Cobimetinib

Cobimetinib is a reversible, selective, allosteric inhibitor of the kinases MEK1 and MEK2, which sit in the middle of the MAPK (RAS/RAF/MEK/ERK) signalling pathway. In melanomas with a BRAF V600 mutation this pathway is permanently switched on. The BRAF inhibitor vemurafenib blocks the mutated BRAF protein, but tumours often escape it by reactivating the pathway downstream; adding cobimetinib blocks the pathway at a second point.

Mechanism of Action

• MEK1/2 inhibition: cobimetinib binds MEK1 and MEK2 and prevents the phosphorylation of ERK1 and ERK2, so it blocks cell proliferation driven by the MAPK pathway.
• Combination with vemurafenib: in preclinical models, targeting mutated BRAF V600 proteins and MEK at the same time inhibited reactivation of the pathway through MEK1/2, giving stronger inhibition of intracellular signalling and decreased tumour cell proliferation.
• Further preclinical findings (DrugBank): in mouse models of tumours with BRAF V600E, the combination increased cell death and reduced tumour growth compared with either medicine alone, and cobimetinib prevented the growth enhancement that vemurafenib caused in a wild-type BRAF tumour line.

Pharmacokinetics

• Absorption: moderate rate of absorption; median time to peak concentration 2.4 hours after a 60 mg dose. At steady state the mean peak concentration (Cmax) is 273 ng/mL and the AUC0–24 is 4,340 ng·h/mL, with accumulation of about 2.4-fold. Pharmacokinetics are linear between about 3.5 mg and 100 mg. Absolute bioavailability is about 46% in healthy subjects; food (including a high-fat meal) does not change exposure.
• Distribution: 94.8% bound to human plasma proteins in vitro, with no preferential binding to red blood cells. The apparent volume of distribution is 806 L in cancer patients. Cobimetinib is a P-glycoprotein substrate in vitro; transport across the blood-brain barrier is unknown.
• Metabolism: oxidation by CYP3A and glucuronidation by UGT2B7 are the main pathways. Cobimetinib is the predominant compound in plasma, and no oxidative metabolite above 10% of circulating radioactivity and no human-specific metabolite was seen.
• Elimination: extensively metabolised and eliminated mainly in faeces; about 94% of a radiolabelled dose was recovered within 17 days, with only 6.6% (faeces) and 1.6% (urine) as unchanged drug. Mean apparent clearance after 60 mg orally is 13.8 L/h. DrugBank gives a mean elimination half-life of about 44 hours (range 23–70).
• Special populations: mild or moderate renal impairment does not call for a dose change; data in severe renal impairment are minimal. Patients with severe hepatic impairment may have higher unbound concentrations.

• Unresectable or metastatic melanoma with a BRAF V600 mutation: in combination with vemurafenib, for the treatment of adult patients.
• BRAF V600 mutation-positive tumour status must be confirmed by a validated test before treatment starts.

• Hypersensitivity to cobimetinib or to any of the excipients.

Safety with vemurafenib was evaluated in 247 patients with advanced BRAF V600-mutated melanoma in the main randomised study, and in 129 patients in a second study with a consistent profile. The most common reactions (more than 20%) occurring more often with cobimetinib plus vemurafenib than with placebo plus vemurafenib were diarrhoea, rash, nausea, pyrexia, photosensitivity reaction, raised alanine and aspartate aminotransferases, raised blood creatine phosphokinase (CPK) and vomiting. The frequencies below come from the main study (data cut-off 19 September 2014); the vemurafenib SmPC lists the effects of vemurafenib itself.

Very common (≥1/10): anaemia; serous retinopathy (chorioretinopathy and retinal detachment), blurred vision; hypertension, haemorrhage; diarrhoea, nausea, vomiting, stomatitis; photosensitivity, rash, maculo-papular rash, acneiform dermatitis, hyperkeratosis, pruritus, dry skin; pyrexia, chills, peripheral oedema; increased blood CPK, ALT, AST, gamma-glutamyltransferase (GGT) and alkaline phosphatase.

Common (≥1/100 to <1/10): basal cell carcinoma, cutaneous squamous cell carcinoma, keratoacanthoma; dehydration, hypophosphataemia, hyponatraemia, hyperglycaemia; visual impairment; pneumonitis; decreased ejection fraction, increased blood bilirubin.

Uncommon (≥1/1,000 to <1/100): rhabdomyolysis.

Selected reactions with the combination:

• Haemorrhage: bleeding occurred in 13% against 7% with placebo plus vemurafenib; most events were grade 1 or 2 and non-serious. Major haemorrhage, including intracranial and gastrointestinal, has been reported after marketing, and the risk may be higher with antiplatelet or anticoagulant therapy.
• Photosensitivity: 47% against 35%; grade 3 or higher in 4% against 0%.
• Skin tumours and hyperkeratosis: cutaneous squamous cell carcinoma (3% against 13%), keratoacanthoma (2% against 9%) and hyperkeratosis (11% against 30%) were less frequent than with vemurafenib alone.
• Laboratory changes: increased ALP (69%), ALT (67%), AST (71%), GGT (62%), bilirubin (33%) and CPK (70%, grade 3 or 4 in 12%).
• Older patients: patients aged 65 years or more were more likely to have serious adverse events and events leading to discontinuation.

Cobimetinib is metabolised by CYP3A, so CYP3A inhibitors and inducers change its exposure.

• Strong CYP3A inhibitors (ritonavir, cobicistat, telaprevir, lopinavir, itraconazole, voriconazole, clarithromycin, telithromycin, posaconazole, nefazodone and grapefruit juice): itraconazole raised cobimetinib exposure (AUC) about 7-fold in healthy subjects; the effect may be smaller in patients. Avoid concurrent use. If unavoidable, monitor safety carefully; for short-term inhibitor use (7 days or less), consider interrupting cobimetinib for the duration.
• Moderate CYP3A inhibitors (amiodarone, erythromycin, fluconazole, miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, imatinib): use with caution and monitor safety carefully.
• Mild CYP3A inhibitors: can be co-administered without dose adjustment.
• CYP3A inducers (for example carbamazepine, rifampicin, phenytoin, St John’s wort): the effect of a strong inducer was not studied, but a fall in cobimetinib exposure is likely. Moderate and strong inducers should be avoided; alternatives with no or minimal induction should be considered.
• Antiplatelet and anticoagulant medicines: may increase the risk of bleeding (see Special Instructions).
• Food: grapefruit and St John’s wort should be avoided (DrugBank). Cobimetinib can be taken with or without food.
• Section 4.5 of the SmPC contains further interaction data that are not summarised here.

Treatment with Cotellic in combination with vemurafenib must be started and supervised by a qualified physician experienced in the use of anticancer medicinal products. BRAF V600 mutation-positive melanoma must be confirmed by a validated test first. The tablets are swallowed whole with water, with or without food.

Recommended Dose

• 60 mg (three 20 mg tablets) once daily, in 28-day cycles: once daily for 21 consecutive days (days 1 to 21), then a 7-day break (days 22 to 28). The next cycle starts after the break.
• Vemurafenib is dosed according to its own SmPC.
• Treatment continues until the patient no longer benefits or toxicity becomes unacceptable.

Dose Adjustments

• General rules: the decision to reduce the dose of either or both medicines rests on the prescriber’s assessment of safety and tolerability. Cotellic dose changes are independent of vemurafenib dose changes. Omitted doses are not replaced, and once the dose has been reduced it is not increased again.
• General scheme (CTCAE grade): grade 1 or 2 (tolerable): no reduction. Grade 2 (intolerable) or grade 3/4: first appearance, interrupt until grade 1 or lower and restart at 40 mg once daily (two tablets); second appearance, interrupt until grade 1 or lower and restart at 20 mg once daily (one tablet); third appearance, consider permanent discontinuation.
• Haemorrhage: for grade 4 events or cerebral haemorrhage, interrupt Cotellic; stop it permanently for haemorrhage attributed to Cotellic. For grade 3 events, interrupt during evaluation and use clinical judgement before restarting. Vemurafenib can continue if clinically indicated.
• Reduced left ventricular ejection fraction (LVEF): asymptomatic patients with LVEF of 50% or more (or 40–49% with less than a 10% absolute fall from baseline) continue unchanged. If LVEF is below 40% (or 40–49% with a fall of 10% or more) with no symptoms, interrupt for 2 weeks; if the patient has symptoms, interrupt for 4 weeks. After the break, if LVEF has recovered to a fall of less than 10% from baseline (and the patient has no symptoms), restart at 40 mg (first occurrence) or 20 mg (second occurrence), and stop permanently at a third occurrence. Stop permanently if LVEF is still below 40% (or has fallen 10% or more), or if the patient is symptomatic whatever the LVEF. Also consider stopping if cardiac symptoms attributed to Cotellic do not improve after a temporary interruption.
• Rhabdomyolysis or symptomatic CPK elevation: interrupt; stop permanently if there is no improvement within 4 weeks. If severity improves by at least one grade within 4 weeks, Cotellic can be restarted at a dose reduced by 20 mg, if clinically indicated. Grade 4 asymptomatic CPK elevation: interrupt, with the same 4-week rule (improvement to grade 3 or lower). Asymptomatic CPK elevation of grade 3 or lower: no change once rhabdomyolysis is excluded.
• Liver laboratory abnormalities (with vemurafenib): grade 1 or 2, continue both. Grade 3, continue Cotellic and reduce vemurafenib as appropriate. Grade 4, interrupt both; if values improve to grade 1 or lower within 4 weeks, restart Cotellic reduced by 20 mg and vemurafenib at an appropriate dose; stop both if they do not improve in 4 weeks or if grade 4 recurs.
• Photosensitivity: tolerable grade 2 or lower is managed with supportive care. For intolerable grade 2 or grade 3 or higher, interrupt both medicines until grade 1 or lower; Cotellic restarts at the same dose and vemurafenib is reduced as appropriate.
• Rash: tolerable grade 2 or lower: supportive care, Cotellic unchanged. Intolerable grade 2 or grade 3 or higher acneiform rash: follow the general scheme for Cotellic. For non-acneiform or maculo-papular rash of that severity, Cotellic can continue unchanged while vemurafenib is interrupted or reduced.
• QT prolongation: if the QTc exceeds 500 msec, follow the vemurafenib SmPC; no Cotellic change is needed.

Special Populations

• Elderly (65 years or older): no dose adjustment.
• Renal impairment: no adjustment in mild or moderate impairment; minimal data in severe impairment, so use with caution.
• Hepatic impairment: no adjustment is recommended, but caution is advised in any degree of hepatic impairment because liver laboratory abnormalities can occur.
• Non-Caucasian patients: safety and efficacy have not been established.
• Children and adolescents below 18 years: safety and efficacy have not been established and no dose can be recommended.

Missed or Vomited Dose

If a dose is missed, it can be taken up to 12 hours before the next dose, to keep the once-daily regimen. If vomiting occurs after a dose, no extra dose is taken that day; treatment continues as prescribed the next day.

Before and During Combination Treatment

BRAF V600 status must be confirmed by a validated test. Data are limited in patients who progressed on a previous BRAF inhibitor, and the combination appears less effective there, so other options should be considered first. In patients with brain metastases the limited safety data are consistent with the known profile, but efficacy has not been evaluated and the intracranial activity of Cotellic is unknown.

Haemorrhage

Haemorrhagic events, including major ones, can occur. Use caution in patients with other bleeding risk factors, such as brain metastases, or taking antiplatelet or anticoagulant medicines.

Serous Retinopathy

Fluid accumulation within the retinal layers (mostly reported as chorioretinopathy or retinal detachment) has been seen with MEK inhibitors including Cotellic; median time to onset was 1 month (range 0–9 months). Patients are assessed at each visit for new or worsening visual disturbance, and an eye examination is recommended if it occurs. Treatment is withheld until symptoms improve to grade 1 or lower, and most events resolved or improved after interruption or dose reduction.

Left Ventricular Dysfunction

LVEF should be measured before treatment, after the first month and at least every 3 months, or as clinically indicated, until treatment stops. Median time to onset of a decrease was 4 months (range 1–13 months). After restarting at a reduced dose, LVEF is measured after about 2, 4, 10 and 16 weeks and then as indicated. Patients with a baseline LVEF below the institutional lower limit of normal or below 50% have not been studied.

Liver Abnormalities, Rhabdomyolysis and Diarrhoea

• Liver: increases in ALT, AST and alkaline phosphatase occur; liver tests are done before the combination starts and monthly during treatment, or more often as indicated.
• Rhabdomyolysis and CPK: serum CPK and creatinine are measured before treatment and monthly. Median time to first grade 3 or 4 CPK elevation was 16 days. If CPK is raised, look for signs of rhabdomyolysis or other causes.
• Diarrhoea: grade 3 or higher and serious diarrhoea have been reported. It is managed with antidiarrhoeal medicines and supportive care; for grade 3 or higher despite this, Cotellic and vemurafenib are withheld until grade 1 or lower, and the doses are reduced if it recurs.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use two effective methods, for example a condom or other barrier method (with spermicide if available), during treatment and for at least 3 months after stopping.
• Pregnancy: there are no human data. Animal studies showed embryolethality and foetal malformations of the great vessels and skull. Cotellic should not be used in pregnancy unless clearly necessary, after careful weighing of the mother’s needs against the risk to the foetus.
• Breastfeeding: it is not known whether cobimetinib passes into breast milk and a risk to the infant cannot be excluded. A decision is made whether to stop breastfeeding or stop treatment.
• Fertility: there are no human data. In animals, effects on reproductive organs were seen; their clinical relevance is unknown.

Lactose and Sodium

Each tablet contains 36 mg lactose; patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it. Each tablet contains less than 1 mmol (23 mg) sodium, so it is essentially sodium-free.

Effect on Driving

Cotellic has a minor influence on the ability to drive or use machines. Visual disturbances have been reported; patients with visual disturbances or other effects that may affect their ability should not drive or use machines.

Cotellic needs no special storage conditions. The tablets are supplied in transparent PVC/PVDC blisters of 21 tablets; each pack contains 63 tablets.

5 years. Do not use after the expiry date on the pack.

Prescription only (Rx), on the prescription of a specialist experienced in the use of anticancer medicinal products. Cotellic is taken together with vemurafenib, which is prescribed separately. The tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.