BRAF and MEK Inhibitor Side Effects in BRAF V600E–Mutated NSCLC
Key Points
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Encorafenib plus binimetinib and dabrafenib plus trametinib are BRAF and MEK inhibitor combinations approved for metastatic BRAF V600E–mutated non-small cell lung cancer (NSCLC).
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While both combinations share several side effects, encorafenib and binimetinib may be more tolerable because of a lower rate of fever.
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Doses of each agent can be adjusted individually to manage specific BRAF-related or MEK-related toxicities.
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Unlike other NSCLC mutations like EGFR, BRAF V600E is susceptible to chemoimmunotherapy, which may be an alternative if toxicity with targeted agents is unmanageable.
Side Effects of BRAF and MEK Inhibitors in Lung Cancer
Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, met with Melissa Johnson, MD, a thoracic medical oncologist at Sarah Cannon Research Institute, to discuss
BRAF and MEK inhibitor side effects in BRAF V600E–mutated NSCLC.
There are currently two BRAF and MEK combinations approved in BRAF V600E–mutated NSCLC: dabrafenib plus trametinib and encorafenib plus binimetinib. Dabrafenib plus trametinib was approved in 2017 based on an open-label phase II study. Encorafenib plus binimetinib was approved in 2023 based on the phase II PHAROS study. Updated data from the PHAROS trial suggest that encorafenib plus binimetinib has slightly better survival outcomes compared with dabrafenib plus trametinib.
While BRAF V600E–mutated NSCLC is sensitive to immunotherapy and chemotherapy, Dr. Johnson tends to sequence BRAF and MEK targeted therapies first, and switches to the other treatments if a patient experiences unmanageable toxicity or resistance.
Side Effects of Encorafenib Plus Binimetinib
Encorafenib plus binimetinib is approved for metastatic NSCLC with BRAF V600E mutation. Encorafenib is associated with dermatologic, cardiac, ocular, and gastrointestinal (GI) toxicities, while binimetinib is associated with dermatologic, cardiac, ocular, and pulmonary toxicities, as well as creatine phosphokinase elevation and edema.
Compared with dabrafenib plus trametinib, encorafenib plus binimetinib has a lower rate of fever, but can have more GI effects. Dr. Johnson does not see a frequent need for antidiarrheals, but she does typically provide patients with a prescription for antiemetics.
Dabrafenib Plus Trametinib Side Effects
Dabrafenib plus trametinib is approved for metastatic BRAF V600E–mutated NSCLC. Dermatologic and GI side effects are associated with dabrafenib, as well as fever and hyperglycemia. Trametinib is associated with edema and dermatologic, cardiac, ocular, and pulmonary toxicities. Distinct from encorafenib and binimetinib, both dabrafenib and trametinib must be taken on an empty stomach.
The most challenging side effect of dabrafenib is fever, which often starts 2 to 4 weeks after starting therapy, and can be episodic. If fever persists, oncologists can try to manage it with steroids. Dr. Johnson attempts to manage fever without stopping doses to maintain treatment exposure, although holds and dose reductions are sometimes necessary.
Monitoring BRAF Plus MEK Inhibitor Side Effects
With either dabrafenib plus trametinib or encorafenib and binimetinib, patients should have a baseline ophthalmology examination and be sent for urgent evaluation if they experience visual changes during treatment. Treatment should be discontinued if patients develop ocular toxicities, which can include central retinal vein occlusion.
Due to the differing cardiac toxicity profiles of BRAF and MEK inhibitors, monitoring with echocardiograms and electrocardiograms (EKG) is recommended, although the EKG can be dropped if no issues are observed.
When modifying treatment to manage toxicities, Dr. Johnson typically reduces the MEK inhibitor dose first. If patients continue to struggle with MEK-related toxicities despite dose reductions, oncologists can consider single-agent BRAF inhibitor therapy. However, Dr. Johnson more often switches to chemoimmunotherapy if side effects with targeted therapy for NSCLC are unmanageable.