A case study on severe psychiatric symptoms induced by lorlatinib

1 |. INTRODUCTION

Lorlatinib is a third-generation tyrosine kinase inhibitor (TKI) approved in the first-line setting for around 5% of the non-small cell lung cancer (NSCLC) patients harboring the ALK gene rearrangement.¹ ROS1 rearrangements are more rare, occurring in 1%–2% of patients with NSCLC and are often treated with crizotinib in the first-line setting. However, most patients develop resistance and relapse. Because the kinase domains of ALK and ROS1 share similar amino acid structures, lorlatinib has demonstrated efficacy in advanced ROS1 NSCLC patients resistant to crizotinib.² Notably, lorlatinib has improved blood brain barrier penetration to crizotinib and is thought to be particularly beneficial in patients with intracranial disease. Behavioral side effects are common (16%–23%) yet often mild and under-recognized; we present a case of a patient who developed severe psychiatric symptoms on lorlatinib.

2 |. CASE REPORT

Ms. L is a pleasant 45-year-old woman with no prior psychiatric history who was diagnosed in late 2018 with stage IV ROS1 rearranged lung adenocarcinoma. Ms. L initially presented to the emergency room with symptoms of fatigue, cough, poor appetite, dyspnea on exertion, and orthopnea which had been slowly progressive for a month. Her baseline physical exam and laboratory findings were unremarkable. A CT scan showed a 4-cm right upper lobe mass and pericardial effusions; the pericardial fluid tested positive for adenocarcinoma. The MRI of the brain showed four sub-centimeter brain metastases. She underwent endobronchial biopsy of the mass, which demonstrated adenocarcinoma with ROS1 rearrangement. She underwent gamma knife radiation to the brain lesions and was started on first-line therapy with crizotinib.

Unfortunately, the brain lesions progressed in the summer of 2019, and she was switched to lorlatinib at the standard dosing of 100 mg. Within 2 weeks of starting the medication, Ms. L noticed she was more depressed and had increasing anxiety, envisioning that she may become unable to breathe; however, she acknowledged that this may be due to the known cancer in her brain. Around 1 month after starting lorlatinib, she developed progressive paranoia. Soon, this was also associated with tactile hallucinations where she would feel her sandals “melt” and bugs walking on her feet. Despite an awareness that this was not real, she was compelled to look down constantly. The hallucinations progressed, and she would see herself as an insect and her husband and friends turning into insects as well. Squirrels running in trees appeared like giant alien spiders. Briefly, she was able to overcome her symptoms by understanding that the psychosis was from the medication. Near end of summer at 2 months after drug initiation, she also took a 3-day break from lorlatinib as guided by her provider, with a slow titration back to the standard dosage. However, the paranoia and hallucinations gradually returned with increased severity in the next 2 months. She often felt like she was going to die, and her body experienced uncontrollable contortions, collapsing on the table at one point.

Lorlatinib was stopped in late 2019 with near immediate and complete resolution of symptoms. She was offered to restart the medication at a lower dose, but she declined due to the extreme side effects. She was then enrolled in a clinical trial with reprotrectinib, but brain lesions continued to progress, for which she underwent whole-brain radiation and treatment with steroids and antiepileptics. In 2020, she was started on carboplatin/pemetrexed/bevacizumab with excellent response in both the lungs and the brain. Most recently in 2023, she had consolidation surgery in the lungs after years of stable disease. She currently has no evidence of disease in the lungs or brain on the latest imaging and has not had any recurrence of her psychiatric symptoms.

3 |. DISCUSSION

In patients with lung cancers, the differential for psychiatric symptoms typically includes underlying psychiatric disorders, the psychological response of patients to the cancer itself, somatic symptoms from the brain tumor, and medication-induced side effects. In this case, the patient had no prior psychiatric history, and her symptoms began with medication induction and abated promptly with its discontinuation, strongly supporting medication-induced psychosis. Lorlatinib is a promising therapy for patients with advanced NSCLC with ROS1 rearrangements and intracranial disease. However, it is correlated with increased psychiatric and neurocognitive symptoms not seen as commonly with other TKIs. The macrocyclic characteristics of lorlatinib are thought to contribute to its enhanced potency in penetrating the blood brain barrier, which may explain the increase in central neurological side effects.³ Lorlatinib was associated with multiple neurocognitive side effects in a phase II clinical trial of 267 patients, including peripheral neuropathy (30%), cognitive dysfunction (18%), mood effects (15%), speech disturbance (7%) and auditory hallucinations (2%).⁴ 39% of the patients in this trial had reported at least one of the above neurocognitive side effects; however, most were mild (almost all grade 1 or 2, 1% grade 3, and no grade 4), dose-dependent, intermittent, and reversible. Severe psychosis with lorlatinib is rare and, to date, has only been reported in one case in the literature.⁵ Antipsychotics such as olanzapine may be helpful in symptom management and had previously been used for lorlatinib-induced psychosis.⁵ However, it is important to remain vigilant and recognize psychiatric symptoms from lorlatinib early in the course, and consider careful collaboration with a psychiatrist for the management of severe symptoms.

Key points.

• Due to its macrocyclic properties, lorlatinib has increased penetrance of the blood brain barrier compared to most other tyrosine kinase inhibitors.

• Lorlatinib is a promising therapy in patients with non-small cell lung cancer with ALK or ROS1 rearrangements, particularly in patients with evidence of intracranial disease.

• However, behavioral and central nervous system side effects are common with lorlatinib.

• Lorlatinib can rarely result in severe psychosis, as with the presented case.

• In patients with lung cancer on lorlatinib, medication-induced psychosis must be considered among the common differentials, including: the psychological response of patients to the cancer itself, somatic symptoms from brain metastases, and unmasking of underlying psychiatric disorders.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.