Acute polyneuropathy in a metastatic melanoma patient treated with vemurafenib and cobimetinib

Compter, Annette; Boogerd, Willem; Thienen, J.V. van; Brandsma, Dieta

doi:10.1212/cpj.0000000000000331

Cited by 10 publications

(13 citation statements)

References 7 publications

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“…Although polyneuropathy and encephalopathy have been reported in studies on BRAF/MEK inhibitor therapies, neurological side effects overall are rare, and the pathophysiology of these side effects is unknown [2, 3]. Immune‐mediated mechanisms may play a role in the development of these side effects, given the effect of BRAF‐targeted therapies on the immune system.…”

Section: Discussionmentioning

confidence: 99%

BRAF Inhibitor Therapy-Related Encephalitis in a Patient with Metastatic Melanoma

2021

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Introduction. BRAF-inhibitors such as encorafenib and vemurafenib in combination with MEK inhibitors are commonly used for the treatment of patients with BRAFV600-mutant melanoma. Case Presentation. A patient with relapsed metastatic melanoma with a BRAFV600 mutation was started on treatment with vemurafenib and cobimetinib. Within two weeks of treatment-start, he was hospitalized and diagnosed with encephalitis through a lumbar puncture and treated with corticosteroids, with subsequent normalization of CSF findings. When he recovered and was switched to encorafenib treatment, the same symptoms recurred and patient was treated with high dose steroids and IVIG, again with improvement in his CSF. He has not had a relapse of his symptoms since BRAF-inhibitor treatment was permanently discontinued. Conclusion. This is the first known report of a patient who has developed encephalitis due to treatment with BRAFinhibitors. The Oncologist 2021;9999:• •

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Section: Discussionmentioning

confidence: 99%

BRAF Inhibitor Therapy-Related Encephalitis in a Patient with Metastatic Melanoma

2021

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“…In addition, the MAPK signaling pathway was found to be significantly enriched in overexpressed genes among patients with GBS [ 64 ]. Second, increasing number of case reports and case series were published in the literature, implicating BRAFi or MEKi in neuropathy [ 65 , 66 , 67 , 68 , 69 , 70 , 71 ] as well as GBS [ 69 , 72 , 73 ]. Third, a relatively frequent drug-related AE occurring with encorafenib monotherapy was transient Bell’s palsy [ 5 , 18 ], a mononeuritic variant of GBS, in most cases [ 74 ].…”

Section: Discussionmentioning

confidence: 99%

Safety of BRAF+MEK Inhibitor Combinations: Severe Adverse Event Evaluation

Meirson

Asher

Bomze

et al. 2020

Cancers

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Aim: The selective BRAF and MEK inhibitors (BRAFi+MEKi) have substantially improved the survival of melanoma patients with BRAF V600 mutations. However, BRAFi+MEKi can also cause severe or fatal outcomes. We aimed to identify and compare serious adverse events (sAEs) that are significantly associated with BRAFi+MEKi. Methods: In this pharmacovigilance study, we reviewed FDA Adverse Event Reporting System (FAERS) data in order to detect sAE reporting in patients treated with the combination therapies vemurafenib+cobimetinib (V+C), dabrafenib+trametinib (D+T) and encorafenib+binimetinib (E+B). We evaluated the disproportionate reporting of BRAFi+MEKi-associated sAEs. Significant associations were further analyzed to identify combination-specific safety signals among BRAFi+MEKi. Results: From January 2018 through June 2019, we identified 11,721 sAE reports in patients receiving BRAFi+MEKi. Comparison of BRAFi+MEKi combinations demonstrates that skin toxicities, including Stevens–Johnson syndrome, were disproportionally reported using V+C, with an age-adjusted reporting odds ratio (adj. ROR) of 3.4 (95%CI, 2.9–4.0), whereas fever was most significantly associated with D+T treatment with an adj. ROR of 1.9 (95%CI, 1.5–2.4). Significant associations using E+B treatment include peripheral neuropathies (adj. ROR 2.7; 95%CI, 1.2–6.1) and renal disorders (adj. ROR 4.1; 95%CI, 1.3–12.5). Notably, we found an increase in the proportion of Guillain–Barré syndrome reports (adj. ROR 8.5; 95%CI, 2.1–35.0) in patients administered E+B. Conclusion: BRAFi+MEKi combinations share a similar safety profile attributed to class effects, yet concomitantly, these combinations display distinctive effects that can dramatically impact patients’ health. Owing to the limitations of pharmacovigilance studies, some findings warrant further validation. However, the possibility of an increased risk for these events should be considered in patient care.

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“…With regard to the first case, in literature, there are only few reported cases of bilateral facial palsy or acute polyradiculoneuropathy in patients treated with Vemurafenib-and Cobimetinib-combined treatment [5][6][7][8][9]. The distinctive trait of our patient is that she developed both the polyradiculoneuropathy and the bilateral cranial nerves involvement 3 years after the beginning of Vemurafenib and 1 year after the combined treatment, while the other cases developed polyradiculoneuropathy or bilateral facial palsy and generally few months after the start of therapy (4-9 weeks).…”

Section: Discussionmentioning

confidence: 99%

“…It is believed that this treatment leads to a suppression of the release of immunosuppressive factors from the melanoma cells and increases melanoma antigen expression leading to more effective T cell recognition [12]. We should remember that melanocytes and Schwann cells share the same origin from neural crest and surface molecules; for these reasons and for the marked steroid response, we think that the neuropathy was triggered by a mechanism of immune-mediated molecular mimicry [9].…”

Section: Discussionmentioning

confidence: 99%

Neuromuscular complications following targeted therapy in cancer patients: beyond the immune checkpoint inhibitors. Case reports and review of the literature

et al. 2020

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Introduction In the last years, many new drugs have been developed targeting different oncology pathways, overall improving both quality of life and survival in several malignancies. However, the increase of those therapies is associated with novel toxicities, mainly immune-related adverse events (irAEs), never observed before. Different irAEs are now well characterized, and, among them, neuromuscular complications, following immune checkpoint inhibitor (ICPi) therapy, are increasingly studied and described. However, there are also neurological complications related to the use of other targeted therapies, less known and probably underestimated. Herein we describe two oncological patients who developed neuromuscular diseases after administration of targeted therapies, different from ICPi. Case reports The first patient was treated with the combination of Vemurafenib and Cobimetinib, BRAF and MEK inhibitors, respectively, for a cutaneous melanoma. One year after the beginning of the combined treatment, she developed a sub-acute motor neuropathy with predominant cranial nerve involvement. She was successfully treated with methylprednisolone. The second patient received therapy with Imatinib, tyrosine kinase inhibitor and precursor of the targeted therapy, for a gastrointestinal stromal tumour. Few days after the first administration, he developed generalized myasthenia gravis with respiratory failure. Clinical remission was obtained with plasma-exchange, intravenous immunoglobulins and steroids. Discussion and Conclusion We strengthen the relevance of neuromuscular complications which may occur long after treatment start or in patients receiving not only the latest ICPi but also "older" and apparently better-known targeted therapies. Also in the latter cases, an immune-mediated "off-target" pathogenic mechanism can be hypothesized, and consequences can be life threatening, if not promptly diagnosed and appropriately managed.

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Acute polyneuropathy in a metastatic melanoma patient treated with vemurafenib and cobimetinib

Cited by 10 publications

References 7 publications

BRAF Inhibitor Therapy-Related Encephalitis in a Patient with Metastatic Melanoma

BRAF Inhibitor Therapy-Related Encephalitis in a Patient with Metastatic Melanoma

Safety of BRAF+MEK Inhibitor Combinations: Severe Adverse Event Evaluation

Neuromuscular complications following targeted therapy in cancer patients: beyond the immune checkpoint inhibitors. Case reports and review of the literature

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