not mutagenic or clastogenic in these assays. However, polyploidy was observed in human peripheral blood lymphocytes in vitro, and was consistent with indications of micronuclei formation through an aneugenic mechanism in an in vivo mouse micronucleus assay.


Carcinogenicity studies were not performed with axitinib.

Reproductive and Developmental Toxicity

In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and foetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose.

Axitinib has the potential to impair reproductive function and fertility in humans. Axitinib did not affect mating or fertility in male mice at any dose tested. However, reduced testicular weights, sperm density and count were noted at all doses. In female mice, reduced fertility and embryonic viability were observed at all doses tested.

The pups of pregnant mice exposed to axitinib had an increased occurrence of cleft palate and common variations in skeletal ossification at sub-therapeutic exposures.

3.2.4 Summary and Conclusion

The non-clinical studies for this drug submission are considered acceptable. Pharmacology studies attributed the anti-tumour activity of axitinib to its ability to inhibit VEGFR-2. Axitinib was demonstrated to be effective in blocking angiogenesis and tumour progression in experimental cancer models in mice.

The non-clinical pharmacology and toxicology studies were considered adequate to assess the safety profile of axitinib. The non-clinical risk/benefit assessment is considered acceptable and all risks are reflected in the appropriate sections of the Product Monograph.

3.3 Clinical basis for decision

The Canadian review of the clinical pharmacology, efficacy, and safety of Inlyta was based on a critical assessment of the Canadian data package with the foreign review completed by the United States Food and Drug Administration (FDA) as an added reference. The Canadian regulatory decision was based on the Canadian review.

The FDA approved United States Product Information and the European Union's centralized procedure European Medicines Agency (EMA), approved Summary of Product Characteristics were consulted during the finalization of the Inlyta Product Monograph.

3.3.1 Pharmacodynamics

In clinical studies, Inlyta (axitinib) increased VEGF, decreased plasma soluble VEGFR-2 and soluble VEGFR-3 but had negligible impact on soluble KIT plasma concentrations.

The drug submission did not include a thorough QTc study to examine the effects of Inlyta on the QT/QTc interval in healthy subjects. Instead, the sponsor assessed QTc effects in a Phase I drug-drug interaction study with ketoconazole. In a randomized, 2-way crossover study, 35 healthy subjects were administered a single oral 5 mg dose of Inlyta alone or on Day 4 of a 7 day treatment with 400 mg/day ketoconazole. Inlyta at 5 mg was associated with a mean decrease in heart rate of 5 beats per minute which is consistent with the results obtained in patients with metastatic RCC in Phase II and Phase III studies. Inlyta did not result in large mean changes in the QTc interval (>20 ms) up to 3 hours post-dose, however smaller increases in the QTc interval (<10 ms) could not be ruled out. Although the study had a number of methodological limitations which precluded a reliable assessment, a large drug effect on the QT interval was ruled out. Health Canada considered this study sufficient for approval, with the provision that information regarding the limitations is conveyed in the Warnings and Precautions section of the Product Monograph.

3.3.2 Pharmacokinetics


Inlyta (axitinib) was absorbed within 4 hours following oral dosing with a median time to maximum concentration ranging from 2.5 to 4.1 hours. The plasma half-life of axitinib ranged from 2.5 to 3.4 hours and the accumulation ranged from 35% to 48% with continuous dosing. The mean absolute oral bioavailability of axitinib was 58%.

Administration of Inlyta with a moderate fat meal resulted in a mean 10% decrease in axitinib exposure compared to overnight fasting, and administration with a high fat meal resulted in a mean 19% increase in exposure compared to overnight fasting. These differences are not anticipated to be clinically significant, therefore Inlyta can be taken with or without food.


Axitinib was found to be highly bound to plasma proteins (>99%) in vitro. The mean volume of distribution of axitinib was 68 L.


Radiolabelled axitinib was metabolized primarily in the liver by CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. In plasma, N-glucuronide, was the predominant radioactive component (50% of circulating radioactivity) and unchanged axitinib and the sulfoxide metabolite each accounted for approximately 20% of the circulating radioactivity.


Following oral administration of a 5 mg radioactive dose of axitinib, 30-60% of the radioactivity was recovered in faeces and 23% of the radioactivity was recovered in urine. Unchanged axitinib, accounting for 12% of the dose, was the major component identified in faeces. Unchanged axitinib was not detected in urine; the carboxylic acid and sulfoxide metabolites accounted for the majority of radioactivity in urine.

Special Populations

Following administration of a single dose of 5 mg twice a day (BID), the systemic exposure of axitinib was similar in subjects with mild hepatic impairment and approximately 2-fold higher in subjects with moderate hepatic impairment as compared to subjects with normal hepatic function. The effects of severe hepatic impairment on axitinib exposure were not studied.

Axitinib was not studied in subjects with renal impairment. Population pharmacokinetic analysis based on baseline renal function indicated that mild to severe renal impairment did not have an impact on axitinib clearance. There was only one subject with end stage renal disease included in the study.

Drug Interactions

Co-administration of axitinib with the strong CYP3A4/5 inhibitor ketoconazole (400 mg every day) resulted in a 2-fold increase in axitinib exposure [mean area under the curve (AUC)]. There were no studies conducted with moderate CYP3A4/5 inhibitors. Co-administration of axitinib with the strong CYP3A4/5 inducer rifampin resulted in a reduction in the mean axitinib AUC by 79%. There were no studies conducted with moderate CYP3A4/5 inducers. Co-administration of axitinib with rabeprazole in 6 patients resulted in a reduction of the mean axitinib AUC by 15%; however, the magnitude of the effect was highly variable. Since the absorption of axitinib is highly pH-dependent, co-administration of axitinib with drugs which increase intra-gastric pH has the potential to reduce axitinib exposure and effectiveness.

3.3.3 Clinical Efficacy

The primary evidence for the clinical efficacy of Inlyta was provided in a multicentre, randomized, open-label Phase III study in 723 patients with metastatic RCC (mRCC), following failure of one prior systemic first-line therapy. The active comparator was the VEGFR-TKI, sorafenib. Patients were randomized 1:1 to receive Inlyta at a starting dose of 5 mg BID administered orally with food, or sorafenib at a starting dose of 400 mg BID administered orally without food. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), objective response rate (ORR) and Quality of Life (QoL). The primary endpoint was assessed by an independent review committee (IRC) consisting of two blinded reviewers and an adjudicator.

The baseline demographic and disease characteristics were similar between the Inlyta and sorafenib treatment groups with respect to age, gender, race, Eastern Cooperative Oncology Group (ECOG) performance status, geographic region, and prior treatment. The majority of the patients in each treatment arm were Caucasian males with a median age of 61. Of the enrolled patients, 389 (53.8%) patients received one prior therapy with the VEGFR-TKI sunitinib; 251 (34.7%) patients received one prior cytokine-based therapy; 59 (8.2%) patients received one prior therapy with the VEGF-targeted antibody bevacizumab; and 24 (3.3%) patients received one prior therapy with the mammalian target of rapamycin (mTOR) inhibitor, temsirolimus.

The overall median PFS was 6.7 months in the Inlyta arm and 4.7 in the sorafenib arm [Hazard ratio (HR) 0.67; 95% confidence interval (CI): 0.55, 0.81]. The increased benefit in PFS was larger in the subset of patients who failed prior cytokine therapy. The median PFS in this subgroup was increased by 5.6 months in the Inlyta arm as compared to the sorafenib arm (HR 0.46; 95% CI: 0.32, 0.68) whereas the median PFS in the sunitinib-refractory subgroup increased by 1.4 months (HR 0.74; 95% CI: 0.57, 0.96). The number of patients in the bevacizumab-refractory subgroup and the temsirolimus-refractory subgroup were insufficient for a reliable assessment of efficacy. The interpretation of these efficacy data for Inlyta was also complicated by the absence of level 1 evidence that sorafenib is active in patients who failed prior sunitinib treatment and that current treatment guidelines for mRCC used in Canada do not recommend first-line treatment with cytokines for most patients.

The median OS was similar between the Inlyta and sorafenib treatment arms; 20.1 months and 19.2 months, respectively. Similarly, there were no significant differences in OS between the Inlyta and sorafenib treatment arms in each of the sunitinib and cytokine refractory subgroups (median OS 15.2 months and 16.5 months, respectively, in the sunitib refractory subgroup; and 29.4 months and 27.8 months, respectively, in the cytokine refractory subgroup).

Overall, 19.4 % (95% CI: 15.4%, 23.9%) of patients in the Inlyta arm and 9.4% (95% CI: 6.6%, 12.9%) patients in the sorafenib arm achieved a confirmed objective response (OR). The risk ratio (RR) was 2.06 (95% CI: 1.41, 3.00). In the cytokine-refractory subgroup, an OR was confirmed in 32.5% (95% CI: 24.5%, 41.5%) of patients in the Inlyta arm and in 13.6% (95% CI: 8.1%, 20.9%) of patients in the sorafenib arm [RR of 2.39 (95% CI: 1.43, 3.99)]. In patients failing prior sunitinib therapy, an OR was confirmed in 11.3% (95% CI: 7.2%, 16.7%) of patients in the Inlyta arm and in 7.7% (95% CI: 4.4%, 12.4%) of patients in the sorafenib arm [RR of 1.48 (95% CI: 0.79, 2.75)].

The QoL assessments based on self-reported global scores from questionnaires EuroQoL EQ-5D and FKSI-15 showed no statistically significant difference in QoL between the Inlyta and sorafenib treatment arms.

The efficacy of Inlyta was studied predominantly in male Caucasians however subgroup analysis indicated that efficacy was independent of gender and race (Caucasian, non-Caucasian). The efficacy of Inlyta was not specifically examined in geriatric patients; however 34% percent of the patients enrolled in the pivotal study were ≥65 years old and the effectiveness of Inlyta in this subpopulation was comparable to that in patients younger than 65 years. No dosage adjustment is required in the geriatric subgroup. The efficacy of Inlyta was not examined in paediatrics; its use for paediatric patients is not recommended in the Inlyta Product Monograph.

3.3.4 Clinical Safety

The safety of Inlyta was evaluated in 699 patients in clinical studies, including 537 patients with mRCC. A total of 359 patients with mRCC were exposed to axitinib in the pivotal Phase III study where the median duration of treatment was 6.4 months (range 0.03 to 22.0 months) for patients in the Inlyta treatment arm and 5.0 months (range 0.03 to 20.1 months) for patients in the sorafenib arm.

The number of patients reporting adverse drug events or serious drug events was comparable across the treatment arms. Permanent discontinuation due to an adverse event occurred in 33/359 patients (9%) receiving Inlyta and 46/355 patients (13%) receiving sorafenib. There were more on-treatment deaths that occurred in the Inlyta arm as compared to the sorafenib arm (9.7% and 6.5%, respectively). There were more deaths due to on-treatment disease progression in the Inlyta arm as compared to the sorafenib arm (7.8% and 4.2%, respectively).

The most common treatment-emergent adverse events reported for ≥20% of patients in the Inlyta treatment group were diarrhoea; hypertension; fatigue; decreased appetite; nausea; dysphonia; palmar-plantar erythrodysesthesia (hand-foot) syndrome; decreased weight; vomiting; asthenia; and constipation. Hypertension, nausea and dysphonia were reported at a higher frequency (difference of ≥10%) in patients receiving Inlyta as compared to those receiving sorafenib. Palmar-plantar erythrodysesthesia syndrome, rash and alopecia were reported more frequently (difference of ≥10%) in the sorafenib treatment arm than in the Inlyta treatment arm. Of the events reported in <20% of patients, those with a higher incidence in the Inlyta treatment arm as compared to the sorafenib treatment arm included hypothyroidism, dizziness, dyspepsia, and reversible posterior leukoencephalopathy.

In addition to hypertension, hypothyroidism, and reversible posterior leukoencephalopathy, other clinically significant adverse events reported in patients receiving Inlyta included hypertensive crisis; arterial thromboembolism, including deaths; venous thromboembolism (pulmonary embolism, deep vein thrombosis, and retinal-vein occlusion occlusion/thrombosis), including deaths; haemorrhage (gastrointestinal, cerebral and respiratory tract); gastrointestinal perforation, including death and gastrointestinal fistulas.

The incidence of laboratory test abnormalities was comparable between patients receiving Inlyta and patients receiving sorafenib with a number of exceptions. Elevated haemoglobin above the upper limit of normal was reported in 10% of patients in the Inlyta arm and 1% of patients in the sorafenib arm. Hypercalcaemia was observed in 5.7% of patients treated with Inlyta and in 1.5% of patients treated with sorafenib. Increased levels of creatinine and hyperkalemia were reported with higher frequency in the Inlyta group than in the sorafenib group (55% versus 41%, and 15.3% versus 9.5%, respectively) Polycythemia was reported in 0.8% of patients receiving Inlyta and in none of the patients receiving sorafenib.

3.4 Benefit/Risk Assessment and Recommendation

3.4.1 Benefit/Risk Assessment

The efficacy and safety results presented in the current submission support the use of Inlyta for patients with metastatic renal cell carcinoma of clear cell origin who have failed one prior systemic therapy either with a cytokine or the VEGFR-TKI, sunitinib.

Based on the efficacy and safety data provided, the benefits of Inlyta are as follows:

  • Inlyta administered at the starting dose of 5 mg BID resulted in a significant improvement in the primary efficacy endpoint, progression-free survival (PFS) as compared to sorafenib, with a statistically significant 33% reduction in the risk of disease progression or death;
  • Inlyta treatment resulted in a clinically-significant increase in the secondary efficacy endpoint, the objective response rate (ORR) as compared to sorafenib (19.4% versus 9.4%);

However, the observed benefit of Inlyta compared to sorafenib in patients previously treated with sunitinib was less than that observed in patients previously treated with a cytokine, a treatment not commonly used in first-line treatment of mRCC in Canada at the current time. In addition, Level 1 evidence (from randomized controlled studies) that sorafenib is an active comparator in patients previously treated with sunitinib is lacking.

As there were very few patients previously treated with bevacizumab or temsirolimus regimens in the pivotal study, the efficacy of Inlyta in this group of patients remains unknown. In addition, the group that failed prior treatment with a VEGFR-TK included only patients who had failed sunitinib. Therefore, it was considered that these study results should not be necessarily extrapolated to patients who had progressed following any systemic therapy or following any VEGFR inhibitor.

Furthermore, while an improvement in PFS is considered a clinical benefit by some, the OS and QoL analyses did not provide evidence of the efficacy of Inlyta on these more direct measures of clinical benefit.

Results from the clinical development program show that dose increases of Inlyta can be permitted for the small proportion of patients who require it and tolerate 5 mg BID satisfactorily in order to optimize plasma exposure and provide an opportunity for better clinical response.

The risks associated with Inlyta treatment are as follows:

  • Inlyta was associated with increased incidence of hypertension compared to sorafenib, including Grade 3/4 events and hypertensive crisis;
  • Other common adverse events observed in more than 20% of patients treated with Inlyta included diarrhoea; fatigue; decreased appetite; nausea; dysphonia; palmar-plantar erythrodysesthesia syndrome; decreased weight; vomiting; asthenia; and constipation;
  • Other less common serious adverse events observed in patients receiving Inlyta included arterial and venous thromboembolic events including death; haemorrhage; elevated haemoglobin; gastrointestinal perforation including death and gastrointestinal fistulas; reversible posterior leukoencephalopathy; hypothyroidism; and proteinuria.

Overall, the data provided in the current submission support a favourable benefit-risk profile for Inlyta as second-line treatment of patients with mRCC previously treated with either a cytokine or sunitinib. Labelling negotiations with the sponsor resulted in revisions to the Inlyta Product Monograph consistent with the risks and benefits associated with Inlyta therapy. Post-marketing surveillance beyond that outlined in the Risk Management Plan is not required.

3.4.2 Recommendation

Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Inlyta is favourable in the treatment of patients with metastatic renal cell carcinoma (mRCC) of clear cell histology after failure of prior systemic therapy with either a cytokine or the vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI), sunitinib. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.

4 Submission Milestones

Submission Milestones: InlytaTM

Submission MilestoneDate
Pre-submission meeting:2010-07-27
Submission filed:2011-06-28
Screening Deficiency Notice issued:2011-08-25
Response filed:2011-09-02
Screening Acceptance Letter issued:2011-09-19
Biopharmaceutics Evaluation complete:2012-03-26
Quality Evaluation complete:2012-07-10
Clinical Evaluation complete:2012-07-05
Biostatistics Evaluation complete:2012-03-19
Labelling Review complete:2012-07-11
Notice of Compliance issued by Director General:2012-07-12