Gastrointestinal perforation following dabrafenib and trametinib administration in non-small cell lung carcinoma with BRAF V600E mutation: a case report and literature review

Shimada, Yuri; Sato, Yuki; Tachikawa, Ryo; Hara, Shigeo; Tomii, Keisuke

doi:10.1007/s10637-021-01135-0

Cited by 7 publications

(5 citation statements)

References 12 publications

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“…Diarrhea and vomiting were the most frequent grade ≥ 3 gastrointestinal toxicities in the clinical trials testing BRAF inhibitors alone or combined with MEK inhibitors [3][4][5]. Rare cases of colitis and intestinal perforation have been reported [6][7][8][9]. The Ras-MEK-ERK pathway plays a crucial role in the proliferation, differentiation, migration and survival of the gastrointestinal epithelium.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, two patients treated with BRAF and MEK inhibitors developed intestinal perforation that required urgent surgical management, leading to a permanent ileostomy in one case. Other cases of intestinal perforation associated to MEK inhibitors have been described, although in some cases tumor regression in response to treatment may be the underlying cause of the event itself [7][8][9].…”

Section: Discussionmentioning

confidence: 99%

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Drug-induced colitis on BRAF and MEK inhibitors for BRAF V600E-mutated non-small cell lung cancer: a case report

et al. 2021

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Summary Introduction. The combination of BRAF and MEK inhibitors has deeply changed the treatment of BRAF V600-mutant non-small cell lung cancer patients. These agents demonstrated high antitumor activity as well as safe and manageable toxicity profile. Hypertension, pyrexia and increased liver enzymes are the most common adverse events. Gastrointestinal toxicities are rare, and mainly consist of mild grade vomiting and diarrhea. Case report. We report the case of 70-year-old man affected by BRAF V600-mutant NSCLC with bilateral lung and bone metastases. First-line treatment with encorafenib (450 mg once daily) and binimetinib (45 mg twice daily) was administered within a clinical trial. At the first radiological assessment, computed tomography (CT) scan showed a partial response and signs of intestinal inflammation were reported. The investigational treatment was timely withheld. The subsequent colonoscopy demonstrated the presence of ulcerative lesions at the caecal tract, and the histological diagnosis suggested a drug-induced colitis. No specific treatment was given as the patient did not report abdominal disturbances. Forty-five days after treatment interruption a new CT scan showed the resolution of bowel inflammation and investigational treatment was resumed at the same doses. The patient is still alive and free of toxicity recurrence after 11 months from treatment initiation. Conclusion. Severe gastrointestinal toxicities are uncommon with BRAF and MEK inhibitors, although cases of colitis and intestinal perforation have already been reported in literature. The pathogenesis seems to be related to the MAPK pathway inhibition performed by MEK inhibitors. These adverse events should be accounted given the potential to evolve into life-threatening conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Drug-induced colitis on BRAF and MEK inhibitors for BRAF V600E-mutated non-small cell lung cancer: a case report

et al. 2021

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“…Additionally, the low solubility of vemurafenib may have played a role in either developing or worsening gastrointestinal toxicity, as undissolved particles could deposit on the gastrointestinal mucosa. On the other hand, gastrointestinal perforations have been described during MEKi therapy [ 27 ]. In case 2, a considerable decrease in left ventricular function was observed after 4 months of treatment, which is a known adverse event from BRAF/MEKi treatment (Risk Ratio: 2.79; 95% CI 1.36–5.73) [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and toxicity of vemurafenib and cobimetinib in relation to plasma concentrations, after administration via feeding tube in patients with BRAF-mutated thyroid cancer: a case series and review of literature

Henegouwen

Wijngaart

Zeverijn

et al. 2022

Cancer Chemother Pharmacol

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Introduction The combination of vemurafenib, a proto-oncogene B-Raf inhibitor (BRAFi) and cobimetinib, an inhibitor of mitogen-activated protein kinase kinase (MEKi) has shown to improve survival in patients with BRAF V600-mutated melanoma. BRAF mutations are also frequently detected driver mutations in other tumor types, including thyroid carcinoma. Since thyroid carcinoma is not a labeled indication for BRAF/MEKi, a cohort for patients with BRAF V600-mutated thyroid carcinoma was opened within the Drug Rediscovery Protocol (DRUP), a national ongoing pan-cancer multi-drug trial, in which patients receive off-label treatment with approved drugs based on their molecular tumor profile. Results Here, we present two patients with BRAF-mutated thyroid carcinoma, who were successfully treated with vemurafenib/cobimetinib administered via a feeding tube. Plasma concentrations of vemurafenib and cobimetinib were determined. A partial response was observed in both patients, but they experienced significant toxicity. Conclusion Our cases show that vemurafenib/cobimetinib treatment is effective in BRAF V600-mutated thyroid carcinoma, also when administered via a feeding tube. Although serious side effects occurred in both patients, we hypothesize that this was not attributable to the administration route. Therefore, administration of vemurafenib/cobimetinib by feeding tube is feasible and effective. Trial registration Clinical trial identification: NCT02925234.

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“…For instance, MEKi treatment (cobimetinib, trametinib, binimetinib), with or without accompanying BRAFi, have been correlated with some cases of perforation in small and large intestine. 67 A retrospective analysis of 119 patients treated with MEKi (cobimetinib, trametinib, binimetinib) for unresectable stage III or stage IV melanoma showed 33% of gastrointestinal toxicities of any grade: patients experienced colitis ( n =3), gastrointestinal perforation grade 4 ( n =2) and diarrhoea ( n =1). No fatal outcomes were reported.…”

Section: Reviewmentioning

confidence: 99%

Non-small-cell lung cancer: how to manage BRAF-mutated disease

Guaitoli¹,

Zullo²,

Tiseo³

et al. 2023

DIC

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BRAF mutations are reported in about 3–5% of non-small-cell lung cancer (NSCLC), almost exclusively in adenocarcinoma histology, and are classified into three different classes. The segmentation of BRAF mutations into V600 (class 1) and non-V600 (classes 2 and 3) relies on their biological characteristics and is of interest for predicting the therapeutic benefit of targeted therapies and immunotherapy. Given the relative rarity of this molecular subset of disease, evidence supporting treatment choices is limited. This review aims to offer a comprehensive update about available therapeutic options for patients with NSCLC harbouring BRAF mutations to guide the physician in the choice of treatment strategies. We collected the most relevant available data, from single-arm phase II studies and retrospective analyses conducted in advanced NSCLC, regarding the efficacy of BRAF and MEK inhibitors in both V600 and non-V600 BRAF mutations. We included case reports and smaller experiences that could provide information on specific alterations. With respect to immunotherapy, we reviewed retrospective evidence on immune-checkpoint inhibitors in this molecular subset, whereas data about chemo-immunotherapy in this molecular subgroup are lacking. Moreover, we included the available, though limited, retrospective evidence of immunotherapy as consolidation after chemo-radiation for unresectable stage III BRAF -mutant NSCLC, and an overview of ongoing clinical trials in the peri-operative setting that could open new perspectives in the future.

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Gastrointestinal perforation following dabrafenib and trametinib administration in non-small cell lung carcinoma with BRAF V600E mutation: a case report and literature review

Cited by 7 publications

References 12 publications

Drug-induced colitis on BRAF and MEK inhibitors for BRAF V600E-mutated non-small cell lung cancer: a case report

Drug-induced colitis on BRAF and MEK inhibitors for BRAF V600E-mutated non-small cell lung cancer: a case report

Efficacy and toxicity of vemurafenib and cobimetinib in relation to plasma concentrations, after administration via feeding tube in patients with BRAF-mutated thyroid cancer: a case series and review of literature

Non-small-cell lung cancer: how to manage BRAF-mutated disease

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