Dabrafenib plus trametinib treatment for a patient with BRAF V600E-mutated large-cell lung carcinoma and a poor performance status

Abstract

Dabrafenib plus trametinib is active against metastatic lung cancer with the BRAF V600E mutation. However, the feasibility of dabrafenib plus trametinib for patients with a poor performance status (PS) has not been reported. We report the case of an 80-year-old woman was diagnosed with metastatic large-cell lung carcinoma. Her general statuses worsened due to cancer, resulting in a PS of 4. Genotype testing revealed a BRAF V600E mutation. The patient received dabrafenib plus trametinib without significant adverse effects. This report is the first to describe dabrafenib plus trametinib administration for large-cell lung carcinoma in a patient with a poor PS.

Introduction

Lung cancer is the most common cancer and the leading cause of cancer-related mortality worldwide [1]. Generally, driver alterations and the expression of programmed death ligand-1 (PD-L1) are assessed before starting chemotherapy for advanced or metastatic non-small cell lung cancer (NSCLC). Important driver alterations for the medical treatment of advanced or metastatic NSCLC include epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ROS oncogene 1, and mesenchymal–epithelial transition. More recently, the efficacy of dabrafenib plus trametinib therapy in BRAF V600E mutation-positive NSCLC patients has been demonstrated [2, 3].

Previous studies have reported that EGFR tyrosine kinase inhibitors (TKIs) and ALK TKIs induce a significant improvement in patients with an extremely poor performance status (PS) [4–6]. However, the efficacy and safety of dabrafenib plus trametinib in NSCLC patients with an extremely poor PS harboring the BRAF V600E mutation have not been reported. This report describes our experience treating a patient with BRAF V600E-mutated large-cell lung carcinoma and a poor PS using dabrafenib plus trametinib.

Case presentation

An 80-year-old Japanese woman was admitted to our hospital with a history of cough and shortness of breath; she never smoked and received methotrexate for rheumatoid arthritis. The patient’s initial PS was 1, and she required crutches for ambulation owing to paralysis of the right lower extremity. Computed tomography (CT) revealed primary lung cancer, separate tumor nodules in the contralateral lobe, and multiple lymph node, bone, and adrenal metastases (Fig. 1). A biopsy specimen of the axillary lymph node revealed large-cell carcinoma. The patient was diagnosed with primary large-cell carcinoma of the lung, stage IVb (cT3N3M1c according to the TNM classification, eighth edition).

Fig. 1.

A Chest and B, C abdominal computed tomography (CT) scans at diagnosis showing a tumor in the lungs (long arrow), multiple lymph metastases (short arrows), and adrenal metastasis (arrowhead)

After hospital admission, her respiratory status and general condition gradually worsened due to cancer, resulting in a PS of 4. The patient was not a candidate for cytotoxic chemotherapy because of her poor PS. However, the BRAF V600E mutation was confirmed in the tumor specimens. Therefore, the patient began a reduced dose of oral dabrafenib (200 mg) plus trametinib (1.5 mg) daily since she was elderly and had a poor PS.

There were no significant adverse events after initiating dabrafenib plus trametinib, and the laboratory data were stable, including the liver enzyme levels. Moreover, symptoms, such as a decreased appetite and difficulty breathing, temporarily improved. A chest CT on treatment day 5 showed no tumor progression in the primary lesions and metastases (Fig. 2).

Fig. 2.

Chest computed tomography images from before and after administering dabrafenib plus trametinib showing A lung lesions before treatment and B no tumor progression in the primary lesions and metastases

On treatment day 8, the patient complained of respiratory distress, productive cough, and fever. Laboratory findings showed the elevated white blood cell and C reactive protein. A chest X-ray revealed an aggravation of infiltrative shadow in the right lower lung field. Consequently, she was suspected of complicating with nosocomial pneumonia, but the drug-induced fever could not be denied. She stopped taking both dabrafenib and trametinib and received antibiotics. Her respiratory condition worsened despite receiving 4.5 g of piperacillin-tazobactam every 6 h, and she died of pneumonia 2 weeks after administering dabrafenib plus trametinib.

Discussion

In this case, the patient received dabrafenib plus trametinib without experiencing significant adverse effects despite a poor PS. To our knowledge, this is the first report of a patient with large-cell lung carcinoma and a poor PS treated with dabrafenib plus trametinib.

V600E is the most common BRAF mutation, occurring in 1–2% of NSCLC cases and more commonly in males and smokers [7]. Large-cell carcinoma has been identified in less than 10% of NSCLC patients [8], but the BRAF V600E mutation has also been observed in this patient population [3]. BRAF is a downstream signaling mediator of the Kirsten rat sarcoma viral oncogene homolog, which activates the mitogen-activated protein kinase (MAPK) pathway. A BRAF mutation activates the MAPK pathway, promoting cell growth, proliferation, and survival, leading to uncontrolled signaling and tumor growth [7]. Dabrafenib, a BRAF inhibitor, blocks RAF activity. Further, trametinib is a MEK1/2 inhibitor that blocks MEK1/2 kinase activity, preventing RAF-dependent MEK phosphorylation [9].

Phase 2 studies of advanced NSCLC patients with the BRAF V600E mutation have identified an association between dabrafenib plus trametinib and a 60–70% response rate. Further, the median progression-free survival was 10–11 months [2, 3]. Common adverse events include pyrexia, nausea, and fatigue, which are usually manageable.

TKIs can induce a pronounced clinical response with an improved toxicity profile compared to cytotoxic chemotherapy. As such, these agents are an option for patients with a poor PS, as demonstrated by previous studies suggesting that TKIs could be beneficial for these patients [4–6]. A phase 2 study showed that EGFR-mutation-positive NSCLC patients with a poor PS benefited from first-line treatment with gefitinib [4]; the PS improvement rate was nearly 80 and 68% of the patients improved from ≥ PS 3 at baseline to ≤ PS 1. These results suggest that other TKIs may also be effective for patients with a poor PS and various driver alterations, such as alectinib, entrectinib, and capmatinib.

The efficacy and safety of dabrafenib plus trametinib in NSCLC patients with an extremely poor PS harboring the BRAF V600E mutation remains unclear. However, dabrafenib plus trametinib is recommended for BRAF V600E-mutation-positive patients with a poor PS in the Japanese and National Comprehensive Cancer Network Clinical Practice guidelines [10, 11]. Each TKI has different toxicity profiles, and it is sometimes necessary for patients with a good PS to reduce the TKI dose. Additionally, significant treatment-related adverse effects are often observed in patients with a poor PS [12]. Thus, it is important to be especially careful when patients with a poor PS begin TKI therapy.

Our patient did not experience any common adverse events during the treatment period, such as nausea or vomiting. Serious adverse events, such as pulmonary thromboembolism and interstitial lung disease, are possible when the patient experiences sudden changes in her overall condition. Also, it was almost 1 month from the hospital admission to dabrafenib plus trametinib administration because the PD-L1 and diver alteration results were required to begin. The patient’s PS deteriorated, and respiratory failure progressed during hospitalization, despite a PS of one before hospitalization. As such, the patient may have survived if she had received TKI therapy earlier. Recently, several trials have evaluated the utility of circulating tumor DNA (ctDNA) genotyping, reporting that the screening duration of ctDNA genotyping was significantly shorter than tissue genotyping [13]. Therefore, starting appropriate treatment earlier may be possible using these methods.

Although the present report details only a single case, this is the first report on administration of dabrafenib plus trametinib for treating large-cell lung carcinoma patients with a poor PS. Certain driver alterations were also detected in lung cancer tissue, except for adenocarcinoma, and patients with driver alterations can be treated with TKIs even if they have a poor PS. Further studies are warranted to evaluate the efficacy and safety of dabrafenib plus trametinib in such patients.

Data availability

There are no available data.

Declarations

Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of this article.

Consent for publication

Consent for publication of the case was provided by the patient.