Help Manage Toxicities With BRAF and MEK Inhibitors

Cutaneous melanoma, a type of skin cancer arising from malignant melanocytes, is the fifth most prevalent cancer in the United States, with 99,780 new cases estimated in 2022.^1,2

Depending on disease stage, the treatment landscape of melanoma includes immunotherapy, local therapies, surgical resection, and targeted agents. For patients with metastatic melanoma, systemic therapy with targeted agents or immunotherapy is the standard of care.³

Approximately half of melanoma cases possess an activating mutation in the BRAF gene, which encodes the BRAF kinase of the mitogen-activated protein kinase (MAPK) pathway.³ Specifically, BRAF V600 mutations have been shown to respond to and benefit from targeted therapy with a BRAF inhibitor. Trial results have supported the addition of a MEK inhibitor to BRAF inhibitor therapy, leading to this combination being established as a standard-of-care option for patients with BRAF V600 mutations.³

The FDA has approved 3 pairs of BRAF and MEK inhibitors to treat melanoma with BRAF V600 mutations: dabrafenib and trametinib (Tafinlar, Mekinist; Novartis), encorafenib and binimetinib (Braftovi, Mektovi; Pfizer), and vemurafenib and cobimetinib (Zelboraf, Cotellic; Genentech). All 6 agents are orally administered and are available through specialty pharmacies.

BRAF and MEK inhibitors are associated with various unique toxicities that may require close monitoring and management. Common toxicities include alopecia, arthralgia, diarrhea, fatigue, nausea, pyrexia, rash, and vomiting. Rarer ones that may require nuanced monitoring plans include cardiac, dermatologic, and ocular toxicities.

Pyrexia

Pyrexia is defined as a temperature of 38.0oC or greater (≥ 100.4oF), and its incidence ranges with the 3 combinations of BRAF and MEK inhibitors.⁴ The dabrafenib-trametinib combination is associated with a higher incidence (57%) than vemurafenib and cobimetinib (22%) and encorafenib and binimetinib (19%).^5-8 Pyrexia may be complicated by chills, hypotension, renal injury, or rigors. At the onset of pyrexia, holding BRAF/MEK inhibitors until its resolution is generally recommended.⁹ Additional management may be warranted, including antipyretics, fluids, rest, and, potentially, low-dose steroids.⁹ Antipyretics may be used as primary or secondary prophylaxis with dabrafenib and trametinib therapy. Pharmacists should counsel patients about the incidence and signs and symptoms of pyrexia, the importance of hydration, and having a thermometer on hand to monitor temperature.

Dermatologic Toxicities

Several dermatologic toxicities are common with BRAF and MEK inhibitor therapy, including hyperkeratosis, palmar-plantar erythrodysesthesia, photosensitivity, and rash. Photosensitivity is most common with vemurafenib, with a reported incidence of up to 49%.¹⁰ Pharmacists should advise patients to avoid intense sun exposure, use broad spectrum sunscreen with a sun protection factor of 30 or higher, and wear protective clothing when outside.

Cutaneous malignancies, including cutaneous squamous cell carcinoma (cSCC) and keratoacanthomas, have been reported with BRAF and MEK inhibitors. This risk of an additional cutaneous malignancy may be particularly alarming for patients with melanoma. The incidence of cSCC is higher with BRAF inhibitor monotherapy because of a paradoxical activation of the MAPK pathway to overcome BRAF inhibition. With the addition of a MEK inhibitor, the risk of cSCC is reduced. For example, there is an 11% incidence with vemurafenib vs 3% with vemurafenib and cobimetinib.⁵ To screen for suspicious skin changes, routine dermatologic evaluation every 2 months is recommended for patients on BRAF/MEK inhibitor therapy.^9-11

Rarely, cases of drug reaction with eosinophilia and systemic symptoms and Stevens-Johnson syndrome have been reported with BRAF and MEK inhibitors. These reactions may be life-threatening or fatal, and treatment should be discontinued if either condition occurs.^9-11 Based on the myriad potential dermatologic changes with BRAF and MEK inhibitors, pharmacists should encourage patients to self-monitor for any new skin changes or growths and to report any changes.

Cardiac Toxicities

Prolongation of the QT interval is a risk with BRAF inhibitors, particularly with vemurafenib and encorafenib, although it has rarely been reported with dabrafenib.^9-11 Baseline and routine electrocardiogram monitoring may be warranted, especially if patients are taking other QT-prolonging medications. The prescribing information for vemurafenib has explicit electrocardiogram monitoring recommendations, with QTc measurement at day 15, monthly during the first 3 months, then every 3 months thereafter.¹⁰ Cardiomyopathy with decreased left ventricular ejection fraction is associated with the use of MEK inhibitors and when MEK inhibitors are used in combination with BRAF inhibitors. Assessment of left ventricular ejection fraction, typically with an echocardiogram, is recommended prior to starting therapy with a MEK inhibitor, 1 month after starting treatment, and every 2 to 3 months thereafter.^12-14 Counsel patients about signs and symptoms of decreased left ventricular ejection fraction and the recommended monitoring schedule for these agents.

Ocular Toxicities

Both BRAF and MEK inhibitors are associated with unique ocular toxicities. With BRAF inhibitors, conjunctivitis, dry eye, and uveitis have been reported, whereas retinal vein occlusions and retinopathies are more frequently associated with MEK inhibitors. Uveitis from BRAF inhibitors may be managed with topical ophthalmic agents and treatment interruption.¹⁰ Only in the prescribing information for encorafenib is routine ophthalmologic monitoring recommended at “regular intervals.” However, patients may benefit from more routine monitoring. When starting these agents, patients should be monitored and counseled to report any ocular pain, photophobia, vision changes, and vision loss.

ABOUT THE AUTHOR

Bryan P. Fitzgerald, PharmD, BCOP, is a clinical specialist in oncology at the University of Rochester Specialty Pharmacy in New York.

REFERENCES

1. Cancer stat facts: melanoma of the skin. National Cancer Instit ute. Accessed March 14, 2022. https://seer.cancer.gov/statfacts/html/melan.html

2. Key statistics for melanoma skin cancer. American Cancer Society. Updated January 12, 2022. Accessed March 14, 2022. https://www.cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.html

3. NCCN. Clinical Practice Guidelines in Oncology. Melanoma: cutaneous, version 3.2022. Accessed March 14, 2022. https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf

4. Common terminology criteria for adverse events (CTCAE). National Cancer Institute. November 27, 2017. Accessed March 14, 2022. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf

5. Larkin J, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867-1876. doi:10.1056/NEJMoa1408868

6. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877-1888. doi:10.1056/NEJMoa1406037

7. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with dabrafenib and trametinib. N Engl J Med. 2015;372(1):30-39. doi:10.1056/NEJMoa1412690

8. Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603-615. doi:10.1016/S1470-2045(18)30142-6

9. Tafinlar. Prescribing information. Novartis Pharmaceuticals Corp; 2022. Accessed April 11, 2022. https://www.novartis.us/sites/www.novartis.us/files/tafinlar.pdf

10. Zelboraf. Prescribing information. Genentech USA, Inc; 2016. Accessed April 11, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/202429s012lbl.pdf

11. Braftovi. Prescribing information. Array BioPharma Inc; 2018. Accessed April 11, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210496lbl.pdf

12. Mekinist. Prescribing information. Novartis Pharmaceuticals Corp; 2021. Accessed April 11, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/204114s018lbl.pdf

13. Cotellic. Prescribing information. Genentech USA, Inc; 2015. Accessed April 11, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206192s000lbl.pdf

14. Mektovi. Prescribing information. Array BioPharma Inc; 2018. Accessed April 11, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210498lbl.pdf