FormalPara Key Points

Lorlatinib is an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) that is highly effective in patients with advanced ALK-positive non-small cell lung cancer (NSCLC).

Similar to other treatments, lorlatinib has adverse events that need to be monitored and treated appropriately to maximize drug efficacy and patient safety.

Considering that the adverse events of lorlatinib can affect different organs and systems, the participation of a multidisciplinary team, including cardiologists, neurologists, internal medicine specialists, and oncology pharmacists, is needed.

1 Introduction

Treatment for advanced non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase gene rearrangement (ALK+) has evolved significantly since the discovery of crizotinib, a first-generation ALK tyrosine kinase inhibitor (TKI) [1,2,3]. To date, there are three generations of ALK-TKIs available, and each successive generation has offered increasing potency, improved CNS penetrance, and an enhanced ability to overcome ALK-resistant mutations. Crizotinib and ceritinib demonstrated benefits over chemotherapy for patients with treatment-naïve ALK+ advanced NSCLC, while second-generation ALK-TKIs (i.e., alectinib, brigatinib, and ensartinib) have demonstrated superior efficacy compared with crizotinib [4,5,6,7,8,9,10,11]. More recently, lorlatinib, a third-generation ALK-TKI, was used to treat patients in the Phase 3 CROWN trial; after 5 years of follow-up, the median progression-free survival was not reached, and the landmark 5-year progression-free survival was 60% (95% CI 51–68). Moreover, lorlatinib was associated with an 81% reduction in the risk of death or progression and a higher intracranial response compared to crizotinib (60% vs 11%). However, lorlatinib was also associated with increased rates of grade 3/4 adverse events (AEs) [12].

Most AEs associated with ALK inhibitors are grade 1–2. The most frequent AE associated with lorlatinib is dyslipidemia, which affects approximately 80% of all patients. Serious AEs have been reported in 7.4% of patients receiving lorlatinib, the most frequent of which were cognitive events and pneumonitis [13]. Table 1 shows the frequency and median time to onset of the most relevant lorlatinib-related AEs [13]. As described in the CROWN trial, treatment-related AEs leading to dose reduction were reported in 21% of patients receiving lorlatinib, temporary treatment discontinuation in 39%, and permanent treatment discontinuation in 5% [12]. The most frequent AEs leading to dose reduction were edema and peripheral neuropathy [13,14,15,16]. Proper monitoring and management of these AEs are critical for maximizing adherence to lorlatinib, achieving the maximum treatment benefit and minimizing patient risk.

Table 1 Most relevant lorlatinib-related adverse events [13]
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Consensus papers on the management of AEs caused by lorlatinib has already been published, but they address their management from oncologists’ point of view and are not easy to follow from clinical practice [14, 17,18,19,20,21]. However, given the variety of different organs that are affected by lorlatinib-related adverse events, appropriate management requires the involvement of a multidisciplinary group of specialists. This article addresses the need for a multidisciplinary expert consensus on the management of AEs associated with lorlatinib in patients with ALK-positive advanced NSCLC.

The focus of the current consensus is to provide specific recommendations and pragmatic information for clinicians treating these patients on the target organs affected by lorlatinib based on the experience that a multidisciplinary group of specialists (cardiologists, neurologists, internal medicine specialists, and oncology pharmacists) discussed in several meetings. This approach is of particular relevance since lorlatinib is a very effective treatment that can be administered for many years.

2 Metabolic and Cardiovascular Adverse Events

Regardless of oncological treatments, cancer patients face increased cardiovascular risk. Recent cardiology guidelines recommend managing risk factors and cardiovascular disease (CVD) upon diagnosis. Treatment with ALK inhibitors adds additional risk for cardiovascular and metabolic events [22]. In the case of lorlatinib, the most common conditions (i.e., those with an incidence rate ≥10%) are dyslipidemia, hypertension, and hyperglycemia/diabetes. Sinus bradycardia is a less common event (i.e., incidence rate from 1 to 10%) [22]. Despite these findings, after a 3-year follow-up, no increase in cardiovascular risk was observed with lorlatinib compared to crizotinib [23].

Before starting treatment with lorlatinib, a baseline cardiovascular toxicity risk assessment, including clinical history, physical examination, electrocardiogram, blood pressure assessment, general blood test, glycosylated hemoglobin (HbA1c) (at least in patients with hyperglycemia), and lipid profile, is recommended. Cardiac serum biomarkers and transthoracic echocardiography should be considered in patients with moderate-to-severe preexisting CVD or new abnormal findings during baseline assessment (i.e., abnormal electrocardiogram). For patients taking lorlatinib, a cholesterol profile assessment at 2, 4 and 8 weeks and every 3–6 months should be considered. Additionally, home blood pressure monitoring and an electrocardiogram are recommended at 4 weeks after starting therapy and every 3–6 months in patients with preexisting CVD. In patients who already have or are at significant risk of developing cardiovascular events, a multidisciplinary cardio-oncology team is needed for optimal management [22].

2.1 Dyslipidemia

Hypercholesterolemia and hypertriglyceridemia are the most common AEs in patients treated with lorlatinib (incidence rates of 81% and 67%, respectively) (Table 1) [13]. Special care should be taken when patients are previously treated with lipid-lowering agents, have a history of coronary/cardiac/vascular disease, have arterial hypertension, or who are obese.

Comprehensive management of dyslipidemia should be based on the estimated cardiovascular risk and requires baseline and follow-up (at 2 weeks, 4 weeks, and 2 months) assessment of low density lipoprotein (LDL)-cholesterol and triglyceride levels of the patient, and LDL-cholesterol and triglyceride levels should guide specific treatment recommendations (Tables 2 and 3) [24].

Table 2 LDL-cholesterol and triglyceride level goals according to cardiovascular risk [24]
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Table 3 Lipid-lowering therapy for hypercholesterolemia and hypertriglyceridemia [24, 29]
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Hypercholesterolemia management does not usually require interruptions or dose reductions of lorlatinib. Among the treatments used for hypercholesterolemia in patients receiving lorlatinib, the statins pitavastatin, pravastatin, and rosuvastatin have a very low risk of interaction with the cytochrome P450 (CYP) enzymes involved in the metabolism of lorlatinib (Table 4) [24]. Dual therapy combining statins and ezetimibe is usually needed to optimize LDL-cholesterol levels. For patients who do not achieve their goals on a maximum tolerated dose of a statin and ezetimibe, combination therapy including a proprotein convertase subtilisin/kexin type 9 inhibitor (iPCSK9) by monoclonal antibodies (alirocumab and evolocumab), small interfering ribonucleic acid (siRNA) targeting PCSK9 (inclisiran) or bempedoic acid is recommended. Figure 1 summarizes the suggested recommendations for the management of hypercholesterolemia [24].

Table 4 Practical management of common lorlatinib interactions
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Fig. 1
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Recommendations for the management of hypercholesterolemia and hypertriglyceridemia. LDL low-density lipoprotein

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For some patients, statin intolerance remains an important clinical challenge. We defined statin intolerance as the inability to tolerate at least two statins at any dose or increasing doses not attributable to other known conditions, and statin intolerance was associated with an increased risk of cardiovascular events. Statin intolerance includes muscle symptoms, increased creatine kinase levels, and an association between the onset of symptoms and the initiation of statin treatment. The overall prevalence of statin intolerance ranges from 5.9 to 9.1%. Female sex, hypothyroidism, high statin dose, advanced age, antiarrhythmic therapy, and obesity are the main factors that increase the risk of statin intolerance [26, 27]. For statin intolerance, ezetimibe monotherapy or combination therapy with other non-statin drugs is recommended. These include the use of alirocumab, evolocumab, inclisiran or bempedoic acid either alone or in combination with ezetimibe [28, 29].

Statins are the recommended first-line therapy for patients with hypercholesterolemia and hypertriglyceridemia. For patients taking statins who have triglycerides >200 mg/dL, the addition of fenofibrate 250 mg/day orally during meals is suggested. However, the combination of statins and fibrates should be used with caution due to the risk of rhabdomyolysis. The use of gemfibrozil in combination with statins is not recommended due to the risk of hepatic and renal toxicity [14, 30]. If hypertriglyceridemia cannot be controlled with fibrates, other alternatives, such as icosapent ethyl 2 g twice daily should be considered (Fig. 1) [31, 32].

2.2 Arterial Hypertension

The prevalence of hypertension in patients treated with lorlatinib is 13% (Table 1) [13,14,15]. The risk is higher in patients with preexisting hypertension or CVDs, advanced age, a history of smoking, hyperlipidemia, and/or obesity. Cardio-oncology guidelines recommend that all cancer patients maintain a blood pressure <140/90 mm Hg, or <130/80 mm Hg for those at very high cardiovascular risk [22]. Blood pressure should be assessed before lorlatinib therapy and monitored 2 weeks after starting therapy and checked at least once a month throughout the treatment period [13].

The first-line treatment for managing hypertension in cancer patients should be an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor antagonist (ARA2), as these drugs have a more favorable profile for reducing the risk of diabetic nephropathy or ventricular dysfunction [22]. For patients with a blood pressure <160/100 mm Hg at diagnosis, monotherapy with ACEI or ARA2 is recommended (Fig. 2). For patients with uncontrolled blood pressure (>140/90 mm Hg), combination therapy with dihydropyridine calcium channel blockers (e.g., amlodipine) is advised. If the blood pressure is ≥160/100 mm Hg at diagnosis, dual antihypertensive therapy combining an ACEI or ARA2 with a dihydropyridine calcium channel blocker is recommended as a first-line treatment. If blood pressure remains above the specified thresholds, it is advisable to add aldosterone inhibitors or α-blockers. Given the increased risk of sinus bradycardia, the use of β-blockers, verapamil or diltiazem should be avoided [15]

Fig. 2
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Recommendations for the management of arterial hypertension

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2.3 Hyperglycemia

The prevalence of hyperglycemia resulting from treatment with lorlatinib is 9% (Table 1) [13,14,15]. Patients at highest risk were those with a previous history of diabetes, with a history of coronary/cardiac/vascular disease or obesity. There are two groups of drugs that have been shown to control glycemia and reduce cardiovascular risk: sodium/glucose cotransporter 2 inhibitors (iSGLT2s) (empagliflozin, canagliflozin, dapagliflozin) and glucagon-like peptide-1 receptor agonists (GLP1-RAs) (liraglutide, semaglutide) [33]. In patients at high vascular risk with chronic kidney disease or heart failure, iSGLT2s should be considered the first treatment option. If the control is inadequate, metformin can be added. The GLP1-RAs are an interesting therapeutic option (either in association with metformin and/or iSGLT2s or in combination with monotherapy in metformin-intolerant patients) in obese patients with a body mass index ≥30 kg/m2. In patients at low vascular risk, metformin is still considered a valid initial therapy. Figure 3 shows the suggested recommendations for the management of hyperglycemia in patients receiving lorlatinib.

Fig. 3
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Recommendations for the management of hyperglycemia. GLP1-RA glucagon-like peptide-1 receptor agonist, HbA1c glycosylated hemoglobin, iSGLT2 sodium/glucose cotransporter 2 inhibitor

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2.4 Atrioventricular Block

The PR interval prolongation and atrioventricular (AV) block have been reported in <1% of patients treated with lorlatinib (Table 1) [13, 14]. Patients at higher risk of developing AV blocks are those with a previous history of arrhythmias. Baseline electrocardiogram assessment is recommended for all patients. Electrocardiogram monitoring at 4 weeks and every 3–4 months should be considered in patients with preexisting CVD. In patients who develop AV block, the risks/benefits of lorlatinib should be discussed by a multidisciplinary cardio-oncology team.

3 Neurological Adverse Events

It has been reported that the neurological or psychiatric AEs related to lorlatinib could be induced by the class effect of ALK-TKIs [34]. Although the mechanism underlying these events is unclear, ALK can play a role in the internalization and regulation of dopamine D2 receptor (D2R), a G protein-coupled receptor expressed in brain regions that control motor function, cognition, and motivation. Its dysregulation may be involved in psychiatric disorders [19, 34]. Nevertheless, lorlatinib has a remarkable ability to enter the brain, mainly due to its low propensity for P-glycoprotein-mediated efflux [35]. Moreover, the mean ratio of cerebral spinal fluid/free plasma concentration for lorlatinib is 0.75 [36]. Hence, there is potential for central nervous system events, including psychotic events and changes in cognitive function, mood, mental status or speech. All of these conditions resolve either by reducing the dose or discontinuing treatment [13, 19].

The overall incidence of these neurological AEs was 35% (62% grade 1, 29% grade 2, 10% grade 3), with a median time to onset of 57 days (1–533 days) and a median duration of 182 days (2–751 days). According to the CROWN study, 62% of patients with such AEs were treated with no specific intervention; 53% of the AEs resolved spontaneously, and only 2% of patients needed permanent discontinuation of lorlatinib [37].

It is important to keep in mind that many of the neurological AEs detected in patients receiving lorlatinib can also be caused by other factors, including brain metastases, brain radiation, brain surgery, preexisting psychiatric disease, and other neurotropic medications, among others [38]. Even more, it is suggested that some AEs are not properly identified in the real-world setting. A recent meta-analysis reported that neurocognitive AEs were more often reported in clinical trials than in retrospective cohort studies [39]. Hence, it is important to establish a differential action protocol both before and after initiating lorlatinib. The patient’s psychiatric history should be explored, and these possible events should be discussed with the patient before initiating treatment with lorlatinib. Figure 4 (Part 1 and Part 2) shows the general recommendations for neurologic AEs in patients receiving lorlatinib, how to adjust lorlatinib, and what supportive treatments are recommended; these recommendations should be used as soon as possible in an attempt to avoid reducing the dose of lorlatinib [13].

Fig. 4
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Recommendations for the management of neurological adverse events. Part 1: Before initiating lorlatinib treatment and how to assess toxicity during treatment. Part 2: After toxicity appears. MRI magnetic resonance imaging

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3.1 Peripheral Neuropathy

The prevalence of peripheral neuropathy associated with lorlatinib has been found to be 43.7% (Table 1) [13,14,15]. Given that peripheral neuropathy associated with lorlatinib is different from that caused by platinum or other anticancer neurotoxic drugs and could be confused with metastatic complications, referring to the neurology department is recommended for initial neurological differential diagnosis.

Once neuropathy appears and other causes have been ruled out, the main recommendation is the use of standard neuropathic treatments in cases of painful or disturbing paresthesia, although it should be remembered that such treatments can worsen the patient’s cognitive condition. The use of duloxetine as a first-line treatment is recommended. In addition, as peripheral neuropathy may be associated with peripheral edema, especially in the upper extremities, diuretics may improve symptoms [13, 14]. It is important to note that there is currently no treatment that has been shown to be beneficial for those neuropathies with negative symptoms (such as hypoesthesia/algesia and hypo-paresthesia) or even for nonpainful positive symptoms.

3.2 Cognitive Events

The prevalence of cognitive events associated with lorlatinib has been found to be 27.7% (Table 1) [13,14,15]. This toxicity includes events related to nervous-system disorders according to the organ classification system (amnesia, cognitive impairment, dementia, attention disturbance, memory impairment, mental deterioration) and events related to psychiatric disorders (attention deficit/hyperactivity disorder, confusional state, delirium, disorientation, reading disorder). It is necessary to discuss the possible occurrence of these AEs with patients and caregivers and offer recommendations to minimize their impact on daily life. However, no sustained deterioration in neurocognitive domains has been recorded in the specifically addressed studies [40]. In addition, it is recommended to review potential new medications introduced during treatment and the psychiatric status of the patient to establish a differential action protocol both before and after initiating lorlatinib.

3.3 Mood Events

The prevalence of mood events associated with lorlatinib has been found to be 21% (Table 1) [13,14,15]. These AEs included affective disorders, affective instability, aggressiveness, nervousness, irritability, anxiety, bipolar disorder type I, depressed mood, depression, depressive symptoms, euphoric mood, irritability, mania, altered mood, mood swings, anxiety crisis, personality change, and stress. These mood disorders appear approximately 4–6 weeks after the initiation of lorlatinib [14]. It should be noted that these AEs are reversible.

Several treatments are proposed to treat anxiety and depression that may arise as a consequence of lorlatinib. Benzodiazepines of short or medium half-lives could be useful for reducing anxiety symptoms. Diazepam and flunitrazepam can be used with caution. In any case, it is advisable to use antidepressants with an anxiolytic profile, especially because benzodiazepines have a negative effect on cognition. Table 4 shows the drug interactions. The antidepressants of choice for lorlatinib are duloxetine and agomelatine. Caution should be taken when using paroxetine, fluoxetine, citalopram, escitalopram, sertraline, fluvoxamine, venlafaxine, and mirtazapine. Nonpharmacological treatments include psychotherapy and mindfulness and can be helpful for some patients [17].

3.4 Speech Events

The prevalence of speech events associated with lorlatinib has been found to be 8.2% (Table 1) [13,14,15]. This group includes dysarthria, bradylalia, and speech disorders, which appear approximately 4 to 6 weeks after the initiation of lorlatinib [14]. Before initiating lorlatinib, patients and caregivers should be made aware that these events are reversible after discontinuation or tapering of treatment. Patient management depends on the impact of these interventions on the patient and whether they manifest continuously or intermittently.

3.5 Psychotic Events

The most common psychotic events associated with lorlatinib are hallucinations. The prevalence of these AEs is 6.5% (Table 1) [13, 37]. Olanzapine is recommended for treating psychosis/mania/hallucinosis, as quetiapine and ziprasidone can induce interactions with lorlatinib. Risperidone and clozapine should be used with caution (Table 4) [17, 41, 42].

4 Other Adverse Events

In addition to the main AEs related to metabolic, cardiovascular and psychiatric health, there are others that affect other systems and functions in the same way as other ALK-TKIs. Table 1 shows the frequency of each AE.

4.1 Edema

Edema is one of the most common AEs in patients receiving lorlatinib (55.7%) and usually appears after 4 weeks of treatment (Table 1) [13,14,15]. Figure 5 shows the general recommendations for treating edema associated with lorlatinib. Once treatment with lorlatinib has been initiated, monitoring the occurrence of edema at each visit is suggested, as it is verified that edema does not arise from other causes. N-terminal pro-brain natriuretic peptide (NT-proBNP) assessment is recommended when significant edema occurs in patients with preexisting cardiovascular disease and/or risk factors for heart failure (diabetes, hypertension, obesity, chronic kidney disease). If the NT-proBNP level is higher than normal, the patient should be referred to the cardio-oncology clinic, and transthoracic echocardiography is recommended.

Fig. 5
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Recommendations for the management of edema

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In patients without heart failure and in those with grade <3 edema, physical measures, such as leg elevation, moderate exercise or compression stockings, are suggested [14, 17]. Although there is no clear evidence on the role of a low-salt diet or water restriction, these are measures that can be considered. Delaying the use of diuretics as late as possible is recommended since there is no evidence to support their use for lorlatinib-associated edema. If a diuretic is used, furosemide at a dosage of 40 mg/day is recommended; however, the dosage should start at 20 mg/day. Caution should also be taken if the patient has renal injury. In these cases, a higher dose of the diuretic could be used under surveillance by nephrologists or internal medicine specialists [13].

4.2 Weight Increase

Mild to moderate weight gain (10–20%) due to increased appetite is another frequent AE associated with lorlatinib [15]. Although there is no specific medical treatment for this weight gain, physical exercise and restriction of food intake are recommended; therefore, it is important to collaborate with a nutritionist or even an endocrinologist if hyperglycemia occurs. If weight gain is associated with edema, treatment of the edema should be managed first. Interruption or reduction of the lorlatinib dose is not usually needed. There are currently no data on the use of semaglutide or other incretins in the management of lorlatinib-induced weight gain [43].

4.3 Diarrhea, Nausea, Vomiting, and Constipation

The frequencies of diarrhea, nausea, vomiting, and constipation are shown in Table 1 [13,14,15]. The primary recommendation for all patients with grade 1–2 disease is to not modify the dose of lorlatinib. For patients with a disease grade ≥3, discontinuation of lorlatinib treatment is recommended until symptoms are resolved to grade ≤2 or baseline values. Treatment can be resumed at a reduced dose [13] (Fig. 6).

Fig. 6
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Recommendations for the management of diarrhea, nausea, vomiting, and constipation. 5-HT3 5-hydroxytryptamine

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During the onset of diarrhea and constipation, general measures such as diet adjustment and good hydration are suggested. Loperamide can be used for diarrhea, and lactulose can be used for constipation. Although it is not recommended to modify lorlatinib treatment for grade 2 diarrhea, sustained diarrhea (15–30 days) that interferes with daily life can be treated by reducing the lorlatinib dose.

For the treatment of nausea and vomiting, the recommendations offered by any oncology guide can be used [44, 45]. The recommended treatments for this level of emesis and for the next level include metoclopramide, domperidone, chlorpromazine or 5-HT3 inhibitors such as ondansetron, granisetron or dolasetron (Fig. 6) [44].

4.4 Amylase/Lipase Activity Increased

Increases in amylase and/or lipase levels were detected in patients receiving lorlatinib (Table 1). Patients should be monitored for increases in amylase and lipase levels prior to initiation of lorlatinib treatment and thereafter on a regular basis as clinically indicated [14]. If a grade 1–2 increase is detected, the same dose of lorlatinib can be administered at every clinical visit. If a grade 3–4 increase is observed, the main recommendation in clinical trials is to discontinue treatment until amylase/lipase levels return to baseline. Treatment with lorlatinib can be subsequently resumed at a lower dose (Fig. 7) [14]. However, since there is no evidence to support that amylase/lipase elevation leads to symptomatic pancreatitis later in patients with grade 3–4 disease, asymptomatic patients, or those without pancreatitis (according to clinical, radiological, and analytical diagnosis), modification of treatment should be left to the physician's discretion.

Fig. 7
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Recommendations for the management of alterations in amylase or lipase levels

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4.5 Interstitial Lung Disease/Pneumonitis

Interstitial lung disease, pulmonary opacity, and pneumonitis are rare AEs in patients treated with lorlatinib (Table 1). Neither a radiological pattern nor a temporal pattern of pneumonitis has been described for lorlatinib. There are no data available on the incidence of pneumonitis associated with lorlatinib according to the patient's ethnicity, previous local treatment (radiotherapy, surgery) or previous pulmonary comorbidities. Similarly, there is no evidence on the best radiological technique to be used or how often pneumonitis should be monitored.

For the diagnosis of pneumonitis, a clinical evaluation, imaging tests, and differential diagnosis are recommended, and bronchoscopy is recommended for ruling out other causes of lung damage, such as infection [14]. In clinical practice, biopsy is not usually performed routinely unless there are clinical doubts or unless an infectious process is ruled out. For patients in whom pneumonitis is detected, clinicians should check whether the patient has a history of pulmonary disease, has undergone previous radiotherapy or has received immunotherapy that could explain the development of pneumonitis. Figure 8 shows the main suggested interventions for the treatment and control of pneumonitis. If pneumonitis is caused by a previous treatment, the full dose of lorlatinib can be used [46]. However, patients should be monitored closely because cross-reactivity with other ALK-TKIs has been described [47].

Fig. 8
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Recommendations for the management of interstitial lung disease or pneumonitis. COPD chronic obstructive pulmonary disease, CT computerized tomography, ECOG Eastern Cooperative Oncology Group, ICU intensive care unit, IFN interferon, TNF tumor necrosis factor

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To monitor pneumonitis, clinical and radiological monitoring should be performed one week after initiating treatment with lorlatinib until lung toxicity is resolved. For grade 1 or 2 pneumonitis, clinical monitoring by imaging should be performed.

5 Pharmacological Interactions

As with any treatment, to preserve its efficacy while ensuring its safety, it is necessary to know which concurrent medication the patient is receiving or may receive, either for other diseases or as support to address AEs. Potential interactions between drugs used for the treatment of NSCLC and concomitant medication can be clinically relevant in some patients, decreasing its efficacy or increasing its toxicity [48].

To evaluate possible drug interactions, two aspects must be considered: the pathways by which the drugs are metabolized and the clearance periods. According to pharmacokinetic data, the main metabolic pathways of lorlatinib are oxidation and glucuronidation. In vitro data show that lorlatinib is metabolized primarily by CYP3A4 and UGT1A4, with minor contributions from CYP2C8, CYP2C19, CYP3A5, and UGT1A3 [13, 49]. This is important to keep in mind when administering treatments that involve the same pathway or interfere with inducers or inhibitors of the same pathway, as this could explain the occurrence of certain AEs. For example, drugs that are CYP3A4/5 inducers can decrease the plasma concentration of lorlatinib, thereby decreasing its efficacy. This would be the case with rifampicin, carbamazepine, enzalutamide, mitotane, phenytoin, and even St. John’s wort. For this reason, the use of the potent CYP3A4/5 inducer lorlatinib is contraindicated [13, 17, 50,51,52,53]. In addition, it has been reported that the use of potent CYP3A inducers with lorlatinib may increase the risk of severe hepatic toxicity [54].

On the other hand, CYP3A4/5 inhibitors increase the plasma concentration of lorlatinib and could increase its toxicity. This would be the case for some antivirals (boceprevir, ritonavir, and paritaprevir) and antifungals (itraconazole, ketoconazole, voriconazole, levoketoconazole, and fluconazole). Grapefruit products may also increase plasma concentrations of lorlatinib. The main recommendation is to avoid the use of CYP3A4/5 inhibitors or to seek an alternative, but if they are administered, it is recommended that the dose of lorlatinib be reduced [13, 17, 55, 56].

Lorlatinib may also interfere with the metabolism of other drugs by acting as an inhibitor or inducer. Lorlatinib is known to be a moderate inducer of CYP3A, which can result in a decreased concentration of drugs such as midazolam. Therefore, concomitant administration of lorlatinib with CYP3A4/5 substrates, especially those with narrow therapeutic indices, should be avoided [13, 17, 57]. Lorlatinib is also a weak inducer of CYP2B6, CYP2C9, UGT, and P-glycoprotein. In these cases, it is not necessary to modify the dose of drugs metabolized by these pathways, although those with a narrow therapeutic margin should be used with caution to avoid excessively increasing their concentration [13, 17].

Table 4 shows in detail various types of interactions and how to administer many of the drugs used in NSCLC patients treated with lorlatinib.

In addition to the metabolization pathway, the lorlatinib washout period should also be considered to avoid possible drug interactions. This washout period depends on the previous treatment, which is usually five times the elimination half-life of the previous drug. For example, when patients discontinue treatment with lorlatinib, which has a plasma half-life of 23.6 h, it is necessary to wait 5 days (i.e., the lorlatinib washout period) before starting any other treatment. It is very important to take into account this washout period when AEs have developed during the previous treatment [13]. On the other hand, if prior to using lorlatinib an inhibitor of its metabolism was being administered, it is suggested to discontinue this inhibitor at least 14 days (as a general safety period and specifically, it would be sufficient to wait for 5 half-lives of the inhibitor drug in question) before starting to use lorlatinib. However, this approach is not usually feasible in clinical practice, which could explain the greater toxicity of lorlatinib during the first days of treatment.

6 Renal or Hepatic Impairment

Although renal or hepatic impairments are not AEs associated with lorlatinib, they may result from treatment with lorlatinib. When renal function is normal or there is mild to moderate renal impairment (absolute estimated glomerular filtration rate [eGFR] ≥30 mL/min/1.73 m2), no dose adjustment of lorlatinib is necessary. However, if renal impairment is severe (absolute eGFR <30 mL/min/1.73 m2), the main recommendation is to use a reduced dose of lorlatinib; for example, an initial dose of 75 mg once daily orally. No information is available for patients requiring renal dialysis [13, 58]. In the case of mild hepatic impairment, no dose adjustment of lorlatinib is necessary, but since there is insufficient information in cases of moderate or severe hepatic impairment, treatment with lorlatinib is not recommended [13].

7 Conclusions

Lorlatinib has been shown to be an effective treatment, but because of its long-term use, it is very important to know how to manage all the possible AEs that may occur during its use to ensure its efficacy and the quality of life of patients. The main recommendation for the management of each of the AEs associated with lorlatinib is to follow the guidelines of the product data sheet. However, there are situations in which it is necessary to approach the management of AEs individually, such as having to reduce the dose of lorlatinib to avoid possible drug interactions with concomitant treatments or to prevent worsening of the patient’s quality of life even when the toxicity is grade 1–2. Similarly, more severe toxicities, that are laboratory findings with no symptomatology (e.g., amylase elevation grade ≥3), may not require discontinuation of treatment or may be left to physician’s discretion.

It is important to note that some AEs have little or questionable evidence. Therefore, both the detection and management of these AEs is necessary in the current clinical context of what is known, and other possible causes must be ruled out.

In addition to all the approaches described above, one of the most important strategies for managing AEs is patient education and direct communication with the patient and family members. It should be discussed with them that lorlatinib is associated with several AEs that are mostly mild and reversible and facilitate the contact with health care professionals to assess these in a timely manner. The ultimate goal is to offer the maximum benefit of lorlatinib for each patient.