Unilateral cystic and bullous lung changes in a patient treated with brigatinib: a case report

Abstract

Approximately 3% to 5% of individuals with oncogenic rearrangements in the anaplastic lymphoma kinase (ALK) gene develop non-small cell lung cancer (NSCLC). Brigatinib, a potent next-generation ALK tyrosine kinase inhibitor (TKI), has demonstrated significant systemic and intracranial responses, as well as improved progression-free survival, with an acceptable safety profile. According to European Society for Medical Oncology guidelines patients with ALK translocation and performance status 0–3 can be offered 1st line treatment with TKI (brigatinib, alectinib, or lorlatinib). To our knowledge, this is the first reported case of cystic or bullous changes in the lungs following incremental dosing of brigatinib. Here, we describe a 37-year-old male, a never-smoker, who developed progressively diffuse cystic changes in the lung parenchyma while receiving brigatinib treatment for NSCLC with intrapulmonary metastases. Clinicians should remain vigilant for this potential atypical pulmonary adverse effect, including the possibility of cystic or bullous transformations in the lung parenchyma.

INTRODUCTION

Brigatinib, a potent ALK tyrosine kinase inhibitor (TKI), has demonstrated significant systemic and intracranial responses, as well as improved progression-free survival, with an acceptable safety profile [1–3]. According to European Society for Medical Oncology guidelines, patients with ALK translocation and performance status 0–3 can be offered 1st line treatment with TKI (brigatinib, alectinib, or lorlatinib) [4]. The commonly reported side effects of brigatinib are fatigue, shortness of breath, cough, visual disturbances, diarrhea, hypoglycemia, hypertension, and blood tests may show high levels of serum amylase and creatinine phosphokinase. The negative effects are manageable and do not build up [5,6]. Pulmonary toxicity is a rare but significant adverse effect and interstitial lung disease or pneumonitis has been observed as a side effect in about 1% of patients who have received ALK inhibitors [7]. Three point seven percent of patients following a dose of 90 mg of brigatinib developed these side effects, while 9.1% of individuals receiving a dose increase from 90 mg to 180 mg did as well [6,7]. There have been no previous adverse side effects like cystic bullous changes in lungs reported in the literature, after incremental dosing of brigatinib, to our knowledge, this is the first reported case with such a side effect. Here, we describe a 37-year-old male, a never-smoker, who developed progressively diffuse cystic changes in the lung parenchyma while receiving brigatinib treatment for non-small cell lung cancer (NSCLC) with intrapulmonary metastases.

CASE REPORT

A 37-year-old male, non-smoker, with a known history of atrial fibrillation, heart failure, and reduced left ventricular ejection fraction (30%), presented to his general practitioner in October 2022 with progressive shortness of breath, dry cough with occasional hemoptysis, fatigue, weight loss, and reduced appetite. These symptoms had been present since February 2022. There was no history of asthma, allergies, tuberculosis exposure, or prior respiratory illness. A chest X-ray and subsequent chest computed tomography (CT) scan revealed a large central infiltrate in the right lung and mediastinal lymphadenopathy (Fig. 1). Lung function tests indicated restrictive changes and reduced diffusion capacity of the lung for carbon monoxide (64%). A positron emission tomography scan was highly suggestive of metastatic malignancy (suspected TNM stage T4 N3 M1c) (Fig. 2A). Bronchoscopy revealed compression and mild bleeding in the right main and intermediate bronchi, while the left bronchial tree was normal. Histopathology confirmed ALK-positive NSCLC, adenocarcinoma subtype, with programmed death ligand 1 (PD-L1) expression >50% and negative EGFR mutation status.

Fig. 1.

Computed tomography scan before chemotherapy showing tumor in the right lung with mediastinal invasion.

Fig. 2.

PET/CT findings after chemotherapy. (A) PET scan showing malignant tumor involving the right lung, mediastinum, pericardium, and superior vena cava. CT scan showing new right pneumothorax and/or giant bullae after chemotherapy. PET, positron emission tomography; CT, computed tomography.

Following a multidisciplinary team discussion, the patient was initiated on brigatinib (starting dose 60 mg daily for 7 days due to underlying cardiac conditions). Two days after initiating treatment, he presented to the emergency department with worsening dyspnea, cough producing yellow-black sputum, and systemic weakness. He exhibited signs of sepsis, elevated C-reactive protein, and was treated empirically with intravenous piperacillin-tazobactam and metronidazole. A thoracic CT ruled out pulmonary embolism but revealed a right-sided pneumothorax. Brigatinib was cautiously resumed at 60 mg under close observation. Three days later, a high-resolution CT of the thorax confirmed persistent pneumothorax with collapsed upper and middle lobes and multiple bullae on the right side (Fig. 2B). Conservative management was pursued, and brigatinib was escalated to 120 mg as planned.

After 4 weeks, a follow-up CT of the thorax demonstrated significant tumor regression in the right hilar region (Fig. 3A). However, a persistent pneumothorax and new pleural fluid accumulation raised suspicion for empyema. Ultrasound-guided chest drain insertion was performed, followed by 3 days of intrapleural fibrinolytic therapy with alteplase. A subsequent CT of the thorax showed reduction in pneumothorax, and the patient was discharged with a 4-week course of antibiotics (Fig. 3B).

Fig. 3.

CT findings after treatment. (A) CT scan showing tumor reduction in the right hilus with large pneumothorax and fluid accumulation. (B) CT scan showing diminished right pneumothorax after pleural drainage. CT, computed tomography.

DISCUSSION

The patient—a 37-year-old male, never-smoker—developed increasing unilateral cystic alterations in the lungs while being treated with brigatinib for NSCLC with intrapulmonary metastases. These findings suggest a rare but noteworthy adverse pulmonary reaction potentially linked to brigatinib. Pulmonary toxicity is a serious side effect of antineoplastic drugs such as gemcitabine, rituximab, fludarabine, paclitaxel, and docetaxel. Adverse effects of antineoplastic drugs may include interstitial lung disease, which involves diffuse alveolar and/or interstitial damage. These side effects primarily occur within the first 3 months of treatment [8]. However, some studies have reported a rare but significant early-onset pulmonary event, or pulmonary adverse event, associated with brigatinib among the approved ALK inhibitors [9]. Moderate to severe pulmonary adverse events have been observed in a small subset of patients within the first 7 days of initiating brigatinib treatment [9].

Studies further show that the incidence of serious pulmonary side effects, such as interstitial lung disease or pneumonitis in connection with brigatinib treatment, has been reported in a minority of patients, incidence of approximately 1%. It is 3.7% in the patients with 90 mg brigatinib treatment and 9.1% of the patients in the 90 to 180 mg group. These side effects occur primarily within the first 7 days after starting treatment [6]. Furthermore, the patient’s clinical background and current status with regard to pre-existing lung conditions should be considered [8]. In this case, cystic changes were not present at baseline and emerged after brigatinib initiation, raising suspicion of a treatment-related side effect. Differential diagnoses considered included cystic lung cancer, congenital cystic lung diseases, pulmonary tuberculosis, and pulmonary sarcoidosis. However, the absence of systemic signs, lack of supporting radiologic features, and the temporal association with brigatinib therapy made these alternatives unlikely.

Cases of cystic metastases lung lesions and subsequent pneumothoraces have previously been reported in other malignancies following chemotherapy—such as with cisplatin in epithelioid trophoblastic tumors—these typically present bilaterally or in connection with known cavitating tumors [10]. However, in this case no cysts were found in either lung at the time of initial chest CT evaluation. The cysts developed unilaterally and were located in regions previously affected by the tumor, without any initial evidence of cavitation or pre-existing cystic disease. Therefore, it could be hypothesized that unknown genetic factors such as EGFR somatic mutations may play a role in the development of cystic lung changes, apart from the gefitinib-induced cystic lung lesions [8,9] However, in our case a genetic connection cannot be considered, because there were only unilateral cystic changes in the lung with previous cancerous changes.

These cystic changes following treatment with brigatinib are an unknown side effect. Therefore, a clear correlation between the cystic changes and brigatinib treatment has not yet been found although some potential mechanisms of lung toxicity can be considered. One possibility involves tumor necrosis secondary to rapid cytotoxic effects of brigatinib, leading to cyst formation through a check-valve mechanism or air trapping [8]. Brigatinib, as a potent ALK inhibitor, may induce rapid apoptosis and necrosis of tumor cells, particularly in metabolically active lesions. This rapid cell death can lead to the breakdown of the tumor mass, forming cavitary lesions or cystic spaces within the lung parenchyma. In some cases, these necrotic cavities may act as one-way valves—known as the “check-valve” mechanism—where air enters but cannot escape, resulting in progressive air trapping. This trapped air can expand the cystic cavity, eventually weakening the surrounding lung tissue and predisposing it to rupture. Cyst rupture, in turn, can lead to pneumothorax, as observed in this case. Alternatively, it can be considered that tumor lysis of the main lesion, or lysis of multiple metastatic nodes due to the direct cytotoxic effect of brigatinib, may have induced the formation of a giant cyst, with subsequent cyst rupture resulting in pneumothorax.

In conclusion, to our knowledge, there have been no documented reports of cystic or bullous lung changes occurring as a side effect of incremental brigatinib dosing. This case presents what appears to be the first report of new-onset, unilateral cystic/bullous lung alterations developing after the initiation of brigatinib treatment in a patient with NSCLC and intrapulmonary metastases. While a definitive correlation between brigatinib and the development of these cystic changes remains unknown, several mechanisms have been hypothesized. Brigatinib remains an important and effective treatment option in NSCLC patients with ALK-positive tumors—especially in those who are also PD-L1-positive or carry concurrent EGFR mutations. However, clinicians should remain vigilant for atypical pulmonary adverse effects, including the possibility of cystic or bullous transformations in the lung parenchyma. Awareness of such rare presentations and early recognition of such unusual side effects is essential for timely intervention and optimal patient care.