scholarly journals Cobimetinib- and vemurafenib-induced granulomatous dermatitis and erythema induratum: A case report

2019 ◽  
Vol 7 ◽  
pp. 2050313X1984735 ◽  
Author(s):  
Marco AJ Iafolla ◽  
Jennifer Ramsay ◽  
Judy Wismer ◽  
Elaine McWhirter
Keyword(s):  
Case Report ◽  
Side Effects ◽  
Metastatic Melanoma ◽  
Clinical Features ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Mek Inhibition ◽  
Granulomatous Dermatitis ◽  
Cutaneous Toxicities

Metastatic melanoma is an aggressive malignancy. Survival can be increased with the combination of BRAF and MEK inhibition. BRAF inhibitor-induced cutaneous toxicities can be attenuated with MEK inhibition. Here, we describe the first reported case of a patient with metastatic melanoma who developed granulomatous dermatitis and erythema induratum when treated with combination BRAF (vemurafenib) and MEK inhibitor (cobimetinib) therapy and discuss the clinical features and management of dermatologic side-effects secondary to BRAF +/– MEK inhibition.

Prospective Case Series of Cutaneous Adverse Effects Associated With Dabrafenib and Trametinib

2016 ◽  
Vol 21 (1) ◽  
pp. 54-59 ◽  
Author(s):  
Jean-Philip Lacroix ◽  
Beatrice Wang
Keyword(s):  
Side Effects ◽  
Adverse Effects ◽  
Metastatic Melanoma ◽  
Case Series ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Braf V600e ◽  
Cutaneous Toxicity ◽  
Palmoplantar Hyperkeratosis ◽  
Acneiform Eruption

Background: Dabrafenib, a novel selective small-molecule inhibitor of BRAF, has been shown to increase overall survival in patients with unresectable metastatic melanoma harboring the BRAF V600E mutation. The development of resistance has led to combination therapy with selective MEK inhibitor trametinib. Compared with vemurafenib, dabrafenib is a more recent BRAF inhibitor approved by the Food and Drug Administration in May 2013 for metastatic melanoma; fewer data are available in the current literature regarding cutaneous toxicity. Objectives: We sought to present additional cutaneous side effects of dabrafenib and trametinib and follow their evolution and management. Methods: We carried out a prospective study of 14 patients treated with dabrafenib alone or with trametinib. Patients were followed every 4 weeks, and we collected detailed cutaneous symptoms, photos, and biopsy specimens. Results: All patients presented with at least 1 adverse skin reaction. The mean duration of treatment was 24 weeks. The most common adverse effect was papillomas (7/14), followed by palmoplantar hyperkeratosis (5/14), alopecia (5/14), and seborrheic dermatitis-like eruption (2/14). Three patients who received trametinib developed an acneiform eruption (3/5). One patient developed a keratoacanthoma-like squamous cell carcinoma. Side effects presented as early as 2 weeks after starting therapy, with a mean time of onset of 9 weeks. Conclusion: Selective BRAF inhibitor dabrafenib and MEK inhibitor trametinib are associated with multiple skin adverse effects. Given their recent approval and the potential for malignant lesions to develop on treatment, awareness of potential adverse effects and their management is necessary.

scholarly journals Salutary Response to Targeted Therapy in Anaplastic Thyroid Cancer

2019 ◽  
Vol 7 ◽  
pp. 232470961989094 ◽  
Author(s):  
Sasan Fazeli ◽  
Edina Paal ◽  
Jessica H. Maxwell ◽  
Kenneth D. Burman ◽  
Eric S. Nylen ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Side Effects ◽  
Combination Therapy ◽  
Braf Inhibitor ◽  
Anaplastic Thyroid Cancer ◽  
Mek Inhibitor ◽  
Braf V600e ◽  
Aggressive Tumor ◽  
Well Differentiated

Context. Anaplastic thyroid cancer (ATC) is an aggressive tumor with a median survival of 3 to 9 months, a 1-year survival of less than 10% and without definitive therapies. Recently, in BRAF V600E mutated ATCs, new targeted therapy using a combination of a BRAF inhibitor, dabrafenib (Dab), with a mitogen-activated extracellular protein kinase (MEK) inhibitor, trametinib (Tram), has shown significant promise. Case Description. We report a case of aggressive ATC with 5 sequence mutations: BRAF V600E (mutation fraction [MF] 34%), TERT E441del (MF 37%), RET N579K (MF 55%), EZH2 D154E (MF 60%), and CDK4 S259L (MF 48%). The patient had a dramatic response to the Dab/Tram combination with near complete resolution of his lung, bone, hepatic, and splenic lesions soon after starting therapy. Unfortunately, intolerable side effects (grade 2-3) on this regimen required tapering and discontinuation of the treatment. He had a quick resurgence of disease after stopping the combination therapy. The patient died approximately 3 months after discontinuing Dab/Tram. Autopsy revealed an atrophic thyroid gland with microscopic subcapsular focus of well-differentiated papillary thyroid carcinoma. There was extensive lymphatic spread of the tumor throughout bilateral lungs with fibrosis. No other metastatic site was identified. Conclusion. We report a unique case of ATC with 2 new mutations of EZH2 D154E and CDK S529L. This case exemplifies the significant promise Dab/Tram therapy holds, the potential side effects that limit their use, and autopsy findings status post use of this combination therapy.

scholarly journals Response to Ipilimumab/Nivolumab Rechallenge and BRAF Inhibitor/MEK Inhibitor Rechallenge in a Patient with Advanced Metastatic Melanoma Previously Treated with BRAF Targeted Therapy and Immunotherapy

2020 ◽  
Vol 2020 ◽  
pp. 1-6 ◽  
Author(s):  
Caitlyn N. Myrdal ◽  
Srinath Sundararajan
Keyword(s):  
Targeted Therapy ◽  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Optimal Sequencing ◽  
The Right

Little is known about the optimal sequencing of targeted therapy and immunotherapy in the treatment of patients with BRAFV600-mutated metastatic melanoma. BRAF/MEK inhibition often has the benefit of rapid disease regression; however, resistance is frequently seen with long-term use. Treatment with immune checkpoint inhibitors offers the potential for long-term response but displays a lower rate of objective response. The benefit of synergy between therapies is apparent; however, there is limited data regarding optimal sequencing in the treatment of advanced melanoma. We present the case of a 62-year-old gentleman with advanced BRAFV600-mutated melanoma who followed an unconventional treatment path. After progressing on single-agent vemurafenib, he had response to multiple modalities of immunotherapy before progression. After, he had a substantial response to multiple BRAF/MEK inhibitor rechallenges before developing resistance. The patient is now stable after a retrial of combination immunotherapy. Our case illustrates that with the right sequencing of therapy, meaningful clinical responses can be elicited with rechallenging of targeted therapy and immunotherapy in metastatic melanoma.

Risperidone-Induced Neuroleptic Malignant Syndrome: A Case Report and Review

1996 ◽  
Vol 41 (1) ◽  
pp. 52-54 ◽  
Author(s):  
Gb Meterissian
Keyword(s):  
Case Report ◽  
Side Effects ◽  
Neuroleptic Malignant Syndrome ◽  
Clinical Features ◽  
Prior History ◽  
Extrapyramidal Side Effects ◽  
Life Threatening ◽  
History Of ◽  
Life Threatening Complication ◽  
The One

Objectives: 1. To report the case of a 53-year-old patient who developed neuroleptic malignant syndrome (NMS) — a rare but potentially life-threatening complication of neuroleptic therapy — 4 days after treatment with risperidone was initiated. 2. To review previously reported cases of NMS associated with risperidone. Methods: A computerized search of several databases, including MEDLINE, was conducted to find all previously reported cases of NMS with risperidone. Results: Five reported cases of risperidone-induced NMS were found in the literature. All cases including the one reported here displayed typical clinical features of NMS and all 6 patients had a prior history of extrapyramidal side effects and/or NMS. Age and duration of exposure to risperidone did not seem to be of significance. Conclusions: These cases illustrate that clinicians should be on the lookout for risperidone-induced NMS.

TOXICITIES OF TARGETED THERAPY AND IMMUNE-RELATED ADVERSE DRUG REACTIONS OF IMMUNOTHERAPY IN THE TREATMENT OF METASTATIC MELANOMA

2018 ◽  
Author(s):  
Lidija Kandolf Sekulović
Keyword(s):  
Overall Survival ◽  
Targeted Therapy ◽  
Side Effects ◽  
Adverse Effects ◽  
Metastatic Melanoma ◽  
Adverse Drug Reactions ◽  
Mek Inhibitor ◽  
Braf Inhibitors ◽  
Drug Reactions ◽  
Acneiform Eruption

Targeted therapy and immunotherapy changed the treatment landscape for metastatic melanoma, which is chemotherapy resistant cancer. In pre-innovation era, the overall survival of patients with metastatic melanoma was 6 months, while today 5-year overall survival rate of 34% (and 50% in good prognostic groups) is evident. However, both treatments have their side effects, and cutaneous are the most frequent. Treating physicians in oncology centres, but also primary care specialists, need to be aware of their spectrum which differs for each class of drug: BRAF inhibitors, MEK inhibitors and immunotherapy with anti-PD1 and anti-CTLA4. While BRAF inhibitors have the most prominent adverse effects which are class specific, there are also drug-specific adverse effects. For example, vemurafenib causes photosensitivity, which is not specific for dabrafenib, while dabrafenib induces pyrexia, that occurs much less frequently with other BRAF inhibitors. Cutaneous rash and cutaneous neoplasms which develop due to paradoxical activation of RAS signalling are described with BRAF inhibitor monotherapy. These side-effects are much less common in combination therapy with BRAF and MEK inhibitor, but MEK inhibitor itself causes characteristic acneiform eruption, and serous retinopathy. Immune related adverse drug reactions are a hallmark of the immune checkpoint inhibitor immunotherapy, which can affect every organ system, and most commonly skin, lungs and gastrointestinal system, with differential frequencies recorded with anti-CTLA4 therapy and anti PD-1 therapy. Skin reactions most frequently include pruritus and eczematous reactions, as well as vitiligo-like hypopigmentation, which is linked Melanom 45 to the better response to treatment. In this review, frequent and rare side effects are presented, as well as the current algorithms for their treatment.

scholarly journals P.022 Myasthenia gravis following dabrafenib and trametinib for metastatic melanoma

2019 ◽  
Vol 46 (s1) ◽  
pp. S19 ◽  
Author(s):  
A Zaloum ◽  
JR Falet ◽  
A Elkrief ◽  
C Chalk
Keyword(s):  
Protein Kinase ◽  
Myasthenia Gravis ◽  
Metastatic Melanoma ◽  
Mapk Pathway ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Proximal Muscle Weakness ◽  
Proximal Muscle ◽  
Mitogen Activated Protein

Background: Inhibitors of BRAF and MEK, enzymes in the mitogen-activated protein kinase (MAPK) pathway, are now widely used in the treatment of metastatic melanoma. We report a case of acetylcholine receptor (AChR) antibody-positive myasthenia gravis developing after exposure to dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor. Methods: A 68-year-old man presented with dysarthria, dysphagia, cough, dyspnea, and fever. Examination revealed fatigable ptosis and proximal muscle weakness. He had started dabrafenib and trametinib for metastatic melanoma two weeks prior. He was diagnosed with myasthenia gravis and superimposed aspiration pneumonia. AChR antibodies were positive. Dabrafenib and trametinib were stopped. He improved rapidly with pyridostigmine alone, and remained free of myasthenic symptoms for the next two months. Another course of dabrafenib and trametinib was given, and seven weeks later, his myasthenic symptoms recurred. Pyridostigmine produced only partial improvement, and treatment with intravenous immunoglobulin and prednisone was initiated. Results: We are unaware of prior reports of an association between BRAF/MEK inhibitors and seropositive myasthenia gravis. The development of myasthenic symptoms twice after BRAF/MEK inhibitor exposure suggests that the association is more than coincidental. Conclusions: Myasthenia gravis may be a complication of treatment of melanoma with dabrafenib and trametinib. The mechanism by which this occurs is unknown.

scholarly journals Efficacy and Adverse Events in Metastatic Melanoma Patients Treated with Combination BRAF Plus MEK Inhibitors Versus BRAF Inhibitors: A Systematic Review

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1950 ◽  
Author(s):  
Austin Greco ◽  
Danish Safi ◽  
Umang Swami ◽  
Tim Ginader ◽  
Mohammed Milhem ◽  
...  
Keyword(s):  
Adverse Events ◽  
Metastatic Melanoma ◽  
Randomized Clinical Trials ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Mek Inhibitor ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Mek Inhibitors

We reviewed the literature to assess the efficacy and risk of constitutional, cardiac, gastrointestinal, and dermatological toxicities of combined BRAF plus MEK inhibitors versus BRAF inhibitors alone in patients with metastatic melanoma with BRAF mutations. Searches were conducted in PubMed, Cochrane Database of Systematic Reviews, Google scholar, ASCO, Scopus, and EMBASE for reports published from January 2010 through March 2019. Efficacy, including progression-free survival (PFS) and overall survival (OS) rates, were assessed by hazard ratio (HR); objective response rates (ORR) were assessed by odds ratio (OR). The randomized clinical trials (RCTs) with comparison to vemurafenib monotherapy were included to determine constitutional, gastrointestinal, cardiac, and dermatological toxicities using PRISMA statistical analysis with relative risk (RR) for equal comparison to avoid inclusion bias. Five RTCs comprising 2307 patients were included to assess efficacy, while three of the five RCTs comprising 1776 patients were included to assess adverse events. BRAF plus MEK inhibitor combination therapy demonstrated overall better efficacy compared to BRAF inhibitor monotherapy. Combination therapies appear to have favorable dermatologic side effect profiles, similar constitutional and cardiac profiles, and slightly worse gastrointestinal profiles compares to monotherapy regimens.

scholarly journals Ocular changes in metastatic melanoma patients treated with MEK inhibitor cobimetinib and BRAF inhibitor vemurafenib

2018 ◽  
Vol 52 (2) ◽  
pp. 213-219 ◽  
Author(s):  
Ana Ursula Gavric ◽  
Janja Ocvirk ◽  
Polona Jaki Mekjavic
Keyword(s):  
Metastatic Melanoma ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Retinal Layers ◽  
Ocular Symptoms ◽  
Ocular Side ◽  
Mitogen Activated Protein ◽  
Melanoma Patients ◽  
Murine Sarcoma

AbstractBackgroundMitogen-activated protein kinase kinase (MEK) inhibitor cobimetinib and V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor vemurafenib have significantly improved the prognosis of BRAF-mutated metastatic melanoma. Some ocular symptoms and signs were recently recognized to follow this treatment. The study was aimed to investigate ocular toxicity in patients with metastatic melanoma treated with cobimetinib in combination with vemurafenib.Patients and methodsIn the prospective, observational study, patients with BRAF-mutated metastatic melanoma treated with cobimetinib in combination with vemurafenib at the Institute of Oncology Ljubljana were asked to participate. Ophthalmic examination was performed including measurement of visual acuity and intraocular pressure, slit lamp examination, funduscopy (CF), infrared-reflectance (IR) imaging and optical coherence tomography (OCT).ResultsFive out of 7 patients noticed changes in vision few days after starting the therapy with cobimetinib. In all patients, small circular lesions, described as MEKAR lesions, were documented in outer retinal layers demonstrated with OCT, IR, and CF. Changes were in the center and/or scattered over the retina almost symmetrical in both eyes in 6 patients, and asymmetrical in one patient, the latter presented also with unilateral anterior uveitis and cystoid macular edema.ConclusionsMultiple bilateral foveal and extrafoveal small retinal lesions in the outer retinal layers develop in patients treated with MEK inhibitor in combination with BRAF inhibitor. Ophthalmologists and oncologists need to be aware of this common, yet relatively benign and often transient ocular side effect to avoid needless intervention, including the discontinuance of a potentially life-prolonging therapy.

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