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Cotellic

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About Cotellic

Cotellic is an orally available inhibitor of MEK1 and MEK2 tyrosine-threonine kinases. It is used to treat metastatic melanoma.

Cotellic is a Prescription Medicine, available as a film-coated 20 mg tablet.

For information on dosage and administration of Cotellic, please refer to the Data Sheet on the Medsafe website here.1

Cotellic is indicated for use in combination with Zelboraf (vemurafenib) for the treatment of patients with unresectable or metastatic melanoma with BRAF V600 mutation. Cotellic’s Mechanism of action 2

The mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (MEK) pathway is a key signalling pathway that regulates cell proliferation, cell cycle regulation, cell survival, angiogenesis, and cell migration.

Cotellic is an orally available inhibitor of MEK1 and MEK2 tyrosine-threonine kinases.

By simultaneously targeting BRAF and MEK the combination of Zelboraf and Cotellic inhibits MAPK pathway reactivation through MEK1/2 resulting in stronger inhibition of signalling, greater tumour cell apoptosis and enhanced tumour responses in pre-clinical models than Zelboraf alone.

Cotellic is not funded by PHARMAC and patients need to pay for it.

We provide a Patient Cost Share Programme to assist with the cost of Cotellic. Click here for details.


If your patient has private health insurance, it may be worthwhile they check their policy regarding cancer treatments like Cotellic.
Reference
1. Cotellic® (cobimetinib) Data Sheet. Available here.
2. Adis Insight Drug Profile Cobimetinib Updated 16TH July 2016 http://adisinsight.springer.com/drugs/800026224 accessed 1st June

All the details of the Cotellic Access Programme are in the healthcare professional brochure. Click on the image to download a copy.

Click on the images to download copies of the Cotellic Access Programme enrolment form and easy order form.


Key Efficacy and Safety Information1,2.

The coBRIM3 study, was a multicentre, randomised, double-blind, placebo-controlled, Phase III study to evaluate the safety and efficacy of COTELLIC in combination with ZELBORAF compared to ZELBORAF plus placebo, in patients with previously untreated BRAF V600 mutation-positive unresectable locally advanced (stage IIIC) or metastatic melanoma (stage IV).


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 and PFS as assessed by an independent review facility (IRF).

Efficacy Results from coBRIM3


COTELLIC+ ZELBORAF
n = 247
Placebo + ZELBORAF
n = 248
PRIMARY ENDPOINT Progression- free survival (Inv)a, g Median by Kaplan Meier (KM) estimate (months)
(95%CI)
12.3
(9.5-13.4)
7.2
(5.6, 7.5)
Hazard ratio (95%CI) 0.58 (0.46, 0.72) (p-value < 0.0001)
KEY SECONDARY ENDPOINTS Progression-free survival (IRF)b,c Median by KM-estimate (months) (95%CI) 11.3
(8.5, NE)
6.0
(5.6,7.5)
Hazard ratio (95%CI) 0.60 (0.45; 0.79) (p-value 0.0003)
Overall survival
MedianKM estimate (months) (95%CI)
22.3 (20.3,NE) 17.4 (15.0,19.8)
Hazard ratio (95%CI)c 0.70 (95% CI: 0.55, 0.90) (p-value= 0.0050e)
Objective responsea
Objective response rate (ORR), n (%) (95%CId)
172 (70%) (63.5%, 75.3%) 124 (50%) (43.6%, 56.4%)



Best Overall Response
Complete Response, n (%)
Partial Response, n (%)
Stable disease, n (%)
Duration of response
Median duration of response (months)
95%CI for median
39 (16.0%)
133 (54%)
44 (18%)
13 (11.1,16.6)
26 (10%)
98 (40 %)
92 (37%)
9.2 (7.5,12.8)

a Assessed and confirmed by the investigator (Inv) using RECIST v1.1

b Assessed and confirmed by an independent review facility (IRF) assessment using RECIST v1.1

c Stratified analysis by geographic region and metastasis classification (disease stage)

d Using Clopper-Pearson method

e The OS p-value (0.0050) crossed the pre-specified boundary (p-value <0.0499)

f Using Hauck-Anderson method

g See text for discussion of post-hoc analysis of PFS NE = not evaluable

Note: The table represents results fromthe primary analysis (cut-off date 9 May 2014). The exception is the pre- planned final analysis of overall survival (cut-off date 28 August 2015)

Figure 1. CoBRIMKaplan-Meier Curves of Progression-free Survival (Inv): Intent-to-Treat Population

Figure 2. CoBRIMKaplan-Meier Curves of Final Overall Survival: Intent-to-Treat Population

Key Safety Information

Precautions (also see Zelboraf Safety Information)

Serous retinopathy

  • prompt ophthalmologic examination for new or worsening visual disturbances
  • interrupt treatment and manage with dosage modification or discontinuation

Left ventricular dysfunction

  • evaluate LVEF before treatment, after first month of treatment and at least every 3 months during treatment
  • manage LVEF decreases with treatment interruption, dosage modification or discontinuation

Liver laboratory abnormalities

  • monitor before treatment and at least monthly during treatment
  • manage abnormalities with treatment interruption, dosage modification or discontinuation

Haemorrhage

  • follow dose modification guidelines

Rhabdomyolysis

  • monitor CPK periodically during treatment
  • if elevated, evaluate for rhabdomyolysis.

Dermatological reactions

  • follow dose modification guidelines

Photosensitivity

  • advise patients to avoid sun exposure and use sun protection
  • manage with dose modification

Pregnancy – Category D

  • not recommended during pregnancy
  • advise patients to use 2 effective forms of contraception during treatment and for at least 3 months after last dose.


Renal impairment

  • caution in patients with severe renal impairment.

Interactions

  • do not use with potent CYP3A inducers or inhibitors
  • avoid if possible, or exercise caution with moderate CYP3A inducers or inhibitors.

Adverse Effects (see Data Sheet for full list)

Very common or common:

  • Chorioretinopathy, blurred vision, retinal detachment
  • diarrhoea, nausea, vomiting
  • pyrexia, chills
  • decreased ejection fraction
  • dehydration, hyponatremia
  • basal cell carcinoma
  • photosensitivity, rash
  • hypertension
  • increased ALP, ALT, AST, GGT, blood bilirubin, CPK
  • anaemia, lymphopenia, thrombocytopenia

The table below summarises the ADRs occurring at a ≥ 5% higher incidence (all grades) or at a ≥ 2% higher incidence (grades 3 - 4) of patients treated with COTELLIC in combination with ZELBORAF in the CoBRIM3 study. The following categories of frequency have been used: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000).

Adverse Reactions of All Grades (Incidence ≥ 5% over the control arm) or Grade 3 - 4 (Incidence ≥ 2% over the control arm)

ADRs Phase III study: coBRIM Frequencya
(All Grades)
COTELLIC+
ZELBORAF (n = 247)
Placebo +
ZELBORAF (n = 246)

All grades
(%)
Grade 3 - 4
(%)
All grades
(%)
Grade 3 -4
(%)

Blood and Lymphatic
SystemDisorders
Anaemia
13 2 8 8 very common
Eye Disorders
Chorioretinopathy
Vision Blurred
Retinal Detachment
13
10
9
<1
-
2
<1
2
<1
-
-
-
very common
General disorders and
administration site conditions

Pyrexia
Chills

28
10

2
-

23
5

-
-

very common
Investigations
Decreased
Ejection
Fraction
9 2 4 1 common
Metabolismand nutrition
disorders

Dehydration
Hyponatremia

4
5

2
2
1
1
-
<1
common
common
Neoplasms benign,
malignant and unspecified

Basal cell carcinoma

4

4

2

2
commom
Skin and subcutaneous
tissue disorders

Photosensitivityb
Maculo−papular rash
Dermatitis acneiform rash

47
15
14

4
7
2

35
15
9

-
5
1

very common
very common
very common
Vascular Disorders
Hypertension
15
4 8 2 very common

a Based on the Phase III study GO28141 adverse events of all grades

b Combined figure includes reports of photosensitivity reaction, sunburn, solar dermatitis, actinic elastosis

ADRs (all grades) Reported with < 5%Greater Incidence in theCOTELLIC-Plus- ZELBORAF Arm than the Placebo-Plus-ZELBORAF Control Arm in the coBRIM Study

Eye disorders: visual impairment (3% in the COTELLICarm vs. 0% in the control arm)
Metabolism and nutrition disorders: hyperglycemia (3% in the COTELLIC arm vs. 1% in the control arm), hypophosphatemia (4% in the COTELLICarmvs 1% in the control arm).

Respiratory, thoracic and mediastinal disorders: pneumonitis (1% in the COTELLICarmvs. < 1% in the control arm).

Skin and subcutaneous tissue disorders: rash (40% in the COTELLICarmvs. 38% in the control arm).
Further Information on Selected Adverse Reactions

Haemorrhage

Bleeding events have been reported more frequently in the COTELLIC arm than in the control arm (all types and grades: 13% vs. 7%). Higher frequencies in the COTELLIC arm were observed for cerebral haemorrhage (1% vs. 0%), gastrointestinal (GI) tract haemorrhage (4% vs. 1%), reproductive system haemorrhage (2% vs.
<1%), and haematuria (3% vs. 1%).
The majority of events were Grade 1 or 2 and non-serious (12% of patients in the COTELLIC arm vs. 7%
patients in the control arm). Most events resolved or were resolving with no change in COTELLIC dose. Grade 3 to 4 events were experienced by 1% of patients in each arm.

Photosensitivity

Photosensitivity has been observed with a higher frequency in the COTELLIC arm vs. the control arm (47% vs.
35%). The majority of events were Grades 1 or 2, with Grade ≥ 3 events occurring in 4% of patients in the
COTELLIC arm vs. 0% in the control arm.
There were no apparent trends in the time of onset of Grade ≥ 3 events. Grade ≥ 3 photosensitivity events in the COTELLIC arm were treated with primary topical medication in conjunction with dose interruptions of both COTELLIC and ZELBORAF (see DOSAGE AND ADMINISTRATION, Dose Modification Recommendations).

No evidence of phototoxicity was observed with COTELLIC as a single agent. Cutaneous Squamous Cell Carcinoma, Keratoacanthoma and Hyperkeratosis
Cutaneous squamous cell carcinoma has been reported with a lower frequency in the COTELLIC arm vs. the control arm (all grade: 3% vs. 13%). Keratoacanthoma has been reported with a lower frequency in the COTELLIC arm vs. control arm (all grade: 2% vs. 9%). Hyperkeratosis has been reported with a lower frequency in the COTELLIC arm vs. control arm (all grades: 11% vs. 30%).

References

  • 1. Cotellic®(cobimetinib) Data Sheet. Available here
  • 2. Zelboraf ( vemurafenib) Data Sheet. Available here
  • 3. Ascierto P et al. Lancet Oncology. 2016; 17(9): 12481260.
  • PM-NZ-0160/NA9202/Jun 2017