Ocular Serous retinopathy and retinal vein occlusion (RVO) have occurred with cobimetinib. Ophthalmologic evaluations at regular intervals and when patients report new or worsening visual disturbances are recommended. In patients who develop serous retinopathy, treatment may be interrupted until visual symptoms improve, and further managed with dose reduction or discontinuing treatment. Cobimetinib should be permanently discontinued in patients who develop retinal vein occlusion.1

Uveitis, including iritis and iridocyclitis, has been reported in patients receiving dabrafenib. Clinicians should assess patients for visual signs and symptoms of uveitis such as a change in vision, photophobia, and eye pain. If uveitis develops, administer ocular therapy and continue dabrafenib treatment without dose modification. In cases of severe uveitis or iridocyclitis, interrupt treatment and treat as clinically indicated. For persistent grade 2 or greater uveitis of 6 weeks or longer in duration, permanently discontinue treatment with dabrafenib.2


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In clinical trials with trametinib, 4 cases of retinal vein occlusion, which can lead to macular edema, decreased visual function, neovascularization, and glaucoma, were reported. Trametinib should be discontinued and an ophthalmologic evaluation performed within 24 hours of a patient report of vision loss or other visual disturbances. If retinal vein occlusion is confirmed, permanently discontinue trametinib. This agent has also been linked to retinal pigment epithelial detachment (RPED). If diagnosis of RPED is confirmed, withhold treatment; reduce the dose or discontinue therapy if no improvement is observed after 3 weeks.3

In clinical trials, vemurafenib has been associated with serious ophthalmologic reactions: uveitis (including iritis), blurry vision, and photophobia. Patients should be assessed for signs and symptoms of uveitis. If the condition develops, treat with steroid and mydriatic ophthalmic drops.4

Pulmonary Interstitial lung disease or pneumonitis occurred in 2% of patients treated with trametinib in clinical trials. If these events occur, permanently discontinue trametinib treatment. For patients who present with new or progressive pulmonary symptoms, such as cough, dyspnea, hypoxia, pleural effusion, or infiltrates, withhold trametinib pending investigation.3

Renal Serum creatinine measurements to assess for renal failure, which may include acute interstitial nephritis and acute tubular necrosis, should be obtained before initiating treatment with vemurafenib and periodically during treatment.4 

Other

Serious hypersensitivity reactions including anaphylaxis and drug reaction with eosinophilia and systemic symptoms (DRESS Syndrome) have been observed in patients taking vemurafenib. Discontinue the agent in patients who experience severe hypersensitivity reactions. Several cases, some severe, of radiation sensitization and radiation recall have also been reported in patients taking vemurafenib. Patients taking this agent concomitantly or sequentially with radiation therapy should be closely monitored.4

In a clinical trial of cobimetinib with vemurafenib, grade 3 or 4 creatinine phosphokinase (CPK) elevations over baseline were observed. Baseline serum CPK and creatinine levels should be obtained prior to initiating cobimetinib treatment, periodically during treatment, and as clinically indicated. If CPK is elevated, evaluate for signs and symptoms of rhabdomyolysis. Dose interruption or discontinuation may be necessary in patients who develop rhabdomyolysis.1

Serious febrile reactions have been reported when trametinib is used with dabrafenib, while the incidence and severity of pyrexia are increased with dabrafenib and trametinib.2,3 Dabrafenib should be withheld for a fever of 101.3°F or higher,2 with trametinib withheld for a fever higher than 104°F. Both agents should be withheld for serious febrile reactions or fever accompanied by hypotension, rigors or chills, dehydration, or renal failure.2,3 Signs and symptoms of infection should be evaluated, with serum creatinine and other evidence of renal function monitored during and following severe pyrexia. Dose modifications are required.2,3

CONCLUSION

The impact of BRAF inhibitors and MEK inhibitors on patient response and overall survival has been significant. However, treatment with these agents includes risk of serious adverse effects. Nurses need to be alert for signs and symptoms of adverse effects and aware of initial steps in managing these events. In addition, the need to alert their oncology team about potential adverse effects cannot be overstated to patients.

References

1. Cotellic® [package insert] South San Francisco, CA: Genentech, Inc; 2016.

2. Tafinlar® [package insert] East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2016.

3. Mekinist® [package insert] East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015.

4. Zelboraf™ [package insert] South San Francisco, CA: Genentech USA, Inc; 2016.

5. Melanoma Treatment (PDQ®) – Health Professional Version. National Cancer Institute Web site. https://www.cancer.gov/types/skin/hp/melanoma-treatment-pdq#section/_889. Accessed February 13, 2017.

6. FDA approves two drugs, companion diagnostic test for advanced skin cancer [news release]. Silver Spring, MD: US Food & Drug Administration; May 29, 2013. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm354199.htm. Accessed February 13, 2017.

7. FDA approves Zelboraf and companion diagnostic test for late-stage skin cancer [news release]. Silver Spring, MD: U.S. Food & Drug Administration; August 17, 2017. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm268241.htm. Accessed February 13, 2017.