Unusual Adverse Events in a Patient With BRAF-Mutated Non–Small Cell Lung Cancer Treated With BRAF/MEK Inhibition

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Rohan Maniar Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York

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Stephanie M. Gallitano Department of Dermatology, Columbia University Irving Medical Center, New York, New York

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Sameera Husain Department of Dermatology, Columbia University Irving Medical Center, New York, New York

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Golnaz Moazami Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
Harkness Eye Center, New York, New York

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Michael J. Weiss Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York
Harkness Eye Center, New York, New York

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Catherine A. Shu Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York

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BRAF/MEK inhibition remains standard of care for treatment of BRAF-mutated non–small cell lung cancer (NSCLC). Although common adverse events (AEs) have been reported through clinical trials and ongoing clinical practice, only a handful of reports have detailed unusual adverse events associated with these medications. This report presents a patient with BRAF-mutated NSCLC treated with dabrafenib and trametinib who experienced 2 unusual AEs—Sweet syndrome and MEK-associated retinopathy—that responded to steroid treatment. The patient was able to continue BRAF/MEK inhibition through a coordinated multidisciplinary approach. This case highlights the importance for all clinicians to recognize unusual AEs associated with BRAF/MEK inhibition, particularly in the setting of expanded use for all BRAF V600E–mutated solid tumors.

Case Report

A 52-year-old female never-smoker with metastatic lung adenocarcinoma and malignant pleural effusion harboring a BRAF V600E mutation (via overlapping multiplex PCR amplification on Illumina MiSeq platform) presented with a painful eruption over the bilateral lower extremities. First-line treatment with a BRAF inhibitor, dabrafenib at 150 mg twice daily, and an MEK inhibitor, trametinib at 2 mg daily, had been initiated 3 months prior. She had no pertinent dermatologic history at the time of evaluation. Physical examination revealed an erythematous and edematous plaque on the left thigh with associated lesional edema (Figure 1A). Scattered erythematous macules were noted on the bilateral lower extremities and the left upper extremity. The lesions were intermittent and occasionally accompanied by low-grade fevers. A skin biopsy of the thigh revealed mild perivascular and subcutaneous infiltrate of lymphocytes and few neutrophils consistent with neutrophilic dermatosis (Figure 1B, C). She was started on 60 mg of oral prednisone for 3 days for management, which resulted in complete resolution of her rash. She remained on dose-reduced BRAF/MEK inhibitors given the significant clinical response of her lung cancer with resolution of her right upper lobe opacity and improved pleural effusion and mediastinal lymphadenopathy.

Figure 1.
Figure 1.

(A) Early erythematous thin plaque on the left thigh that resolved without intervention. (B) Histopathology of the skin biopsy on low power magnification (hematoxylin-eosin, original magnification ×40) exhibits a mild infiltrate in the dermis and subcutaneous adipose tissue. (C) High-power magnification of the subcutis (hematoxylin-eosin, original magnification ×600) shows that the infiltrate is composed of lymphocytes and neutrophils.

Citation: Journal of the National Comprehensive Cancer Network 21, 3; 10.6004/jnccn.2022.7084

Approximately 3 months later, the patient noted progressive visual changes, including seeing yellow and purple colors in the left eye, visual distortions, and conjunctival hyperemia. Ocular history was notable for myopia. She was referred to ophthalmology, where she was noted on slit light examination to have 2+ episcleral hyperemia. Anterior chambers showed 2+ cell and flare in the right eye and fibrous deposits on the lens and iris in the left eye. Indirect ophthalmoscopy was notable for vitreous cells and swollen discs of both eyes, as well as serous retinal detachment involving the macula and peripheral retina (Figure 2A). Visual acuity (corrected) was noted to be 20/80 in the right eye and 20/150 in the left eye. BRAF/MEK inhibition was discontinued immediately given concern for serous retinopathy/uveitis, and the patient was started on topical corticosteroid drops with no improvement and even progression of symptoms. On repeat examination, visual acuity (corrected) had worsened to 20/200 in the right eye and 20/800 in the left eye. She was subsequently escalated to 1 g of intravenous solumedrol for 3 days followed by prednisone at 1 mg/kg daily thereafter. After significant improvement of her ocular symptoms, she was reinitiated on BRAF/MEK inhibition (dabrafenib, 75 mg twice daily, and trametinib, 1 mg daily), with simultaneous steroid taper based on biweekly ophthalmic evaluations (Figure 2B).

Figure 2.
Figure 2.

(A) Optical coherence tomography (OCT) B-scans of the left and right eyes at the time of diagnosis revealed dome-shaped fluid accumulation in the subretinal space with displacement of the outer and inner retinal layers. (B) OCT B-scans of the left and right eyes on-treatment with systemic corticosteroids showed near complete resolution.

Citation: Journal of the National Comprehensive Cancer Network 21, 3; 10.6004/jnccn.2022.7084

Discussion

Lung cancer remains one of the most common malignancies in the United States, with an estimated 119,100 new cases and 69,410 deaths in 2021, with NSCLC accounting for 80% to 85% of all cases.1,2 BRAF mutations have been described in a number of malignancies, including melanoma and colon cancer, and account for approximately 2% to 4% of NSCLC.3 Although a number of BRAF mutations have been identified, clinical efficacy of targeted therapies has largely been confined to the class I mutations at the V600 position.4 For patients with a V600E mutation, the combination of dabrafenib + trametinib was approved by the FDA in 2017 based on the results of the BRF113928 study (ClinicalTrials.gov identifier: NCT01336634).5,6 Common adverse events (AEs) affecting >30% of patients receiving this combination treatment include pyrexia, chills, fatigue, peripheral edema, nausea/vomiting, diarrhea, abdominal pain, headache, and rash.

Therapeutic agents targeting BRAF and MEK have been associated with numerous dermatologic AEs, including maculopapular rash, phototoxic reactions, palmoplantar hyperkeratosis, and acneiform eruption. Drug-induced neutrophilic dermatoses, such as Sweet syndrome (SS) and neutrophilic panniculitis, have also been reported in these patients. SS is a febrile neutrophilic dermatosis characterized by abrupt onset of tender erythematous nodules and associated with constitutional symptoms, including fever, malaise, arthralgias/myalgias, and leukocytosis. Drug-induced SS was first reported in 1986 in a patient receiving trimethoprim-sulfamethoxazole.7 Since that report, numerous medications have been associated with drug-induced SS and formal criteria for diagnosis have been suggested.8 Several recent case reports have associated BRAF inhibitors with drug-induced SS and histiocytoid SS, a rare variant of SS.911 The case described herein adds to the increasing literature on BRAF inhibitor–related SS.

Complicating serous retinopathy and uveitis has also been well described since the initial clinical studies evaluated BRAF/MEK inhibition in the treatment of cutaneous melanoma, where it was reported as a subfoveal neurosensory retinal detachment similar to central serous chorioretinopathy (CSR).12,13 Since its initial description, unique clinical and morphologic characteristics, including bilateral involvement, multifocal fluid foci, subretinal shifting fluid, subfoveal focus, normal choroidal thickness, and association with intraocular inflammation, have helped define MEK-associated retinopathy (MEKAR) as a separate entity from CSR.14 In contrast to CSR, which may be triggered by steroid use, MEKAR is primarily treated with systemic steroids. Risk factors for MEKAR include history of ocular disease and inflammatory disorders of the anterior eye, decreased estimated glomerular filtration rate, and advanced age.15

Conclusions

Overall, this case highlights some of the unusual AEs associated with BRAF/MEK inhibition and the importance of early recognition and multidisciplinary collaboration to guide management. The prompt diagnosis and initiation of treatment for BRAF/MEK-associated SS and MEKAR resulted in resolution of active dermatologic and ocular symptoms, although there remain ongoing sequelae of the patient’s vision changes. However, given the limited therapeutic options for BRAF V600E lung adenocarcinoma and the desire to remain off chemotherapy, the patient and her team opted to restart and continue trametinib + dabrafenib for as long as possible. She is currently on dabrafenib, 150 mg twice daily, and trametinib, 1 mg daily, while she continues with oral prednisone and careful ophthalmologic monitoring. The team decision to recommend continuation of BRAF/MEK inhibition was based on the development of a collaborative monitoring and communication plan. It remains vitally important for clinicians to be aware of uncommon but clinically significant adverse reactions, especially because use of these agents expands into all solid tumors harboring BRAF V600E mutations after the recent FDA accelerated approval.16

References

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    Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin 2021;71:733.

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    Minguet J, Smith KH, Bramlage P. Targeted therapies for treatment of non-small cell lung cancer—recent advances and future perspectives. Int J Cancer 2016;138:25492561.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Nguyen-Ngoc T, Bouchaab H, Adjei AA, et al. BRAF alterations as therapeutic targets in non-small-cell lung cancer. J Thorac Oncol 2015;10:13961403.

  • 4.

    Johnson DB, Nebhan CA, Noel MS. MEK inhibitors in non-V600 BRAF mutations and fusions. Oncotarget 2020;11:39003903.

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    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;18:13071316.

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    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;17:103115.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Su WP, Liu HN. Diagnostic criteria for Sweet’s syndrome. Cutis 1986;37:167174.

  • 8.

    Walker DC, Cohen PR. Trimethoprim-sulfamethoxazole-associated acute febrile neutrophilic dermatosis: case report and review of drug-induced Sweet’s syndrome. J Am Acad Dermatol 1996;34:918923.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Morgado-Carrasco D, Moreno-Rivera N, Fustà-Novell X, et al. Histiocytoid Sweet’s syndrome during combined therapy with BRAF and MEK inhibitors for metastatic melanoma. Melanoma Res 2018;28:256257.

    • PubMed
    • Search Google Scholar
    • Export Citation
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    Yorio JT, Mays SR, Ciurea AM, et al. Case of vemurafenib-induced Sweet’s syndrome. J Dermatol 2014;41:817820.

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    Scarfì F, Melotti B, Veronesi G, et al. Sweet syndrome in metastatic melanoma during treatment with dabrafenib and trametinib. Australas J Dermatol 2019;60:e242243.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Schoenberger SD, Kim SJ. Bilateral multifocal central serous-like chorioretinopathy due to MEK inhibition for metastatic cutaneous melanoma. Case Rep Ophthalmol Med 2013;2013:673796.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    McCannel TA, Chmielowski B, Finn RS, et al. Bilateral subfoveal neurosensory retinal detachment associated with MEK inhibitor use for metastatic cancer. JAMA Ophthalmol 2014;132:10051009.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Francis JH, Habib LA, Abramson DH, et al. Clinical and morphologic characteristics of MEK inhibitor-associated retinopathy: differences from central serous chorioretinopathy. Ophthalmology 2017;124:17881798.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Booth AEC, Hopkins AM, Rowland A, et al. Risk factors for MEK-associated retinopathy in patients with advanced melanoma treated with combination BRAF and MEK inhibitor therapy. Ther Adv Med Oncol 2020;12:1758835920944359.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    U.S. Food and Drug Administration. FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation. Accessed June 23, 2022. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dabrafenib-combination-trametinib-unresectable-or-metastatic-solid

    • PubMed
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Submitted June 27, 2022; final revision received September 23, 2022; accepted for publication September 29, 2022. Published online February 9, 2023.

Disclosures: Dr. Shu has disclosed serving on an advisory board for AstraZeneca, Genentech, Janssen, and Mirati Therapeutics. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Correspondence: Catherine A. Shu, MD, Columbia University Irving Medical Center, 161 Fort Washington Avenue, 3rd Floor, New York, NY 10032. Email: cas2145@cumc.columbia.edu
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  • Figure 1.

    (A) Early erythematous thin plaque on the left thigh that resolved without intervention. (B) Histopathology of the skin biopsy on low power magnification (hematoxylin-eosin, original magnification ×40) exhibits a mild infiltrate in the dermis and subcutaneous adipose tissue. (C) High-power magnification of the subcutis (hematoxylin-eosin, original magnification ×600) shows that the infiltrate is composed of lymphocytes and neutrophils.

  • Figure 2.

    (A) Optical coherence tomography (OCT) B-scans of the left and right eyes at the time of diagnosis revealed dome-shaped fluid accumulation in the subretinal space with displacement of the outer and inner retinal layers. (B) OCT B-scans of the left and right eyes on-treatment with systemic corticosteroids showed near complete resolution.

  • 1.

    Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin 2021;71:733.

  • 2.

    Minguet J, Smith KH, Bramlage P. Targeted therapies for treatment of non-small cell lung cancer—recent advances and future perspectives. Int J Cancer 2016;138:25492561.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Nguyen-Ngoc T, Bouchaab H, Adjei AA, et al. BRAF alterations as therapeutic targets in non-small-cell lung cancer. J Thorac Oncol 2015;10:13961403.

  • 4.

    Johnson DB, Nebhan CA, Noel MS. MEK inhibitors in non-V600 BRAF mutations and fusions. Oncotarget 2020;11:39003903.

  • 5.

    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;18:13071316.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    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;17:103115.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Su WP, Liu HN. Diagnostic criteria for Sweet’s syndrome. Cutis 1986;37:167174.

  • 8.

    Walker DC, Cohen PR. Trimethoprim-sulfamethoxazole-associated acute febrile neutrophilic dermatosis: case report and review of drug-induced Sweet’s syndrome. J Am Acad Dermatol 1996;34:918923.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Morgado-Carrasco D, Moreno-Rivera N, Fustà-Novell X, et al. Histiocytoid Sweet’s syndrome during combined therapy with BRAF and MEK inhibitors for metastatic melanoma. Melanoma Res 2018;28:256257.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Yorio JT, Mays SR, Ciurea AM, et al. Case of vemurafenib-induced Sweet’s syndrome. J Dermatol 2014;41:817820.

  • 11.

    Scarfì F, Melotti B, Veronesi G, et al. Sweet syndrome in metastatic melanoma during treatment with dabrafenib and trametinib. Australas J Dermatol 2019;60:e242243.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Schoenberger SD, Kim SJ. Bilateral multifocal central serous-like chorioretinopathy due to MEK inhibition for metastatic cutaneous melanoma. Case Rep Ophthalmol Med 2013;2013:673796.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    McCannel TA, Chmielowski B, Finn RS, et al. Bilateral subfoveal neurosensory retinal detachment associated with MEK inhibitor use for metastatic cancer. JAMA Ophthalmol 2014;132:10051009.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Francis JH, Habib LA, Abramson DH, et al. Clinical and morphologic characteristics of MEK inhibitor-associated retinopathy: differences from central serous chorioretinopathy. Ophthalmology 2017;124:17881798.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Booth AEC, Hopkins AM, Rowland A, et al. Risk factors for MEK-associated retinopathy in patients with advanced melanoma treated with combination BRAF and MEK inhibitor therapy. Ther Adv Med Oncol 2020;12:1758835920944359.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    U.S. Food and Drug Administration. FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation. Accessed June 23, 2022. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dabrafenib-combination-trametinib-unresectable-or-metastatic-solid

    • PubMed
    • Search Google Scholar
    • Export Citation
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