
==== Front
Discov Oncol
Discov Oncol
Discover Oncology
2730-6011
Springer US New York

1339
10.1007/s12672-024-01339-9
Case Report
New findings on the incidence and management of CNS adverse reactions in ALK-positive NSCLC with lorlatinib treatment
Chu Fanfan 1
Zhang Wenxi 1
Hu Hong cffhh2011@zju.edu.cn

2
1 grid.13402.34 0000 0004 1759 700X Department of Admission Preparation Center, College of Medicine, QianTang Campus of Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang China
2 grid.13402.34 0000 0004 1759 700X Department of Medical Oncology, College of Medicine, QianTang Campus of Sir Run Run Shaw Hospital, Zhejiang University, No. 368, Xiasha Road, Hangzhou, Zhejiang China
13 9 2024
13 9 2024
12 2024
15 44419 3 2024
11 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
To explore the presentation and control of CNS adverse reactions in patients with ALK-positive NSCLC treated with lorlatinib. This study includes a retrospective case report from Sir Run Run Shaw Hospital on a lorlatinib-treated patient with CNS adverse reactions and a systematic literature review of similar cases until January 2023. The report detailed a case of a 74-year-old male with Grade III CNS adverse reactions 25 days after starting lorlatinib, which were reversible with dose modification and pharmacotherapy. The review indicated a 19.39% occurrence rate of such reactions, with a 17% improvement rate post-dose adjustment. CNS adverse reactions frequently occur in ALK-positive NSCLC patients on lorlatinib, yet they are reversible with appropriate management. Research should continue to optimize treatment protocols to decrease these reactions' frequency.

Highlights

This study provides the first detailed report in China on CNS adverse reactions induced by lorlatinib and its management.

It emphasizes the scientific issues and objectives addressed in resolving CNS adverse reactions during lorlatinib treatment.

The study reveals that CNS adverse reactions caused by lorlatinib can be effectively managed through dose adjustment.

It fills the data gap on CNS adverse reactions to lorlatinib in the Asian population.

The study highlights the importance and scientific value of optimizing lorlatinib treatment protocols to improve patient's quality of life.

Keywords

Lorlatinib
ALK-positive
NSCLC
CNS toxicity
Management strategies
the CSCO-BMS Cancer Immunotherapy Research FoundationGrant No. Y-BMS2019-098 Hu Hong the CSCO-Xinda Cancer Immunotherapy Research FoundationGrant No. Y-XD2019-225 Hu Hong issue-copyright-statement© Springer Science+Business Media, LLC 2024
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pmcIntroduction

Lung cancer is one of the most common cancers globally and the leading cause of cancer-related mortality [1]. According to global cancer statistics, lung cancer ranks second in incidence and first in mortality worldwide [2, 3]. Non-small cell lung cancer (NSCLC), accounting for 80–85% of all lung cancer cases, often harbors targeted genetic mutations in over 60% of advanced cases [4, 5]. The anaplastic lymphoma kinase (ALK) fusion gene, as the second most common tumor-driving gene in NSCLC, affects approximately 5–8% of NSCLC patients [4, 6]. NSCLC encompasses various histological types, each potentially responding differently to treatment [7, 8]. Introducing first and second-generation ALK tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of ALK-positive NSCLC [8–10]. However, drug resistance often emerges post-treatment, with the central nervous system (CNS) being a common site of progression [11]. Lorlatinib, a novel third-generation ALK TKI, can penetrate the blood–brain barrier [12]. Regardless of the type of EML4-ALK variant or the presence of ALK kinase mutations, the lorlatinib group showed superior overall response (OR), duration of remission, and progression-free survival (PFS) compared to the crizotinib group [13–15]. However, adverse drug reactions (ADRs) or adverse events (AEs) induced by lorlatinib may necessitate treatment interruption or discontinuation in some patients [14, 16, 17].

Central nervous system (CNS) reactions are one of the common adverse drug reactions (ADRs) or adverse events (AEs) during treatment with lorlatinib [16]. Patients receiving lorlatinib may experience a range of CNS reactions, including seizures, mental effects, cognitive functions (such as consciousness, memory, spatial and temporal orientation, and attention), emotions (including suicidal ideation), speech, mental state, and sleep changes [16–18]. Methods for assessing the mental state of patients include the Symptom Checklist 90 (SCL-90) [19], Beck Depression Inventory (BDI) [20], Mini-Cog [21], and open and closed questionnaires [22]. The grading standards for CNS reactions refer to the National Cancer Institute Common Terminology Criteria for Adverse Event v5.0 (NCI CTCAE v5.0) [23] (Table 1). When CNS reactions occur, lorlatinib dosage can be adjusted based on severity. Studies indicate that dosage adjustment effectively manages CNS AEs without compromising treatment outcomes [24]. If CNS ADRs significantly affect a patient's daily life, a reduced lorlatinib dosage is necessary [25]. While CNS adverse reactions can be managed to some extent through dosage adjustment or combination with other medications, current research and guidelines remain insufficient for effectively preventing and controlling these reactions. Addressing this issue requires a deeper understanding and further research into CNS adverse reactions induced by Lorlatinib.Table 1 Central nervous system disease classification criteria

CTCAE terminology	I	II	III	IV	V	
Cognitive function changes	
 Memory impairment	Mild memory impairment	Moderate memory impairment; limited instrumental Activities of daily living	Severe memory impairment; limited self-care activities of daily living	–	–	
 Blurring of consciousness	Mild disorientation	Moderate disorientation; limited instrumental Activities of daily living	Severe disorientation; limited self-care activities of daily living	Life-threatening consequences; An indication for emergency intervention	–	
Mood changes	
 Inquietude	Mild symptoms; no indication for intervention	Moderate symptoms; limited in instrumental activities of daily living	Severe symptoms; self care Activities of daily living are limited; There are indications for hospitalization	Life-threatening consequences; An indication for emergency intervention	–	
 Irritability	Mild symptoms; easy to comfort	Moderate symptoms; limited instrumental activities of daily living; indications that require more attention	Severe abnormalities or excessive reactions; self care Activities of daily living are limited; Unable to comfort; there are indications for medical or psychiatric intervention	–	–	
 Depression	Mild depressive symptoms	Moderate depressive symptoms; limited in instrumental activities of daily living	Severe depressive symptoms; self care Activities of daily living are limited; no indication for hospitalization	Life-threatening consequences; threatening to harm oneself or others; there are indications for hospitalization	death	
Language function changes	
 Dysarthrosis	Mild inarticulate	Moderate pronunciation disorder or unclear speech	Severe dyspticulia or slticulspeech	–	–	
CTCAE: Common Terminology Criteria for Adverse Events

This article reviews the epidemiology, pathogenesis, diagnosis, treatment, and management strategies of CNS reactions as ADRs to lorlatinib treatment. It aims to provide clinicians with an in-depth understanding of CNS reactions to better manage ALK-positive NSCLC patients receiving lorlatinib treatment. Through this study, we hope to optimize Lorlatinib's usage protocols, reduce adverse reactions, and thus improve patient treatment outcomes and quality of life. Additionally, the results of this study will offer valuable reference information for future drug development, contributing to the creation of safer and more effective ALK inhibitors.

Case presentation

On December 13, 2022, a 74-year-old male patient was admitted to the hospital with mental disorders due to abnormal speech and behavior after being diagnosed with lung adenocarcinoma and receiving targeted treatment with lorlatinib. The patient was first diagnosed with lung adenocarcinoma (LUAD) in 2015. Chest CT showed a left upper lung mass of uncertain nature, with possible chronic inflammation and a tumor to be ruled out. On June 24, 2015, an EBUS + TBNA examination revealed a very small number of atypical epithelial cells, indicating a high possibility of adenocarcinoma. To further clarify the diagnosis, a thoracoscopic left chest exploration, left pleural biopsy, and pleural fixation surgery were performed. During the operation, a small amount of adhesion was observed in the left chest cavity without pleural effusion. A mass with a diameter of about 4.5cm and a hard texture was found in the lingual segment of the left upper lobe near the hilum of the lung, involving the visceral pleura and invading the lower pulmonary vein and part of the pericardium. Multiple lymphadenectasis in the interstitium, hilum, and mediastinum. Resection of a chest wall nodule for examination, pathological examination combined with clinical diagnosis of left upper lung adenocarcinoma and chest wall metastatic adenocarcinoma. The disease stage was cT3N2M1c. Due to the immunohistochemical results of ALK ( +), Her-2 (−), ROS1 (−), and gene sequencing analysis of EGFR as wild-type, targeted therapy with oral administration of crizotinib has been administered until now (Fig. 1).Fig. 1 Timeline of patient diagnosis and treatment

Chest CT scans were performed regularly. Subsequently, in April 2018, an enlarged mass was observed in the left upper lung's lingular segment. After five cycles of the PC + B regimen (carboplatin AUC = 5 on day 1, paclitaxel 175 mg/m2 on day 1, and bevacizumab 15 mg/kg on day 1), the overall efficacy evaluation reached PR. During the treatment, the patient developed prominent bilateral mammary glands, which were confirmed to be gynecomastia, suspected to be a side effect induced by crizotinib or other treatment drugs. Due to severe anemia caused by chemotherapy side effects, the patient switched to maintenance therapy with crizotinib. A chest CT scan on April 2, 2020, showed an enlarged mass in the left upper lung's lingular segment. The patient began oral ceritinib treatment. The CT scan indicated an increase in pulmonary lesions, so ceritinib was discontinued on November 18, 2022, and lorlatinib 100 mg/day treatment was initiated. All these procedures were fully informed to patients. Twenty-five days into the lorlatinib treatment, the patient exhibited atypical behaviors, including hallucinations, sleep disturbances, and agitation. Following an intense altercation with the family on December 15, 2022, the patient was admitted to the psychiatric department with police assistance. A multidisciplinary assessment, including psychiatry and medical oncology, diagnosed the patient with Grade III lorlatinib-induced CNS adverse reactions. Comprehensive evaluations of the patient's cardiovascular, abdominal, reproductive, urinary, skeletal, muscular, and integumentary systems revealed no abnormalities, and pain assessment indicated no discomfort. The nursing staff conducted a series of admission assessments, finding the patient in a state of moderate consciousness impairment according to the Glasgow Coma Scale. The Braden Scale, Morse Fall Scale (MFS), Nutritional Risk Screening 2002 (NRS2002), and Barthel Index indicated the patient was at high risk and required close monitoring. Nursing staff administered 3 L/min of oxygen via a nasal cannula and monitored vital signs hourly, including pulse, respiration, blood pressure, heart rate, and oxygen saturation. Lorlatinib was initially discontinued to manage the adverse reactions. The patient was then administered 5 mg of haloperidol for sedation and 0.05 g of quetiapine to alleviate abnormal emotions and cognitive impairments. Fortunately, he regained consciousness and responded rapidly and effectively to the management of the adverse reactions. On December 17, 2022, the patient was re-administered lorlatinib at 100 mg/day. After nearly 2 hours, adverse reactions re-emerged, including incoherent speech, hallucinations, and disorientation, with a GCS assessment indicating mild impairment of consciousness. Given the positive response to previous treatment, the same management was continued to help the patient return to his prior state of health. The patient's adverse reactions did not progress further, and he regained consciousness and emotional control the following day. After observing no signs of adverse events in the central nervous system, a decision was made to adjust the dosage of lorlatinib on December 20, 2022. Considering the patient's severe adverse events profile, a dosage of 50 mg per day was administered [24]. Subsequently, it was found that the patient did not experience any adverse reactions, indicating the reversibility of the reactions with dose reduction. Post-discharge, nursing staff conducted bi-weekly follow-up calls to monitor the patient's physical condition, consciousness, and emotional state. They assessed the patient's compliance with lorlatinib treatment and repeatedly emphasized the availability of consultation with the follow-up nurse or doctor for any concerns. A CT scan on April 25, 2023, showed tumor shrinkage, indicating the effectiveness of lorlatinib treatment (Fig. 2).Fig. 2 Imaging comparison of space-occupying lesions before and after lorlatinib therapy

In summary, the patient exhibited Grade III central nervous system adverse reactions 25 days into lorlatinib treatment, characterized by incoherent speech, anger, hallucinations, and disorientation. Sedation with 5mg of haloperidol and subsequent intervention with 0.05 g of quetiapine facilitated recovery. Reducing the lorlatinib dosage from 100 mg/day to 50 mg/day resulted in no further adverse drug reactions. Follow-up CT scans showed tumor shrinkage with no signs of brain metastasis, indicating effective disease control.

Discussion

The role and challenges of lorlatinib in the treatment of ALK-positive NSCLC

In treating ALK-positive NSCLC, lorlatinib has emerged as a groundbreaking therapeutic option [26]. As a third-generation ALK inhibitor, lorlatinib was developed to overcome resistance issues associated with earlier generations of ALK inhibitors and to offer a more effective treatment for brain metastases [27]. Its unique ability to penetrate the blood–brain barrier has demonstrated unprecedented potential in treating intracranial lesions [28]. However, this capability also introduces new challenges related to CNS adverse reactions [29]. These adverse reactions range from mild symptoms such as headaches and fatigue to severe cognitive impairments and hallucinations, significantly impacting patients' quality of life [30]. By reviewing the latest research, this article aims to explore management strategies for CNS adverse reactions during lorlatinib treatment, intending to provide clinicians with a more comprehensive guide to therapy [31].

Epidemiology and clinical characteristics of CNS adverse reactions induced by lorlatinib

As of January 2023, a comprehensive search of published studies on lorlatinib was conducted, focusing on adverse drug reactions, AEs, and impacts on the CNS. The inclusion criteria for the studies were: (1) reports on ALK-positive NSCLC patients; (2) documentation of lorlatinib administered at any therapeutic duration and its standard dosage; (3) descriptions of adverse reactions or events attributed to lorlatinib.

After screening 64 records containing the keywords “lorlatinib,”d “adverse events,” and “non-small cell lung cancer,” and excluding review articles and studies not addressing CNS adverse effects, ten studies specifically related to lorlatinib-induced CNS adverse reactions were included. These studies encompassed a total of 1450 participants. A summary of the CNS adverse reactions observed in patients treated with lorlatinib (100 mg/day) was compiled (Table 2). CNS adverse reactions were categorized into cognitive, emotional, speech, and hallucinatory types. Cognitive and emotional reactions were the most frequently reported CNS adverse reactions across all included lorlatinib studies [29]. The incidence rates of CNS adverse reactions were as follows [29]: cognitive reactions at 19.17% (278/1450), emotional reactions at 13.52% (196/1450), speech reactions at 2.48% (36/1450), and hallucinatory reactions at 0.97% (14/1450) [32]. Moreover, studies indicated that the incidence rates of these AEs were higher in non-Asian populations than in Asian populations, suggesting potential ethnic differences in susceptibility (Soo RA) [25, 32]. The proportion of CNS AEs with grade III or higher is 2.97% (43/1450). These findings suggest that lorlatinib’s adverse reactions are generally mild to moderate, with only a minority reaching Grade III to IV severity [33]. Unfortunately, most published clinical studies have only documented the occurrence and severity of adverse reactions under the standard lorlatinib dose of 100 mg without implementing measures to manage these reactions [34]. A post-hoc analysis of the safety and efficacy in the CROWN Phase III trial [24] revealed that the median onset time for CNS AEs post-lorlatinib treatment was 57 (1–533) days, with a median duration of 182 (2–751) days, and 33% of CNS AEs resolved naturally without intervention.Table 2 Studies included after a systematic review

Authors ref year	Type and stage	No. of patients	Symptom (No. of patients)	Grade (No. of patients)	III–IV(%)	Time to-symptoms, days (range)	Median duration of AE, days (range)	Intervention	
Solomon et al. [18] 2018	ALK-positive or

ROS1-positive NSCLC

	275	Cognitive effects: 49

Mood effects: 41

Hallucination, auditory: 5

	I–II: 89

III: 6

	2.18%	Unclear	Unclear	Unclear	
Peled et al. [47] 2020	ALK/ROS1( +) NSCLC	123	Cognitive effects: 22

Mood effect: 19

	I: 32

II: 9

	0.00%	Unclear	Unclear	Unclear	
Shaw et al. [14] 2020 2020a	Advanced ALK-positive NSCLC	149	Cognitive effects: 32

Mood effects: 24

	I: 34

II: 17

III: 5

	3.36%	Unclear	Unclear	Unclear	
Seto et al. [48] 2020	ALK-rearranged advanced NSCLC	39	Cognitive effects: 7

Mood effect: 5

Hallucination, auditory: 4

	I–II: 14

III–IV: 2

	5.13%	Unclear	Unclear	Unclear	
Felip et al. [49] 2021	ALK-positive non-small-cell lung cancer previously treated with second-generation ALK TKIs	295	Cognitive effects: 70

Mood effect: 46

Speech effects: 25

	I–II: 132

III: 9

	3.05%	Unclear	Unclear	Unclear	
Baldacci et al. [50] 2022	Advanced or metastatic ALK + NSCLC	208	Cognitive effects: 11

Mood effect: 3

	III: 12

IV: 2

	6.73%	Unclear	Unclear	Unclear	
Solomon et al. [24] 2022a	locally advanced or metastatic ALK + NSCLC	149	Cognitive effects: 32 Mood effects: 24

Speech effects: 7

Hallucination, auditory: 5

	I: 44

II: 18

III: 6

	4.03%	57 (1–533)	182 (2–751)	DR only: 3

DI only: 10

DR plus DI: 2

DR plus CM: 2

DI plus CM: 2

DR plus DI plus CM: 1

	
Shaw et al. [51] 2019	Advanced, ROS1-positive NSCLC	69	Cognitive effects: 19

Mood effects: 11

	I–II: 29

III: 1

	1.45%	Unclear	Unclear	Unclear	
Soo et al. [25] 2022	ALK-positive advanced NSCLC	269	Asian (N = 108)

Cognitive effects: 13

Mood effects: 9

	Asian

I–II: 21

III: 1

	Asian

0.93%

	Unclear	Unclear	Unclear	
Non-Asian (N = 161)

Cognitive effects: 43

Mood effects: 28

	Non-Asian

I–II: 65

III: 6

	Non-Asian3.73%	
Dagogo-Jack et al. [52] 2022	ALK-positive lung cancer	23	Cognitive effects: 12

Mood effects: 10

Speech effects: 4

	I: 16

II: 9

III: 1

	4.35%	Unclear	Unclear	Unclear	
aBoth studies by Solomon et al. [24] and Shaw et al. [51] are based on the CROWN trial, comparing lorlatinib and crizotinib in advanced ALK-positive non-small-cell lung cancer (NSCLC) patients. Solomon et al. [24] conducted a post hoc analysis focusing on intracranial efficacy and safety, while Shaw et al. [51] provided overall efficacy and adverse events data. The studies demonstrated that lorlatinib significantly improved progression-free survival (PFS) and intracranial response rates compared to crizotinib, but was associated with higher rates of grade 3 or 4 adverse events, primarily due to altered lipid levels. To avoid double counting, we only used the data from Solomon et al. [24] when counting enrolled patients and adverse reactions

Management strategies for central nervous system adverse reactions induced by lorlatinib

Lorlatinib, an effective ALK inhibitor for treating ALK-positive NSCLC, has introduced therapeutic breakthroughs and challenges related to CNS adverse reactions [35]. The early identification and timely intervention of CNS AEs is key to ensuring clinical treatment success. A comprehensive assessment of the patient's baseline characteristics and medication history before initiating treatment is essential [36]. Furthermore, enhancing communication between the medical team, patients, and their families is crucial for accurately reporting potential cognitive disorientation, emotional changes, hallucinations, or alterations in speech and sleep during treatment [37].

When CNS adverse reactions occur in patients receiving lorlatinib, healthcare professionals must promptly follow up on the patient's treatment response. Establishing effective communication channels ensures patients and their families receive the necessary support and guidance [38]. For instance, a case reported in the literature experienced hallucinations and restlessness on day 25 of treatment, which worsened due to delayed notification to the treatment team [37]. It underscores family members' significant role in monitoring changes in the patient's condition, where timely identification and reporting of CNS adverse reactions are critical to preventing further deterioration [39]. Management strategies for CNS adverse reactions induced by lorlatinib include dose adjustment, treatment interruption, or symptomatic treatment [40]. Dose adjustment deserves particular attention, as studies have shown that appropriately reducing the lorlatinib dose can effectively mitigate CNS adverse reactions without compromising treatment efficacy [41]. The CROWN study [24] provides empirical support, demonstrating that 17% of CNS AEs were reversed following dose adjustment, with no negative impact on the patients' progression-free survival (PFS) or treatment outcomes.

During hospitalization, the nursing team should conduct a comprehensive assessment of the patient, including mental status, self-care capabilities, nutritional status, and potential risk for pressure ulcers, to determine the appropriate level of care [42]. Personalized care plans, such as implementing safety measures, fall prevention, nutritional support, and sleep interventions, are crucial for alleviating CNS adverse reactions caused by lorlatinib [43].

Optimizing the management of CNS adverse reactions in lorlatinib treatment

Lorlatinib offers new therapeutic hope for ALK-positive NSCLC patients, especially those with brain metastases [24]. However, CNS AEs are common side effects during lorlatinib treatment, negatively affecting patients’ quality of life [44]. Notably, the incidence rate of CNS AEs in the Chinese population is significantly lower than in the general population, at 6.4% compared to 35% [24, 45]. Additionally, the cognitive, emotional, and speech impact rates in the Chinese population were reported as 2.8%, 1.8%, and 0.9%, respectively [45]. Our study found that the incidence rate of cognitive impairment was 19.39%, emotional disorders 13.76%, and speech difficulties 2.25%. The prevalence of cognitive and emotional side effects in non-Asian populations is twice that of Asian populations [25]. Patients typically experience various types of CNS adverse reactions. These findings help to better understand the variations in CNS AE incidence rates across different populations [44].

Our research emphasizes that CNS AEs typically induced by lorlatinib are less severe, with uncommon clinical symptoms. The reported incidence rates of CNS AEs at Grade III or above vary, ranging from 0.00 to 6.73%. Importantly, the incidence rate of CNS AEs at Grade III or above in the Asian population is significantly lower, at only 0.93% [25]. AEs affecting the CNS are usually responsive to treatment, and timely intervention can often prevent the need for premature or indefinite medication discontinuation. Dose adjustment is an effective method for managing CNS AEs without compromising efficacy [46]. Solomon et al.'s research indicated no significant difference in the 12-month PFS rate between the standard-dose subgroup and the reduced-dose subgroup within 16 weeks (93% compared to 89%). Likewise, there was no significant difference in the 12-month PFS rate between subgroups above and below the average relative dose intensity (90% compared to 93%). The reported case employed a dose reduction strategy from 100 mg/day to 50 mg/day, with no further adverse reactions observed, allowing for continued benefit from lorlatinib treatment.

Limitations

Through case reports and a literature review, this study explored the clinical characteristics and management strategies of CNS adverse reactions caused by lorlatinib in treating ALK-positive NSCLC patients. However, the limitations of this study are noteworthy. Firstly, the anecdotal nature of case reports implies that the observed outcomes may not be easily generalizable to a broader patient population, and the absence of a control group makes it difficult to ascertain whether the outcomes were due to the intervention itself or other confounding factors. Moreover, selection bias might lead to results skewed towards reporting exceptional, rare, or notably successful treatment cases, overlooking more common or median scenarios. Due to the design and nature of case reports, establishing causality also presents a challenge. Regarding the literature review, the quality of the study highly depends on the selection criteria and quality of the chosen literature, while selection bias, heterogeneity in study design, delays in updating due to rapidly advancing scientific research, and subjectivity in interpreting results could all affect the conclusions of the review. Therefore, despite this study providing valuable insights into understanding and managing CNS adverse reactions induced by lorlatinib, the limitations above should be considered when interpreting the findings. Future research should employ broader samples and more rigorous study designs to enhance the generalizability and accuracy of the findings.

Our study and case reports underscore the importance of effectively identifying and managing CNS AEs during lorlatinib treatment for ALK-positive NSCLC (Fig. 3). By leveraging the collaboration of a multidisciplinary team, educating patients and their families, and implementing personalized treatment and care strategies, it is possible to minimize CNS AEs during lorlatinib treatment, thereby improving patients’ quality of life and treatment outcomes.Fig. 3 Mechanism of action, management of central nervous system adverse reactions, and long-term monitoring strategies for lorlatinib treatment in ALK-positive NSCLC

Acknowledgements

The authors wish to acknowledge Na Yan, Key Laboratory of Digital Technology in Medical Diagnostics of Zhejiang Province, for her help in providing a part of reference materials for this study and her meaningful guidance in the internal revision of the initial manuscript.

Author contributions

Hong Hu and Fanfan Chu conceived and designed the study and analyzed the data. Fanfan Chu and Wenxi Zhang performed the experiments and wrote the manuscript. All authors reviewed and approved the final version of the manuscript.

Funding

This study was supported by the CSCO-BMS Cancer Immunotherapy Research Foundation (Grant No. Y-BMS2019-098) and the CSCO-Xinda Cancer Immunotherapy Research Foundation (Grant No. Y-XD2019-225).

Data availability

The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This research was rigorously conducted in adherence to international and domestic medical ethics standards and regulations throughout its design and implementation phases. It specifically focused on the clinical characteristics and management strategies of CNS adverse reactions in ALK-positive NSCLC patients undergoing Lorlatinib treatment. Before enrollment, all patients participating in this study were fully informed about the research objectives, potential risks, benefits, and possible alternative treatment options. Stringent privacy protection measures were implemented to safeguard participants' privacy and personal information. Each participant or their legal representative voluntarily signed a written informed consent form after fully understanding the content and procedures of the research. The study protocol received approval from the Ethics Review Committee of Sir Run Run Shaw Hospital (Approval Number: 2023-861-01), ensuring all research activities complied with the Declaration of Helsinki and other relevant medical ethics guidelines. Throughout the research process, patient welfare was prioritized, maintaining the highest ethical standards. Data collection and analysis were conducted carefully to protect patient privacy and dignity. Appropriate measures were taken to anonymize any patient information acquired, preventing the leakage of personal data.

Informed consent

Informed consent was obtained from the patient and/or their legal guardian to publish identifying information and images in an online open-access publication. The patient or their legal representative was thoroughly informed about the objectives of the study, the potential risks and benefits, and their right to withdraw from the study at any time without any consequences. All procedures followed the ethical standards set forth by the institutional and national research committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Competing interests

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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