Optimizing combination dabrafenib and trametinib therapy in BRAF mutation‐positive advanced melanoma patients: Guidelines from Australian melanoma medical oncologists

Atkinson, Victoria; Long, Georgina V.; Menzies, Alexander M.; McArthur, Grant A.; Carlino, Matteo S.; Millward, Michael; Roberts‐Thomson, Rachel; Brady, Benjamin; Kefford, Richard; Haydon, Andrew; Cebon, Jonathan

doi:10.1111/ajco.12656

Cited by 27 publications

(26 citation statements)

References 31 publications

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“…To avoid hypovolaemia with hypotension and possible acute renal failure, sufficient fluid substitution is important. As soon as the fever ceased for at least 24 hours, BRAFi+MEKi therapy can be restarted 48. Patients experience a median of two events of fever, with 21% of patients having > 4 events 47.…”

Section: Methodsmentioning

confidence: 99%

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Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management

Heinzerling¹,

et al. 2019

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The inhibition of the mitogen-activated protein kinases signalling pathway through combined use of BRAF and MEK inhibitors (BRAFi+MEKi) represents an established therapeutic option in patients with BRAF-mutated, advanced melanoma. These efficient therapies are well tolerated with mostly moderate and reversible side effects and a discontinuation rate due to adverse events of 11.5%–15.7%. Median duration of therapy ranges between 8.8 and 11.7 months. Based on data from confirmatory trials, safety profiles of three BRAFi+MEKi combinations were reviewed, that is, dabrafenib plus trametinib, vemurafenib plus cobimetinib and encorafenib plus binimetinib. Many adverse events are class effects, such as cutaneous, gastrointestinal, ocular, cardiac and musculoskeletal events; some adverse events are substance associated. Fever (dabrafenib) and photosensitivity (vemurafenib) are the most common and clinically prominent examples. Other adverse events are less frequent and the association to one substance is less strong such as anaemia, facial paresis (encorafenib), neutropenia (dabrafenib), skin rash, QTc prolongation and increased liver function tests (vemurafenib). This narrative review provides recommendations for monitoring, adverse event evaluation and management focusing on the clinically relevant side effects of the three regimens.

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Section: Methodsmentioning

confidence: 99%

“…A dose reduction is recommended if fever recurs. However, clinical experience shows that short ‘drug holidays’ (about 2–7 days) are much more effective and the full dose can be maintained 48. In recurrent cases, intermittent treatment might be an option to avoid additional fever events.…”

Section: Methodsmentioning

confidence: 99%

Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management

Heinzerling¹,

et al. 2019

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“…Thus, the clinical blood markers that reflect the course of pyrexia during combi‐DT may be helpful for the appropriate management and may result in a shortened drug holiday. For pyrexia management, temporary withdrawal or the dose reduction of combi‐DT and the administration of anti‐inflammatory agents, including corticosteroids, has been recommended . However, some reports have indicated that the dose reduction of the combi‐DT may be ineffective for the prevention of pyrexia and may confer clinical benefits .…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3] Pyrexia during combi-DT is known to be refractory and is characterized by accompanying chills and influenza-like reactions; 4,5 therefore, the clinical management of the condition is important for the continuation of combi-DT. Although previous reports have suggested management strategies for pyrexia, [3][4][5][6][7][8] no appropriate procedure has been established. Moreover, accurate evaluation of the condition of pyrexia during combi-DT allows appropriate management, but blood markers that reflect the course of pyrexia have not yet been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Dynamics of neutrophil and C‐reactive protein reflect the clinical course of pyrexia during combination therapy with dabrafenib and trametinib

Maeda

Yoshino

Yamashita

et al. 2019

The Journal of Dermatology

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Pyrexia is the most common adverse event in patients with melanoma or other solid organ malignancies that are treated with the combination of dabrafenib and trametinib (combi‐DT). Given the expanded indication for combi‐DT, management of pyrexia is a high priority. No previous case series has revealed which blood markers reflect the course of pyrexia and there is no consensus on the management strategy for pyrexia. The current case series study describes the utility of neutrophil count (NC), neutrophil ratio (NR) and C‐reactive protein (CRP) in 11 patients with metastatic melanoma and BRAF V600 mutations who experienced pyrexia during combi‐DT in our department. We also described the clinical course of pyrexia episodes that were managed with the concomitant use of oral prednisolone and immediate withdrawal of combi‐DT. Consequently, the analysis of 37 pyrexia episodes in 11 patients showed that the differences in NC, NR and CRP at the onset of pyrexia were significantly different from those at pyretolysis (P = 0.01, 0.006 and 0.03, respectively). Additionally, in the 24 pyrexia episodes treated with the concomitant use of oral prednisolone and the immediate withdrawal of combi‐DT, the mean duration of pyrexia and the mean time to restart combi‐DT were 3 and 6 days, respectively. Therefore, the blood markers that reflect the course of pyrexia during combi‐DT may be helpful for the appropriate management of pyrexia; also, our management strategy for pyrexia successfully reduced the duration of pyrexia and did not require a long‐term drug holiday. Further large‐scale studies are required to verify our results.

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“…However, combination therapy leads to higher toxicity compared to a single agent [12] . Anti PD-1 inhibitors (Nivolumab and Pembrolizumab) are also used in melanoma.…”

Section: Newer Tumor Markersmentioning

confidence: 99%

An update in the management of malignant melanoma

Pandiaraja

2017

J Surg Dermatol

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Malignant melanoma is one of the most dangerous forms of cutaneous malignancies. It is classified as cutaneous melanoma and non-cutaneous melanoma based on the location of the lesion. Ultraviolet (UV) radiation exposure is a predisposing factor for cutaneous melanoma, although in other forms such as mucous and anorectal malignant melanomas, ultraviolet radiation does not play a significant role. Human papilloma virus and human retroviral infections are commonly associated with non-cutaneous melanomas.

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Optimizing combination dabrafenib and trametinib therapy in BRAF mutation‐positive advanced melanoma patients: Guidelines from Australian melanoma medical oncologists

Cited by 27 publications

References 31 publications

Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management

Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management

Dynamics of neutrophil and C‐reactive protein reflect the clinical course of pyrexia during combination therapy with dabrafenib and trametinib

An update in the management of malignant melanoma

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