Summary Basis of Decision for Zelboraf ™

3.3.1 Pharmacodynamics

Clinical studies on the mechanism of action of vemurafenib were not submitted for review (see 3.2.1 Pharmacodynamics for the non-clinical studies). Dose-escalation studies were carried out in patients in order to establish an appropriate dose of 960 mg twice daily (BID) for a total daily dose of 1,920 mg (8 tablets total) for the Phase II and Phase III studies. This is considered the maximum tolerated daily dose.

3.3.2 Pharmacokinetics

A population PK analysis using pooled data from 458 patients estimated the median of the steady-state C_max, C_min and AUC_0-12hours to be 62 μg/mL, 59 μg/mL and 734 μg*h/mL, respectively. A one-compartment open model with first-order absorption and first-order elimination adequately describes the vemurafenib concentration-time profile in the population PK analysis.

Absorption

Using the to-be-marketed 240 mg tablets, vemurafenib demonstrated linear pharmacokinetics between 240 and the recommended daily dose of 960 mg BID. Steady-state levels of vemurafenib were achieved at Day 22 in most patients (range: 15 to 29 days). The bioavailability of vemurafenib has not been established and the effect of food on absorption of vemurafenib is not currently known.

Vemurafenib at 960 mg BID (using the 240 mg tablets) was absorbed with a median time to reach maximum plasma concentration of approximately 4 hours. Vemurafenib exhibited marked accumulation after repeat dosing at 960 mg BID with high inter-patient variability.

Distribution

In patients with metastatic melanoma , the apparent volume of distribution for vemurafenib was estimated to be 91 L (with 64.8% inter-patient variability). Vemurafenib was highly bound to human plasma proteins in vitro (>99%).

Metabolism

In a human mass balance study using radiolabelled vemurafenib, vemurafenib underwent limited metabolism by the liver. Metabolites were on average <6% of the plasma radioactivity. In faeces, the parent compound and three primary metabolites accounted for 54.6% and 13.5% of the total starting radioactivity, respectively, when collected up to 96 hours.

Excretion

Results from the mass balance study showed that the majority of the radioactivity was excreted in the faeces (94%) and very little (<1%) was found in the urine.

Drug Interaction Studies

Vemurafenib may increase the plasma exposure of drugs predominantly metabolized by CYP1A2 and CYP2D6 and decrease the plasma exposure of drugs predominantly metabolized by CYP3A4. Dose reductions for medications predominantly metabolized via CYP1A2 and CYP2D6 should be considered based on their therapeutic windows before concomitantly treating with vemurafenib. When a single dose of warfarin was co-administered after repeat dosing with vemurafenib for 15 days, some patients exhibited increased warfarin exposure (mean 20%). Additional studies demonstrated that vemurafenib inhibited CYP2C9 in vitro. Therefore caution should be exercised when vemurafenib is co-administered with warfarin (a CYP2C9 substrate) in patients.

In vitro studies suggested that vemurafenib was only metabolized to a small extent by human hepatocytes and this was mainly due to CYP3A4-mediated oxidation. Studies in humans to determine the effects of either a strong CYP3A4 inhibitor or inducer on vemurafenib pharmacokinetics have not been conducted.

Special Populations

The kidneys account for less than 1% of excreted vemurafenib (mass balance study) and renal impairment is not expected to affect exposure to vemurafenib. Studies in rats suggest that the major route of elimination is biliary excretion and therefore hepatic impairment may increase systemic exposure to the drug. Based on population pharmacokinetic analysis, no adjustment to the starting dose is needed for patients with pre-existing mild and moderate hepatic impairment. The safety and efficacy of Zelboraf in patients with severe hepatic impairment have not been established. Limited pharmacokinetic data suggest that patients with severe hepatic impairment may have higher systemic concentrations of vemurafenib, and this could result in more frequent exposure-related adverse events including QTc prolongation. Therefore, Zelboraf should be used with caution in patients with severe hepatic impairment as outlined in the Product Monograph.

The mean steady-state exposure in females was approximately 14% higher than in males. Although there is no need to adjust the dose based on gender it remains unclear whether this exposure difference is related to gender or a body size effect.

3.3.3 Clinical Efficacy

The efficacy of Zelboraf (vemurafenib) in melanoma was evaluated in a Phase III comparative clinical study of 675 patients and a Phase II single-arm clinical study of 132 patients. Prior to study enrolment, tumour specimens from all patients were tested for the presence of BRAF V600 mutations by the cobas^® 4800 BRAF V600 Mutation Test. Approximately 50% of the patients with melanoma screened for clinical studies had BRAF V600 mutation-positive tumours. The test was designed for, and has a high specificity for, detecting V600E. It is less sensitive for detecting other V600 mutations including the second most common mutation, V600K. Clinical data supporting use of Zelboraf in patients with BRAF mutations other than V600E are limited. Non-clinical and limited clinical data suggest that vemurafenib will not be effective in patients whose tumours are not positive for BRAF V600 mutations, and for this reason the efficacy and safety of Zelboraf have not been evaluated in this patient population.

Phase III Study in Treatment Naïve Patients

In an open-label, multicentre, international, randomized Phase III study in previously untreated patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, 337 patients were randomized to treatment with Zelboraf (960 mg BID) and 338 patients were randomized to dacarbazine (1,000 mg/m² every 3 weeks). Fifteen percent of patients (48) randomized to dacarbazine did not receive any study medication. This selective drop-out, however, was considered unlikely to impact the efficacy analyses. Thirty-two of the 48 patients had follow-up data for survival and subsequent anti-cancer therapy was reported for 9 patients (18.8%). Consistent with the intent-to-treat (ITT) principle, all available data for such patients were included in the ITT analyses, including any data reported after use of subsequent anti-cancer therapies. In addition, assessment of patients who received at least one course of study medication indicated that the measured baseline characteristics remained well balanced between the two study arms.

Treatment was continued until time of disease progression, unacceptable toxicity and/or consent withdrawal. The co-primary efficacy endpoints of the study were overall survival (OS) and progression-free survival (PFS). Key secondary efficacy endpoints included confirmed best overall response rate (BORR) and response duration.

A statistically significant and clinically meaningful improvement in OS was found for patients treated with Zelboraf with a hazard ratio of 0.37 [95% confidence interval (CI): 0.26, 0.55] which represents a 63% decrease in the hazard of death with Zelboraf compared to dacarbazine. Progression-free survival by investigator assessment was longer with Zelboraf compared to dacarbazine with a hazard ratio for PFS of 0.26 (95% CI: 0.20, 0.33) which represents a 74% decrease in the hazard of progression or death for Zelboraf compared to dacarbazine. The benefit in OS was maintained at the 90-day safety update analysis.

The secondary endpoint BORR (complete response plus partial response) as assessed by the investigator, was significantly improved (probability <0.0001) in the Zelboraf arm (48.4%) (95% CI: 41.6%, 55.2%) compared to the dacarbazine arm (5.5%) (95% CI: 2.8%, 9.3%). Among the 106 Zelboraf patients with a confirmed response, the median time to response was 1.4 months (range: 1.0 to 5.5). Among the 12 dacarbazine patients with a confirmed response, the median time to response was 2.7 months (range: 1.6 to 5.8).

Quality of life was assessed using the Functional Assessment of Cancer Therapy-Melanoma v.4 (FACT-M) questionnaire. Analyses of FACT-M and its subscales suggested that there was no difference in quality of life measured over time on study treatment in patients treated with Zelboraf compared with patients treated with dacarbazine. The proportion of patients with improvement in the physician's assessment of performance status was higher in the patients treated with Zelboraf (63.4%) (95% CI: 57%, 69%) than in the patients treated with dacarbazine (20.2%) (95% CI: 15%, 26%).

A total of 19 patients out of 220 whose tumours were retrospectively analysed by sequencing were reported to have BRAF V600K mutation-positive melanoma in this Phase III study. Although limited by the low number of patients, compared to V600E patients, efficacy analyses suggested a benefit of Zelboraf in patients with the V600K mutation. Four out of 10 V600K patients treated with Zelboraf responded to treatment compared to zero out of 9 patients in the dacarbazine arm. Furthermore, the treatment benefit of Zelboraf on OS and PFS in the V600K subpopulation was observed by the hazard ratios of 0.27 (95% CI: 0.05, 1.51) and 0.09 (95% CI: 0.02, 0.45), respectively.

Phase II Study in Patients who Failed at least One Prior Systemic Therapy

A Phase II single-arm, multicentre, multinational study was conducted in 132 metastatic melanoma patients with BRAF V600 mutation-positive tumours. More patients received prior therapy with IL-2 (39%) than with dacarbazine treatment (23%) in this study. The median duration of follow-up was 6.9 months (range 0.6 to 11.3).

The endpoint of confirmed best overall response rate (BORR) as assessed by an independent review committee was 52% (95% CI: 43%, 61%). Patients with prior IL-2 or dacarbazine therapy had a BORR of 48% (95% CI: 34%, 62%) or 60% (95% CI: 41%, 77%), respectively. The median time to response was 1.4 months with 75% of responses occurring by month 1.6 of treatment. The median duration of response was 6.5 months.

Nine of the 132 patients had BRAF V600K mutations confirmed by Sanger sequencing. Amongst these patients, 3 had a partial response, 3 had stable disease, 2 had progressive disease and 1 was not evaluable.

The Product Monograph clearly states that the effectiveness of Zelboraf in patients with prior therapy, including dacarbazine and IL-2 treatments, is based on the objective response rate data from a single-arm Phase II study. In the absence of additional effective therapies and unprecedented response rates of significant duration in these patients, Health Canada granted market authorization appropriate for patients with BRAF V600 mutations who failed prior therapies based on this single-arm study.

3.3.4 Clinical Safety

The adverse drug reactions were reported from the two clinical studies described in section 3.3.3 Clinical Efficacy. The median duration of treatment in the Phase III and Phase II studies were 4.2 months and 5.7 months, respectively.

The most common adverse events reported with the use of Zelboraf were arthralgia; rash; alopecia; fatigue; photosensitivity reaction; nausea; pruritus; and skin papilloma. Other very common events (>10%) included: sunburn; depression; decreased appetite; headaches; fever; arthritis; back pain; hand-foot syndrome; alopecia; and peripheral oedema. Common events (>1% and <10%) included: dehydration; loss of consciousness/syncope; facial paralysis; joint swelling; muscle weakness; and skin lesions. Less common but serious events included QTc prolongation, ophthalmologic reactions (including uveitis, iritis and retinal vein occlusion); serious hypersensitivity reactions (including anaphylactic shock, Stevens-Johnson syndrome, toxic epidermal necrolysis and hypotension); and grade 3 and grade 4 liver enzyme abnormalities.

Females experienced approximately twice as many clinically significant events (either > Grade 3 or serious adverse events) of arthralgia, photosensitivity reactions and rash compared to males in this study. In the clinical studies, elderly patients (>65 years of age) experienced more adverse events including cutaneous squamous cell carcinoma (cuSCC); decreased appetite; and cardiac disorders. Tumour lysis syndrome was also observed in the clinical studies and has been included in the Warnings and Precautions section of the Product Monograph.

Second malignancies are of significant concern with Zelboraf. While Zelboraf is effective in treating metastatic melanoma in the BRAF V600-mutation positive population, there is a paradoxical increase in other malignancies, primarily the less invasive cuSCC but also in potentially more aggressive melanomas and non-cutaneous SCCs. Cutaneous SCCs (24% across all studies) and new primary melanomas (2% in the Phase III study) have been reported in the submitted clinical studies, and two cases of non-cutaneous SCCs of the head and neck (tonsils and tongue) have recently been reported in ongoing studies.

Zelboraf at the therapeutic dose of 960 mg BID was associated with QTc prolongation, decreased heart rate, and increased blood pressure in the Phase II and Phase III studies. Exposure-dependent QTc prolongation was observed. The magnitude of QTc prolongation ranged from a mean of 11-15 msec in the Phase II study and reached a maximum effect of 22.1 msec (90% CI: 14.2, 30.0) by Cycle 6 in the Phase III study. Elevations in blood pressure have been reported in association with Zelboraf. In the Phase III study, the mean change from baseline ranged from 4-10 mm Hg for systolic blood pressure and 0-8 mm Hg for diastolic blood pressure over the course of treatment.

Despite important safety concerns for Zelboraf and the limitations of the available safety data (limited patient population over a relatively short duration), the overall safety profile of Zelboraf is acceptable and manageable. The Health Canada-approved labelling will help ensure proper monitoring and mitigating, where possible, of some serious adverse events. A Serious Warnings and Precaution box has been added to the Product Monograph listing QTc prolongation and second malignancies as clinically significant adverse events. A statement that Zelboraf has not been studied in patients with severe hepatic impairment has also been included in the Serious Warnings and Precautions box. In the Warnings and Precautions section, it is stated that Zelboraf should not be used in patients with wild-type BRAF tumours or in patients where the BRAF mutational status is not known; and that the clinical data supporting use of Zelboraf in patients with BRAF mutations other than V600E are limited.