Cotellic

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 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 5. Table 5 Efficacy results from Study GO28141 (coBRIM) Cotellic + vemurafenib N=247 Placebo + vemurafenib N=248 Primary Endpoint a, f Progression-Free Survival (PFS) Median (months) (95 % CI) 12.3 (9.5, 13.4) 7.2 (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) (95 % CI) 22.3 (20.3, NE) 17.4 (15.0, 19.8) Hazard ratio (95% CI) b 0.70 (95% CI: 0.55, 0.90) (p-value = 0.0050 e ) Objective response rate (ORR) 172 (69.6%) 124 (50.0%) (95% CI) for ORR c (63.5%, 75.3%) (43.6%, 56.4%) Difference in ORR % (95% CI) d 19.6 (11.0, 28.3) 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) (95% CI) for median 13 (11.1, 16.6) 9.2 (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%).