Cobimetinib (Cotellic) is a drug used to treat melanoma with BRAF V600E or V600K mutations, and it is administered in combination with Vemurafenib. BRAF V600E or V600K mutations are the most common types of mutations in melanoma, accounting for approximately 50%. These mutations lead to abnormal activation of the BRAF kinase, which in turn promotes the proliferation and growth of tumor cells. Cobimetinib works by inhibiting the activity of BRAF kinase, thereby blocking the mutant signaling pathway and reducing the growth and spread of tumor cells. At present, Cobimetinib has not been marketed in China. This article provides a detailed description of the precautions for Cobimetinib.

Precautions for Cobimetinib

Review the complete prescribing information for the combination of Cobimetinib and Vemurafenib to understand the serious risks associated with their combined use.

New Primary Malignant Tumors

Cobimetinib can cause new primary malignant tumors, both cutaneous and non-cutaneous.

(1) Cutaneous Malignant Tumors

A dermatological assessment should be performed before the start of treatment and every two months during treatment. Suspected skin lesions should be managed by excision and skin pathological evaluation. It is not recommended to adjust the dose of Cobimetinib. When used in combination with Vemurafenib, dermatological monitoring should be conducted within 6 months after discontinuing Cobimetinib.

(2) Non-cutaneous Malignant Tumors

Based on its mechanism of action, Vemurafenib may promote the growth and development of malignant tumors. Patients receiving the combination of Cobimetinib and Vemurafenib should be monitored for signs or symptoms of non-cutaneous malignant tumors.

Bleeding

(1) The use of Cobimetinib can lead to bleeding, including major bleeding defined as symptomatic bleeding in critical sites or organs.

(2) In case of grade 3 bleeding events, discontinue Cobimetinib. If the bleeding improves to grade 0 or 1 within 4 weeks, resume Cobimetinib at a lower dose level. Discontinue Cobimetinib in case of grade 4 bleeding events and grade 3 bleeding events that do not improve.

Cardiomyopathy

(1) The use of Cobimetinib can cause cardiomyopathy. The safety of Cobimetinib in patients with a baseline ejection fraction (LVEF) below the lower limit of normal (LLN) or below 50% of the LLN has not been established.

(2) Ejection fraction should be assessed before the start of treatment, 1 month after the start of treatment, and every 3 months thereafter until Cobimetinib is discontinued. Left ventricular dysfunction events should be managed by suspending treatment, reducing the dose, or discontinuing treatment. For patients restarting Cobimetinib treatment after dose reduction or suspension, ejection fraction should be assessed at approximately 2 weeks, 4 weeks, 10 weeks, and 16 weeks, and then as clinically indicated.

Severe Skin Reactions

Cobimetinib can cause severe rashes and other skin reactions. In such cases, suspend, reduce the dose, or discontinue Cobimetinib.

Serous Retinopathy and Retinal Vein Occlusion

Cobimetinib can cause ocular toxicity, including serous retinopathy (subretinal fluid accumulation). Regular ophthalmic assessments should be performed, and assessments should be conducted when patients report new or worsening visual disturbances. If serous retinopathy is confirmed, Cobimetinib should be suspended until visual symptoms improve. Serous retinopathy should be managed by suspending treatment, reducing the dose, or discontinuing treatment.

Hepatotoxicity

Cobimetinib can cause hepatotoxicity. Liver function tests should be monitored before starting Cobimetinib and monthly during treatment, or more frequently as clinically needed. If grade 3 or 4 liver function abnormalities occur, suspend, reduce the dose, or discontinue Cobimetinib.

Rhabdomyolysis

Cobimetinib can cause rhabdomyolysis. Baseline levels of serum creatine phosphokinase and creatinine should be measured before starting Cobimetinib, regularly during treatment, and when clinically indicated. If creatine phosphokinase is elevated, assess for signs and symptoms of rhabdomyolysis or other causes. Depending on the severity of symptoms or elevated creatine phosphokinase, administration may be suspended or discontinued.

Severe Photosensitivity Reactions

The use of Cobimetinib may cause photosensitivity reactions, including severe ones. It is recommended that patients avoid sun exposure, wear protective clothing, use broad-spectrum UVA/UVB sunscreens and lip balms (SPF ≥ 30) during outdoor activities. Dose adjustment should be made for grade 2 or higher photosensitivity reactions that are intolerable.

Embryo-Fetal Toxicity

Administration of Cobimetinib to pregnant women can cause harm to the fetus. Pregnant women should be informed of the potential risks to the fetus. Women of reproductive potential are advised to use effective contraception during treatment with Cobimetinib and for 2 weeks after the last dose of Cobimetinib.