OR Oncology Reports 1021-335X 1791-2431 D.A. Spandidos 10.3892/or.2020.7851 or-45-01-0013 Review Safety and efficacy of anaplastic lymphoma kinase tyrosine kinase inhibitors in non-small cell lung cancer WangLi 1 2 WangWen 1 2 Shanghai R&D Center, Jiangsu Simcere Pharmaceutical Co., Ltd., Shanghai 201318, P.R. China The State Key Laboratory of Translational Medicine and Innovative Drug Development, Affiliated with Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, Jiangsu 210042, P.R. China Correspondence to: Dr Wen Wang, Shanghai R&D Center, Jiangsu Simcere Pharmaceutical Co., Ltd., 118, Furonghua Road, Pudong, Shanghai 201318, P.R. China, E-mail: wangwen@simcere.com; ortho123@hotmail.com 012021 13112020 45 1 13 28 26022020 31072020 Copyright: © Wang et al. 2020 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Since the discovery of targeted therapy with epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have been introduced as the first-line treatment for non-small cell lung cancer (NSCLC) patients who carry sensitizing ALK-activating mutations. Compared with conventional chemotherapeutic regimens, small-molecule ALK-TKIs exhibit excellent clinical efficacy in ALK-positive NSCLC. A series of studies have indicated that ALK-TKI agents as the first-line treatment, including crizotinib, ceritinib, brigatinib, alectinib and entrectinib, can benefit patients with ALK-positive NSCLC. However, resistance to ALK-TKIs has emerged. ALK-TKIs are associated with significantly disabling and undesirable effects that adversely impact quality of life and compliance. This study reviews the pharmacodynamics, efficacy and safety of ALK-TKI agents in order to summarize these effects as well as the relevant management strategies. It is worth emphasizing that the frequency and severity of an adverse effect often varies across different trials.

 anaplastic lymphoma kinase tyrosine kinase inhibitors crizotinib ceritinib brigatinib alectinib lorlatinib entrectinib safety non-small cell efficacy Introduction

NSCLC is considered as one of the main causes of cancer-related deaths worldwide, accounting for approximately 80–85% of all histological subtypes of lung cancer (1,2). Patients with NSCLC are often diagnosed at advanced stages of the disease (3,4). The administration of conventional chemotherapeutic regimens only marginally improves the outcomes of these individuals. The median survival time of these individuals is less than one year after diagnosis and is driven by the molecular expression and genetic mutations of the tumor (3,4). The identification of patients harboring activated EGFR mutations and ALK rearrangements, which account for approximately 15 and 5% of advanced non-squamous lung carcinomas in Western countries (5), respectively, has led to the targeting of genomic alterations for the treatment of these patients. The development of EGFR-TKIs has fueled efforts to identify additional targeted therapies for NSCLC (6).

ALK, a transmembrane tyrosine kinase, belongs to the superfamily of insulin receptors that regulate cellular growth and may trigger neoplastic transformation, including platelet-derived growth factor receptors, the epidermal growth factor receptor, human epidermal growth factor receptor type 2, and insulin-like growth factor-1 receptors. ALK catalyzes the phosphorylation reaction of a tyrosine residue on a substrate protein (7,8). In fact, the activation mechanism of ALK is still not completely understood. Phosphorylation of these ALK residues can transmit ALK-mediated signals to downstream signaling pathways (7).

With the development of targeted therapy, the discovery that ALK mutations and rearrangements in NSCLC patients lead to abnormal signaling pathways has markedly changed the targeted therapy in this subset of patients (6). Aberrantly formed ALK oncogenes, mainly caused by fusion mutations, ALK gain-of-function mutations, or ALK amplification, have been identified in various cancers, such as NSCLC, anaplastic large-cell lymphoma (ALCL), inflammatory myofibroblastic tumors (IMTs), and neuroblastoma (9). In patients with NSCLC, the gene rearrangement of echinoderm microtubule-associated protein-like 4 (EML4) ALK is the most common ALK alteration, accounting for 4 to 7% of lung adenocarcinomas (9,10). Compared with conventional chemotherapeutic regimens, small-molecule ALK-TKIs exhibit excellent clinical efficacy in ALK-positive NSCLC (11). In recent years, several ALK inhibitors have been developed to target dysregulated kinases. Crizotinib, which was launched in 2011, is a first-generation ALK inhibitor (12,13). The second-generation inhibitors include ceritinib, alectinib, brigatinib and entrectinib (Fig. 1). Lorlatinib (Table I) is a third-generation inhibitor (13–16). In addition, ensartinib, repotrectinib, and belizatinib are being investigated in ongoing clinical studies (17). It has been revealed that the median progression-free survival in patients using crizotinib was longer than that in patients undergoing chemotherapy in advanced ALK-positive lung cancer patients (12). However, resistance to the first-generation agent crizotinib has emerged in some clinical trials (18,19). Due to the poor blood-brain barrier penetration of crizotinib, brain metastases can present during the first year or two years of treatment (20).

This resistance of ALK is underpinned by different genetic mechanisms that include i) the development of secondary resistance mutations in ALK, such as L1196M (21,22), which most likely corresponds to a gatekeeper residue or a residue located in the ATP-binding pocket of a protein kinase that, when mutated, causes a change in the structure of the kinase that prevents TKI binding; ii) ALK copy number alterations; iii) aberrant activation of alternate kinases leading to ALK-independent growth, such as EGFR; and iv) epithelial-mesenchymal transition (23). L1196M (7%), G1269A (4%), C1156Y (2%), G1202R (2%), I1171T (2%), S1206Y (2%), and E1210K (2%) are the most common ALK-resistant mutations associated with crizotinib (21,22). The next-generation ALK inhibitors are generally active in crizotinib-resistant mutations, and novel mutations resistant to each of these agents have rapidly become apparent (22). Brigatinib was also found to inhibit nine different mutants with 3–54-fold greater potency than ceritinib and/or alectinib (24).

This review summarizes the pharmacology and clinical safety/efficacy associated with ALK-TKIs. The review is based principally on drug evaluation reports and the latest prescribing information provided by the United States Food and Drug Administration (FDA) supplemented as appropriate by published literature on agents under investigation. It is worth emphasizing that the frequency and severity of an adverse effect often varies across different trials, especially when there are different patient populations or indications under investigation, different treatment regimens and different sample sizes.

 Approved ALK-TKIs

Thus far, six ALK-TKIs have been approved by the FDA and the European Medicines Agency (EMA). They are listed in Table I. The currently approved agents are different in terms of their selectivity and reversibility due to the presence of compound structures, which have been listed in Fig. 1. Table II revealed that the physicochemical properties of agents may be associated with compound structures.

<sec> <title>First-generation ALK-TKI, crizotinib

Crizotinib is considered as a first-generation inhibitor of ALK indicated for the treatment of patients with metastatic NSCLC whose tumors are ALK-positive or c-ros oncogene 1 (ROS1)-positive (25). Crizotinib was approved by the US FDA in 2011. The recommended dosage of crizotinib is 250 mg orally twice daily with or without food (26). A pharmacokinetics study demonstrated that there was no statistically significant difference between fasted and fed in patients with crizotinib, while the exposure of crizotinib with a high-fat meal was slightly reduced compared with the exposure without a meal (27). Additional PK analyses (Table III) revealed that the bioavailability was 43%. Furthermore, ethnicity and age have been found to influence crizotinib PK (28). A clinical trial demonstrated that the mean Cmax and AUC in Asian patients were 1.50 and 1.57, respectively, compared with those in non-Asian patients (29). A phase I dose-escalation study in adolescents revealed that the recommended dose exceeded the dosage in adults. Hepatic impairment and renal impairment affect the exposure of crizotinib in plasma (30,31). Therefore, crizotinib should be administered to these types of patients with an appropriate dose adjustment.

The concentration of crizotinib in plasma may be affected by its interaction with other drugs. Because crizotinib is metabolized by hepatic cytochrome enzyme P450, particularly CYP3A4 (28), the drug may be affected by inhibitors and inducers of CYP3A4, which are listed in able Table IV. Ketoconazole can increase the AUCinf of crizotinib by 3.2-fold, and rifampin can decrease crizotinib exposure (32). Patients should thus be made aware of this fact when concomitantly using crizotinib and inhibitors and inducers of CYP.

Crizotinib has demonstrated safety and antitumor activity in patients with ALK-positive advanced NSCLC in a series of clinical trials. The PROFILE series showed consistent safety and efficacy superior to chemotherapy (33). The phase III (PROFILE 1007, PROFILE 1014), randomized, open-label study (34,35) was a milestone for ALK-TKIs, revealing superior progression-free survival (PFS) and objective response rates (ORRs) comparing crizotinib with standard chemotherapy. In the PROFILE 1007 study, which is the second-line setting, the median progression-free survival (PFS) of crizotinib compared with chemotherapy was 7.7 months vs. 3.0 months [hazard ratio (HR) 0.49; 95% confidence intervals (CIs), 0.37 to 0.64], and the response rate was higher with crizotinib than with chemotherapy [65% (95% CI, 58 to 72) vs. 20% (95% CI, 14 to 26)]. However, there was a statistically significant difference in the median overall survival between the two arms, which is listed in Table V. In the firstline setting (PROFILE 1014), the median PFS of crizotinib vs. chemotherapy was 10.9 vs. 7.0 (HR, 0.45; 95% CIs, 0.35 to 0.60). The objective response rates (ORR) was 74% vs. 45%. In another study (data from PROFILE 1007 and PROFILE 1014) (36), a randomized trial in Asian patients demonstrated the same result, revealing that the PFS was longer in the crizotinib group than in the chemotherapy group, with a median PFS of 8.1 and 2.8 months, respectively. However, due to ALK mutations and poor blood-brain barrier penetration, patients still experienced relapse and brain metastases within 11 months of treatment (37,38).

 Second-generation ALK-TKIs Ceritinib

Ceritinib is a tyrosine kinase inhibitor against multiple targets, including ALK, the insulin-like growth factor 1 receptor (IGF-1R), the insulin receptor (InsR), and ROS1 (39). As a selective oral ALK inhibitor, ceritinib has a 20 times greater potency than crizotinib against ALK-rearranged lung cancer cell lines in enzymatic assays (40). In addition, it can cross the blood-brain barrier (41). Ceritinib received approval from the FDA as a first-line treatment in patients with NSCLC, and in 2017, it was indicated for metastatic ALK-positive NSCLC. Ceritinib should be taken at a dosage of 450 mg once daily with food (42). The PK profile of ceritinib is listed in Table III and reveals that the drug is similar to crizotinib. Furthermore, ceritinib is mainly metabolized by P450 in the liver (37). Consequently, CYP3A inhibitors may increase the exposure of ceritinib in plasma. Warfarin, midazolam, and rifampin, which are strong CYP3A inhibitors, augment ceritinib in plasma (32).

Due to the poor blood-brain barrier penetration of crizotinib, a large number of patients develop CNS metastases and experience relapse within one year (37). Ceritinib has good blood-brain barrier penetration and can overcome some resistance caused by crizotinib (13). Ceritinib is sensitive to L1196M, G1269A, C1156Y, I1171T, and S1206Y (22). The ASCEND series revealed consistent and durable antitumor activity and tolerable safety in the ASCEND-1 and ASCEND-2 studies (11,37). Ceritinib provided a first-line treatment due to potent activity in crizotinib-naïve patients and significant improvements in PFS (16.6 vs. 8.1 months) compared with the chemotherapy group in the ASCEND-4 study (43). In the ASCEND-5 study (44), 231 patients with ALK-positive NSCLC were randomized. The results revealed that the median PFS resulting from ceritinib was longer than that resulting from chemotherapy [5.4 months (95% CI, 4.1–6.9) in the ceritinib arm vs. 1.6 months (95% CI, 1.4–2.8) in the chemotherapy arm (HR, 0.0.49; 95% CI, 0.36–0.67; Table V)].

 Alectinib

Alectinib is a selective tyrosine kinase inhibitor that targets ALK and receptor of tyrosine kinase (RET); it has CNS activity and has been approved for advanced ALK-positive NSCLC patients with/without previous treatment with crizotinib (20). Alectinib has a five-fold higher potency than crizotinib for inhibiting ALK and maintains activity against several of the secondary mutants associated with resistance to crizotinib (45). Due to its clinical efficacy, good blood-brain barrier penetration, and tolerance, alectinib was approved in 2015 by the FDA as a front-line therapy for parents with advanced ALK-positive NSCLC (18,20). The recommended dose is 600 mg orally twice daily, and it should also be taken with food. A clinical trial demonstrated that a high-fat meal could increase the concentration of alectinib in plasma (46). Due to the similar structure between alectinib and ceritinib, the PK profiles of both are similar. The metabolism of alectinib occurs mainly through CYP3A4 in the liver, indicating that CYP3A4 inhibitors and inducers affect the PK of alectinib administration. The plasma protein binding rate was 99%. However, for patients with mild or moderate renal or hepatic impairment, there is no need to adjust the dose (20).

Alectinib is another ALK-TKI that can overcome the poor CNS penetration of crizotinib and crizotinib resistance, and it is sensitive to C1156, G1269A, S1206Y, and L1152R (19). The ALUR trial (47) revealed that the systemic and CNS efficacy in the alectinib arm was significantly improved compared with that in the chemotherapy arm for crizotinib-pretreated ALK-positive NSCLC patients; the median investigator-assessed PFS was 9.6 months vs. 1.4 months. Furthermore, the PFS assessed by the Independent Review Committee was 7.1 months for alectinib and 1.6 months for chemotherapy (HR, 0.32; 95% CI, 0.17–0.59, P<0.001). In a subgroup of patients with measurable baseline central nervous system (CNS) disease, the CNS ORR was significantly higher with alectinib (54.2%) vs. chemotherapy (0%; P<0.001) (47). The J-ALEX and ALEX trials (48,49), which compared alectinib with crizotinib in treatment-naïve patients with advanced ALK-positive NSCLC, were phase III studies that revealed the superiority of alectinib over crizotinib. In the J-ALEX trials, the median PFS was not yet reached in the alectinib cohort [95% CI, 20.3 months-not estimable (NE)] and was 10.2 months in the crizotinib cohort (95% CI, 8.2–12) in the preplanned interim analysis. ALEX results were similar to those in J-ALEX, with significant improvements in median PFS [alectinib (95% CI, 17.7 months-NE) vs. crizotinib 11.1 months (95% CI, 9.1–13.1)].

 Brigatinib

Brigatinib is a tyrosine kinase inhibitor with broad-spectrum activity against ALK, ROS1, the insulin-like growth factor-1 receptor (IGF-1R), and Fms-like tyrosine kinase 3 (FLT-3), as well as EGFR deletions and point mutations, including L1152R, V1180L, G1202R, R1275Q, T790M, C797S, and L858R (24,25,50). Brigatinib has a 12-fold higher potency than crizotinib for inhibiting ALK. It inhibits crizotinib-, ceritinib-, and alectinib-resistant ALK mutants (24). Brigatinib received approval from the US FDA in 2017 and is indicated for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib. Brigatinib should be taken at a dosage of 90 mg orally once daily for the first 7 days. If patients are tolerant, the dosage should be increased to 180 mg orally once daily. It may be taken with or without food (51). The PK profile of brigatinib is presented in Table III (52). Because brigatinib is primarily metabolized by CYP2C8 and CYP3A (52), this strong inhibitor and inducer, respectively, must affect its exposure. Ariad Pharmaceuticals is investigating the drug-drug interaction between brigatinib and midazolam (52).

Although ceritinib and alectinib can overcome resistance mutations associated with crizotinib, some new resistance mutations still arise. It has been reported that there are seventeen mutations associated with crizotinib, ceritinib and alectinib, including G1202R (22). Brigatinib exhibited activity against this and other mutations. ALTA-1L is a pivotal trial of brigatinib for 1st-line treatment (53). In a randomized, open-label study (53), 275 patients with advanced ALK-positive NSCLC who had been treated with ALK inhibitors were randomly assigned to receive brigatinib or crizotinib. At the follow-up of 12 months, the rate of PFS in the brigatinib arm was higher than that in the crizotinib arm [67% (95% CI, 56 to 75) vs. 43% (95% CI, 32 to 53)].

 Entrectinib

Entrectinib is a selective inhibitor of the tyrosine kinases tropomyosin receptor kinases (Trk) A/B/C, ROS1 and ALK with central nervous system activity (54,55). Entrectinib is 30 times more potent against ROS1 than crizotinib (54). It was approved by the FDA in 2019 as a first-line treatment for adult patients with ROS1-positive metastatic NSCLC and for adult and pediatric patients (12 years of age and older) with solid tumors (55). Adult patients with ROS1-positive metastatic NSCLC and neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive solid tumors should be administered a dosage of 600 mg orally once daily. For patients 12 years and older with NTRK gene fusion-positive solid tumors, the recommended dosage is based on body surface area (BSA) (55). The PK profile of entrectinib is listed in Table III (56). The clinical activity of entrectinib was assessed in four trials (SATARTRK-1/SATARTRK-2/SATARTRK-NG/ALKA-372-001) (57), and the efficacy of entrectinib was assessed in patients with ROS1-positive NSCLC [ORR 78%;65%, 89%], DOR≥9 months 70%). Responses were observed in SATARTRK-1 ALK-rearranged cancer patients (n=7) with an ORR of 57% and a median PFS of 8.3 months.

 Third-generation ALK-TKIs Lorlatinib

Lorlatinib is a kinase inhibitor with activity against ALK and ROS1 as well as TYK1, FER, FPS, TRKA/B/C, FAK, FAK2, and ACK, and it can penetrate the blood-brain barrier to overcome known ALK resistance mutations (58). In addition, lorlatinib is effective against all known resistant mutants of first- and second-generation ALK inhibitors, such as crizotinib-resistant ALK G1202R and ROS1 G2032R mutants (16). Lorlatinib demonstrates significantly improved (>50-fold) inhibitory potency (59). Lorlatinib received approval from the FDA in 2018 and is indicated for the treatment of patients with ALK-positive metastatic NSCLC whose disease has progressed while taking crizotinib/ceritinib/alectinib as first-line ALK inhibitors for metastatic disease and at least one other ALK inhibitor for metastatic disease. The recommended dosage of lorlatinib is 100 mg orally once daily (58). The PK profile is demonstrated in Table III. Because lorlatinib has high membrane and blood-brain barrier permeability, it is transported by ABCB1 and ABCG2 since inhibitors of the transporters ABCB1 and ABCG2 influence the concentration of lorlatinib in the brain (60).

Lorlatinib is active against all known acquired resistance mutations associated with earlier TKIs. A phase I dose-escalation study of lorlatinib (NCT03052608) in an array of cancer indications, including ALK-positive NSCLC with two or more previous ALK TKI treatments and ALK-positive NSCLC with brain metastases, demonstrated that lorlatinib was effective for NSCLC patients with acquired resistance to ALK TKIs (33). These impressive results were confirmed by a phase II trial with expansion cohorts in patients with ALK-positive or ROS1-positive advanced NSCLC, revealing that the objective response was 47% in patients with at least one prior ALK TKI treatment and that the ORR was 90% in ALK-positive and treatment-naïve patients (33).

 Safety evaluation

Data from certain clinical trials have reported that nausea/vomiting and diarrhea are the most common side effects (34,35,43,44,47–49,53,61), which are listed in Table VI. Pneumonitis/interstitial lung disease/pulmonary disease has been described as a relatively rare but serious side effect (62). In ASCEND-1, which aimed to evaluate the safety of ceritinib in a multicenter, single-arm, open-label clinical study of 255 ALK-positive patients, up to 5% of patients experienced adverse reactions, including (but not limited to) pneumonia, respiratory failure, ILD/pneumonitis, pneumothorax, and gastric hemorrhage. Even fatal events were reported (occurring in 0.2% of patients) (26).

<sec> <title>Hepatotoxicity

Hepatotoxicity is reported relatively frequently in preapproved clinical trials for TKIs as a serious class-related safety issue (63). Concurrently, hepatotoxicity is the leading cause of drug withdrawal in the market. ALK inhibitors are also associated with hepatotoxicity (63). A systematic meta-analysis of clinical trials assessed the incidence and risk of ALK inhibitors (64). Among 1,908 patients from 10 clinical trials, aspartate aminotransferase (AST) elevation accounted for 25.2%, and alanine transaminase (ALT) elevation accounted for 26.0%.

In a clinical trial, hepatobiliary disorders also appeared in patients treated with alectinib, and these disorders included increased levels of AST (3.7%), ALT (3.7%) (65) and bilirubin (3.2%) (64); 1.2–1.5% of the patients withdrew from treatment due to these adverse reactions (ARs). In the NP28761 study, the levels of alanine aminotransferase and aspartate aminotransferase in patients with alectinib increased by 6 and 5%, respectively, and two patients withdrew from the study due to hepatotoxicity. In another trial, blood bilirubin levels increased by 15% (19).

A meta-analysis revealed that the frequencies of grade ≥3 hepatotoxicity induced by ceritinib are greater than those induced by crizotinib or alectinib (66). IGF receptors play an important role, as revealed by the fact that ceritinib inhibits insulin-like growth factor 1 (IGF-1) and insulin receptors and that the IGF receptor is ubiquitous at the cell surface and exists on the surface of cells. Therefore, patients who use alectinib and brigatinib have lower hepatotoxicity than patients who use ceritinib and crizotinib (66). Two analyses reported that the hepatotoxicity induced by alectinib was lower than that induced by crizotinib and ceritinib (64,67).

Although a dose reduction or interruption can occur due to the hepatotoxicity associated with ALK inhibitors, there have been limited studies on the influencing factors. Jung et al (68) reported that the presence of liver disease or HBV and the use of an H2 antagonist or H2 antagonist/proton pump inhibitor were the main risk factors for hepatotoxicity induced by crizotinib. A study (67) reporting a histological analysis of patients with acute hepatitis who were treated with alectinib demonstrated that acute hepatitis led to significantly high levels of hepatotoxicity.

 Gastrointestinal toxicities

The common toxicities associated with ALK-TKIs are gastrointestinal toxicities, including nausea, vomiting, diarrhea and constipation (65). Although the severity of these toxicities is mild, they are potentially life threatening and can be distressing for patients, affecting their quality of life. Severe diarrhea can result in electrolyte imbalance, renal insufficiency, malnutrition, and extreme dehydration, all of which can lead to cardiovascular compromise and death (69). In a phase I study, a large number of patients (96%; 14% severe cases) experienced gastrointestinal (GI) adverse events (AEs) as a result of taking the recommended dose of ceritinib (70). In the XALKORI (n=171) study, up to 61% of patients who took crizotinib experienced diarrhea, with grade 3–4 diarrhea accounting for 2% across all clinical trials (26).

GI AEs are one of the most common reasons for dose modification (38% of patients) (70). Other severe gastrointestinal toxicities, such as vomiting and nausea, occur in patients treated with brigatinib (24%, grade 3–4 1.8%; 33%, grade 3–4 0.9%) (71). The incidence and severity of gastrointestinal adverse reactions, including diarrhea, nausea, and vomiting, account for 56/45/35% of patients, respectively, and can be reduced with a dose of 450 mg ceritinib taken with food. Nausea (1.8%) is one of the most frequent adverse reactions that leads to dose reduction in patients taking crizotinib (65). Schaefer and and Baik (70) suggested strategies for potential GI AEs resulting from ceritinib treatment in nine patients, and these recommendations can prevent the need for dose reduction due to GI AEs so that patients can continue taking the prescribed dose (750 mg/d ceritinib dose). Regimens A and B can be implemented as follows: Regimen A consists of ondansetron and diphenoxylate/atropine or loperamide taken 30 min prior to the dose of ceritinib, and Regimen B consists of dicyclomine, which should be taken with the first dose of ceritinib; ondansetron, which should be taken 30 min prior to the dose of ceritinib for the first seven doses; and loperamide, which should be taken as needed with the onset of diarrhea. Although these strategies are not currently recommended or implemented in clinical studies, they provide an option for physicians.

 Interstitial lung disease (ILD)

ILD has been described as a relatively rare but fatal complication associated with tyrosine kinase inhibitors (72). Lung toxicity has been reported in patients taking ALK-TKIs such as crizotinib, ceritinib, and alectinib, with incidence rates of 1.8, 1.1, and 2.6%, respectively (72). In a retrospective study, only 1.2% of 1,669 patients treated with crizotinib in clinical trials exhibited crizotinib-related ILD. However, 50% of those patients succumbed due to ILD (73). Treatment-related deaths (TRDs) were reported in 12 of the 1,365 evaluable patients, resulting in an overall prevalence of 0.9%. The main cause of death was ILD or pneumonitis (66). Severe pulmonary adverse reactions consistent with ILD or pneumonitis occurred with 90 mg brigatinib treatment in 3.7% of the overall patients and 9.1% of patients in the 90/180 mg group (74).

The risk factors for ILD are not fully understood, but some studies have reported that smoking history, previous or concomitant ILD, and comorbid pleural effusion are associated with ILD, regardless of patient characteristics (73). In other words, ILD represents a potential reason for pulmonary harm. The management strategies for this toxicity are mainly discontinuation and steroid treatment. However, rechallenge with another ALK inhibitor in patients with a previous history of ALK-related ILD and ILD risk factors must be approved via a collegial decision. For example, brigatinib was used in a patient with ALK-rearranged lung adenocarcinoma who developed crizotinib-induced ILD. A cross-link with lung toxicity was not demonstrated in this patient; rather, the patient benefited from that treatment (75).

 Cardiac AEs

Cardiac AEs such as Corrected QT (the time between the start of the Q-wave and the end of the T-wave) Interval (QTc) interval prolongation/bradycardia have been reported in patients taking ceritinib/crizotinib/alectinib and brigatinib (26,71,76,77). Symptomatic bradycardia has reportedly emerged in patients treated with alectinib in the NP28761, NP28673 and ALEX studies (78), accounting for 8%. The heart rates of these patients were less than 50 beats per minute (bpm). Furthermore, patients taking ceritinib experienced QTc interval prolongation and bradycardia. Heart rate decreases and sinus bradycardia were observed in some patients treated with crizotinib, with a reduction of 2.5 bpm.

The most effective way to prevent cardiac AEs is to monitor the heart rate and blood pressure of patients regularly during treatment with ALK-TKIs because bradycardia cannot be avoided. Products that cause bradycardia should be avoided when combined with ceritinib/crizotinib/alectinib and brigatinib.

 Future directions

Since the discovery of targeted therapy with ALK, it has been reported that compared to chemotherapeutic agents, ALK inhibitors show improvements in PFS, ORR, and quality of life (2). Furthermore, several new compounds have been synthesized and are under investigation in different phases of clinical trials (Table VII). Based on our own experience, we encourage the early review of potential side effects to minimize any impact of AEs on the quality of life of patients and to help avoid any unnecessary dose reductions or early discontinuations of this effective treatment. With the development of resistance to ALK-TKIs, later-generation ALK-TKIs have been discovered to improve safety profiles (17). However, with disease progression in patients, the switching of ALK-TKIs can be used to identify the mutations and rearrangements of ALK (11,17). In other words, it is helpful to understand the resistance mechanisms. While the current technology used for liquid biopsy to detect late mutations in ALK is well justified, greater efforts are also required to minimize the clinical risks that adversely impact morbidity and quality of life. Finally, chemotherapy is also a valid choice for patients with ALK-positive metastatic NSCLC.

 Acknowledgements

Not applicable.

 Funding

No funding was received.

 Availability of data and materials

Not applicable.

 Authors' contributions

WL wrote the paper. WW reviewed and edited the manuscript. Both authors read and approved the manuscript.

 Ethics approval and consent to participate

Not applicable.

 Patient consent for publication

Not applicable.

 Competing interests

The authors declare that they have no competing interests.

 References DuffyMJO'ByrneKTissue and blood biomarkers in lung cancer: A reviewAdv Clin Chem86121201810.1016/bs.acc.2018.05.001 KhanMLinJLiaoGTianYLiangYLiRLiuMYuanYALK inhibitors in the treatment of ALK positive NSCLCFront Oncol8557201910.3389/fonc.2018.00557 MeloskyBCheemaPAgulnikJAlbadineRBebbDGBlaisNBurkesRButtsCCardPBChanAMYCanadian perspectives: Update on inhibition of ALK-positive tumours in advanced non-small-cell lung cancerCurr Oncol25317328201810.3747/co.25.4379 SodaMChoiYLEnomotoMTakadaSYamashitaYIshikawaSFujiwaraSWatanabeHKurashinaKHatanakaHIdentification of the transforming EML4-ALK fusion gene in non-small-cell lung cancerNature448561566200710.1038/nature05945 ChanBAHughesBGTargeted therapy for non-small cell lung cancer: Current standards and the promise of the futureTransl Lung Cancer Res436542015 D'ArcangeloMWynesMWHirschFRThe role of anaplastic lymphoma kinase inhibitors in the treatment of advanced nonsmall cell lung cancerCurr Opin Oncol25121129201310.1097/CCO.0b013e32835d8175 HuangHAnaplastic lymphoma kinase (ALK) receptor tyrosine kinase: A catalytic receptor with many facesInt J Mol Sci193448201810.3390/ijms19113448 GoldingBLuuAJonesRViloria-PetitAMThe function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC)Mol Cancer1752201810.1186/s12943-018-0810-4 RoskoskiRJrAnaplastic lymphoma kinase (ALK) inhibitors in the treatment of ALK-driven lung cancersPharmacol Res117343356201710.1016/j.phrs.2017.01.007 ZhangZGuoHLuYHaoWHanLAnaplastic lymphoma kinase inhibitors in non-small cell lung cancer patients with brain metastases: A meta-analysisJ Thorac Dis1113971409201910.21037/jtd.2019.03.76 SgambatoACasaluceFMaionePGridelliCTargeted therapies in non-small cell lung cancer: A focus on ALK/ROS1 tyrosine kinase inhibitorsExpert Rev Anticancer Ther187180201810.1080/14737140.2018.1412260 CuiSZhaoYGuAGeXSongYZhangWLouYDongLHanBJiangLEfficacy and tolerability of crizotinib in the treatment of ALK-positive, advanced non-small cell lung cancer in Chinese patientsMed Oncol32626201510.1007/s12032-015-0626-7 CalifanoRGreystokeALalRThompsonJPopatSManagement of ceritinib therapy and adverse events in patients with ALK-rearranged non-small cell lung cancerLung Cancer1115158201710.1016/j.lungcan.2017.06.004 ZhuVOuSHSafety of alectinib for the treatment of metastatic ALK-rearranged non-small cell lung cancerExpert Opin Drug Saf16509514201710.1080/14740338.2017.1299706 SabariJKSantiniFCSchramAMBergagniniIChenRMradCLaiWVArbourKCDrilonAThe activity, safety, and evolving role of brigatinib in patients with ALK-rearranged non-small cell lung cancersOnco Targets Ther1019831992201710.2147/OTT.S109295 BauerTMFelipESolomonBJThurmHPeltzGChiodaMDShawATClinical management of adverse events associated with lorlatinibOncologist2411031110201910.1634/theoncologist.2018-0380 SpagnuoloAMaionePGridelliCEvolution in the treatment landscape of non-small cell lung cancer with ALK gene alterations: From the first- to third-generation of ALK inhibitorsExpert Opin Emerg Drugs23231241201810.1080/14728214.2018.1527902 GadgeelSMThe use of alectinib in the first-line treatment of anaplastic lymphoma kinase-positive non-small-cell lung cancerFuture Oncol1418751882201810.2217/fon-2018-0027 VavalaTNovelloSAlectinib in the treatment of ALK-positive non-small cell lung cancer: An update on its properties, efficacy, safety and place in therapyTher Adv Med Oncol101758835918789364201810.1177/1758835918789364 PaikJDhillonSAlectinib: A review in advanced, ALK-positive NSCLCDrugs7812471257201810.1007/s40265-018-0952-0 CortinovisDCanovaSAbbateMIColoneseFCogliatiVBidoliPChallenges in ALK inhibition of ALK-positive non-small-cell lung cancer: From ALK positivity detection to treatment strategies after relapseFuture Oncol1423032317201810.2217/fon-2018-0066 PetersSZimmermannSManagement of resistance to first-line anaplastic lymphoma kinase tyrosine kinase inhibitor therapyCurr Treat Options Oncol1937201810.1007/s11864-018-0553-x Dagogo-JackIShawATCrizotinib resistance: Implications for therapeutic strategiesAnn Oncol27(Suppl 3)iii42iii50201610.1093/annonc/mdw305 AliRArshadJPalacioSMudadRBrigatinib for ALK-positive metastatic non-small-cell lung cancer: Design, development and place in therapyDrug Des Devel Ther13569580201910.2147/DDDT.S147499 BediSKhanSAAbuKhaderMMAlamPSiddiquiNAHusainAA comprehensive review on Brigatinib-A wonder drug for targeted cancer therapy in non-small cell lung cancerSaudi Pharm J26755763201810.1016/j.jsps.2018.04.010 Pfizer Inc.: XALKORI 2011https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202570s028lbl.pdfJanuary102019 XuHO'GormanMBoutrosTBregaNKantaridisCTanWBelloAEvaluation of crizotinib absolute bioavailability, the bioequivalence of three oral formulations, and the effect of food on crizotinib pharmacokinetics in healthy subjectsJ Clin Pharmacol55104113201510.1002/jcph.356 HamiltonGRathBBurghuberOPharmacokinetics of crizotinib in NSCLC patientsExpert Opin Drug Metab Toxicol11835842201510.1517/17425255.2015.1021685 FujiwaraYHamadaAMizugakiHAikawaHHataTHorinouchiHKandaSGotoYItahashiKNokiharaHPharmacokinetic profiles of significant adverse events with crizotinib in Japanese patients with ABCB1 polymorphismCancer Sci10711171123201610.1111/cas.12983 El-KhoueiryABSarantopoulosJO'BryantCLCiomborKKXuHO'GormanMChakrabartiJUsariTEl-RayesBFEvaluation of hepatic impairment on pharmacokinetics and safety of crizotinib in patients with advanced cancerCancer Chemother Pharmacol81659670201810.1007/s00280-018-3517-8 TanWYamazakiSJohnsonTRWangRO'GormanMTKirkovskyLBoutrosTBregaNMBelloAEffects of renal function on crizotinib pharmacokinetics: Dose recommendations for patients with ALK-positive non-small cell lung cancerClin Drug Investig37363373201710.1007/s40261-016-0490-z HirotaTMurakiSIeiriIClinical pharmacokinetics of anaplastic lymphoma kinase inhibitors in non-small-cell lung cancerClin Pharmacokinet58403420201910.1007/s40262-018-0689-7 PirkerRFilipitsMFrom crizotinib to lorlatinib: Continuous improvement in precision treatment of ALK-positive non-small cell lung cancerESMO Open4e000548201910.1136/esmoopen-2019-000548 ShawATKimDWNakagawaKSetoTCrinóLAhnMJDe PasTBesseBSolomonBJBlackhallFCrizotinib versus chemotherapy in advanced ALK-positive lung cancerN Engl J Med36823852394201310.1056/NEJMoa1214886 SolomonBJMokTKimDWWuYLNakagawaKMekhailTFelipECappuzzoFPaoliniJUsariTFirst-line crizotinib versus chemotherapy in ALK-positive lung cancerN Engl J Med37121672177201410.1056/NEJMoa1408440 NishioMKimDWWuYLNakagawaKSolomonBJShawATHashigakiSOhkiEUsariTPaoliniJCrizotinib versus chemotherapy in asian patients with ALK-positive advanced non-small cell lung cancerCancer Res Treat50691700201810.4143/crt.2017.280 DeeksEDCeritinib: A review in ALK-positive advanced NSCLCTarget Oncol11693700201610.1007/s11523-016-0460-7 TomasiniPEgeaJSouquet-BressandMGreillierLBarlesiFAlectinib in the treatment of ALK-positive metastatic non-small cell lung cancer: Clinical trial evidence and experience with a focus on brain metastasesTher Adv Respir Dis131753466619831906201910.1177/1753466619831906 ClaxtonLO'ConnorJWoolacottNWrightKHodgsonRCeritinib for untreated anaplastic lymphoma kinase-positive advanced non-small-cell lung cancer: An evidence review group evaluation of a NICE single technology appraisalPharmacoeconomics37645654201910.1007/s40273-018-0720-8 FribouletLLiNKatayamaRLeeCCGainorJFCrystalASMichellysPYAwadMMYanagitaniNKimSThe ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancerCancer Discov4662673201410.1158/2159-8290.CD-13-0846 ShawATKimDWMehraRTanDSFelipEChowLQCamidgeDRVansteenkisteJSharmaSDe PasTCeritinib in ALK-rearranged non-small-cell lung cancerN Engl J Med37011891197201410.1056/NEJMoa1311107 GainorJFShawATFast, food and ceritinib in ALK-positive NSCLCJ Thorac Oncol1213411343201710.1016/j.jtho.2017.07.012 SoriaJCTanDSWChiariRWuYLPaz-AresLWolfJGeaterSLOrlovSCortinovisDYuCJFirst-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): A randomised, open-label, phase 3 studyLancet389917929201710.1016/S0140-6736(17)30123-X ShawATKimTMCrinòLGridelliCKiuraKLiuGNovelloSBearzAGautschiOMokTCeritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): A randomised, controlled, open-label, phase 3 trialLancet Oncol18874886201710.1016/S1470-2045(17)30339-X BeardsleeTLawsonJAlectinib and brigatinib: New second-generation ALK inhibitors for the treatment of non-small cell lung cancerJ Adv Pract Oncol9941012018 ParrottNJYuLJTakanoRNakamuraMMorcosPNPhysiologically based absorption modeling to explore the impact of food and gastric pH changes on the pharmacokinetics of alectinibAAPS J1814641474201610.1208/s12248-016-9957-3 NovelloSMazieresJOhIJde CastroJMigliorinoMRHellandÅDziadziuszkoRGriesingerFKotbAZeaiterAAlectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: Results from the phase III ALUR studyAnn Oncol2914091416201810.1093/annonc/mdy121 HidaTNokiharaHKondoMKimYHAzumaKSetoTTakiguchiYNishioMYoshiokaHImamuraFAlectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): An open-label, randomised phase 3 trialLancet3902939201710.1016/S0140-6736(17)30565-2 PetersSCamidgeDRShawATGadgeelSAhnJSKimDWOuSIPérolMDziadziuszkoRRosellRAlectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancerN Engl J Med377829838201710.1056/NEJMoa1704795 UmbelaSGhachaSMatuknauthRGauseSJosheeSDeshmukhRRBrigatinib: New-generation ALK inhibitor for nonsmall cell lung cancerCurr Probl Cancer43100477201910.1016/j.currproblcancer.2019.03.005 MarkhamABrigatinib: First global approvalDrugs7711311135201710.1007/s40265-017-0750-0 TugnaitMGuptaNHanleyMJSonnichsenDKersteinDDorerDJVenkatakrishnanKNarasimhanNEffects of strong CYP2C8 or CYP3A inhibition and CYP3A induction on the pharmacokinetics of brigatinib, an oral anaplastic lymphoma kinase inhibitor, in healthy volunteersClin Pharmacol Drug Dev9214223202010.1002/cpdd.723 CamidgeDRKimHRAhnMJYangJCHanJYLeeJSHochmairMJLiJYChangGCLeeKHBrigatinib versus crizotinib in ALK-positive non-small-cell lung cancerN Engl J Med37920272039201810.1056/NEJMoa1810171 Al-SalamaZTKeamSJEntrectinib: First global approvalDrugs7914771483201910.1007/s40265-019-01177-y GenentechIncROZLYTREK 2019https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212726s000lbl.pdfJanuary102019 WangQFangPZhengLYeLQuantification and pharmacokinetic study of entrectinib in rat plasma using ultra-performance liquid chromatography tandem mass spectrometryBiomed Chromatogr33e44672019 LiuDOffinMHarnicarSLiBTDrilonAEntrectinib: An orally available, selective tyrosine kinase inhibitor for the treatment of NTRK, ROS1, and ALK fusion-positive solid tumorsTher Clin Risk Manag1412471252201810.2147/TCRM.S147381 PfizerIncLorbrena 2018https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210868s000lbl.pdfJanuary102019 AkamineTToyokawaGTagawaTSetoTSpotlight on lorlatinib and its potential in the treatment of NSCLC: The evidence to dateOnco Targets Ther1150935101201810.2147/OTT.S165511 LiWSparidansRWWangYLebreMCWagenaarEBeijnenJHSchinkelAHP-glycoprotein (MDR1/ABCB1) restricts brain accumulation and cytochrome P450-3A (CYP3A) limits oral availability of the novel ALK/ROS1 inhibitor lorlatinibInt J Cancer14320292038201810.1002/ijc.31582 WuYLLuSLuYZhouJShiYKSriuranpongVHoJCMOngCKTsaiCMChungCHResults of PROFILE 1029, a phase III comparison of first-line crizotinib versus chemotherapy in east asian patients with ALK-positive advanced non-small cell lung cancerJ Thorac Oncol1315391548201810.1016/j.jtho.2018.06.012 YonedaKYScrantonJRCadoganMATassellVNadanacivaSWilnerKDStollenwerkNSInterstitial lung disease associated with crizotinib in patients with advanced non-small cell lung cancer: Independent review of four PROFILE trialsClin Lung Cancer18472479201710.1016/j.cllc.2017.03.004 ShahRRMorganrothJShahDRHepatotoxicity of tyrosine kinase inhibitors: Clinical and regulatory perspectivesDrug Saf36491503201310.1007/s40264-013-0048-4 LiuBYuanMSunYChengZZhangZHouSWangXLiuJIncidence and risk of hepatic toxicities associated with anaplastic lymphoma kinase inhibitors in the treatment of non-small-cell lung cancer: A systematic review and meta-analysisOncotarget994809488201710.18632/oncotarget.23840 CostaRBCostaRLBTalamantesSMKaplanJBBhaveMARademakerAMillerCCarneiroBAMahalingamDChaeYKSystematic review and meta-analysis of selected toxicities of approved ALK inhibitors in metastatic non-small cell lung cancerOncotarget92213722146201810.18632/oncotarget.25154 ZhuQHuHWengDSZhangXFChenCLZhouZQTangYXiaJCPooled safety analyses of ALK-TKI inhibitor in ALK-positive NSCLCBMC Cancer17412201710.1186/s12885-017-3405-3 ZhuVWLuYOuSISevere acute hepatitis in a patient receiving alectinib for ALK-positive non-small-cell lung cancer: Histologic analysisClin Lung Cancer20e77e80201910.1016/j.cllc.2018.09.006 JungDHanJMYeeJKimJYGwakHSFactors affecting crizotinib-induced hepatotoxicity in non-small cell lung cancer patientsMed Oncol35154201810.1007/s12032-018-1213-5 Van SebilleYZGibsonRJWardillHRBowenJMErbB small molecule tyrosine kinase inhibitor (TKI) induced diarrhoea: Chloride secretion as a mechanistic hypothesisCancer Treat Rev41646652201510.1016/j.ctrv.2015.05.011 SchaeferESBaikCProactive management strategies for potential gastrointestinal adverse reactions with ceritinib in patients with advanced ALK-positive non-small-cell lung cancerCancer Manag Res83338201610.2147/CMAR.S96471 AriadALUNBRIG. 2017https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208772lbl.pdfJanuary102019 PellegrinoBFacchinettiFBordiPSilvaMGnettiLTiseoMLung toxicity in non-small-cell lung cancer patients exposed to ALK inhibitors: Report of a peculiar case and systematic review of the literatureClin Lung Cancer19e151e161201810.1016/j.cllc.2017.10.008 GemmaAKusumotoMKuriharaYMasudaNBannoSEndoYHouzawaHUenoNOhkiEYoshimuraAInterstitial lung disease onset and its risk factors in Japanese patients with ALK-positive NSCLC after treatment with crizotinibJ Thorac Oncol14672682201910.1016/j.jtho.2018.11.022 GettingerSNBazhenovaLALangerCJSalgiaRGoldKARosellRShawATWeissGJTugnaitMNarasimhanNIActivity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: A single-arm, open-label, phase 1/2 trialLancet Oncol1716831696201610.1016/S1470-2045(16)30392-8 DomenechMJoveMAsoSMarinMNadalESuccessful treatment with brigatinib in a patient with ALK-rearranged lung adenocarcinoma who developed crizotinib-induced interstitial lung diseaseLung Cancer11999102201810.1016/j.lungcan.2018.03.014 Novartis Inc: Zykadia2014https://www.pharma.us.novartis.com/product/pi/pdf/zykadia.pdfJanuary102019 Hoffmann-LaRocheALECENSA. 2015https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208434s004lbl.pdfJanuary102019 MorcosPNBogmanKHubeauxSSturm-PellandaCRufTBordognaWGoldingSZeaiterAAbtMBalasBEffect of alectinib on cardiac electrophysiology: Results from intensive electrocardiogram monitoring from the pivotal phase II NP28761 and NP28673 studiesCancer Chemother Pharmacol79559568201710.1007/s00280-017-3253-5

Structural formula of approved ALK-TKIs. (A) Crizotinib, (B) ceritinib, (C) brigatinib, (D) alectinib, (E) lorlatinib and (F) entrectinib. ALK-TKIs, anaplastic lymphoma kinase tyrosine kinase inhibitors.

Currently approved ALK-TKIs.

Drug FDA approval EMA approval Generation Line of treatment Targets Broad indications Company agreements
Crizotinib 2011 2012 First First-line ALK, ROS1, and MET Metastatic NSCLC Pfizer
Ceritinib 2014 2015 Second First-line ALK, IGF-1R, InsR, and ROS1 Metastatic NSCLC with ALK-positive tumours Novartis
Brigatinib 2017 2018 Second First-line ALK, ROS1, IGF-1R, and FLT-3 as well as EGFR deletion and point mutations. ALK-positive metastatic NSCLC Ariad
Alectinib 2015 2016 Second First-line ALK and RET with CNS activity. ALK-positive metastatic NSCLC Hoffmann-La Roche
Lorlatinib 2018 2019 Third – ALK and ROS1 as well as TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK ALK-positive metastatic NSCLC Pfizer INC
Entrectinib 2019 2019 Second First-line (Trk) A/B/C, ROS1, NTRK, and ALK Metastatic NSCLC with ROS1-positive tumours Genentech

ALK-TKIs, anaplastic lymphoma kinase tyrosine kinase inhibitors; NSCLC, non-small-cell lung cancer; EGFR, epidermal growth factor receptor; ROS1, c-ros oncogene 1; MET, mesenchymal-epithelial transition factor; IGF-1R, the insulin-like growth factor-1 receptor; RET, rearranged during transfection; CNS, central nervous system; Trk A/B/C, tropomyosin receptor kinases A/B/C; NTRK, neurotrophic tyrosine receptor kinase.

Physicochemical properties of approved ALK-TKIs.

Properties Crizotinib Ceritinib Brigatinib Alectinib Lorlatinib Entrectinib
Molecular formula (mg/mole) 450.34 558.14 584.10 482.62 406.41 560.64
Molecular weight C21H22Cl2FN5O C28H36ClN5O3S C29H39ClN7O2P C30H34N4O2 C21H19FN6O2 C31H34F2N6O2
Octanol/water 1.65 (pH 7.4) 5.23 5.17 NA 2.45 (pH 9) NA
Water solubility 0.00611 mg/ml 0.00222 mg/ml 0.022 mg/ml NA 32.38–0.17 (pH 2.55–8.02) NA
pKa 9.4 and 5.6 9.7 and 4.1 NA 7.05 (base) 4.9 NA

ALK-TKIs, anaplastic lymphoma kinase tyrosine kinase inhibitors; NA, not available; pKa, symbol for acid dissociation constant at logarithmic scale.

Clinically relevant pharmacokinetics of currently approved ALK-TKIs.

PK parameter Crizotinib Ceritinib Brigatinib Alectinib Lorlatinib Entrectinib
Available dosage strengthsa (mg) 250/200 150 30/90 150 25/100 100/200
Recommended dose 250 mg bid 450 qd 90 mg qd 600 mg bid 100 mg qd 600 mg qd
T max 4–6 h 4–6 h 1–4 h 4 h 2 h 4–6 h
Bioavailability 43% NA NA 37% NA NA
Plasma protein binding 91% 97% 66% 99% 66% >99%
t1/2 42 h 41 h 25 h 33 h 24 h 20–40 h
Metabolism CYP3A CYP3A CYP2C8, CYP3A4 CYP3A4 CYP3A4, UGT1A4 CYP 3A4

Available dosage strengths signify the strength of a drug product, which indicates the amount of active ingredient in each dosage. ALK-TKIs, anaplastic lymphoma kinase tyrosine kinase inhibitors; CYP, cytochrome P450; UGT, UDP-glucuronosyltransferase; NA, not available, bid, bis in die; qd, quaque die.

DDI between ALK-TKIs and inhibitors/inducers of CYP.

Drug DDI Mechanism Consequences Current recommendations
Crizotinib Ketoconazole CYP3A4 inhibitor AUCinf augmentation of crizotinib with ketoconazole 3.2-fold CYP3A4 inhibitors or inducers significantly affect the pharmacokinetics of crizotinib after single- and multiple-dose administration
Rifampin CYP3A4 inducer AUCinf diminution of crizotinib with rifampin 82%
Midazolam CYP3A4 inhibitor It can increase midazolam plasma AUC by 3.7-fold
Ceritinib PPI P-gp inhibitor Augmentation of ceritinib with ketoconazole Cmax by 22% and AUC by 186% The drug label of ceritinib warns against the co-administration of strong CYP3A inhibitors. It is preferable to avoid the co-administration of strong CYP3A inducers
Warfarin Strong CYP3A inhibitor
Midazolam Strong CYP3A inhibitor
Brigatinib Rifampin Strong CYP3A inducer The co-administration of rifampin decreases the AUCinf of ceritinib by 70%
Itraconazole CYP3A inducer Augmentation of ceritinib with itraconazole Cmax by 21% and AUC by 101%
Ketoconazole Strong CYP3A inhibitor
Gemfibrozil Strong CYP2C8 inhibitor Diminution of brigatinib with gemfibrozil AUC and Cmax by 12% and 41%, respectively. The effects of gemfibrozil on the pharmacokinetics of brigatinib are not clinically significant; however, the concomi tant use of brigatinib with strong CYP3A inhibitors needs to be avoided
Rifampin CYP 3A4 inducer Rifampin decreases brigatinib Cmax and AUCinf by 60% and 80%, respectively The co-administration of strong CYP3A inducers with brigatinib needs to be avoided
Alectinib Posaconazole CYP 3A4 inhibitor
Esomeprazole CYP 3A4 inhibitor
Rifampin CYP 3A4 inhibitor Diminution of alectinib and M4 with rifampin AUC and Cmax by 26.8% and 48.6% and 220% and 179%, respectively
Midazolam CYP 3A4 substrate Alectinib does not affect midazolam exposure
Lorlatinib Rifampin CYP 3A4 inducer UK UK

ALK-TKIs, anaplastic lymphoma kinase tyrosine kinase inhibitors; AUC, area under the curve; AUCinf, AUC from zero to infinity; Cmax, maximum plasma concentration; CYP, Cytochrome P450; CYP 3A4, Cytochrome P450 3A4; DDI, drug-drug interaction; P-gp, P-glycoprotein; PPI, Proton-pump inhibitor; UK, unknown.

Pivotal clinical efficacy of ALK-TKIs for the treatment of NSCLC.

Study (n), (Ref.) TKI treatment Control Targeted patients Median PFS (months) [HR; 95% CIs]a ORR%a Median OS (HR; 95% CIs]a
PROFILE 1007 (n=347), (34) Crizotinib Docetaxel or Pemetrexed ALK-positive lung cancer with one prior platinum-based regimen Locally advanced or metastatic 7.7 vs. 3.0 [0.49; 0.37 to 0.64] 65% vs. 20% 20.3 vs. 22.8 [1.02; 0.68 to 1.54]
PROFILE 1014 (n=343), (35) Crizotinib Pemetrexed plus a platinum or carboplatin Advanced ALK-positive non-squamous NSCLC patients without previous systemic treatment 10.9 vs. 7.0 [0.45; 0.35 to 0.60] 74% vs. 45% NR vs. 47.5 [0.76; 0.548 to1.053]
PROFILE 1029 (n=207), (61) Crizotinib Docetaxel or Pemetrexed Previously untreated ALK-positive advanced NSCLC 11 vs. 6.8 [0.402; 0.286 to 0.565] 87.5% vs. 45.6% NA
ASCEND-4 (n=376), (43) Ceritinib Platinum-based chemotherapy ALK-rearranged non-squamous NSCLC 16.6 vs. 8.1 [0.55; 0.42 to 0.73] NA NR vs. 26.2 [0.73; 0.50 to 1.08]
ASCEND-5 (n=231), (44) Ceritinib Docetaxel or Pemetrexed ALK-rearranged NSCLC patients with previous chemotherapy and crizotinib 5.4 vs. 1.6 [0.49; 0.36 to 0.67] 39.1% vs. 6.9% NA
ALUR (n=107), (47) Alectinib Docetaxel or Pemetrexed Advanced/metastatic ALK-positive NSCLC 7.1 vs. 1.6 [0.32; 0.17 to 0.59] 36.1% vs. 11.4% 12.6 vs. NR [0.89; 0.35 to 2.24]
J-ALEX (n=207), (48) Alectinib Crizotinib ALK-positive non-small cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen NR vs. 10.2 [0.34; 0.17 to 0.71] – NR
ALEX (n=303), (49) Alectinib Crizotinib Previously untreated, advanced ALK-positive NSCLC NR vs. 11.1 [0.47; 0.34 to 0.65] NA NA [0.76; 0.48 to 1.20]
ALTA-1L (n=275), (53) Brigatinib Crizotinib Advanced ALK-positive NSCLC NR vs. 9.8 [0.49; 0.33 to 0.74] 71% vs. 60% NA

ALK-TKIs, anaplastic lymphoma kinase tyrosine kinase inhibitors; PFS, progression-free survival; HR, hazard ratio; Cis, confidence intervals; NSCLC, non-small cell lung cancer; NA, not available; ORR, overall response rate; OS, overall survival; NR, not reached; NA, not available.

AEs with ALK-TKIs across pivotal phase III clinical trials on advanced NSCLC.

Study (n)a, (Ref.) Timeb Common AEs (number and percentage of all grades) Common grade ≥3AEs (number and percentage) Dose change related to AEs
PROFILE 1007 February 2012 Vision disorder (103; 60%) Elevated aminotransferase levels (27; 16%) –
(n=173), (34) Diarrhea (103; 60%) Dyspnea (7; 13%)
Nausea (94; 55%) Constipation (4; 2%)
Vomiting (80; 47%) Fatigue (4; 2%)
PROFILE 1014 January 20, 2011 Vision disorder (122; 71%) Elevated aminotransferases (24; 14%) –
(n=171), (35) Diarrhea (105; 61%) Neutropenia (19; 11%)
Vomiting (78; 46%) Dyspnea (5; 3%)
Constipation (74; 43%) Fatigue (5; 3%)
PROFILE 1029 September 2012 Increased transaminase level (72; 69.2%) Neutropenia (17; 16.3%) –
(n=104), (61) Diarrhea (61; 58.7%) Increased transaminase level (12; 11.5%)
Vision disorder (58; 55.8%) Leukopenia (3; 2.9%)
Vomiting (55; 52.9%) Anemia (3; 2.9%)
ASCEND-4 Aug 19, 2013 Diarrhea (160; 85%) Alanine aminotransferase increased (58; 31%) Dose adjustment or
(n=189), (43) Nausea (130; 69%) Gamma-glutamyltransferase increased (54; 29%) interruption were reported in
Vomiting (125; 66%) Aspartate aminotransferase increased (32; 17%) 152 (80%)
Alanine aminotransferase increased (114; 60%) Blood alkaline phosphatase increased (14; 7%)
ASCEND-5 June 28, 2013 Diarrhea (78; 68%) ALT concentration increased (22; 19%) Dose adjustment or interruption or
(n=115), (44) Nausea (67; 58) GGT concentration increased (21; 18%) delay were reported in 92 (80%)
Vomiting (51; 44%) AST concentration increased (15; 13%)
ALT concentration increased (25; 22%) Vomiting (9; 8%)
Nausea (9; 8%)
ALUR – Fatigue (4; 4.7) Asthenia (2; 2.9%) Dose adjustment or interruption in
(n=72), (47) Constipation (13; 18.6%) Pneumonia (2; 2.9%) 20 (28.6%)
Neutropenia (2; 2.9%) Syncope (2; 2.9%)
Diarrhea (2; 2.9%) Acute kidney injury (2; 2.9%)
Dyspnea (6; 8.6%)
J-ALEX Nov 18, 2013 Constipation (36; 35%) Blood creatine phosphokinase increase (5; 5%) Dose adjustment or interruption in
(n=103), (48) Nasopharyngitis (21; 20%) Respiratory, thoracic, mediastinal disorders and 39 (38%)
Blood creatine phosphokinase increased (18; 17%) interstitial lung disease (5; 5%)
Dysgeusia (19; 18%) Maculopapular rash (3; 3%)
Neutrophil count decrease (2; 2%)
Electrocardiogram QT prolonged (2; 2%)
ALEX August 18, 2014 Anemia (30; 20%) Blood bilirubin increased (3; 2%) Dose adjustment or interruption
(n=152), (49) Peripheral edema (26; 17%) Anemia (7; 5%) 70 (46%)
Myalgia (24; 16%) ALT increased (7; 5%)
Blood bilirubin increased (23; 15%) AST increased (8; 5%)
ALTA-1L April 2016 Diarrhea (67; 49%) Increased blood creatine kinase level (22; 16%) Dose adjustment in 12%
(n=136), (53) Increased blood creatine kinase level (53; 39%) Increased lipase level (18; 13%)
Nausea (36; 26%) Hypertension (13; 10%)
Cough (34; 25%) Increased amylase level (7; 5%)

The number of patients in the treatment group.

Subject to time of first posted for clinical trial. Common AEs define the top four AEs, unless there are multiple rankings in the fourth. ALK-TKIs, anaplastic lymphoma kinase tyrosine kinase inhibitors; NSCLC, non-small-cell lung cancer; AEs, adverse events; ALT, alanine transaminase; AST, aspartate transaminase; QT, the time between the start of the Q-wave and the end of the T-wave; GGT, gamma-glutamyl transpeptidase.

On-going clinical trials of ALK-TKIs in NSCLC.

NCT Drug Identifier Sponsor No. of samples Phase Primary endpoint
NCT03874273 Crizotinib Inflammatory myofibroblastic tumour Federal Research Institute of Pediatric Hematology, Oncology and Immunology 25 II/III ORR
NCT03620643 Crizotinib Lobular breast carcinoma gastric cancer Royal Marsden NHS Foundation Trust 58 II Percentage of participants with objective responses
NCT03088930 Crizotinib Lung cancer, NSCLC University of Colorado, Denver 18 II Objective tumour response rate
NCT03646994 Crizotinib ROS1 arranged non-squamous NSCLC Hunan Province Tumor Hospital 40 II PFS
NCT03672643 Crizotinib ALK or ROS1-positive NSCLC Pfizer 75 IV Long-term safety of crizotinib
NCT02419287 Crizotinib Anaplastic large cell lymphoma, ALK-positive University of Milano Bicocca 12 II ORR Duration
NCT03647111 Crizotinib ALK rearranged non-squamous NSCLC Hunan Province Tumor Hospital 120 II PFS
NCT03052608 Lorlatinib/Crizotinib ALK-positive NSCLC Pfizer 280 III PFS
NCT02201992 Crizotinib Stage IB-IIIA NSCLC that has been removed by surgery and ALK fusion mutations ECOG-ACRIN Cancer Research Group 168 III OS
NCT02679170 Crizotinib Advanced/Metastatic NSCLC Pfizer 100 II Incidence of ALK-positive NSCLC PFS
NCT03087448 Ceritinib + Trametinib NSCLC University of California, San Francisco 69 I/II MTD
NCT02299505 Ceritinib NSCLC Novartis Pharmaceuticals 306 I Plasma concentration of ceritinib
NCT01828099 Ceritinib/Chemotherapy NSCLC Novartis Pharmaceuticals 375 III PFS
NCT02513667 Ceritinib ALK-positive NSCLC University of Texas Southwestern Medical Center 33 II PFS
NCT02393625 Ceritinib With Nivolumab ALK-positive NSCLC Novartis Pharmaceuticals 57 I MTD, ORR
NCT01828112 Ceritinib/Chemotherapy NSCLC previously treated with chemotherapy (platinum doublet) and crizotinib Novartis Pharmaceuticals 232 III PFS
NCT03501368 Ceritinib Melanoma Unresectable Melanoma Advanced Melanoma H. Lee Moffitt Cancer Center and Research Institute 27 II ORR
NCT03611738 Ceritinib + Docetaxel ALK-negative, EGFR WT advanced NSCLC H. Lee Moffitt Cancer Center and Research Institute 48 I MTD Phase Ib: OR
NCT02321501 Ceritinib + Everolimus ALK-positive locally advanced or metastatic solid tumors or stage IIIB-IV NSCLC M.D. Anderson Cancer Center 66 I MTD
NCT03399487 Ceritinib NSCLC harbouring ROS1 rearrangement Yonsei University 46 II ORR
NCT01964157 Ceritinib NSCLC, cancer harbouring ROS1 rearrangement Yonsei University 32 II ORR
NCT03445000 Alectinib Advanced NSCLC European Thoracic Oncology Platform 44 II Best overall response
NCT02521051 Alectinib + Bevacizumab NSCLC Massachusetts General Hospital 43 I/II RP2D
NCT03202940 Alectinib + Cobimetinib Advanced ALK-rearranged (ALK+) NSCLC Massachusetts General Hospital 31 IB/II MTD
NCT03271554 Alectinib ALK-positive, locally advanced or metastatic NSCLC Hoffmann-La Roche 167 II Percentage of participants with AEs
NCT03596866 Brigatinib/Alectinib ALK+NSCLC who have progressed on crizotinib Ariad Pharmaceuticals 246 III PFS
NCT03194893 Alectinib/Crizotinib ALK+NSCLC rearranged during transfection (RET)-positive cancer Hoffmann-La Roche 200 III Number of patients with SAEs, non-SAEs and AEs of special interest
NCT03420742 Brigatinib ALK-positive or ROS1-positive solid tumors Ariad Pharmaceuticals 20 I AUC, Cmax, Tmax
NCT03410108 Brigatinib ALK-positive NSCLC Takeda 110 II ORR 12 months PFS Rate
NCT03535740 Brigatinib ALK+, advanced NSCLC progressed on alectinib or ceritinib (ALTA-2) Ariad Pharmaceuticals 103 II ORR
NCT03596866 Brigatinib/Alectinib Advanced ALK+NSCLC participants who have progressed on crizotinib (ALTA-3) Ariad Pharmaceuticals 246 III PFS
NCT02706626 Brigatinib NSCLC Criterium, Inc. 120 II ORR
NCT02094573 Brigatinib ALK-positive, NSCLC previously, treated with Crizotinib Ariad Pharmaceuticals 222 II ORR
NCT01449461 Brigatinib Antitumour activity of the oral ALK/EGFR Ariad Pharmaceuticals 137 I/II RP2D ORR
NCT03707938 Brigatinib Patients with Stage IV or recurrent NSCLC M.D. Anderson Cancer Center 35 I Incidence of AE
NCT03389399 Brigatinib NSCLC Academic Thoracic Oncology Medical Investigators Consortium 43 I The incidence of EOPEs (time frame: 8 days)
NCT03546894 Any FDA Approved ALK Inhibitors Anaplastic lymphoma kinase-positive Carcinoma NSCLC Millennium Pharmaceuticals, Inc. 160 II Prescriber-confirmed PFS
NCT03909971 Lorlatinib ALK inhibitor-treated ALK-positive NSCLC Pfizer 100 II OR
NCT03505554 Lorlatinib Relapsed ALK-positive lymphoma University of Milano Bicocca 12 II ORR
NCT04127110 Lorlatinib ALK-positive NSCLC patients European Organisation for Research and Treatment of Cancer-EORTC 84 II PFS
NCT03726333 Lorlatinib Advanced cancers Pfizer 76 I Plasma lorlatinib AUC24 at steady state
NCT03961997 Lorlatinib Healthy participants Pfizer 16 I AEs
NCT03439215 Lorlatinib Crizotinib pretreated ROS1-positive NSCLC Fondazione Ricerca Traslazionale 20 II Response rate to PF-06463922 in patients with ROS1 translocation resistant to crizotinib
NCT02927340 Lorlatinib Advanced ALK and ROS1 rearranged lung cancer with CNS metastasis Massachusetts General Hospital 30 II Intracranial disease control rate
NCT03107988 Lorlatinib Neuroblastoma New Approaches to Neuroblastoma Therapy Consortium 40 I RP2D, AE
NCT03542305 Lorlatinib Renal impairment Pfizer 32 I AUC, Cmax
NCT03727477 Lorlatinib NSCLC Intergroupe Francophone de Cancerologie Thoracique 250 II PFS
NCT03796260 Entrectinib Healthy participants Genentech, Inc. 14 I AUC, Cmax
NCT02568267 Entrectinib Solid tumours harbouring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK gene rearrangements (fusions) (STARTRK-2) Hoffmann-La Roche 300 II ORR
NCT02650401 Entrectinib Children and adolescents with solid tumours CNS tumours Hoffmann-La Roche 65 I MTD, RP2D, ORR
NCT02767804 Ensartinib NSCLC Xcovery Holding Company, LLC 290 III PFS
NCT04056572 TQ-B3139 ALK-positive NSCLC previously treated with Crizotinib Chia Tai Tianqing Pharmaceutical Group Co., Ltd. 135 II ORR
NCT04009317 TQ-B3139 ALK-positive NSCLC Chia Tai Tianqing Pharmaceutical Group Co., Ltd. 260 III PFS

ORR, overall response rate; NSCLC, non-small-cell lung cancer; ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; ROS1, c-ros oncogene 1; NTRK, neurotrophic tyrosine kinase; CNS, central nervous system; PFS, progression-free survival; OS, overall survival; MTD, maximum tolerated dose; OR, overall response; RP2D, recommended phase II dose; AEs, adverse events; SAEs, serious adverse events; non-SAEs, non-serious adverse events; EOPEs, early onset pulmonary events; AUC, area under the curve; Cmax, maximum plasma concentration; Tmax, time to achieve peak concentration.