Clinicians Must Address Unusual AEs of BRAF/MEK Inhibition for BRAF-Mutated NSCLC

Common adverse events (AEs) have been observed in clinical trials evaluating BRAF/MEK inhibition for patients with BRAF-mutated non–small cell lung cancer (NSCLC). However, only some reports have detailed unusual AEs associated with these medications.¹

Since BRAF/MEK inhibition is the standard of care for patients with BRAF-mutated NSCLC, it is important that clinicians be mindful of the potential AEs that can affect patients when receiving this treatment, according to investigators led by Rohan Maniar, MD, Indiana University School of Medicine.

"With the growing use of next-generation sequencing and expanded indication for BRAF/MEK inhibitors, it is crucial for clinicians to maintain vigilance for uncommon adverse events. Identifying and treating these effects early, using a collaborative approach, can facilitate prompt symptom resolution and provide an opportunity for continued use of these effective agents," Maniar told Targeted Oncology^TM.

A number of BRAF mutations have been identified, and in 2017, the combination of dabrafenib plus trametinib was approved by the FDA based on the results of the BRF113928 study (NCT01336634). However, some of the most frequent AEs reported in >30% of patients receiving this combination treatment include pyrexia, chills, fatigue, peripheral edema, nausea/vomiting, diarrhea, abdominal pain, headache, and rash.^2,3

Additional AEs caused by therapeutic agents which target BRAF and MEK include maculopapular rash, phototoxic reactions, palmoplantar hyperkeratosis, and acneiform eruption. There have also been reports of drug-induced neutrophilic dermatoses, including Sweet syndrome (SS) and neutrophilic panniculitis, reported in these patients, according to Maniar et al.¹

In a case report published in The Journal of the National Comprehensive Cancer Center, experts discussed a patient with BRAF-mutated NSCLC who was treated with dabrafenib and trametinib and who experienced 2 unusual AEs.¹

This 52-year-old, female, never-smoker with a diagnosis of metastatic lung adenocarcinoma and malignant pleural effusion that harbors a BRAF V600E mutation presented with a painful eruption over the bilateral lower extremities. Three months prior, the patient was administered first-line treatment with dabrafenib, a BRAF inhibitor, at 150 mg twice a day as well as a MEK inhibitor, trametinib at 2 mg daily.

At the time of the evaluation, the patient had no pertinent dermatologic history, and a physical examination revealed there to be an erythematous and edematous plaque on the left thigh. Of note, scattered erythematous macules were seen on the bilateral lower extremities and the left upper extremity. The lesions were intermittent and occasionally accompanied by low-grade fevers.

Through examining a skin biopsy of the thigh, investigators saw mild perivascular and subcutaneous infiltrate of lymphocytes and few neutrophils which were consistent with neutrophilic dermatosis. As a result, the patient was given 60 mg of oral prednisone for 3 days as a form of management. This resulted in complete resolution of her rash.

Dose-reduced BRAF/MEK inhibitors continued to be given to the patient and there was a significant clinical response of her lung cancer with resolution of her right upper lobe opacity and improved pleural effusion and mediastinal lymphadenopathy.

Looking ahead approximately 3 months, the patient had progressive visual changes. These included seeing yellow and purple colors in the left eye, visual distortions, and conjunctival hyperemia. Ocular history was notable for myopia. Once referred to an ophthalmologist, a slit light examination showed her to have 2+ episcleral hyperemia. Anterior chambers showed 2+ cell and flare in the right eye. In the left eye, there were fibrous deposits on the lens and iris. Indirect ophthalmoscopy was seen for vitreous cells and swollen discs of both eyes, Additionally, there was serous retinal detachment involving the macula and peripheral retina. The patient's visual acuity was noted to be 20/80 in the right eye and 20/150 in the left eye.

The patient discontinued BRAF/MEK inhibition immediately as experts were concerned about serous retinopathy/uveitis. Therefore, the patient was started on topical corticosteroid drops. There was no improvement followed by a progression of symptoms.

During a repeat examination, her visual acuity had worsened to 20/200 in the right eye and 20/800 in the left eye. This resulted in a subsequent escalation to 1 g of intravenous solumedrol for 3 days followed by prednisone at 1 mg/kg each day thereafter.

Once a significant improvement of her ocular symptoms was observed, the patient was BRAF/MEK inhibitiors consisting of dabrafenib 75 mg twice a day in combination with trametinib 1 mg each day were re-administered. This was accompanied by a taper of steroids based on biweekly ophthalmic evaluations.

Through looking at this case, researchers demonstrate the importance and need to recognize unusual AEs that correlate with BRAF/MEK inhibition. This is particularly important when discussing the expanded use for all BRAFV600E-mutated solid tumors.

This case specifically highlights some of the unusual AEs associated with BRAF/MEK inhibition, like Sweet syndrome and MEK-associated retinopathy, the importance of early recognition, and the benefit of multidisciplinary collaboration to guide management. With the quick turnaround in time of diagnosis to the start of treatment for this patient’s BRAF/MEK-associated Sweet syndrome and MEK-associated retinopathy, there was a resolution of active dermatologic and ocular symptoms. While ongoing changes may remain regarding the patient's vision, the promptness of clinicians allowed for better outcomes for this patient.

However, there are limited therapeutic options for patients with BRAF V600E lung adenocarcinoma. This led the patient and her team to restart and continue her treatment regimen of trametinib plus dabrafenib while she continues to be treated with oral prednisone and ophthalmologic monitoring.

Overall, it is important for clinicians to be aware of uncommon, yet clinically significant AEs in this patient population when treated with BRAF/MEK inhibitors. This is especially true as these agents expand into all solid tumors harboring BRAF V600E mutations because of the recent FDA accelerated approval.

"While being treated with dabrafenib and trametinib, our patient initially experienced intermittent erythematous and edematous plaques and macules on her upper and lower extremities that were associated with low-grade fevers. She underwent a skin biopsy which was consistent with a neutrophilic dermatosis leading to the diagnosis of drug-induced Sweet's syndrome. She received oral prednisone with complete resolution of the symptoms. Given her great response to BRAF/MEK inhibition, she was continued on dose reduced treatment. Unfortunately, she experienced another unusual adverse effect 3 months later when she reported progressive vision changes. An evaluation by ophthalmology led to the diagnosis of MEK associated retinopathy which was treated initially with topical steroids but required escalation to intravenous treatment with eventual transition to oral steroids. Despite these setbacks, she was able to continue the dabrafenib and trametinib with close monitoring from her multidisciplinary team," concluded Maniar.

REFERENCES:

1. Maniar R, Gallitano SM, Husain S, Moazami G, Weiss MJ, Shu CA. Unusual adverse events in a patient with BRAF-mutated non-small cell lung cancer treated with BRAF/MEK inhibition. J Natl Compr Canc Netw. 2023;21(3):232-234. doi:10.6004/jnccn.2022.7084

2. Planchard D, Smit EF, Groen HJ, et al. Dabrafenib plus trametinib in patients with previously untreated BRAF V600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18(10):1307–1316. doi: 10.1016/S1470-2045(17)30679-4

3. Planchard D, Besse B, Groen HJ, et al. Phase 2 study of dabrafenib plus trametinib in patients with BRAF V600E-mutant metastatic NSCLC: updated 5-year survival rates and genomic analysis. J Thorac Oncol. 2022;17(1):103–115. doi: 10.1016/j.jtho.2021.08.011