Summary Basis of Decision for Cotellic

 

Clinical Pharmacology

The clinical pharmacology program for Cotellic included reports on human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Cotellic for the specified indication.

Cotellic (cobimetinib) is a reversible inhibitor of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1 (MEK1) and MEK2. MEK proteins are upstream regulators of the extracellular signal related kinase (ERK) pathway, which promotes cellular proliferation. In vitro, cobimetinib inhibited MEK1 and MEK2 with half maximal inhibitory concentration (IC₅₀) values of 0.95 nM and 199 nM, respectively.

The major pathways of metabolism for cobimetinib are oxidation by the cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5, and glucuronidation by UDP-Glucuronosyltransferase 2 Family, Polypeptide B7 (UGT2B7), therefore cobimetinib has the potential for drug-drug interactions with CYP3A modulators. Coadministration of cobimetinib with a strong CYP3A inhibitor (itraconazole) resulted in a significant increase in cobimetinib exposure (a 6.7-fold increase).The effect of strong and moderate CYP3A inhibitors on the increased exposure of cobimetinib is of clinical significance and they should not be used concomitantly with Cotellic. An appropriate warning is included in the Serious Warnings and Precautions box in the Cotellic Product Monograph.

Study results have also suggested that strong and moderate inducers of CYP3A (rifampicin and efavirenz) could decrease cobimetinib system exposure by 83% and 72%, respectively. Therefore, co-administration of cobimetinib with strong or moderate CYP3A inducers should be avoided.

The pharmacokinetics of cobimetinib have not been studied in patients with moderate to severe hepatic impairment; therefore, no dosing recommendations have been established for Cotellic in these patients. Given that cobimetinib is metabolized and eliminated via the liver, patients with hepatic impairment may have increased exposure. The precaution that Cotellic has not been studied in patients with moderate and severe hepatic impairment has been included within the Serious Warnings and Precautions box in the Cotellic Product Monograph.

The sponsor submitted the results of a food effect study comparing the bioavailability of a prototype of the Cotellic commercial tablet formulation following its administration in the fasted and high-fat fed states in healthy volunteers. There were excipient changes in formulation between the prototype of Cotellic used in this study and the final commercial tablet formulation; however, the commercial formulation of Cotellic was used during the pivotal Phase III clinical study, during which product administration was conducted without regards to food, consistent with the dosing administration instructions in the Cotellic Product Monograph. The results of the food effect study met standards for bioequivalence, indicating that the rate and extent of absorption of cobimetinib were not significantly different when the proposed Cotellic prototype tablets were administered under standard fasting and high-calorie, high-fat fed conditions.

For further details, please refer to the Cotellic Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Cotellic in combination with vemurafenib for the treatment of adult patients with BRAF V600-mutation positive unresectable or metastatic melanoma was evaluated in a pivotal Phase III Study GO28141 (coBRIM) and in a supportive Phase Ib Study NO25395 (BRIM7). Clinical data to support the efficacy of Cotellic monotherapy were limited to a small number of patients with advanced melanoma treated in a Phase I study. No further monotherapy studies are planned and monotherapy is not recommended for the treatment of patients with advanced melanoma.

Study G028141 was an international, multicentre randomized (1:1), double-blind, placebo-controlled Phase III study conducted in patients with previously untreated BRAF V600 mutation-positive unresectable locally advanced or metastatic melanoma. Eligible patients were randomized to receive Cotellic in combination with vemurafenib (number of patients [n] = 247) or to receive placebo in combination with vemurafenib (n = 248). The Cotellic plus vemurafenib group received 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. The placebo plus vemurafenib group received placebo once daily on Days 1-21 of each 28-day treatment cycle and 960 mg vemurafenib twice daily on Days 1-28.

Overall, demographic characteristics and patient baseline disease characteristics were well balanced between the two treatment groups. Key baseline characteristics included: 58% of patients were male, 93% reported White race, median age was 55 years (range 23-88 years), 60% had metastatic melanoma stage M1c, Eastern Cooperative Oncology Group performance status was 0 in 72% and 1 in 28%, serum lactate dehydrogenase was elevated in 45%, prior adjuvant therapy had been administered to 10%, and <1% had previously-treated brain metastases.

Treatment continued until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurred earliest. Patients in the placebo plus vemurafenib group were not eligible to cross over to the Cotellic plus vemurafenib group at disease progression.

The primary efficacy endpoint was progression-free survival (PFS) as assessed by the investigator (Inv) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Secondary efficacy endpoints included overall survival (OS), objective response rate (ORR), and PFS as assessed by a blinded independent review facility (IRF). Global health status/health-related quality of life by patient-report was an additional secondary efficacy endpoint. This endpoint was measured for each treatment group using the European Organisation for Research on the Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30).

Cotellic in combination with vemurafenib demonstrated a statistically significant increase in PFS (Inv) with a hazard ratio of 0.51 (95% confidence interval [CI] 0.39-0.68, p<0.0001). The median PFS (Inv) was 9.9 months for the Cotellic plus vemurafenib group versus 6.2 months for the placebo plus vemurafenib group. The effect on PFS was also supported by the analysis of PFS (IRF). The PFS (Inv) benefit for Cotellic in combination with vemurafenib was observed in pre-specified BRAF V600 mutation subgroups (V600E and V600K).

The ORR (complete response or partial response) in the Cotellic plus vemurafenib group was 67.6% of patients versus 44.8% in the placebo plus vemurafenib group. A pre-specified interim OS analyses was performed at the time of the primary PFS analysis. Median OS had not been reached in either treatment group and the analysis did not cross the pre-specified boundary for statistical significance. A clinically meaningful change between the two treatment groups was not demonstrated in quality of life.

Study NO25395 was designed to assess the safety, tolerability, pharmacokinetics and efficacy of Cotellic when combined with vemurafenib for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. A total of 129 patients were enrolled, 63 were BRAF inhibitor therapy naïve (BRAFi-naïve) and 66 had previously progressed on prior vemurafenib therapy (vemurafenib-progressive disease [PD]). BRAFi-naïve patients achieved an 87% ORR, including complete response in 10% of patients, and a median PFS of 13.7 months. Vemurafenib-PD patients achieved a 15% ORR, all partial responses, and a median PFS of 2.8 months. A total of 66 patients in this study were treated with the recommended dose and schedule, 39 of whom were BRAFi-naïve and 27 of whom were vemurafenib-PD. In this subgroup, BRAFi-naïve patients achieved an 85% ORR and median PFS of 12.7 months; and vemurafenib-PD patients achieved a 26% ORR and median PFS of 2.8 months.

Efficacy Limitations

Clinical data supporting the efficacy of Cotellic in combination with vemurafenib in patients with a BRAF V600K mutation are limited and there are no clinical data for other less common BRAF V600 mutations. This lack of data is communicated in the Indications and Clinical Use section of the Cotellic Product Monograph; however, inclusion of all BRAF V600 mutations (V600E, V600K, and other rare mutations) in the indication is considered reasonable.

Patients with active central nervous system lesions were excluded from the Phase III study, and <1% of enrolled patients had previously treated brain metastases. A tissue distribution study conducted in rats demonstrated low levels of cobimetinib in central nervous system tissues protected by the blood-brain barrier. As a result, a warning was placed in the Cotellic Product Monograph stating that Cotellic is not recommended for patients with BRAF V600 mutation-positive melanoma who have active untreated brain metastases.

Patients with non-cutaneous malignant melanoma were not enrolled in clinical studies; however, these patients are rare and it can be anticipated that similar biological activity would be observed.

The efficacy of the addition of Cotellic in patients who have progressed on vemurafenib has not been established. The efficacy results in the Phase Ib study N025395 reported fewer responses and shorter PFS for the subgroup with vemurafenib-PD compared with the BRAFi-naïve group. Furthermore, the pivotal Phase III study G028141, by design, excluded patients who had progressed on a prior BRAF inhibitor, and did not allow patients in the vemurafenib plus placebo arm to cross over to the vemurafenib plus Cotellic group at disease progression. Thus, efficacy data from the Phase 1b study are not included in the Cotellic Product Monograph.

Indication

The sponsor proposed the following indication:

Cotellic (cobimetinib) is indicated for use in combination with Zelboraf (vemurafenib) for the treatment of patients with unresectable or metastatic melanoma with BRAF V600 mutation.

Patients treated with Cotellic in combination with Zelboraf must have BRAF V600 mutation-positive melanoma tumour status confirmed by a validated test.

Health Canada recommended the following indication in order to communicate additional limitations of usefulness and situations where use of the product is not therapeutically appropriate:

Cotellic (cobimetinib) is indicated for use in combination with vemurafenib for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Prior to initiation of treatment with Cotellic in combination with vemurafenib, patients must have BRAF V600 mutation-positive melanoma tumour status confirmed by a validated test.

Effectiveness of Cotellic in combination with vemurafenib is based on progression-free survival (PFS) and objective response rate (ORR) results. Prolongation of overall survival (OS) has not been demonstrated.

Clinical data supporting the effectiveness of Cotellic in combination with vemurafenib in patients with a BRAF V600K mutation are limited. There are no clinical data for other less common BRAF V600 mutations.

There are no clinical data to support the effectiveness of Cotellic in combination with vemurafenib in patients with non-cutaneous malignant melanoma.

For more information, refer to the Cotellic Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Cotellic in combination with vemurafenib at the recommended dose and schedule was primarily based on data from the safety population in the pivotal Phase III Study GO28141 (n = 254). For patients in the Cotellic in combination with vemurafenib group, the median duration of Cotellic exposure was 179 days and the median duration of vemurafenib exposure was 183 days. Supportive safety data were provided from the Phase Ib Study N025395. Both studies are described in the Clinical Efficacy section.

Overall, the safety profile of Cotellic in combination with vemurafenib was tolerable and adverse events (AEs) were manageable with dosing modification and/or supportive care. In Study GO28141, the most common AEs (≥ 20%) that occurred with greater frequency in the Cotellic plus vemurafenib group were diarrhea, rash, nausea, increased blood creatine phosphokinase (CPK) levels, photosensitivity reaction, pyrexia, increased alanine transaminase (ALT) levels, increased aspartate aminotransferase (AST) levels, and vomiting. Diarrhea was the AE most commonly reported while taking Cotellic plus vemurafenib. The majority of AEs were Grade 1 or 2, and Grade 3 or 4 events were less common and were generally managed adequately with dose modification guidelines. There were few patients who experienced Grade 5 AEs, and for most patients the underlying disease was considered a contributing factor. Adverse events leading to permanent discontinuation of the combination were documented in 10.6% of patients receiving Cotellic plus vemurafenib compared with 7.1% of patients receiving placebo plus vemurafenib. Adverse events led to dose interruption or reduction of the combination in 42.1% of patients treated with Cotellic plus vemurafenib versus 32.6% treated with placebo plus vemurafenib.

The addition of Cotellic to vemurafenib attenuated the development of secondary cutaneous lesions such as squamous cell carcinomas and keratoacanthomas which are well-recognized toxicities associated with use of single-agent BRAF inhibitors such as vemurafenib. While the frequency of cutaneous squamous cell carcinomas and keratoacanthomas was decreased, the incidence of basal cell carcinomas was increased. Second primary melanoma occurred uncommonly and was reported at a decreased frequency compared with the placebo plus vemurafenib group.

Events of serous retinopathy and visual disturbances, elevations in CPK, and reductions in left ventricular ejection fraction (LVEF), all recognized effects of drugs that are MEK inhibitors, were observed with higher frequency in the Cotellic plus vemurafenib group compared with the placebo plus vemurafenib group. Rhabdomyolysis may also occur with Cotellic use. Retinal vein occlusion, observed with other MEK inhibitors and with vemurafenib, was reported in a single patient in each treatment group.

The incidence of severe photosensitivity, rash, and liver laboratory abnormalities (hepatotoxicity) was higher in the Cotellic plus vemurafenib group compared to the placebo plus vemurafenib group.

Hypertension and atrial fibrillation were also identified as clinically significant adverse drug reactions. The frequency of QT interval prolongation was comparable across treatment groups, as was the frequency of Grade ≥3 QTc prolongation group term events.

Bleeding events which included major hemorrhage, defined as symptomatic bleeding in a critical area or organ, were observed more frequent in the Cotellic plus vemurafenib group. In the Phase III study, Grade 3-5 hemorrhagic events were experienced by 1.6 % in the Cotellic plus vemurafenib group and 0.4% in the placebo plus in vemurafenib group.

Grade 3 hypersensitivity events were reported in 1.2% of the patients that received Cotellic in combination with vemurafenib compared with no such events in the placebo plus vemurafenib group.

Compared with patients <65 years old, more patients ≥65 years old experienced AEs that led to discontinuation of the treatment regimen and to dose modification of the treatment regimen. Increased sensitivity of some geriatric patients cannot be ruled out.

A thorough QT study was not conducted. Cotellic causes a decrease in heart rate and increases in the PR interval and QRS duration. In a Phase I, non-randomized, open-label, safety and pharmacokinetic dose-escalation and expansion study, 20 cancer patients received Cotellic at a dose of 60 mg/day for 28 day cycles (21 days on-treatment, 7 days off treatment).Serial electrocardiogram (ECG) recordings were performed on Day 21 (pre-dose, 1.5 h, 3 h, and 6 h) of Cycle 1, for 13 of the patients. Statistically significant decreases in heart rate from pre-treatment baseline were observed on Cycle 1, Day 21 at all time points, with a maximum mean decrease of -10.7 bpm at 1.5 h post-dosing. Statistically significant mean increases from baseline in the PR interval and QRS duration were observed at all time points on Day 21. The maximum mean increase in the PR interval was 15.0 ms at 3 h post-dosing and the maximum mean increase in the QRS duration was 5.8 ms at 1.5 h post-dosing. For the QTcF interval, the maximum mean increase from baseline was 1.2 ms. Based on these findings, revisions were made to the Cotellic Product Monograph to communicate that caution should be observed in patients with concurrent cardiac conditions or medications that affect heart rate or ECG parameters. Patients should be assessed for electrocardiogram intervals prior to initiating treatment and periodically during steady-state treatment with Cotellic.

Overall, Cotellic has a tolerable and manageable safety profile. Appropriate warnings and precautions are in place in the approved Cotellic Product Monograph to address the identified safety concerns. Warnings of left ventricular dysfunction, hemorrhage (including major hemorrhage), serous retinopathy, and retinal vein occlusion have been included in a Serious Warnings and Precautions box. Also included are warning statements that Cotellic has not been studied in patients with moderate and severe hepatic impairment, that Cotellic should not be used concomitantly with a strong or moderate cytochrome P450 (CYP) 3A inhibitor, and that Cotellic in combination with vemurafenib should be prescribed and supervised by a qualified physician experienced in the use of anti-cancer agents. To mitigate risk, the Monitoring and Laboratory Tests section of the Cotellic Product Monograph provides advice on monitoring patients who are taking Cotellic while the Dosage and Administration section of the Cotellic Product Monograph provides dose modification recommendations for concomitant drugs and for adverse drug reactions.

For more information, refer to the Cotellic Product Monograph, approved by Health Canada and available through the Drug Product Database.