Safety of Lorlatinib in ALK-Positive Non-Small-Cell Lung Cancer and Management of Central Nervous System Adverse Events

Plain Language Summary

The use of tyrosine kinase inhibitors has made a breakthrough in the treatment of non-small-cell lung cancer (NSCLC). Recently, lorlatinib, a third-generation tyrosine kinase inhibitor, has demonstrated significant systemic and intracranial activity in both first-line and subsequent-line therapy in ALK-positive NSCLC patients. In this review, general characteristics of lorlatinib, its efficacy in the treatment of ALK-positive NSCLC patients and the safety of lorlatinib, particularly addressing central nervous system adverse events, are discussed. Management of central nervous system adverse events, which seem to be specific to lorlatinib therapy, is outlined.

Safety of lorlatinib in ALK-positive non-small-cell lung cancer and management of central nervous system adverse events

Lung cancer is a common disease and affects patients badly. Lorlatinib is a new and useful drug for this disease. But this drug has also some undesirable effects for the brain. These effects are generally mild and can be treated. This article discusses the undesirable effects of this drug on the brain and how to cope with these effects.

Keywords::

• adverse drug reactions
• central nervous system
• hyperlipidemia
• lorlatinib
• lung cancer

Lung cancer remains the leading cause of cancer-related deaths [1]. Recently, there have been significant developments in the treatment of non-small-cell lung cancer (NSCLC). Identification of the roles of various oncogenes, such as ROS1 and ALK, has drawn attention to the molecular characteristics of NSCLC patients [2,3]. Use of tyrosine kinase inhibitors (TKI) as a targeted therapy for patients carrying mutations in these genes has resulted in dramatic improvements in treatment [3]. ALK mutations are found in 3–7% of NSCLC patients, while ROS1 rearrangements occur in approximately 1–2% [2,4].

Crizotinib was the first TKI approved for the treatment of ALK-positive advanced NSCLC patients. After successful outcomes were achieved with crizotinib, second-generation TKIs (ceritinib, alectinib, brigatinib and ensartinib) were developed. Recently, lorlatinib, a third-generation TKI, has also been introduced [3]. Lorlatinib shows strong systemic and intracranial antitumor activity in treatment-naive ALK-positive advanced NSCLC patients and in those who have failed with a previous ALK TKI therapy [4]. Moreover, it also improved survival in patients with ROS1-positive NSCLC who progressed after crizotinib [5].

This review will provide a brief overview of the general characteristics of lorlatinib and its efficacy in the treatment of ALK-positive advanced NSCLC patients, and the safety and tolerability of lorlatinib will be discussed, particularly addressing central nervous system (CNS) adverse events.

Indications & pharmacological characteristics of lorlatinib

Lorlatinib (PF-06463922) is a potent ALK and ROS1 inhibitor. It has been developed specifically to overcome second-generation ALK-TKI resistance mutations and to achieve much higher penetration into the CNS [6].

Lorlatinib is an ALK inhibitor with activity against most known ALK resistance mutations. Secondary ALK resistance mutations occur in more than 50% of patients receiving second-generation ALK TKIs, and more than 50% of these patients harbor the highly resistant G1202R mutation. Lorlatinib also overcomes the G1202R mutation [7]. However, resistance to TKIs is a problem also for third-generation agents. ‘On-target’ and ‘off-target’ mechanisms of acquired resistance have been reported in patients who progressed while on lorlatinib therapy [8]. Further understanding these resistance mechanisms would be beneficial for developing effective treatment strategies.

Lorlatinib is administered by the oral route, with or without food. The recommended dose is 100 mg once a day unless there is disease progression or intolerable toxicity [9]. It is absorbed immediately, with peak plasma concentration achieved in 1–2 h. Elimination half-life is 19–29 h when given at a daily dose of 100–200 mg [7]. Pharmacokinetic studies have demonstrated that variables such as age, sex and race do not affect plasma exposure [7]. It has high penetration into the CNS; cerebrospinal fluid concentration is about 70% of the free plasma concentration [10,11].

Lorlatinib is metabolized primarily by CYP3A and UGT1A4. The major metabolite is PF-06895751, which is pharmacologically inactive [11]. Lorlatinib has limited renal excretion [11]. It has been reported that dose adjustment is not necessary in those with mild and moderate renal dysfunction; however, the initial dose is recommended to be reduced to 75 mg in patients with severe renal impairment [12]. In November 2018 the US FDA approved lorlatinib for second- or third-line treatment of ALK-positive metastatic NSCLC. Thereafter, in March 2021, it was approved as a first-line treatment for ALK-positive advanced NSCLC [13].

Clinical efficacy

In the multicenter phase II study, lorlatinib use was evaluated in treatment-naive ALK-positive NSCLC patients or in ALK-positive NSCLC patients who received a TKI as the first-line or subsequent-line therapy with or without chemotherapy. Lorlatinib demonstrated significant systemic and intracranial activity as both first-line and subsequent-line therapy [14]. Subgroup analyses demonstrated a clinically significant effect of lorlatinib in ALK-positive advanced NSCLC patients (n = 139) who had previously been treated with a second-generation ALK TKI with or without chemotherapy as the first-line or subsequent-line therapy [15]. The phase III trial (CROWN study) was conducted to compare lorlatinib with crizotinib in ALK-positive NSCLC patients (n = 296) who received no previous systemic treatment for metastatic disease. First-year evaluation of the study outcomes revealed a progression-free survival (PFS) rate of 78% in those receiving lorlatinib and 39% in those receiving crizotinib. Confirmed objective response rate (ORR) in the lorlatinib and crizotinib users was 76 and 58%, respectively, whereas confirmed intracranial response rate (IRR) in those with baseline measurable brain metastasis was 82 and 23%, respectively [16]. According to the recent analysis of the CROWN study with a median follow-up duration of 36.7 months, lorlatinib continued to show superior overall and intracranial efficacy compared with crizotinib in ALK-positive NSCLC patients. 3-year PFS rate in the lorlatinib and crizotinib groups was 63.5 and 18.9%, respectively; confirmed ORR was 77.2 and 58.5%, respectively; and confirmed IRR in those with baseline measurable brain metastasis was 83.3 and 23.1%, respectively [17,18]. The efficacy of lorlatinib has also been supported by real-world data [5,19–22]. In a recently published multicenter retrospective study in heavily treated ALK-positive NSCLC patients, median PFS was 14.7 months and 1-year PFS rate was 55% [21].

CNS metastasis is more frequent in ALK-positive NSCLC patients at baseline and follow-up and worsens the prognosis. It has been reported that ALK rearrangement at the onset of disease shows a strong correlation with CNS metastasis and that CNS progression is frequently encountered during first-line and subsequent-line therapies [23]. A phase II study demonstrated that lorlatinib is active in the prevention and treatment of CNS metastases in ALK-positive NSCLC patients who show progression on first- and/or second-generation TKI therapy [24]. In another phase II study, intracranial disease control was 95% and intracranial ORR was 59% with lorlatinib therapy in ALK-positive NSCLC patients with CNS progression while on second-generation TKIs [25]. Additionally, the median intracranial PFS was 24.6 months [25].

Systematic reviews and meta-analysis have also demonstrated that lorlatinib is an appropriate option for first-line therapy, has favorable effects on PFS and has the highest probability of achieving confirmed objective and intracranial responses [26–29]. A recent meta-analysis demonstrated that for the first-line therapy of ALK-positive NSCLC patients, lorlatinib was the most effective in prolonging PFS, followed by brigatinib, alectinib, ensartinib, ceritinib, crizotinib and chemotherapy [30]. Lorlatinib was also demonstrated to have the most favorable effect according to the analysis of the subgroup of patients with CNS metastases. While lorlatinib was significantly more effective as compared with ensartinib, ceritinib, crizotinib and chemotherapy, the difference between lorlatinib and brigatinib was not significant [30]. Similarly, in another meta-analysis, lorlatinib as the first-line therapy was demonstrated to have the best PFS in ALK-positive NSCLC patients, followed by alectinib, ensartinib, brigatinib, crizotinib and ceritinib [31]. On the other hand, in terms of its safety profile, lorlatinib was poorer; alectinib was the best. Moreover, lorlatinib had the best PFS benefit in patients with CNS metastases at baseline [31].

Safety of lorlatinib & management of non-CNS adverse events

Hypercholesterolemia, hypertriglyceridemia, edema, weight gain and peripheral neuropathy are the most common adverse events associated with lorlatinib [14,16,32–34]. Other adverse events with varying frequencies (≥10%) include anemia, fatigue, hypertension, vision disorder, tinnitus, prolonged QT interval, dizziness, arthralgia, headache, gastrointestinal adverse events, abnormal laboratory values and CNS adverse events [14,16,32–34]. It has been reported that the majority of adverse events are similar to those experienced with other targeted therapies; however, hyperlipidemia (hypercholesterolemia and hypertriglyceridemia) and CNS adverse events are specific to lorlatinib therapy [35,36]. Non-CNS adverse events associated with lorlatinib therapy are summarized in Table 1. The CNS adverse events, which are the main focus of the current review, will be discussed under a separate heading below.

Table 1. Non-central nervous system adverse events associated with lorlatinib therapy.

Adverse event	Grade and frequency, %
	Any grade	Grade 1–2	Grade 3–4
Any adverse event	97.3–100.0	23.0–54.1	44.0–72.0
Laboratory adverse events
Hypercholesterolemia	70.5–92.7	54.4–80.7	11.9–17.9
Hypertriglyceridemia	60.7–90.8	43.6–63.3	15.6–27.5
Hyperglycemia	16.5	13.8	2.8
Hyperuricemia	10.3	10.3	0.0
Increased ALT	8.7–43.1	8.0–41.3	0.0–2.7
Increased AST	10.2–40.4	9.8–37.6	0.0–2.8
Increased GGT	23.9	22.0	1.8
Increased LDL	19.3	19.3	0.0
Increased amylase/lipase	11.6–19.3	8.0–12.5	3.6–6.8
Prolonged QT interval	5.4–16.5	5.1–16.5	0.0–0.3
Clinical adverse events
Edema	26.6–55.0	25.7–51.0	0.9–7.7
Weight gain	15.4–38.3	15.4–25.7	0.0–16.8
Peripheral neuropathy	11.0–43.7	11.0–43.6	0.0–2.4
Diarrhea	10.5–21.5	10.2–20.5	0.0–1.3
Anemia	5.5–19.5	4.7–16.8	0.7–2.7
Fatigue	10.2–23.1	9.8–22.7	0.3–1.3
Hypertension	2.9–18.1	1.5–8.1	1.5–10.1
Vision disorder	9.5–18.1	9.5–18.1	0.0–0.3
Tinnitus	5.4–17.9	5.4–17.9	0.0–0.0
Constipation	9.8–17.9	9.8–17.9	0.0–0.0
Dizziness	9.1–15.4	8.1–12.8	0.7–2.6
Nausea	9.2–14.8	9.2–14.1	0.0–0.7
Vomiting	4.4–12.8	4.0–12.1	0.0–0.7
Arthralgia	10.2–19.7	10.2–19.7	0.0–0.3
Headache	7.1–10.3	7.1–10.3	0.0–0.0

The table illustrates the adverse events occurring at a rate of >10% in any of the clinical trials (the table was created based on data from [14,16,32-34]. CNS adverse events are listed in Table 3.

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: γ-glutamyl transferase; LDL: Low-density lipoprotein.

Adverse event-related drug interruption is seen in 21.7–49% and dose reduction in 19.7–22% of the patients. Permanent drug discontinuation due to adverse events has been reported less frequently (2–7%) [14,16,32,33].

Grade 3 and 4 adverse events are more frequently detected in cases with hypercholesterolemia and hypertriglyceridemia [14–16,33]. Patients and their caregivers should be informed about the risk of hyperlipidemia before starting on lorlatinib therapy. Patients’ baseline lipid levels should be documented and monitored [37,38]. Hyperlipidemia usually develops within the first few weeks of lorlatinib therapy. Median time to onset of hyperlipidemia was reported to be 15 days (range: 1–219) [33]. Hyperlipidemia occasionally requires the interruption of lorlatinib therapy or dose reduction, but does not require permanent drug discontinuation. It can be controlled using lipid-lowering drugs (Table 2) [39]. Rosuvastatin and pitavastatin are preferred as lipid-lowering drugs because they are quite potent and do not interact with lorlatinib. Ezetimib should be added when cholesterol levels remain above the targeted levels despite statin therapy. Fenofibrate should be prescribed when the triglyceride level is >500 mg/dl [38]. In the CROWN study, as compared with the crizotinib group, the lorlatinib group had a higher number of patients with hyperlipidemia at baseline or during the study but a lower incidence of cardiovascular adverse events [18], suggesting that lorlatinib-associated hyperlipidemia did not increase cardiovascular adverse events in the follow-up period [18].

Table 2. Management of hyperlipidemia, the most common adverse event during lorlatinib therapy.

Hyperlipidemia severity	Management
Mild hypercholesterolemia (Cholesterol: ULN: 300 mg/dl) OR Moderate hypercholesterolemia (Cholesterol: 301–400 mg/dl) OR Mild hypertriglyceridemia (Triglycerides: 150–300 mg/dl) OR Moderate hypertriglyceridemia (Triglycerides: 301–500 mg/dl)	Introduce or modify lipid-lowering therapy in accordance with respective prescribing information; continue lorlatinib at same dose
Severe hypercholesterolemia (Cholesterol: 401–500 mg/dl) OR Severe hypertriglyceridemia (Triglycerides: 501–1000 mg/dl)	Introduce lipid-lowering therapy; if currently on lipid-lowering therapy, increase the dose of this therapy in accordance with respective prescribing information; or change to a new lipid-lowering therapy. Continue lorlatinib at the same dose without interruption
Life threatening hypercholesterolemia (Cholesterol: >500 mg/dl) OR Life threatening hypertriglyceridemia (Triglycerides: >1000 mg/dl)	Introduce lipid-lowering therapy or increase the dose of this therapy in accordance with respective prescribing information or change to a new lipid-lowering therapy. Withhold lorlatinib until recovery of hypercholesterolemia and/or hypertriglyceridemia to moderate or mild severity grade Rechallenge at same lorlatinib dose while maximizing lipid-lowering therapy in accordance with respective prescribing information If severe hypercholesterolemia and/or hypertriglyceridemia recur despite maximal lipid-lowering therapy in accordance with respective prescribing information, reduce lorlatinib by one dose level

ULN: Upper limit of normal.

Table created using data from [39].

Weight gain occurs in the first 2 months of treatment. In order to prevent this adverse event, baseline body weight must be documented and monitored. Moreover, patients must be warned about increased appetite and should be encouraged to comply with a healthy diet. Lorlatinib therapy can be interrupted or the dose can be reduced by 25 mg, if necessary [40].

Edema is usually seen after at least 4 weeks of treatment, and is not generally alleviated with furosemide. If there is severe edema, lorlatinib therapy can be interrupted or the dose can be reduced by 25 mg [40]. The drug must be permanently discontinued in the presence of grade 4 edema. Compression bandage/socks, extremity elevation, salt restriction and physical exercise are recommended for the management of peripheral edema [38].

Median time to onset of peripheral neuropathy was reported to be 77 days (range: 1–723). Many patients respond to dose interruption or reduction, and vitamin B1, B6, gabapentin or pregabalin provides symptom relief in some patients [40].

Apart from the above-mentioned adverse events, those with an incidence of <10% in clinical trials – some of which have been reported in only a single case – include leukocytosis, thrombosis, hypophosphatemia, hypermagnesemia, hyponatremia, hyperkalemia, creatinine elevation, rash, mucocutaneous candidiasis, dyspnea, hypoxia, pneumonia/pneumonitis, interstitial lung disease, pulmonary edema, respiratory failure, decreased ejection fraction, bradycardia, pericardial effusion, glossitis, gastritis, ascites, pancreatitis, dysgeusia, abdominal pain, decreased appetite, muscle weakness, myalgia, localized edema, night sweats, presyncope, hydrocephalus and diabetes mellitus [5,14–16,41]. In addition to these, some adverse events such as lorlatinib-induced pulmonary arterial hypertension [42], pulmonary embolism [43], proteinuria [44] and recent-onset myasthenia gravis [45] have been presented as case reports.

CNS adverse events

CNS adverse events may also be seen in patients receiving lorlatinib. Bauer et al. demonstrated that 39.7% of 295 patients had CNS adverse events, with 11.9% having more than one effect [33]. A majority (71.8%) of the patients with CNS adverse events had CNS metastasis at baseline, and 26.2% of the patients with metastases had previously received whole-brain radiation therapy [33]. In a recent analysis of the CROWN study, Solomon et al. reported that 35% of the patients treated with lorlatinib experienced CNS adverse events (a total of 86 events in 52/149 patients) [46]. More than one CNS adverse event was reported in 13% of the patients. CNS adverse events seemed to be similar regardless of brain metastases; 42% of 38 patients had brain metastases at baseline, while 32% of 111 patients did not [46].

The pathogenesis of lorlatinib-associated CNS adverse events has not yet been established, but several factors have been suggested to have a role. Certain neurotropic medications and comorbid medical conditions such as cognitive impairment, psychiatric illness and speech disorders have been considered to increase the risk of developing CNS adverse events. In an analysis of 372 patients receiving lorlatinib, it was concluded that although not the primary factor, CNS involvement of the NSCLC may have a role in CNS adverse events [47]. In addition, potential factors related to CNS adverse events have been reported as CNS radiation, pre-existing psychiatric illness and baseline use of certain neurotropic medications [47].

CNS adverse events include alterations in cognitive functions, mood changes, speech disorders and psychotic disorders [40,46]. The frequency of CNS adverse events reported in the international multicenter trials is summarized in Table 3. The grading for CNS adverse events according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (v. 3.0) [48] is summarized in Table 4.

Table 3. Central nervous system adverse events encountered during lorlatinib therapy.

Reference	Solomon et al. [14]^†	Bauer et al. [33]^†	Felip et al. [15]^†	Solomon et al. [46]^†	Peled et al. [41]^‡
Patient group	ALK-positive or ROS1-positive NSCLC	ALK-positive or ROS1-positive NSCLC	ALK-positive or ROS1-positive NSCLC	ALK-positive NSCLC	ALK-positive or ROS1-positive NSCLC
Lorlatinib therapy line	First or subsequent	First or subsequent	First or subsequent	First	Second or subsequent
CNS adverse events	Any grade (grade 1–2/grade 3–4)
Cognitive effects, %	17.8 (16.7/1.1)	23.1 (21.4/1.7)	23.7 (22.0/1.7)	21.5 (19.5/2.0)	17.9 (17.9/0.0)
Mood effects, %	14.9 (14.2/0.7)	21.0 (19.7/1.4)	15.6 (14.6/1.0)	16.1 (14.8/1.3)	15.4 (15.4/0.0)
Speech effects, %	7.3 (6.9/0.4)	9.5 (9.2/0.3)	8.5 (8.1/0.3)	4.7 (4.0/0.7)
Psychotic effects, %	1.8 (1.5/0.4)		6.4 (5.8–0.6)	3.4 (3.4/0.0)

† Prospective.

‡ Retrospective.

NSCLC: Non-small-cell lung cancer.

Table 4. Grading of central nervous system adverse events.

CTCAE term	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Cognitive disturbance	Mild cognitive disability; not interfering with work/school/life performance; specialized educational services/devices not indicated	Moderate cognitive disability; interfering with work/school/life performance but capable of independent living; specialized resources on part-time basis indicated	Severe cognitive disability; significant impairment of work/school/life performance	Unable to perform ADL; full-time specialized resources or institutionalization indicated	Death
Mood alteration	Mild mood alteration not interfering with function	Moderate mood alteration interfering with function, but not interfering with ADL; medication indicated	Severe mood alteration interfering with ADL	Suicidal ideation; danger to self or others	Death
Speech impairment	–	Awareness of receptive or expressive dysphasia, not impairing ability to communicate	Receptive or expressive dysphasia, impairing ability to communicate	Inability to communicate	–
Psychosis (hallucinations/delusions)	–	Transient episode	Interfering with ADL; medication, supervision or restraints indicated	Harmful to others or self; life-threatening consequences	Death

ADL: Activities of daily living; CTCAE: Common Terminology Criteria for Adverse Events (v. 3.0).

Table created using data from [48].

Cognitive effects

Lorlatinib-related cognitive alterations are as follows: memory impairment, mental impairment, confusion, cognitive disorder, amnesia, confused state, disturbances in attention, delirium and dementia [33].

The frequency of lorlatinib-related cognitive adverse effects has been reported as being between 17.8 and 23.7%, the majority of which are grade 1–2 adverse effects [14–16,33,41,46]. The median time to onset of cognitive changes has been reported to be 53 days (range: 1–423) [33].

The frequency of cognitive effects has been found to be similar in patients aged <65 and ≥65 years (22.4 and 25.9%, respectively), with such effects being more frequent in non-Asians than in Asians (28.0 and 12.0%, respectively) [33]. The frequency of lorlatinib-induced (second- or subsequent-line) cognitive effects has been reported as 17.9% in Japanese patients (n = 39; all were grade 1–2) [32].

Mood effects

Reported mood changes associated with lorlatinib include irritability, aggression, agitation, anxiety, depression, unstable affect, personality change, euphoria and mania [33].

The frequency of mood effects has been reported to be 14.9–21%, with the majority being grade 1–2 [13–15,27,34,39]. The median time to onset of mood changes was 43 days (range: 1–452) [33].

The frequency of mood effects has been found to be similar in patients aged <65 and ≥65 years (21.6 and 18.5%, respectively), with such effects being more frequent in non-Asians than in Asians (27.3 and 10.2%, respectively) [33]. The frequency of lorlatinib-induced (second- or subsequent-line) mood effects has been reported as 12.8% (10.3% grade 1–2) in Japanese patients (n = 39) [32].

Speech effects

The reported lorlatinib-related speech effects are dysarthria, slow speech and speech disorder [33]. The frequency of speech effects has been reported as 4.7–9.5%, with the majority being grade 1–2 [13,14,33,46]. The median time to onset of speech disorders has been reported to be 42 days (range: 1–404) [33].

Psychotic effects

Psychotic effects related to lorlatinib treatment are visual hallucinations, auditory hallucinations and delusions [46].

The frequency of psychotic effects has been reported as 1.8–6.4%, with the majority being grade 1–2 [14,15,46]. Auditory hallucinations at any grade were observed at a rate of 10.3% in Japanese patients (7.7% grade 1–2) [32]. The median time to onset of psychotic effects has been reported to be 44 days (range: 9–479) [46].

Management of CNS adverse events

While the high CNS penetration of lorlatinib provides an advantage in treatment, it forms a basis for CNS adverse events. In addition, the brain metastases commonly seen in ALK-positive NSCLC patients can also be the cause of neurological symptoms and signs. MRI is a preferred method for diagnosing brain metastasis and discriminating new metastases from the old ones. MRI is recommended in all patients before starting lorlatinib therapy [37,38]. In addition, in order to identify any pre-existing problems, all patients are recommended to have mental status and neurological examination before initiation of lorlatinib therapy [38].

Patients and their families/caregivers should be informed about potential CNS adverse events before starting lorlatinib therapy, and it should be highlighted that these adverse events would be mild and reversible. The symptoms for early detection of cognitive, mood and speech changes should also be explained in simple terms. The patients must be regularly monitored by the treating physician for CNS adverse events during the treatment period [37]. Bauer et al. reported that 24 of 117 patients with CNS adverse events required one or more dose modifications, and 62.5% of them showed improvement [33]. In the same study, the authors reported four patients who required permanent discontinuation of lorlatinib due to cognitive disorder, confusional state, affect lability or anxiety (each seen in one patient). The median time to resolution of CNS adverse events was reported as 12.5 days (range: 2–112) [33].

In a recent analysis of the CROWN study, of 86 CNS adverse events, 62% were managed without any intervention (of which 53% resolved spontaneously) and 23% were managed with dose modification. Permanent treatment discontinuation was only required in 2% of the patients [46]. As it could be hard to evaluate CNS adverse events, it was also reported that there could be overlooked events [46]. Moreover, pointing out that there were unresolved events (38%) during the follow-up period, it was further stated that assessment of the full duration of all CNS adverse events was not possible [46]. It was also suggested that more specific neurological scales could be beneficial in order to evaluate the effects of CNS adverse events on the quality of life of the patients [46]. In every step of management, psychiatric and neurological consultation should be performed, if needed. According to the CNS adverse event profile, appropriate antidepressants, antipsychotics, anxiolytics and antiepileptics as mood stabilizers can be used according to the recommendations of psychiatrists and neurologists.

In brief, cognitive and mood alterations are generally mild (grade 1), transient and rapidly reversible after modification of the drug dose [14,16,33,46]. The impact of dose modification on the efficacy of lorlatinib was evaluated in a group of patients (n = 149) of the CROWN study [46]. In that particular study, at least one lorlatinib dose reduction was performed due to adverse events in 28% of the patients (n = 41). According to the landmark analysis of PFS, the 1-year PFS rate was reported as 84% for patients both with (n = 17) and without (n = 105) dose reduction, indicating the maintenance of lorlatinib efficacy in the case of dose reduction [46].

Approaches to the CNS adverse events are summarized in Table 5. If the CNS adverse event is of grade 4 (life-threatening, urgent intervention indicated), lorlatinib must be permanently discontinued (Table 5) [39].

Table 5. Recommended dose modifications for central nervous system adverse events encountered during lorlatinib therapy.

CNS adverse events	Approach
Grade 2 (moderate) OR Grade 3 (severe)	Withhold dose until toxicity is grade ≤1, then resume lorlatinib at one reduced dose level
Grade 4 (life-threatening / urgent intervention indicated)	Permanently discontinue lorlatinib

Table created using data from [39].

CNS: Central nervous system.

The lack of a definitive and accepted guide on the management of CNS adverse events leads to difficulties in evaluating patients. Nevertheless, it is possible to take a rational approach by specifically considering some points. In patients receiving lorlatinib therapy, in addition to clinical efficacy, clinically significant improvement in global quality of life and improved physical, emotional and social and role function have also been reported [32,46,49]. Furthermore, the efficacy of lorlatinib continues in the case of dose reduction due to adverse events [46]. No strong evidence is available that CNS adverse events associated with lorlatinib are more common in a particular group of patients, such as those having initial CNS metastasis or prior radiotherapy [46]. Accordingly, in the light of this evidence, making a hasty decision to discontinue lorlatinib therapy due to an adverse event should be avoided; patients should be evaluated in every aspect, and efforts should be made to treat the adverse events.

Conclusion

Lorlatinib is a third-generation TKI with good systemic and intracranial activity due to its potency and high CNS penetration, and its efficacy in ALK-positive NSCLC has been demonstrated in clinical trials. The most common lorlatinib-induced adverse events include hyperlipidemia, edema, weight gain and peripheral neuropathy. Hyperlipidemia and CNS adverse events seem to be specific to lorlatinib therapy. Adverse events are usually mild and tolerable, and are reversible when the drug is interrupted or the dose is reduced. Moreover, the efficacy of lorlatinib continues in the case of dose reduction due to adverse events. Management of adverse effects with a multidisciplinary approach and early diagnosis with neurological and psychiatric consultations when necessary, particularly for CNS adverse events, may provide continuation of treatment without changing the dose of lorlatinib. In conclusion, lorlatinib is a good therapeutic option with manageable adverse events in ALK-positive NSCLC patients.

Future perspective

Lorlatinib is a good therapeutic option in ALK-positive NSCLC patients. The use of lorlatinib in more ALK-positive NSCLC patients is likely in the coming years and would warrant further clinical studies on its adverse effects. As real-world data on lorlatinib increase, information regarding more effective management of adverse events would also increase. It can be envisaged that there will be a trend toward the production of molecules similar to lorlatinib with fewer adverse effects. Under the guidance of all this information for lorlatinib, breakthroughs that will increase awareness of adverse events can be made in the future and accordingly adverse events can be managed more effectively.

Executive summary

Background

• The lack of a definitive and accepted guide on the management of lorlatinib-related central nervous system (CNS) adverse events leads to difficulties in evaluating patients.

• This review aimed to evaluate the general characteristics of lorlatinib, its efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC) patients and its safety, particularly addressing the CNS adverse events.

Clinical efficacy

• Lorlatinib, a third-generation tyrosine kinase inhibitor, has been demonstrated to be effective in ALK-positive NSCLC in clinical trials.

• Lorlatinib has good systemic and intracranial activity due to its potency and high CNS penetration.

Safety of lorlatinib & management of non-CNS adverse events

• Among adverse events associated with lorlatinib, hyperlipidemia and CNS adverse events seem to be lorlatinib-specific but are usually mild and tolerable, and they are reversible when the drug is interrupted or the dose is reduced.

• A multidisciplinary approach and early diagnosis with neurological and psychiatric consultations when necessary, particularly for CNS adverse events, should be considered for likely continuation of treatment without changing the dose of lorlatinib in ALK-positive NSCLC patients.

Author contributions

All authors made substantial contributions to the conception and design of the work, drafted the work and revised it critically for important intellectual content, and had final approval of the version to be published. All authors agree to be accountable for all aspects of the work.

Financial & competing interests disclosure

This study was funded by Pfizer. S Kilickap, S Ak, MAN Sendur, N Karadurmus and U Demirci declare that they have no conflicts of interests. OU Dursun is an employee of Pfizer Biopharmaceuticals Group, Istanbul, Turkey. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Medical writing support was provided by M Akkeçi at Omega CRO, Ankara, Turkey and was funded by Pfizer.

Additional information

Funding

This study was funded by Pfizer. S Kilickap, S Ak, MAN Sendur, N Karadurmus and U Demirci declare that they have no conflicts of interests. OU Dursun is an employee of Pfizer Biopharmaceuticals Group, Istanbul, Turkey. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.