Cerebral infarction after treatment with dabrafenib plus trametinib for BRAF‐V600E‐positive non–small cell lung cancer: A case report

Abstract

Dabrafenib plus trametinib is the standard treatment for BRAF V600E‐mutated non‐small cell lung cancer. No treatment‐related cerebral infarction (CI) has been reported in previous clinical trials. Here, we described a 61‐year‐old Japanese man with BRAF V600E‐mutated lung adenocarcinoma treated with dabrafenib plus trametinib as a third‐line treatment. On the 10th day of dabrafenib plus trametinib treatment, the patient developed fever and was urgently hospitalized on the 18th day owing to impaired consciousness. The patient had disseminated intravascular coagulation because of infection, was treated with thrombomodulin and ceftriaxone, and subsequently improved. On the 44th day, dabrafenib plus trametinib was resumed with a one‐step dose reduction. Three hours after the first oral administration, the patient developed chills, fever, and hypotension. He received intravenous fluids. On the 64th day, 20 mg prednisolone was administered from the previous day, and dabrafenib plus trametinib was resumed with a further one‐step reduction in dose. Five hours after the first oral administration, the patient developed fever, hypotension, paralysis of the right upper and lower limbs, and dysarthria appeared. Head magnetic resonance imaging revealed multiple cerebral infarcts. Hemoconcentration because of intravascular dehydration may have caused CI. In conclusion, CI should be taken into consideration during treatment with dabrafenib plus trametinib.

We report a case of BRAF V600E‐mutated lung adenocarcinoma treated with dabrafenib plus trametinib as a third‐line treatment. Five hours after the first oral administration, the patient developed fever, hypotension, paralysis of the right upper and lower limbs, and dysarthria appeared. Head magnetic resonance imaging revealed multiple cerebral infarcts. Cerebral infarction should be taken into consideration during treatment with dabrafenib plus trametinib.

INTRODUCTION

Targeted therapies have significantly changed the treatment of non–small cell lung cancer (NSCLC). BRAF is mutated in 1% to 3% of lung cancers. ¹ Dabrafenib plus trametinib is the standard treatment for BRAF V600E‐mutated NSCLC. ² , ³

Because BRAF mutation is a rare genetic mutation, strategies of treating this mutation by dabrafenib plus trametinib are scarce and determining its rare side effects is important.

Here, we described a patient with BRAF V600E‐mutated lung adenocarcinoma treated with dabrafenib plus trametinib who developed cerebral infarction (CI) after fever and hypotension, because there have been no reports of such cases.

CASE REPORT

A 61‐year‐old Japanese man with a history of smoking (40 pack‐years) was referred to our hospital after a chest X‐ray abnormality was detected during a medical checkup at his workplace. The patient had a history of cervical spondylosis. Chest computed tomography (CT) revealed a mass in the left upper segment and bronchoscopy revealed pulmonary adenocarcinoma. The clinical stage was cT4N1M1b, stage IVA, and radiotherapy was performed for metastases in the first thoracic vertebra.

The patient received cisplatin, pemetrexed, and bevacizumab as a first‐line treatment. The secondary treatment was nivolumab. Radiofrequency snare ablation was performed for the left main bronchial obstruction. At that time, a BRAF V600E mutation in the biopsy specimen was detected. Radiation was applied to the left lung.

As a third‐line treatment, dabrafenib (300 mg) plus trametinib (2 mg) was initiated. On the 10th day, the patient developed fever (39°C) and was urgently hospitalized on the 18th day owing to impaired consciousness. The patient had disseminated intravascular coagulation (DIC) because of infection, was treated with thrombomodulin and ceftriaxone, and subsequently improved.

On the 44th day, we reduced the dose in one step and resumed treatment with dabrafenib (200 mg) and trametinib (1.5 mg). Three hours after the first oral administration, he developed chills and fever (39°C). His blood pressure dropped and he was administered an infusion. CT on admission revealed that the mass in the left upper lobe shrank compared to that at the beginning of treatment, and the left hilar lymph node also shrank. The risks were explained to the patient, but he wished to continue the treatment because he felt that the drug was effective (Figure 1).

FIGURE 1.

(a) Chest computed tomography (CT) on the day of dabrafenib plus trametinib treatment initiation. (b) Chest CT after 17 days of dabrafenib plus trametinib treatment. The mass in the left upper lobe shrank from 76 to 58 mm in long diameter.

On the 64th day, with reference to the optimal use guide to prevent fever, prednisolone (20 mg) was administered from the previous day, and treatment was resumed with dabrafenib (150 mg) and trametinib (1.5 mg), with one further dose reduction. Five hours after the first oral administration, the patient developed fever (40°C), his systolic blood pressure dropped to the 80‐mm Hg range, and paralysis of the right upper and lower limbs and dysarthria appeared. After rapid fluid infusion, paralysis persisted, and head magnetic resonance imaging revealed multiple cerebral infarcts in the left occipital and frontal lobes (Figure 2). The patient was transferred to a neurosurgery hospital where emergency tissue plasminogen activator was administered. Paralysis of the right lower extremity and dysarthria improved, but paralysis of the right hand persisted.

FIGURE 2.

Diffusion‐weighted magnetic resonance imaging at stroke onset. Acute cerebral infarction (CI) is observed with high signal in the left (a)–(c) occipital and (d) frontal lobes.

After 5 months of rehabilitation, treatment with carboplatin and nab‐paclitaxel was initiated.

DISCUSSION

Dabrafenib plus trametinib is a clinically meaningful and manageable antitumor agent in BRAF V600E‐mutant NSCLC. In previous clinical trials for NSCLC and metastatic melanoma, several cerebrovascular diseases were reported as complications, none of which were related to treatment. ³ , ⁴ To the best of our knowledge, this is the first case report of CI immediately after dabrafenib plus trametinib treatment.

The patient in this case had a sudden high fever and a drop in blood pressure 5 h after taking dabrafenib plus trametinib internally. Immediately thereafter, paralysis occurred, suggesting that hemoconcentration caused by intravascular dehydration because of high fever may have caused the CI. Although not reported in clinical trials, there has been one report of fever and hypotension in cases of melanoma. ⁵ As is well known, CI is a common disease and the CI might have occurred by chance, or the sequelae of DIC or steroid use might have influenced the onset of CI. However, the pyrexia and hypotension immediately after administration occurred and then CI occurred. Therefore, hypotension and dehydration are main risks for CI because of dabrafenib plus trametinib in this case.

Cerebral infarction ruling out the causes of CI is very important, and one of them is trousseau syndrome, which produces neurological symptoms associated with latent malignant tumors. ⁶ In patients with cancer, the overall risk of thrombosis is seven times higher than that of patients without cancer. ⁷ Coagulability increases when the lung cancer relapses, but improves when the cancer is suppressed, indicating that the tumor itself likely causes the increased coagulability. ⁸ In our case, the chest CT findings indicated the efficacy of treatment.

An electrocardiogram (ECG) test on another day showed that he was in sinus rhythm, but no ECG data remained at the time of the CI. Moreover, echocardiography was not performed. Therefore, atrial fibrillation or intra‐atrial or intraventricular thrombus cannot be ruled out.

Furthermore, CI is an adverse effect of steroid use. Moreover, although its mechanisms remain unclear, short‐term use of corticosteroids is a risk factor for venous thromboembolism. ⁹ It is unclear whether 2 days of corticosteroid administration would affect CI; however, the risk of corticosteroid administration should always be considered.

In conclusion, we encountered a case of CI with fever and hypotension immediately after dabrafenib plus trametinib administration. Because dabrafenib plus trametinib may cause fever, dehydration, and hypotension, it is necessary to pay attention to signs of CI while taking precautions, such as prophylactic infusion and steroids.

CONFLICT OF INTEREST STATEMENT

Y.T. reports personal fees from AstraZeneca, Ono Pharmaceutical, and Chugai Pharmaceutical, outside the submitted work. A.T. reports grants and personal fees from Astrazeneca, personal fees from Boehringer Ingelheim, Eli Lilly, Ono Pharmacaceutical, Chugai Pharmacaceutical, Bristol‐Myers Squibb, Pfizer, Taiho Pharmaceutical, Amgen, MSD, Kyowa Kirin, Takeda Pharmaceutical, Merck BioFarma, Nihon‐Kayaku, Novartis, and Thermo Fischer; and grants from Daiichi‐Sankyo and Beigene outside the submitted work. Y.I. reports personal fees from AstraZeneca, Chugai Pharmaceutical, Chugaiigakusya, and Pfizer; and grants from Osaka Cancer Society, outside the submitted work. Y.M. reports personal fees from Takeda Pharmaceutical, Nippon Boehringer Ingelheim, Chugai Pharmaceutical, Hisamitsu Pharmaceutical, and Fujimoto Pharmaceutical Corporation, outside the submitted work. K.O. reports personal fees from Bristol‐Myers Squibb K.K, AstraZeneca K.K., Chugai Pharmaceutical, Nippon Kayaku, Takeda Pharmaceutical, TAIHO PHARMACEUTICAL, and Sawai Seiyaku, outside the submitted work. The remaining authors state that they have no conflict of interest.

Taniguchi Y, Tamiya A, Yanagisawa A, Shimaya M, Kawakami M, Inagaki Y, et al. Cerebral infarction after treatment with dabrafenib plus trametinib for BRAF‐V600E‐positive non–small cell lung cancer: A case report. Thorac Cancer. 2023;14(13):1201–1203. 10.1111/1759-7714.14852