Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EE02 
Mechanism of action

Cobimetinib is a reversible, selective, allosteric, oral inhibitor that blocks the mitogen-activated protein kinase (MAPK) pathway by targeting the mitogen-activated extracellular signal-regulated kinase (MEK) 1 and MEK 2 which results in inhibition of phosphorylation of the extracellular signal- regulated kinase (ERK) 1 and ERK 2. Therefore, cobimetinib blocks the cell proliferation induced by the MAPK pathway through inhibition of the MEK1/2 signalling node.

In the preclinical models, the combination of cobimetinib and vemurafenib showed that by simultaneously targeting mutated BRAF V600 proteins and MEK proteins in melanoma cells, the combination of the two products inhibits MAPK pathway reactivation through MEK1/2, resulting in a stronger inhibition of intracellular signalling and decreased tumour cell proliferation 
Clinical efficacy and safety

Unresectable or Metastatic Melanoma
There is limited data on the safety and no data on efficacy of Cotellic in combination with vemurafenib in patients with central nervous system metastasis. There is no data in patients with non- cutaneous malignant melanoma.

Study GO28141 (coBRIM)

Study GO28141 is a multi-centre, randomised, double-blind, placebo-controlled, Phase III study to evaluate the safety and efficacy of Cotellic in combination with vemurafenib as compared to vemurafenib plus placebo, in previously untreated patients with BRAF V600 mutation-positive unresectable locally advanced (Stage IIIc) or metastatic melanoma (Stage IV).

Only patients with ECOG performance status 0 and 1 were enrolled in Study GO28141. Patients with ECOG performance status 2 or higher were excluded from the study.

Following confirmation of a BRAF V600 mutation, using the cobas® 4800 BRAF V600 mutation test, 495 previously untreated patients with unresectable locally advanced or metastatic melanoma were randomised to receive either:
•    Placebo once daily on Days 1-21 of each 28-day treatment cycle and 960 mg vemurafenib twice daily on Days 1-28, or
•    Cotellic 60 mg once daily on Days 1-21 of each 28-day treatment cycle and 960 mg vemurafenib twice daily on Days 1-28

Progression-free survival (PFS) as assessed by the investigator (INV) was the primary endpoint.
Secondary efficacy endpoints included overall survival (OS), objective response rate, duration of response (DoR) as assessed by INV and PFS as assessed by an independent review facility (IRF).

Key baseline characteristics included: 58% of patients were male, median age was 55 years (range 23 to 88 years), 60% had metastatic melanoma stage M1c and the proportion of patients with elevated LDH was 46.3% in the cobimetinib plus vemurafenib arm and 43.0% in the placebo plus vemurafenib arm.

In Study GO28141, there were 89 patients (18.1%) aged 65-74, 38 patients (7.7%) aged 75-84 and 5 patients (1.0%) aged 85 years and older.

Efficacy results are summarized in Table 7.

Table 7 Efficacy results from Study GO28141 (coBRIM)
Cotellic + vemurafenib                 Placebo + vemurafenib
N=247                                 N=248


Primary Endpoint a,f
Progression-Free Survival (PFS)
Median (months)                                  12.3                                    7.2 (95 % CI)                                     (9.5, 13.4)                             (5.6, 7.5) Hazard ratio (95% CI) b                                         0.58 (0.46; 0.72) Key Secondary Endpoints a,f
Overall Survival (OS)g
Median (months)                                  22.3                                  17.4 (95 % CI)                                     (20.3, NE)                            (15.0, 19.8) Hazard ratio (95% CI)b                                      0.70 (95% CI: 0.55, 0.90) (p-value = 0.0050e)
Objective response rate
172 (69.6%)                             124 (50.0%)
(ORR) c
(95% CI) for ORR                            (63.5%, 75.3%)                          (43.6%, 56.4%) Difference in ORR %
19.6 (11.0, 28.3)
(95% CI) d
Best Overall Response (BOR)
Complete Response                             39 (15.8%)                              26 (10.5%) Partial Response                             133 (53.8%)                              98 (39.5%) Stable disease                                44 (17.8%)                              92 (37.1%) Duration of Response (DoR)
Median DoR (months)                                   13                                   9.2 (95% CI) for median                              (11.1, 16.6)                          (7.5, 12.8) NE = Not evaluable a
Assessed and confirmed by the investigator (INV) using RECIST v1.1 b
Stratified analysis by geographic region and metastasis classification (disease stage) c
Using Clopper-Pearson method d
Using Hauck-Anderson method e
The OS p-value (0.0050) crossed the pre-specified boundary (p value <0.0499) f
The data cut-off date for this updated PFS analysis and the secondary endpoints of ORR, BOR and DoR is 16- January 2015. The median follow up was 14.2 months.
g
The data cut-off date for the final OS analysis is 28 August 2015 and median follow-up was 18.5 months.
The primary analysis for Study GO28141 was conducted with a data cut-off date of 09 May 2014.
Significant improvement in the primary endpoint, investigator-assessed PFS, was observed in patients assigned to the Cotellic plus vemurafenib arm compared to the placebo plus vemurafenib arm (HR 0.51 (0.39; 0.68); p-value < 0.0001). The median estimate for investigator-assessed PFS was 9.9 months for the Cotellic plus vemurafenib arm vs. 6.2 months for the placebo plus vemurafenib arm.
The median estimate for independent review of PFS was 11.3 months for the Cotellic plus vemurafenib arm vs. 6.0 months for the placebo plus vemurafenib arm (HR 0.60 (0.45; 0.79); p-value = 0.0003). The objective response rate (ORR) in the Cotellic plus vemurafenib arm was 67.6% vs 44.8% in the placebo plus vemurafenib arm. The difference in ORR was 22.9 % (p-value<0.0001).

The final OS analysis for Study GO28141 was conducted with a data-cut off date of 28 August 2015.
Significant improvement in OS was observed in patients assigned to the Cotellic plus vemurafenib arm compared to the placebo plus vemurafenib arm (Figure 1). The 1-year (75 %) and 2-year (48 %) OS estimates for the Cotellic plus vemurafenib arm were greater than those for placebo plus vemurafenib arm (64 % and 38 % respectively).

Figure 1 Kaplan-Meier curves of final overall survival – Intent to treat population (cut-off date: 28 August 2015)



Figure 2: Forest plot for hazard ratios of final overall survival subgroup analyses – Intent to treat population (cut-off date: 28 August 2015)


Global health status / health-related quality of life by patient-report were measured using the EORTC Quality of Life Questionnaire – Core 30 (QLQ-C30). Scores for all functioning domains and most symptoms (appetite loss, constipation, nausea and vomiting, dyspnoea, pain, fatigue) showed that the mean change from baseline was similar between the two treatment arms and did not demonstrate a clinically meaningful change (all scores were ≤ 10 point change from baseline).

Study NO25395 (BRIM7)

The efficacy of Cotellic was evaluated in Phase Ib Study, NO25395, which was designed to assess the safety, tolerability, pharmacokinetics and efficacy of Cotellic when added to vemurafenib for the treatment of patients with BRAFV600 mutation-positive (as detected by the cobas® 4800 BRAF V600 Mutation Test), unresectable or metastatic melanoma.
This study treated 129 patients with Cotellic and vemurafenib: 63 were BRAF inhibitor (BRAFi) therapy naïve and 66 patients had previously progressed on prior vemurafenib therapy. Among the 63 BRAFi naïve patients, 20 patients had received prior systemic therapy for advanced melanoma with the majority (80%) being immunotherapy.

Results of the BRAFi naïve population from Study NO25395 were generally consistent with those from Study GO28141. The BRAFi-naïve patients (n=63) attained an 87% objective response rate, including a complete response in 16% of patients. The median duration of response was 14.3 months.
The median PFS for BRAFi-naïve patients was 13.8 months, with median follow-up time of 20.6 months.

Among patients who had progressed on vemurafenib (n=66), the objective response rate was 15%. The median duration of response was 6.8 months. The median PFS for patients who had progressed on vemurafenib was 2.8 months, with median follow-up time of 8.1 months.

In patients who were naive to BRAF inhibitor therapy, the median overall survival was 28.5 months (95% CI 23.3-34.6). In patients who had progressed on BRAF inhibitor therapy, the median overall survival was 8.4 months (95% CI 6.7-11.1).

Paediatric population

A phase I/II, multi-centre, open-label, dose-escalation study was conducted in paediatric patients (< 18 years, n=55) to evaluate the safety, efficacy and pharmacokinetics of Cotellic. The study included paediatric patients with solid tumours with known or potential RAS/RAF/MEK/ERK pathway activation, for which standard therapy has proven to be ineffective or intolerable or for which no curative standard-of-care treatment options exist. Patients were treated with up to 60 mg of Cotellic orally once daily on Days 1-21 of each 28-day cycle. Overall response rate was low with only 2 partial responses (3.6%).

Histiocytic Neoplasms
A single-center, single-arm trial (Study ML29733) was conducted to evaluate the efficacy, safety, and tolerability of Cotellic as a single agent in adult patients with histologically confirmed histiocytic neoplasms of any mutational status. Patients with documented BRAF V600E mutations were enrolled if they were unable to access a BRAF inhibitor or discontinued a BRAF inhibitor due to toxicity.
Enrolled patients had multi-system disease, recurrent or refractory disease, or single-system disease that is unlikely to benefit from conventional therapies, based on best available evidence.
The trial included 26 patients with histiocytic neoplasms including Langerhans Cell Histiocytosis (n=4), Rosai-Dorfman Disease (n=4), Erdheim-Chester Disease (n=13), Xanthogranuloma (n=2) and Mixed Histiocytosis (n=3). Patients with BRAF V600 mutant positive (n=6) and BRAF V600 Wild type (n=20) received Cotellic. Twenty-one patients (81%) had received prior systemic therapies. The median age was 50.5 years (range, 18 to 79 years). Sixty-five percent of patients were men (n=17) and 35% were women (n=9). The majority of patients were White (85%), 8% were Black or African American and 4% were Asian; 96% were neither Hispanic nor Latino.
Patients were treated with Cotellic 60 mg once daily for 21 days on, then 7 days off, in a 28-day treatment cycle (n=26). Eighteen patients required a dose reduction to 40 mg, and five patients required an additional dose reduction to 20 mg. The median duration of treatment following a dose reduction to 40 mg and 20 mg was 6.6 months and 3.9 months respectively.
The major efficacy outcome was best overall response rate (BORR), maintained on two occasions at least four weeks apart, as assessed by the investigator using the PET Response Criteria (PRC). Other clinical outcomes included PRC-based duration of response (DOR), and BORR maintained on two occasions at least four weeks apart, as assessed by investigator using RECIST v1.1.
The median duration of follow-up was 11.4 months (range, 0.2 to 36.8 months). The median time to PRC-based response was 2.0 (range, 0.2 to 17.3 months). The median PRC-based DOR was 31 months (range, 2 to 31 months). See Table 8 below for efficacy results.
Table 8             Efficacy of Cotellic in patients with Histiocytic neoplasms (Study ML29733) PET Response, a, b                   RECIST Response,
Response                                        Enrolled Patients                 Enrolled Patients (n=26)** (n=26)*
Overall response rate, n (%)                       20 (76.9%)                               12 (46.2%) (95% Clopper-Pearson CI)                            (56.4, 91)                              (26.6, 66.6) 

Best Response, n (%)
Complete Response                                 16 (61.5%)                               3 (11.5%) Partial Response                                  4 (15.4%)                                9 (34.6%) *24 PET-evaluable patients out of 26 enrolled patients. 1 patient had missing baseline scan. 1 patient had short follow-up duration (not enrolled at least 16 weeks prior to the clinical cutoff date (CCOD) **19 RECIST-evaluable patients out of 26 enrolled patients. 6 patients had missing baseline scans; these patients had lesions that were not measurable by RECIST 1.1 definition. 1 patient had short follow-up duration (not enrolled at least 16 weeks prior to CCOD) a
Complete Response by PRC was defined as a normalization of all lesions’ (target and non-target) standardized uptake values (SUV) to background SUVliver (or SUVbrain for brain lesions only) b
Partial Response by PRC was defined as a ≥50% decrease from baseline in sum of SUV of all target lesions relative to SUVliver (or SUVbrain for brain lesions only)

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Absorption

Following oral dosing of 60 mg in cancer patients, cobimetinib showed a moderate rate of absorption with a median T max of 2.4 hours. The mean steady-state Cmax and AUC0-24 were 273 ng/mL and 4340 ng.h/mL respectively. The mean accumulation ratio at steady state was approximately 2.4-fold.
Cobimetinib has linear pharmacokinetics in the dose range of ~3.5 mg to 100 mg.

The absolute bioavailability of cobimetinib was 45.9% (90% CI: 39.7%, 53.1%) in healthy subjects.
A human mass balance study was conducted in healthy subjects, and showed that cobimetinib was extensively metabolised and eliminated in faeces. The fraction absorbed was ~88% indicating high absorption and first pass metabolism.

The pharmacokinetics of cobimetinib are not altered when administered in the fed state (high-fat meal) compared with the fasted state in healthy subjects. Since food does not alter the pharmacokinetics of cobimetinib, it can be administered with or without food.

Distribution

Cobimetinib is 94.8% bound to human plasma proteins in vitro. No preferential binding to human red blood cells was observed (blood to plasma ratio 0.93).
The volume of distribution was 1050 L in healthy subjects given an intravenous dose of 2 mg. The apparent volume of distribution was 806 L in cancer patients based on population pharmacokinetic analysis.

Cobimetinib is a substrate of P-gp in vitro. The transport across the blood brain barrier is unknown.

Biotransformation
Oxidation by CYP3A and glucuronidation by UGT2B7 appear to be the major pathways of cobimetinib metabolism. Cobimetinib is the predominant moiety in plasma. No oxidative metabolites greater than 10% of total circulating radioactivity or human specific metabolites were observed in plasma. Unchanged medicinal product in faeces and urine accounted for 6.6% and 1.6% of the administered dose, respectively, indicating that cobimetinib is primarily metabolised with minimal renal elimination. In vitro data indicate cobimetinib is not an inhibitor of OAT1, OAT3 or OCT2.

Elimination

Cobimetinib and its metabolites were characterised in a mass balance study in healthy subjects. On average, 94% of the dose was recovered within 17 days. Cobimetinib was extensively metabolised and eliminated in faeces.

Following intravenous administration of a 2 mg dose of cobimetinib, the mean plasma clearance (CL) was 10.7 L/hr. The mean apparent CL following oral dosing of 60 mg in cancer patients was 13.8 L/hr.
The mean elimination half-life following oral dosing of cobimetinib was 43.6 hours (range: 23.1 to 69.6 hours). Therefore, it may take up to 2 weeks following treatment cessation for cobimetinib to be completely removed from systemic circulation.

Special populations

Based on a population pharmacokinetic analysis, gender, race, ethnicity, baseline ECOG, mild and moderate renal impairment did not affect the pharmacokinetic of cobimetinib. Baseline age and baseline body weight were identified as statistically significant covariates on cobimetinib clearance and volume of distribution respectively. However, sensitivity analysis suggests neither of these covariates had clinically significant impact on steady state exposure.

Gender
Gender does not have an effect on the exposure of cobimetinib, based on a population pharmacokinetic analysis including 210 women and 277 men.

Elderly
Age does not have an effect on the exposure of cobimetinib, based on a population pharmacokinetic analysis including 133 patients ≥ 65 years of age.

Renal impairment
Based on preclinical data and the human mass balance study, cobimetinib is mainly metabolised, with minimal renal elimination. No formal pharmacokinetic study has been conducted in patients with renal impairment.

A population pharmacokinetic analysis using data from 151 patients with mild renal impairment (creatinine clearance (CRCL) 60 to less than 90 mL/min), 48 patients with moderate renal impairment (CRCL 30 to less than 60 mL/min), and 286 patients with normal renal function (CRCL greater than or equal to 90 mL/min), showed that CRCL had no meaningful influence on exposure of cobimetinib.
Mild to moderate renal impairment does not influence cobimetinib exposure based on the population pharmacokinetic analysis. There are minimal data for Cotellic in patients with severe renal impairment.


Hepatic impairment
The pharmacokinetics of cobimetinib were evaluated in 6 subjects with mild hepatic impairment (Child Pugh A), 6 subjects with moderate hepatic impairment (Child Pugh B), 6 subjects with severe hepatic impairment (Child Pugh C) and 10 healthy subjects. Systemic total cobimetinib exposures after a single dose were similar in subjects with mild or moderate hepatic impairment compared to healthy subjects, while subjects with severe hepatic impairment had lower total cobimetinib exposures (AUC0-∞ geometric mean ratio of 0.69 compared to healthy subjects) which is not considered to be clinically significant. Unbound cobimetinib exposures were similar between subjects with mild and moderate hepatic impairment compared to subjects with normal hepatic function while subjects with severe hepatic impairment had approximately 2-fold higher exposures (see section 4.2).

Paediatric population

The maximum tolerated dose (MTD) in paediatric patients with cancer for the tablet and suspension formulations were declared at 0.8 mg/kg/day and 1.0 mg/kg/day, respectively. The geometric mean (CV%) steady state exposures in paediatric patients at the declared MTD of 1.0 mg/kg/day (suspension formulation) was Cmax,ss 142 ng/mL (79.5%) and AUC0-24,ss 1862 ng.h/mL (87.0%), which is approximately 50% lower than in adults at a dose of 60 mg once daily.