Expert consensus of management of adverse drug reactions with anaplastic lymphoma kinase tyrosine kinase inhibitors

Abstract

Anaplastic lymphoma kinase (ALK) rearrangements occur in ∼3%-6% of patients with advanced non-small-cell lung cancer (NSCLC). Small molecular drugs that effectively inhibit ALK gene have revolutionized the therapeutic paradigm for patients with ALK rearrangements, resulting in significant improvements in objective response rate, progression-free survival, and overall survival compared with classical platinum-based chemotherapy. Several ALK tyrosine kinase inhibitors (ALK-TKIs), including crizotinib, alectinib, ceritinib, brigatinib, ensartinib, and lorlatinib, have been recommended as standard first-line treatment for advanced NSCLC patients with ALK rearrangements. Patients with ALK rearrangements typically exhibit long-term durable responses to ALK-TKIs; therefore, the management of adverse drug reactions (ADRs) with ALK-TKIs is crucial in clinical practice to maximize clinical benefits, prevent an adverse impact on quality of life, and improve patient compliance. In general, ALK-TKIs are well tolerated. There are, however, a number of serious toxicities that may necessitate dose modification or even discontinuation of treatment and the management of ADRs with ALK-TKIs has grown in importance. The therapeutic use of this class of medications still carries some risk because there are currently no pertinent guidelines or consensus recommendations for managing ADRs caused by ALK-TKIs in China. In order to improve the clinical management of ADRs with ALK-TKIs, the Chinese Society of Clinical Oncology (CSCO) Non-small Cell Lung Cancer Professional Committee led the discussion and summary of the incidence, diagnosis and grading standards, and prevention and treatment of ADRs caused by ALK-TKIs.

Highlights

• •Though ALK-TKIs are well tolerated, certain toxicities may necessitate dosage adjustments or treatment cessation.
• •The management of ADRs with ALK-TKIs has grown in importance.
• •The CSCO NSCLC Professional Committee led the expert consensus of management of ADRs with ALK-TKIs.
• •The current consensus can help in improving the clinical management of ADRs with ALK-TKIs.

Introduction

During the past two decades, the clinical management of non-small-cell lung cancer (NSCLC) has evolved dramatically with the development of targeted therapies, less invasive procedures, and personalized therapies.¹ Importantly, ∼3%-7% of NSCLC patients exhibit genetic alterations, namely the rearrangement of the anaplastic lymphoma kinase (ALK) gene that codes for the CD246 or ALK tyrosine kinase receptor.² Crizotinib, the first-generation ALK tyrosine kinase inhibitor (ALK-TKI), was approved for treating metastatic NSCLC patients with ALK rearrangements in 2011.^3,4 Subsequently, several next-generation ALK-TKIs, including alectinib,5, 6, 7 ceritinib,^8,9 brigatinib,^10,11 ensartinib,^12,13 and lorlatinib,¹⁴ have been developed to with activity against a wide spectrum of secondary resistance mutations affecting the ALK kinase domain and been demonstrated to be active in patients after failure on crizotinib. Now, these ALK-TKIs have been licensed and are administered as the first line of treatment for metastatic NSCLC patients with ALK rearrangements.15, 16, 17, 18, 19, 20, 21

Patients with ALK rearrangements typically exhibit long-term durable responses to ALK-TKIs, indicating that these patients might be at high risk of adverse drug reactions (ADRs). Thus, appropriate clinical management strategies are critical to maximize the clinical benefits, prevent an adverse impact on quality of life (QoL), and improve compliance. However, there are currently no pertinent guidelines or consensus recommendations for managing ADRs caused by ALK-TKIs in China. Since different ALK-TKIs have distinct profiles of ADRs (Table 1), the Chinese Society of Clinical Oncology (CSCO) of Non-Small Cell Lung Cancer Professional Committee has led the expert consensus of management of ADRs with China National Medical Products Administration (NMPA)-approved ALK-TKIs, based on prescribing information,22, 23, 24, 25, 26, 27 investigator’s brochure, the clinical and biomedical reports of these drugs, as well as the diagnosis and grading of ADRs in cancer patients, to improve the clinical management of ADRs with ALK-TKIs. Here, we present the final version of the consensus approved by the consensus conference panel of experts.

Table 1.

Summarized ADRs across pivotal first-line ALK-TKI clinical trials in NSCLC

Drug	Study	Dose	Common AEs (all grades) (%)	Common AEs (grade ≥3) (%)	AEs leading to dose modification (%)
Crizotinib	PROFILE 10143 (n = 171)	250 mg b.i.d.	Vision disorder (71) Diarrhea (61) Nausea (56) Edema (49) Vomiting (46)	Elevated aminotransferases (14) Neutropenia (11) Dyspnea (3) Fatigue (3)	Treatment discontinuation (12)
	PROFILE 10294 (n = 104)	250 mg b.i.d.	Elevated aminotransferases (69.2) Diarrhea (58.7) Vision disorder (55.8) Vomiting (52.9)	Neutropenia (16.3) Elevated aminotransferases (11.5) Leukopenia (2.9) Anemia (2.9)	Treatment discontinuation (18.3)
Ceritinib	ASCEND-415 (n = 189)	750 mg q.d.	Diarrhea (85) Nausea (69) Vomiting (66) Elevated ALT (60) Elevated AST (53)	Elevated ALT (31) Elevated GGT (29) Elevated AST (17) Diarrhea (5)	Dose adjustment or interruption (80)
	ASCEND-816 (n = 108)	450 mg q.d. with food	Diarrhea (57.4) Nausea (41.7) Elevated ALT (40.7) Vomiting (38.9) Elevated AST (35.2)	Elevated GGT (22.2) Elevated ALT (17.6) Elevated AST (7.4) Hyperglycemia (7.4)	Treatment discontinuation (9.1) Dose adjustment or interruption (31.8)
Alectinib	ALEX17 (n = 152)	600 mg b.i.d.	Anemia (20) Peripheral edema (17) Myalgia (16) Elevated blood bilirubin (15) Elevated ALT (15)	Anemia (5) Elevated ALT (5) Elevated AST (5) Elevated blood bilirubin (2)	Treatment discontinuation (11) Dose reduction (16) Dose interruption (19)
	ALESIA18 (n = 125)	600 mg b.i.d.	Elevated blood bilirubin (49) Elevated blood CK (44) Elevated ALT (42) Constipation (36)	Elevated CK (5) Weight gain (3) Elevated ALT (2) Elevated bilirubin conjugated (2)	Treatment discontinuation (7) Dose reduction (24) Dose interruption (26)
Ensartinib	eXalt319 (n = 143)	225 mg q.d.	Rash (67.8) Elevated ALT (48.3) Elevated AST (37.8) Pruritus (26.6) Nausea (22.4)	Rash (11.2) Elevated ALT (4.2) Pruritus (2.1)	Treatment discontinuation (9.1) Dose reduction (23.8)
Brigatinib	ALTA-1L20 (n = 136)	180 mg q.d. (90 mg for 7 days)	Diarrhea (49) Elevated blood CK (39) Nausea (26) Cough (25) Hypertension (23)	Elevated blood CK (16) Elevated lipase (13) Hypertension (10) Elevated amylase (5)	Treatment discontinuation (12) Dose reduction (29)
Lorlatinib	CROWN21 (n = 149)	100 mg q.d.	Hypercholesterolemia (70) Hypertriglyceridemia (64) Edema (55) Weight gain (38) Peripheral neuropathy (34) Cognitive effects (21)	Hypertriglyceridemia (20) Weight gain (17) Hypercholesterolemia (16) Hypertension (10)	Treatment discontinuation (7) Dose reduction (21) Dose interruption (49)

ADR, adverse drug reaction; AE, adverse event; ALK-TKI, anaplastic lymphoma kinase tyrosine kinase inhibitor; ALT, alanine transaminase; AST, aspartate transaminase; CK, creatine kinase; GGT, γ-glutamyltransferase; NSCLC, non-small-cell lung cancer.

Summary of Approved ALK-TKIs

Crizotinib is a broad-spectrum TKI that was initially developed as a MET inhibitor but can also act as a potent inhibitor for the ALK/ROS1 oncogene.²⁸ It is the first ALK-TKI that showed dramatically improved clinical benefits over chemotherapy as first-line therapy in ALK-rearranged NSCLC patients.³ The most common crizotinib-associated ADRs included vision disorder (71%), diarrhea (61%), and nausea (56%).

Alectinib is a potent, highly selective, second-generation ALK-TKI that can effectively penetrate the central nervous system (CNS). In the ALEX study, the median progression-free survival (PFS) was 34.8 months for the alectinib group versus 10.9 months for the crizotinib group [hazard ratio (HR) = 0.43].²⁹ Median overall survival was not reached with alectinib versus 57 months with crizotinib (stratified HR = 0.67). In line with the ALEX study, the ALESIA study has further confirmed the clinical benefits of alectinib as the first line of treatment in ALK-rearranged NSCLC patients from China, South Korea, and Thailand (median PFS was 41.6 months for alectinib versus 11.1 months for crizotinib, HR = 0.33).^18,30 The most common alectinib-associated ADRs included increased blood bilirubin (49%), increased blood creatine phosphokinase (44%), and increased alanine aminotransferase (ALT) (42%) in the ALESIA study.¹⁸

Brigatinib is a next-generation ALK-TKI that targets a broad range of ALK mutations¹⁰ and has demonstrated superior efficacy over crizotinib in the first-line treatment of ALK-rearranged NSCLC.²⁰ In the ALTA-1L study, median PFS was 24.0 months for brigatinib versus 11.1 months for crizotinib (HR = 0.48).^20,31 Notably, 4% of patients in the brigatinib group and 2% in the crizotinib group reportedly suffered from interstitial lung disease (ILD)/pneumonitis. Grade 3 or 4 ILD/pneumonitis occurred in 3% of patients in the brigatinib group and 0.7% in the crizotinib group, respectively. Importantly, brigatinib-associated ILD/pneumonitis could be ameliorated by a step-up dosing strategy (90 mg once daily for 7 days; if tolerated, then increased to 180 mg once daily).

Ceritinib is a next-generation ALK-TKI that is more potent than chemotherapy. In the ASCEND-4 study, patients assigned to the ceritinib (750 mg/day) group experienced improved PFS (16.6 versus 8.1 months, HR = 0.55), objective response rate (72.5% versus 26.7%), and duration of response (23.9 versus 11.1 months) compared with those assigned to the platinum-based chemotherapy group.¹⁵ The most frequently reported ceritinib-associated ADRs included diarrhea (85%), nausea (69%), vomiting (66%), and increased ALT (60%).¹⁵

Ensartinib is another next-generation ALK-TKI that potently and selectively inhibits ALK activity.³² In the eXalt3 study, among 290 patients with ALK-rearranged NSCLC, patients assigned to the ensartinib group experienced a significant improvement in median PFS relative to those assigned to the crizotinib group (25.8 versus 12.7 months, HR = 0.51).¹⁹ The most common ensartinib-associated ADRs included rash (67.8%), increased ALT (48.3%), and increased aspartate aminotransferase (AST) (37.8%).

Lorlatinib is a third-generation ALK-TKI with a broad-spectrum activity against identified ALK resistance mutations. In the CROWN study, the median PFS for lorlatinib was not evaluable and was 9.3 months for crizotinib (HR = 0.28 by blinded independent central review).²¹ Grade 3-4 ADRs were found in 72% of lorlatinib-treated patients compared to 56% of crizotinib-treated patients.²¹ The most common lorlatinib-associated ADRs included hypercholesterolemia (70%), hypertriglyceridemia (64%), and edema (55%). Notably, cognitive effects and mood effects were observed in 21% and 16% of lorlatinib-treated patients, respectively.

To date, crizotinib, alectinib, ceritinib, brigatinib, and lorlatinib have been approved by the United States Food and Drug Administration, European Medicines Agency, and China NMPA, and ensartinib has only been approved by China NMPA for the first-line treatment of metastatic NSCLC patients with ALK rearrangements.

Summary of ADRs Associated With ALK-TKIs

Despite the fact that ALK-TKIs are generally well tolerated, there are a number of serious toxicities that may necessitate dosage adjustment or even treatment cessation (Table 1). Recent research has revealed that the most typical ADRs for almost all ALK-TKIs include gastrointestinal disturbances and drug-induced liver injury (DILI). Nevertheless, certain TKIs can also cause additional and distinct ADRs, including visual impairment, sinus bradycardia, and neurologic toxicity. As a result, an important aspect of ALK-TKI therapy is to devise ADR management measures toward preventing a negative impact on QoL and improving compliance. The therapeutic use of these ALK-TKIs is still under potential risk due to the absence of relevant or standard guidelines for the management of ADRs with ALK-TKIs in China. The management of ALK-TKI-related ADRs could thus be unified and standardized with the help of professional guidance obtained through evidence-based practice and clinical experiences.

Management of ALK-TKI-Associated ADRs

Gastrointestinal ADRs

Gastrointestinal (GI) ADRs, including diarrhea, constipation, nausea, and vomiting, are the most common ADRs with ALK-TKIs.

Diarrhea

Incidence

Diarrhea is a common ADR but can rarely be severe. Patients who received ceritinib, crizotinib, or brigatinib are at high risk of diarrhea (Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2023.101560).

Evaluation and grading

The National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0) grading system is frequently used to describe the severity of diarrhea.³³ Severity is determined by an increase in the number of stools per day or ostomy output compared with baseline, the need for hospitalization, and the effect on activities of self-care. It is critical to ascertain the patient’s baseline bowel pattern when grading the severity of diarrhea (Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2023.101560).

Treatment and prevention

Treatment for diarrhea includes nonpharmacological and pharmacological interventions, regular monitoring of treatment outcomes, and identification of any secondary complications that may require specialized care or hospitalization. Initial management depends on the severity of diarrhea and the assessment of any additional risk factors.

In this regard, the application of epidermal growth factor receptor TKI (EGFR-TKI) can be referred to for the prevention and management of diarrhea (Table 2). It is crucial to collect the patients’ bowel habits and amounts for 6 weeks before initiating ALK-TKI therapy, which can be helpful in assessing the possible diarrhea. Before initiating ALK-TKI therapy, information on the patients’ concurrent medicines and other clinical conditions should also be gathered. In addition, drug interactions might have adverse effects on the digestive system. Patients receiving ALK-TKIs are generally recommended to follow a low-fat, low-fiber diet and avoid intake of caffeine, alcohol, dairy products, fat, fiber, orange juice, grape juice, and spicy foods. It is also advised that patients spread out their meals into several small meals throughout the course of treatment and refrain from using laxatives unless indicated. For patients who received ceritinib treatment, 450 mg with food was recommended as the incidence and severity of GI-ADRs were reduced in a dose optimization study (ASCEND-8).¹⁶

Table 2.

Management of diarrhea

Severity	Management	Treatment
Grade 1-2	(1) Observe closely to avoid dehydration; stop stool softeners and drink isotonic fluid (1 l/day) (2) Change diet (avoid dairy products, light diet, eating multiple small meals) (3) Persistent grade 2 diarrhea (>48 h): evaluate whether there is dehydration or electrolyte imbalance, and consider giving infusion, drinking 1-1.5 l per day of isotonic fluid	(1) Continue treatment with the same dose (2) Use loperamide, probiotics, and Smecta. Loperamide starts from 4 mg (2 tablets), after which, take 2 mg (1 tablet) after each diarrhea or every 4 h (maximum dose 16 mg/day) until diarrhea ceases for 12 h (3) For grade 2 diarrhea lasting >48 h, the drug will be discontinued and treatment with loperamide (maximum dose 16 mg/day), probiotics, and Smecta, plus codeine (30 mg, b.i.d.) will continue until relieved to grade ≤1, reduce the initial dose of ALK-TKIs and restart treatment at a lower dose
Grade 3-4	(1) Patients were hospitalized for surveillance, and stool samples were collected for microscopic examination (2) Drink 1-1.5 l per day of isotonic fluid, and actively give intravenous fluids to supplement it for at least 24 h	(1) Suspend the use of ALK-TKIs until relieved to grade ≤1, reduce the initial dose of ALK-TKIs, and restart the treatment at a lower dose (2) Use loperamide (maximum dose 16 mg/day) (3) Continue treatment with probiotics and Smecta, plus codeine (30 mg b.i.d.); consider prophylactic antibiotic therapy if the patient has an increased proportion of leukocyte and neutrophil: (i) in severe cases, somatostatin may be added; (ii) diarrhea did not relieve to grade ≤1 within 14 days after treatment, the best supportive therapy should be given and ALK-TKIs should be discontinued

ALK-TKI, anaplastic lymphoma kinase tyrosine kinase inhibitor.

Nausea and vomiting

Incidence

Nausea and vomiting symptoms are most common on crizotinib and ceritinib therapy and can lead to serious conditions in ceritinib-treated patients (5% of grade ≥3) in the ASCEND-4 study¹⁵ (Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2023.101560).

Evaluation and grading

The severity of nausea and vomiting is usually described using the NCI-CTCAE grades³³ (Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2023.101560).

Treatment and prevention

It is suggested that individualized prevention and treatment plan should be formulated according to the vomiting risks of the indicated anticancer treatment, the patient’s high-risk factors, and a history of the severity of nausea and vomiting in the past. Also, while prescribing antiemetic regimens, the potential of nausea and vomiting from medication interactions with any concomitant non-anticancer therapy, such as opioid analgesics, should be carefully taken into account. Additional practical considerations include the background at the time of treatment (inpatient or outpatient), the preferred route of administration (oral, percutaneous, or parenteral), the duration and interval of 5-hydroxytryptamine 3 receptor antagonists, the patient’s tolerance, compliance, and other issues with daily antiemetic medications (such as glucocorticoids), and individual risk factors. For grade 1-2 nausea, it is recommended to maintain the dosage and adjust the antiemetic regimen according to the symptomatic manifestation. For grade 1 vomiting, the drug dosage should be maintained and can be adjusted as per the patient’s response to treatment, while for grade 2 vomiting, the drug should be discontinued until the ADR condition improved to grade ≤1, and then the dose can be restarted. For persistent grade >2 vomiting, the drug should be stopped until the symptoms are relieved to grade ≤1, and then the drug should be resumed at a reduced dose level. Likewise, for grade 3-4 nausea and/or vomiting conditions, a similar treatment course should be followed as for grade 2.

Constipation

Incidence

Constipation is defined as a decreased frequency of defecation (usually less than three bowel movements per week) accompanied by stomach discomfort or difficulty with bowel excretion. Patients who received ensartinib, crizotinib, or alectinib are at high risk of constipation (Supplementary Table S5, available at https://doi.org/10.1016/j.esmoop.2023.101560).

Evaluation and grading

Constipation can cause nausea, vomiting, hemorrhoids, anal fissures, bowel obstruction, and urinary retention in addition to having a significant detrimental impact on QoL. The severity of constipation is often evaluated using the NCI-CTCAE grades³³ (Supplementary Table S6, available at https://doi.org/10.1016/j.esmoop.2023.101560).

Treatment and prevention

Anticipation and prevention are the first steps in the treatment of constipation. If there is no additional relationship with any underlying illnesses, increasing fluid intake, changing to a diet high in fiber, and exercising regularly can usually be enough to relieve the symptoms. When constipation initially appears, laxatives can be used; furthermore, it should be routinely prescribed for patients using opioid analgesics or antiemetic drugs. The most frequently used laxatives in patients with advanced cancer include osmotic agents (such as polyethylene glycol and lactulose) and stimulant laxatives.³⁴ Polyethylene glycol is recommended as the initial laxative option for patients with advanced cancer based on evidence in the general population, expert opinion, and clinical experience.³⁵ Nonabsorbable soluble dietary fiber or bulk agents should be avoided in patients with low fluid intake due to increased risk of mechanical bowel obstruction.³⁶

Pulmonary toxicity

Incidence

Severe, life-threatening, or fatal treatment-related pneumonitis has been reported in 0.88%-1.87% of NSCLC patients treated with either crizotinib or ceritinib.³⁷ However, brigatinib treatment poses an even higher incidence rate of ILD (4.11% of all-grade pneumonitis),³⁷ while alectinib is associated with a 0.08% incidence of ILD/pneumonitis in grade 3-4 without any fatal cases.³⁷ Notably, an unusual early-onset pulmonary event (respiratory symptoms after one to two doses, accompanied by the development of ground-glass opacities on chest imaging) can be observed in brigatinib-treated patients, but related ADRs can be relieved by a step-up dosing strategy. In a phase I/II trial, with higher starting doses, the incidence of early-onset pulmonary events rose, from 2% (1/50) at 90 mg once daily to 14% (6/44) at 180 mg once daily. Notably, no early-onset pulmonary events were observed among patients who received the 180-mg once-daily regimen with a 7-day lead-in at 90 mg.¹⁰ Severe or life-threatening ILD/pneumonitis has occurred in <1% of patients treated with lorlatinib in clinical trials.¹⁴

Evaluation and grading

The clinical presentation of TKI-induced ILD is variable, and several clinical symptoms have been described in relation to TKIs.³⁸ Most clinical trials have reported pulmonary toxicity based on the clinical and/or radiographic criteria (e.g. acute lung injury, pneumonitis, noncardiogenic pulmonary edema, acute respiratory distress syndrome), as well as pathological findings, such as diffused alveolar damage, pneumonia, and neutrophilic alveolitis. The diagnosis for TKI-induced pulmonary toxicity is usually made on the basis of a compatible clinical pattern, a drug that is a known or suspected culprit, and the exclusion of infection or pulmonary involvement from the underlying malignancy. Laboratory tests (e.g. complete cell counting, coagulation tests, serum B-type natriuretic peptide level, blood cultures, sputum cultures, viral serology) are employed to determine whether other disease processes are contributing to the patient’s respiratory distress. Pulmonary function tests are more important in assessing the severity of pulmonary impairment than in making a specific diagnosis. Radiographic examinations are rarely specific enough to confirm the diagnosis but are useful for evaluating the disease severity and ruling out other suspected pathologies (e.g. pulmonary embolism). The severity of pulmonary toxicity is described using the NCI-CTCAE grades³³ (Supplementary Table S7, available at https://doi.org/10.1016/j.esmoop.2023.101560).

Treatment and prevention

The immediate key components of TKI-induced pulmonary injury management include drug discontinuation, glucocorticoid therapy, and supportive care. The therapeutic goals of ILD include inhibiting inflammatory responses, promoting exudation and absorption, preventing pulmonary interstitial fibrosis, and protecting normal cardiopulmonary functions. The first-line treatment methods include oxygen therapy, mechanical ventilation, glucocorticoids, empirical anti-infective therapy, and timely assessment of the patient’s health condition. For treatment-related ILD/pneumonitis of any severity, permanent discontinuation of ALK-TKIs is generally recommended. Notably, for patients who received brigatinib treatment, if the patients had grade 3-4 ILD/pneumonitis or recurred grade 1-2 ILD/pneumonitis, permanent discontinuation of brigatinib is recommended.

For specific treatment measures, refer to the management of EGFR-TKI-related ILD: (i) ALK-TKIs should be discontinued immediately once ILD is clinically suspected or diagnosed; concurrent medications that can cause or aggravate ILD (such as bleomycin and amiodarone) should also be taken with extreme caution; (ii) for a confirmed or highly suspected ILD, glucocorticoid treatment should be started immediately. Calcium and vitamin D supplements, blood sugar monitoring, and gastrointestinal bleeding prevention should all be taken into consideration. (1) Grade 1: closely monitor symptoms, signs, and carry out hematological examinations. Once worsened, for treatment refer to grade 2-4; (2) grade 2: start with methylprednisolone at 0.5-1.0 mg/kg/day or equivalent drugs for 2-4 weeks, then gradually reduce the dose after symptoms and signs are relieved, and the total course of treatment should last at least for 6 weeks; (3) grade 3: start with methylprednisolone at 1.0-2.0 mg/kg/day or equivalent drugs for 2-4 weeks, and then gradually reduce the dose after symptoms and signs recover, and the total course of treatment should last at least for 8 weeks; (4) grade 4: pulse therapy should be started along with methylprednisolone at 500-1000 mg/day, and then after 3 days, a maintenance dose of 1-2 mg/kg/day of methylprednisolone should be administered for 2-4 weeks, and then gradually reduce the dose after symptoms and signs are improved, and the total course of treatment should last at least for 8-10 weeks; (iii) empirical anti-infective therapy (select sensitive anti-infective drugs as needed or based on the results of microbiological examinations); (iv) oxygen therapy is recommended to chronic obstructive pulmonary diseases, and ILD patients with resting hypoxemia [arterial partial pressure of oxygen (PaO₂) ≤55 mmHg or blood oxygen saturation (SaO₂) ≤88%] are recommended to receive long-term oxygen therapy for at least 15 h per day; and (v) during the respiratory failure, mechanical ventilation should be immediately implemented for adjustment.

Cardiac toxicity

Incidence

Patients with NSCLC receiving ALK-TKIs frequently experience sinus bradycardia, and in some cases, it can be fatal and life-threatening. Patients who received alectinib, crizotinib, and brigatinib are at high risk of bradycardia.^18,22,31 It is generally asymptomatic and not associated with other events such as arrhythmias. In 42 NSCLC patients receiving crizotinib, there was an average decrease of 26.1 beats per minute (bpm) among all patients, while 69% of patients had at least one episode of sinus bradycardia (heart rate <60 bpm).³⁹ Profound sinus bradycardia (heart rate <50 bpm) developed in 13 (31%) patients. Interestingly, none of these patients were either symptomatic or had electrocardiographic changes such as QTc interval prolongation during the treatment.²³

The incidence of bradycardia induced by other ALK-TKIs, including ceritinib, ensartinib, and lorlatinib, is low. In 255 NSCLC patients receiving ceritinib, profound bradycardia (heart rate <50 bpm) has been reported in only 1% of cases. In addition to bradycardia, QTc interval prolongation has also been observed, although it is uncommon. Consistently, 3% of these patients have experienced a QTc interval increase over a baseline of 60 ms;⁴⁰ in another larger cohort of 304 patients receiving ceritinib, only 1 (<1%) patient developed a QTc interval of >500 ms.⁴¹

Evaluation and grading

The severity of cardiac toxicity is usually evaluated using the NCI-CTCAE grades³³ (Supplementary Table S8, available at https://doi.org/10.1016/j.esmoop.2023.101560).

Treatment and prevention

Since some patients may have a history of cardiac dysfunctions and/or hypertension at the baseline, the risk of ALK-TKI treatment in these patients should be carefully evaluated before initiating treatment. Extra attention should be given if formularizing for a pharmacological combination therapy, which may bear an even higher risk of inducing QTc interval prolongation. For patients with a history of QTc prolongation or bradycardia, ALK-TKIs should be used cautiously and electrocardiography (ECG) readouts should be monitored and interpreted carefully. Also, it should be highlighted that any patient who exhibits drug-induced GI-ADRs, such as vomiting, diarrhea, or renal damage, needs close attention because an electrolyte imbalance could further aggravate the risk of QTc prolongation. ECG monitoring should be considered in patients with a history of cardiac disease and/or those with a higher risk of QTc interval prolongation due to existing medications (Table 3). Generally, dose modification is not required in cases of asymptomatic bradycardia. In cases of symptomatic bradycardia that is not life-threatening, withhold ALK-TKIs until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above and evaluate concomitant medications known to cause bradycardia, as well as antihypertensive medications. If attributable to a concomitant medication, resume ALK-TKIs at a reduced dose upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring as clinically indicated. Permanently discontinue ALK-TKIs in case of recurrence and in cases of life-threatening bradycardia if no contributing concomitant medication is identified.

Table 3.

Treatment of adverse cardiac reaction

Severity	Treatment
Grade 1	No need to treat.
Grade 2	Firstly, evaluate whether there is a known combination of bradycardia and antihypertensive drugs. If a combination drug causing bradycardia is found, the drug dose should be adjusted or the drug should be discontinued, and the previous dose of ALK-TKIs should be restarted until recovery to asymptomatic bradycardia or heart rate ≥60 bpm; if no combination drug causing bradycardia is found, or if the combined drug dose causing bradycardia cannot be discontinued or adjusted, ALK-TKIs will be reduced until recovery to asymptomatic bradycardia or heart rate ≥60 bpm.
Grade 3	The drug should be discontinued until recovery to asymptomatic bradycardia or heart rate ≥60 bpm. If the combination drug can be adjusted or discontinued, it is recommended to reduce the dose of ALK-TKIs and restart the treatment with regular monitoring.
Grade 4	Permanently discontinue.

ALK-TKI, anaplastic lymphoma kinase tyrosine kinase inhibitor; bpm, beats per minute.

Hepatotoxicity

Incidence

Hepatotoxicity has been reported frequently as a serious class-related safety issue for ALK-TKIs and patients who received ceritinib, crizotinib, and ensartinib are at high risk of hepatotoxicity (Supplementary Table S9, available at https://doi.org/10.1016/j.esmoop.2023.101560). Concurrently, hepatotoxicity is the leading cause of drug withdrawal in clinical practice.⁴² Crizotinib, lorlatinib, and ceritinib are metabolized by cytochrome P-450 3A4 (CYP3A4). Thus, caution should be taken when these agents are given concomitantly with CYP3A4 inhibitors, and care is required when these agents are administered with other agents that are predominantly metabolized by this system.

Evaluation and grading

The clinical presentation of DILI can range from asymptomatic biochemical abnormalities to an acute illness with jaundice. The severity of DILI is assessed by measuring the levels of γ-glutamyl transpeptidase, AST, ALT, bilirubin, and alkaline phosphatase (ALP). The degree of hepatocellular damage is often indicated by an elevated AST/ALT ratio, whereas cholestasis is typically shown by an increase in bilirubin and ALP levels. The severity of DILI is usually described using the NCI-CTCAE grades³³ (Supplementary Table S10, available at https://doi.org/10.1016/j.esmoop.2023.101560).

Treatment and prevention

Since the overall incidence rate of grade 3-4 DILI is <30%, the actual progression to severe DILI is relatively uncommon. As a result, liver enzyme elevation may not be considered an indication for immediate treatment discontinuation in most cases. However, attention must be increased when the level of total bilirubin is excessively elevated, since continued medication therapy could result in chronic liver failure. The dosage adjustment for different ALK-TKIs can be recommended by referring to the drug instructions (Table 4). Additionally, it has been reported that TKIs can activate viral replication in cancer patients accompanied by viral hepatitis, such as hepatitis B virus (HBV) or hepatitis C virus,⁴³ by a yet unknown mechanism, which may be related to the off-target interaction of TKIs with viral factors. Therefore, for patients treated with ALK-TKIs, there may be a potentially increased risk of clinically significant HBV activation during the treatment. Nowadays, for surface antigen of HBV (HBsAg)-positive, anti-HBsAg-negative/anti-hepatitis B core (anti-HBc)-positive patients, HBV DNA level testing should be carried out before initiating ALK-TKI treatment. Antiviral prophylactic therapy may be considered for cancer patients with elevated HBV DNA levels. For patients with known HBV infection, it is recommended to carry out routine liver enzyme tests every 4 weeks, and HBV viral loads before and after ALK-TKI treatment every 3 months or whenever abnormal liver enzyme occurs. Once the HBV DNA level rises, antiviral therapy should be considered.

Table 4.

Treatment of liver injury

Therapeutic measure	Details of treatment
Discontinuation	(1) Timely discontinuation of suspected liver injury drugs is the most important treatment measure, and the re-use of suspected or similar drugs should be avoided as much as possible. (2) If one of the following situations occurs, it is recommended to consider discontinuation of the drug: (i) serum ALT or AST >8 × ULN; (ii) ALT or AST >5 × ULN for 2 weeks; (iii) ALT or AST >3 × ULN, and TBil >2 × ULN or INR >1.5; (iv) ALT or AST >3 × ULN, with progressive fatigue, nausea, vomiting, right upper abdominal pain or tenderness, fever, rash, and/or eosinophilia (>5%).
Medical treatment	(1) N-acetyl-cysteine can be used in severe adult patients, and the earlier the clinical application, the better the effect. General usage for adults: 50-150 mg/kg/day, the total course of treatment should not be <3 days. (2) Glucocorticoids should only be used in patients with obvious signs of hypersensitivity or autoimmune reactions and no significant improvement or worsening of biochemical indicators after discontinuation of ALK-TKIs, and the benefits of treatment and possible adverse reactions should be fully weighed. (3) Magnesium isoglycyrrhizinate can be used to treat acute hepatocyte type or mixed type liver injury with significantly elevated ALT. (4) Experience has shown that for mild-to-moderate hepatocellular injury type and mixed type DILI, bicyclol and glycyrrhizic acid preparations can be tried in those with severe inflammation; silymarin can be tried in those with milder inflammation. For cholestatic DILI, ursodeoxycholic acid can be used. It has been reported that S-adenosylmethionine is effective in the treatment of cholestatic DILI. The exact efficacy of the above drugs needs to be confirmed by rigorous prospective randomized controlled studies.
Liver transplantation	Liver transplantation may be considered for hepatic encephalopathy and acute/subacute liver failure with severe coagulopathy and decompensated cirrhosis.

ALK-TKI, anaplastic lymphoma kinase tyrosine kinase inhibitor; ALT, alanine transaminase; AST, aspartate transaminase; DILI, drug-induced liver injury; GGT, γ-glutamyltransferase; INR, international normalized ratio; TBil, total bilirubin; ULN, upper limit of normal.

Anemia

Incidence

Anemia is defined as a reduction in one or more of the major red blood cell (RBC) measurements obtained as a part of the complete blood count: hemoglobin (Hb) concentration, hematocrit, or RBC count. A low Hb concentration and/or low hematocrit are the parameters most widely used to diagnose anemia in clinical trials for ALK-TKIs and patients who received ensartinib, crizotinib, and alectinib are at high risk of anemia (Supplementary Table S11, available at https://doi.org/10.1016/j.esmoop.2023.101560). Notably, hemolytic anemia is rare but has been reported with alectinib,^24,44 including cases associated with a negative direct antiglobulin test result.

Evaluation and grading

The severity of anemia is usually described using the NCI-CTCAE grades³³ (Supplementary Table S12, available at https://doi.org/10.1016/j.esmoop.2023.101560).

Treatment and prevention

Iron supplements, erythropoietin therapy, and blood transfusions are the mainstays of anemia treatment. For detailed treatment measures, refer to the treatment of anemia in Table 5. Recent studies reveal that alectinib may include ubiquitous acanthocytosis and subclinical hemolysis though most patients do not suffer significant hemolytic anemia.^45,46 Abnormal erythrocyte morphology, increased reticulocytes, and decreased eosin-5-maleimide binding are helpful for the diagnosis of alectinib-induced hemolysis.⁴⁶ Withhold alectinib and initiate appropriate laboratory testing if hemolytic anemia is suspected. If hemolytic anemia is confirmed, it is recommended to resume alectinib at a reduced dose upon resolution or permanently discontinue it and switching to alternative ALK-TKI is also an option.⁴⁷

Table 5.

Treatment of anemia

Therapeutic measure	Details of treatment
Blood transfusion	Hemoglobin <60 g/l, if: (i) symptomless, no obvious complication: regular re-evaluation; (ii) symptomless, but with complication (heart disease including transfusion-related circulatory overload and coronary heart disease, pulmonary heart disease, cerebrovascular disease) or high risk (recent chemotherapy or radiotherapy accompanied by rapid decline in hemoglobin): consider transfusion of red blood cells; (iii) with symptoms (persistent tachycardia, tachypnea, chest pain, exercise-induced dyspnea, mild headache, syncope, moderate fatigue affecting work and routine activities): transfusion of red blood cells.
EPO treatment	EPO 150 U/kg or 10 kU 3 times a week, or 36 kU once a week, subcutaneous injection, 1 course of treatment for 4-6 weeks. In any case, hemoglobin ≥120 g/l, discontinue EPO.
Iron supplement	Oral iron supplementation: Advantages: easy to use. Disadvantages: only ∼10% is absorbed by the human body after taking it, and the symptoms of gastrointestinal irritation are relatively serious. Some patients are allergic to it. Oral iron supplementation include ferrous sulfate (commonly used), ferrous fumarate (commonly used), ferrous gluconate, ferrous succinate, and ferrous lactate. Parenteral iron supplementation: Advantages: it can be completely absorbed by the human body, has a rapid onset of action, and has no symptoms of gastrointestinal irritation. Disadvantage: requires injection. Parenteral iron supplementations include iron dextran, iron gluconate, and iron sucrose. Considering the tolerability and pharmacokinetics of patient, iron sucrose is recommended for iron deficiency treatment in patients who are intolerant or unresponsive to oral iron, and can also be used in cancer patients receiving EPO treatment. Iron dextran: test doses should be used first, especially in patients with previous allergies to other drugs. The recommended iron dextran is low-molecular-weight iron dextran.

EPO, erythropoietin.

Hypercholesterolemia

Incidence

Hypercholesterolemia is the most frequently occurring toxicity associated with lorlatinib treatment. In the CROWN study, hypercholesterolemia was reported in 70% (16% for grade ≥3) and hypertriglyceridemia in 64% (20% for grade ≥3) of patients who received lorlatinib treatment.²¹

Evaluation and grading

The severity of hypercholesterolemia assessing the level of serum cholesterol is described using the NCI-CTCAE grades³³ (Supplementary Table S13, available at https://doi.org/10.1016/j.esmoop.2023.101560).

Treatment and prevention

β-Hydroxy β-methylglutaryl-CoA reductase inhibitor therapy is advised, with pravastatin or rosuvastatin being the preferable drugs. Fibrates, not gemfibrozil, should be used to treat hypertriglyceridemia.⁴⁸ If the patients have grade 4 hypercholesterolemia or hypertriglyceridemia, withhold lorlatinib until hypercholesterolemia and/or hypertriglyceridemia recover to grade ≤2. Resume lorlatinib at the same dose. If severe hypercholesterolemia and/or hypertriglyceridemia recurs, resume lorlatinib at a reduced dose.

Visual toxicity

Incidence

Visual disturbances have been reported in up to 65% of patients treated with crizotinib in phase II studies.⁴⁹ The main complaints include photopsia, flashes, and brief image persistence, which are mostly related to the transition from dark to light.⁵⁰ Uncommon visual manifestations, including photophobia, decreased visual acuity, and blurred vision, have also been noticed. Optic neuropathy and blindness have been reported, although they may have been related to prior whole-brain radiation therapy.⁵¹ Across all clinical trials, the incidence of grade 4 visual field defect with vision loss was 0.2% (4 of 1719) in patients treated with crizotinib.²² The onset of visual disturbances typically begins in the first week of crizotinib therapy. Symptoms tend to recur daily, lasting up to 1 min, and generally have little to no impact on daily activity. Similar symptoms have also been reported with other ALK-TKIs, but the overall incidence rate of all grades of visual disturbances is <15%.

Evaluation and grading

Visual disturbances include blurred vision, diplopia, reduced visual acuity, vision impairment, presbyopia, vitreous floaters, photophobia, photopsia, and asthenopia. The severity of visual disturbances assessing the level of serum cholesterol is described using the NCI-CTCAE grades.³³

Treatment and prevention

Advise patients to report any visual symptoms. Withhold ALK-TKIs and obtain an ophthalmologic evaluation in patients with new or deteriorating visual symptoms of grade 2 or greater severity. Upon recovery of grade 2 or 3 visual disturbances to grade 1 severity or baseline, resume ALK-TKIs at a reduced dose. Permanently discontinue treatment with ALK-TKIs for grade 4 visual disturbances. Treatment discontinuation is typically unnecessary because symptoms frequently get better as therapy continues.⁴⁹ If visual impairments persist or deteriorate, visual function and/or neurological evaluation should also be considered to rule out retinopathy caused by other reasons, like optic neuropathy and CNS diseases.

Neurologic toxicity

Approximately 40% of NSCLC patients receiving lorlatinib therapy experience CNS-related impairments.¹⁴ The CNS ADRs include changes in cognitive function (e.g. forgetfulness or difficulties with multitasking), mood disturbances (e.g. mood lability and/or irritability), and speech disturbances (e.g. word-finding difficulties or slowing of speech). In the CROWN study, 21% of patients treated with lorlatinib experienced cognitive impairments, and 16% had mood-related disorders.²¹ In the later-line treatment of lorlatinib, it is reported that 54% of patients have experienced at least one of the following CNS effects: (i) seizures; (ii) hallucinations; (iii) changes in cognitive functions; (iv) mood alterations (including suicidal ideation); (v) speech alterations; (vi) mental status changes; or (vii) sleep-related adverse effects.⁵² For grade 1 CNS effects, continue at the same dose or withhold the dose until recovery to baseline. Resume lorlatinib at the same dose or at a reduced dose. For grade 2 or 3 CNS effects, withhold dose until grade 0 or 1. Resume lorlatinib at a reduced dose. For grade 4 CNS effects, permanently discontinue lorlatinib.⁴⁸

Endocrine toxicity

Endocrinal complications have been observed during crizotinib therapy, including rapid depression in serum testosterone level. In 32 patients treated with crizotinib, the mean serum testosterone level that was below the lower limit of the normal level was found in 84% (27/32) of patients compared with 32% (6/19) of patients not receiving crizotinib.⁵³ Furthermore reduced levels of luteinizing hormone and follicle-stimulating hormone point to a general regulation of the endocrine system brought on by crizotinib therapy. A large component of the lowered total testosterone level may be due to a significant depression of sex hormone-binding globulin. Male patients with symptoms of hypogonadism can be referred to endocrinologists to discuss potential testosterone replacement therapy.

Other toxicities

Renal cysts Renal cysts have been reported in 4% of NSCLC patients on crizotinib therapy.³ Although the natural course of crizotinib-associated renal cysts is not entirely understood, one report found that complex renal cysts regress when treatment with crizotinib is discontinued.⁵⁴

Hypersensitivity reaction Hypersensitivity reactions have been described in two patients treated with crizotinib, manifested by a generalized rash developing hours after the administration of oral dosing.³ Desensitization was accomplished with escalating doses of crizotinib given every 15 min over the course of 3 h, preceded by a 1-h interval in which single doses of loratadine (10 mg), cetirizine (10 mg), and fexofenadine were provided (180 mg). There were no more symptoms after desensitization, which pointed to a chronic hypersensitivity reaction.

Photosensitivity reaction Brigatinib has been associated with photosensitivity reactions. In the ALTA-1L study, photosensitivity occurred in 3.7% of patients receiving brigatinib, with 0.7% being grade 3 or 4.²⁰ In addition, the adverse reaction of photosensitivity was also reported in patients receiving ceritinib or alectinib therapy. Patients are advised to limit their sun exposure, wear a hat, use sun-protective clothing, and use broad-spectrum sunscreens [UVA/UVB sunscreens and lip balm (SPF ≥50)] while taking these drugs. Depending on the severity of the reaction, treatment may need to be interrupted, modified, or discontinued.

Musculoskeletal toxicity Alectinib can cause myalgias, including muscle pain, tenderness, or weakness, particularly in the first month of treatment. In the ALEX study, myalgia (including musculoskeletal pain) was reported in 24/152 (16%) patients receiving alectinib.¹⁷ Most cases were mild or moderate and have been recovered by subsequent follow-up. For the first month of the treatment, the serum levels of creatine kinase should be monitored every 2 weeks, especially in patients reporting muscle symptoms. Brigatinib, ensartinib, and lorlatinib can also cause myalgia and creatine kinase elevation;²⁰ hence, the serum levels of creatine kinase should also be monitored in patients with suspected symptoms when taking these drugs.

Future Directions

With more and more ALK-TKIs being approved in clinic, standard management of ADRs becomes increasingly important. An early awareness of the potential ADRs could reduce the unfavorable impact on QoL and assist avoid any unnecessary dosage reduction or early discontinuation of the effective treatment. The incidence of grade ≥3 ADRs in ALK-TKI-related phase III trials is almost >50%; additionally, the management may be more challenging in clinical practice. We expect the current consensus can aid clinicians improve the management of ALK-TKI-associated ADRs and we also realize that the current version of consensus would not be the last edition and require updating when novel ALK-TKIs are emerging in the future.