Metastatic melanoma with a BRAF V600 mutation

The recommended dose of cobimetinib is 60 mg once daily.

Cobimetinib is taken on a 28 day cycle. Each dose consists of three 20 mg tablets (60 mg) and should be taken once daily for 21 consecutive days (Days 1 to 21-treatment period); followed by a 7-day break (Days 22 to 28-treatment break). Each subsequent cobimetinib treatment cycle should start after the 7-day treatment break has elapsed.

Duration of treatment

Treatment with cobimetinib should continue until the patient no longer derives benefit or until the development of unacceptable toxicity (see Table 1 below).

Missed doses

If a dose is missed, it can be taken up to 12 hours prior to the next dose to maintain the once-daily regimen.

Vomiting

In case of vomiting after administration of cobimetinib, the patient should not take an additional dose on that day and treatment should be continued as prescribed the following day.

General dose modifications

The decision on whether to reduce the dose for either or both treatments should be based on the prescriber’s assessment of individual patient safety or tolerability. Dose modification of cobimetinib is independent of vemurafenib dose modification.

If doses are omitted for toxicity, these doses should not be replaced. Once the dose has been reduced, it should not be increased at a later time.

Table 1 below gives general cobimetinib dose modification guidance.

Table 1. Recommended cobimetinib dose modifications:

* The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE)

Dose modification advice for haemorrhage

Grade 4 events or cerebral haemorrhage: Cobimetinib treatment should be interrupted. Cobimetinib treatment should be permanently discontinued for haemorrhage events attributed to cobimetinib.

Grade 3 events: cobimetinib treatment should be interrupted during evaluation to avoid any potential contribution to the event. There is no data on the effectiveness of cobimetinib dose modification for haemorrhage events. Clinical judgment should be applied when considering restarting cobimetinib treatment. Vemurafenib dosing can be continued when cobimetinib treatment is interrupted, if clinically indicated.

Dose modification advice for left ventricular dysfunction

Permanent discontinuation of cobimetinib treatment should be considered if cardiac symptoms are attributed to cobimetinib and do not improve after temporary interruption.

Table 2. Recommended dose modifications for cobimetinib in patients with left ventricular ejection fraction (LVEF) decrease from baseline:

Vemurafenib treatment can be continued when cobimetinib treatment is modified, if clinically indicated.

Dose modification advice for rhabdomyolysis and Creatine phosphokinase (CPK) elevations

Rhabdomyolysis or symptomatic CPK elevations

Cobimetinib treatment should be interrupted. If rhabdomyolysis or symptomatic CPK elevations do not improve within 4 weeks, cobimetinib treatment should be permanently discontinued. If severity is improved by at least one grade within 4 weeks, cobimetinib could be restarted at a dose reduced by 20 mg, if clinically indicated. Patients should be closely monitored. Vemurafenib dosing can be continued when cobimetinib treatment is modified.

Asymptomatic CPK elevations

Grade 4: Cobimetinib treatment should be interrupted. If CPK elevations do not improve to Grade ≤3 within 4 weeks following dose interruption, cobimetinib treatment should be permanently discontinued.

If CPK improves to Grade ≤3 within 4 weeks, cobimetinib could be restarted, if clinically indicated, at a dose reduced by 20 mg and the patient should be closely monitored. Vemurafenib dosing can be continued when cobimetinib treatment is modified.

Grade ≤3: After rhabdomyolysis has been ruled out, cobimetinib dosing does not need to be modified.

Dose modification advice for cobimetinib when used with vemurafenib

Liver laboratory abnormalities

For Grade 1 and 2 liver laboratory abnormalities, cobimetinib and vemurafenib should be continued at the prescribed dose.

Grade 3: Cobimetinib should be continued at the prescribed dose. The dose of vemurafenib may be reduced as clinically appropriate.

Grade 4: Cobimetinib treatment and vemurafenib treatment should be interrupted. If liver laboratory abnormalities improve to Grade ≤1 within 4 weeks, cobimetinib should be restarted at a dose reduced by 20 mg and vemurafenib at a clinically appropriate dose, per its SmPC.

Cobimetinib treatment and vemurafenib treatment should be discontinued if liver laboratory abnormalities do not resolve to Grade ≤1 within 4 weeks or if Grade 4 liver laboratory abnormalities recur after initial improvement.

It can be taken with or without food.