Management of Treatment-Related Adverse Events with Agents Targeting the MAPK Pathway in Patients with Metastatic Melanoma

Daud, Adil; Tsai, Katy K.

doi:10.1634/theoncologist.2016-0456

Cited by 73 publications

(64 citation statements)

References 52 publications

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“…6,7 LVEF-D induced by BRAF and MEKis, although widely reported in clinical trials, has never been thoroughly described to date and data regarding its management are limited. [8][9][10] The main objective of the study presented herein was therefore to describe the characteristics of LVEF-D in a large cohort of metastatic melanoma patients treated with BRAF and/or MEKis in a real-life setting. Secondary objectives were to determine whether laboratory, electrocardiogram (ECG) or transthoracic echocardiography (TTE) markers could identify sub-clinical cardiac damage and be predictive of a LVEF-D.…”

Section: Introductionmentioning

confidence: 99%

Left ventricular ejection fraction decrease related to BRAF and/or MEK inhibitors in metastatic melanoma patients: A retrospective analysis

et al. 2020

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BRAF and MEKis have revolutionized the management of BRAF V600 -mutated melanoma patients. Left ventricular ejection fraction decrease (LVEF-D) related to these treatments has not been thoroughly evaluated to date. The main objective of this study was to describe characteristics of LVEF-D in melanoma patients treated with BRAF and/or MEKis. Metastatic melanoma patients treated with BRAF and/ or MEKis between March 1, 2012 and May 18, 2018 were included retrospectively (Lyon Sud University Hospital, Hospices Civils de Lyon). LVEF-D was defined as a reduction in LVEF ≥10% from baseline to a value <55%; normalization was defined as a value ≥55%. Among the 88 patients included, 12 (13.6%) experienced a LVEF-D, including 10 grade 2 and 2 grade 3. The median onset of which was 11 months (IQR [3-21]). No patient previously treated with beta-blockers (n = 12) experienced a LVEF-D. Analysis of laboratory parameters, electrocardiogram, and transthoracic echocardiography during the follow-up did not find any predictive marker of LVEF-D. All patients who benefited from a specific treatment of LVEF-D had a normalization of LVEF at the end of follow-up. LVEF recovery was significantly better for patients treated with angiotensin converting enzyme inhibitors and beta-blockers than those who did not (P = .019). Ophthalmological adverse events were significantly more frequent in patients who experienced a LVEF-D (P = .006) and the latter did not influence overall-survival (P = .117) or progression-free-survival (P = .297). LVEF-D is a common and easily manageable adverse event due to BRAF and MEKis. Its association with ocular toxicity suggests a close ophthalmological monitoring when LVEF-D occurs. K E Y W O R D Sadverse events, BRAF inhibitor, cardiac toxicity, heart failure, left ventricular ejection fraction, left ventricular systolic dysfunction, MEK inhibitor, metastatic melanoma 2612 | BERGER Et al.

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Section: Introductionmentioning

confidence: 99%

Left ventricular ejection fraction decrease related to BRAF and/or MEK inhibitors in metastatic melanoma patients: A retrospective analysis

et al. 2020

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“…18 26,27 To alleviate the BRAFi-induced phototoxicity, we tested a panel of antioxidants as an attempt to find feasible alternatives for the management of phototoxicity. 28,29 Accordingly, the physiological antioxidants vitamin C, vitamin E, trolox, and GSH were added to the 3T3 NRU phototoxicity assay with the BRAFi vemurafenib, dabrafenib, and encorafenib. Interestingly, we observed that high-dose GSH was able to fully rescue the UVA-induced phototoxicity of vemurafenib.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of the phototoxicity induced by BRAF inhibitors and alleviation through antioxidants

Heppt

Clanner‐Engelshofen

Marsela

et al. 2019

Photoderm Photoimm Photomed

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Background Small molecules tackling mutated BRAF (BRAFi) are an important mainstay of targeted therapy in a variety of cancers including melanoma. Albeit commonly reported as side effect, the phototoxic potential of many BRAFi is poorly characterized. In this study, we evaluated the phototoxicity of 17 distinct agents and investigated whether BRAFi‐induced phototoxicity can be alleviated by antioxidants. Methods The ultraviolet (UV) light absorbance of 17 BRAFi was determined. Their phototoxic potential was investigated independently with a reactive oxygen species (ROS) and the 3T3 neutral red uptake (NRU) assay in vitro. To test for a possible phototoxicity alleviation by antioxidants, vitamin C, vitamin E phosphate, trolox, and glutathione (GSH) were added to the 3T3 assay of selected inhibitors. Results The highest cumulative absorbance for both UVA and UVB was detected for vemurafenib. The formation of ROS was more pronounced for all compounds after irradiation with UVA than with UVB. In the 3T3 NRU assay, 8 agents were classified as phototoxic, including vemurafenib, dabrafenib, and encorafenib. There was a significant correlation between the formation of singlet oxygen (P = .026) and superoxide anion (P < .001) and the phototoxicity observed in the 3T3 NRU assay. The phototoxicity of vemurafenib was fully rescued in the 3T3 NRU assay after GSH was added at different concentrations. Conclusion Our study confirms that most of the BRAF inhibitors exhibited a considerable phototoxic potential, predominantly after exposure to UVA. GSH may help treat and prevent the phototoxicity induced by vemurafenib.

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“…On average, fevers last approximately 9 days. Generally, half of patients who experience pyrexia have recurrent events that typically last 4–5 days .…”

Section: Adverse Events and Managementmentioning

confidence: 99%

“…Patients should also be encouraged to immediately report fever or related symptoms while undergoing dabrafenib plus trametinib treatment . If pyrexia does occur, the recommended course of action is to rule out infection , although an infectious workup (i.e., complete blood count, comprehensive metabolic panel, and blood and urine cultures) is not recommended if pyrexia is uncomplicated, with no evidence of localizing symptoms . If pyrexia is severe, serum creatinine should be monitored.…”

Section: Adverse Events and Managementmentioning

confidence: 99%

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Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib

2018

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Therapies for advanced non‐small cell lung cancer (NSCLC) continue to become more sophisticated. Chemotherapeutics are giving way to newer approaches such as immune checkpoint inhibitors and targeted therapies for greater efficacy and improved outcomes. Dabrafenib plus trametinib combination therapy was first approved for the treatment of metastatic melanoma harboring the BRAF V600‐mutation in 2014. In 2017, the U.S. Food and Drug Administration approved the combination for patients with NSCLC with the same mutation based on an ≈ 65% response rate and median progression‐free survival of 10–11 months. BRAF mutations are a high‐frequency event in melanoma (≈ 50%), whereas the overall incidence in lung cancer is ≈ 2%, but similar in number, because of the high incidence of the disease. As a new approach in NSCLC treatment, dabrafenib plus trametinib has a unique toxicity profile that is likely unfamiliar to care providers in thoracic and general oncology who have not used the combination to treat patients with melanoma. Common adverse events such as pyrexia, fatigue, and nausea, as well as a range of less frequent cutaneous, ocular, and hemorrhagic events, can be observed during treatment with dabrafenib plus trametinib. Previous experience in metastatic melanoma revealed that these events can be effectively managed to improve patient quality of life and reduce unnecessary drug discontinuation. The aim of this review is to summarize treatment guidelines, along with key insights obtained from previous clinical‐trial and real‐world experience in patients with metastatic melanoma, to properly manage toxicities associated with dabrafenib plus trametinib for NSCLC. Implications for Practice The combination of dabrafenib plus trametinib has demonstrated substantial clinical activity in patients with BRAF V600E‐mutant non‐small cell lung cancer, leading to U.S. Food and Drug Administration approval. Although the combination has a manageable safety profile, many toxicities associated with the regimen may not be familiar to thoracic specialists or general oncologists. Extensive clinical experience with the combination in patients with metastatic melanoma has provided a wealth of strategies to identify and manage adverse events associated with dabrafenib plus trametinib. These can be used by medical oncologists to enhance early recognition of toxicities and facilitate effective management, thereby improving quality of treatment for patients.

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Management of Treatment-Related Adverse Events with Agents Targeting the MAPK Pathway in Patients with Metastatic Melanoma

Cited by 73 publications

References 52 publications

Left ventricular ejection fraction decrease related to BRAF and/or MEK inhibitors in metastatic melanoma patients: A retrospective analysis

Left ventricular ejection fraction decrease related to BRAF and/or MEK inhibitors in metastatic melanoma patients: A retrospective analysis

Comparative analysis of the phototoxicity induced by BRAF inhibitors and alleviation through antioxidants

Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib

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