Dermatologic Cobimetinib is associated with severe rash and other skin reactions. Management recommendations include interrupt, reduce, or discontinue treatment in cases of intolerable grade 2 rash or grade 3, or 4 rash.1 First reduction is 40 mg daily, second reduction is 20 mg daily, and if the patient cannot tolerate the 20-mg dose, then discontinue the drug.

Serious skin toxicity can occur with dabrafenib. This agent should be withheld for intolerable or severe skin toxicity. Treatment can resume at the next lower dose level in patients who improve or recover within 3 weeks.2

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Patients receiving trametinib should be monitored for skin toxicities and secondary infections. The agent should be withheld for up to 3 weeks in cases of intolerable grade 2 skin toxicity or grade 3 or 4 skin toxicity. Patients who improve or recover within 3 weeks can resume treatment at a reduced dose. However, trametinib should be discontinued if these symptoms do not improve despite the interruption in treatment.3

Treatment with cobimetinib and vemurafenib was found to cause mild to severe photosensitivity. Patients should be advised to avoid sun exposure. They should wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm with SPF 30 or higher when outdoors. Grade 2 or greater photosensitivity with cobimetinib is managed with dose modifications.1 Vemurafenib should be permanently discontinued in cases of severe dermatologic reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis.4

Endocrine and metabolic Therapy with dabrafenib and trametinib can cause hyperglycemia requiring more intensive hypoglycemic therapy. Serum glucose levels  in patients with preexisting diabetes or hyperglycemia should be monitored at initiation of treatment with either agent and as clinically appropriate.2,3

Hematologic Risk of hemolytic anemia in patients with a glucose-6-phosphate dehydrogenase deficiency is increased with dabrafenib; therefore, these patients should be monitored closely during treatment.2

Hemorrhage has been reported in patients who received dabrafenib with trametinib. For that reason, dabrafenib should be permanently discontinued for all grade 4 and any persistent grade 3 hemorrhage events. In cases of grade 3 events, withhold then continue treatment at the next lower dose level if improvement is seen.2

In clinical trials, cobimetinib and trametinib were associated with hemorrhagic events, including gastrointestinal and cerebral hemorrhages. If a grade 4 hemorrhagic event occurs or a grade 3 event does not improve, recommendations are to permanently discontinue treatment with both agents. Withhold treatment for grade 3 hemorrhagic events for up to 4 weeks. Treatment can be resumed at the next lower dose levels if grade 3 hemorrhagic event improves.1,3

Deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving trametinib with dabrafenib. Patients should be advised to seek immediate medical care if they develop any symptoms of DVT or PE: shortness of breath, chest pain, or swelling of an arm or leg. If pulmonary embolism is life threatening, trametinib should be permanently discontinued. In uncomplicated DVT or PE, withhold the agent for up to 3 weeks. Trametinib can be resumed at a lower dose if the patient improves.3

Hepatic Hepatotoxicity has been reported in patients receiving cobimetinib; therefore, monitor liver function before treatment initiation and monthly during treatment.1

Risk for liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction was noted in clinical trials of vemurafenib. Laboratory tests to monitor transaminases, alkaline phosphatase, and bilirubin should be conducted before initiating treatment and monthly during treatment.

If laboratory results indicate grade 3 or 4 adverse events with either cobimetinib or vemurafenib, interrupt treatment for up to 4 weeks. Treatment can be resumed with the next lower dose when results show improvement to grade 0 or 1. If the patient cannot tolerate the lowest dose, discontinue treatment.1,4