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Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer
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Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer
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Literature review current through: Jul 2017. | This topic last updated: Jun 20, 2017.

INTRODUCTION — A group of patients with non-small cell lung cancer (NSCLC) have tumors that contain an inversion in chromosome 2 that juxtaposes the 5' end of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the 3' end of the anaplastic lymphoma kinase (ALK) gene, resulting in the novel fusion oncogene EML4-ALK [1]. This fusion oncogene rearrangement is transforming both in vitro and in vivo and defines a distinct clinicopathologic subset of NSCLC. It is found in approximately 5 percent of NSCLCs [2].

Tumors that contain the EML4-ALK fusion oncogene or its variants are associated with specific clinical features, including never or light smoking history, younger age, and adenocarcinoma with signet ring or acinar histology. ALK gene arrangements are largely mutually exclusive with epidermal growth factor receptor (EGFR) and KRAS mutations [3]. Screening for this fusion gene in NSCLC is important, as "ALK-positive" tumors (tumors harboring a rearranged ALK gene/fusion protein) are highly sensitive to therapy with ALK-targeted inhibitors.

The molecular pathogenesis, clinical features, and treatment of NSCLC associated with the ALK fusion oncogene are discussed here.

An overview of the treatment of metastatic NSCLC is presented separately, as are the methods and indications for molecular testing. (See "Overview of the treatment of advanced non-small cell lung cancer" and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'Molecular testing'.)

DIAGNOSIS — ALK gene rearrangements or the resulting fusion proteins may be detected in tumor specimens using fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and reverse transcription polymerase chain reaction of cDNA (RT-PCR) [4]. In the United States, FISH and IHC are approved companion diagnostic tests to identify ALK-positive NSCLC. Next-generation sequencing (NGS) is also effective at detecting ALK rearrangements [5], but is not yet approved by the US Food and Drug Administration (FDA). In Europe, IHC is widely used to detect ALK rearrangement.

FISH – The gold standard assay for diagnosing ALK-positive NSCLC is FISH [6-9]. The commercial break-apart probes include two differently colored (red and green) probes that flank the highly conserved translocation breakpoint within ALK. In non-rearranged cells, the overlying red and green probes result in a yellow (fused) signal; in the setting of an ALK rearrangement, these probes are separated, and splitting of the red and green signals is observed (picture 1A-B). Atypical patterns of rearrangement have also been identified, and these are also responsive to ALK inhibition. ALK gene amplification alone is not predictive of responsiveness to these agents and does not carry the same significance as rearrangement.

IHC – Multiple monoclonal antibodies have been developed for the IHC detection of the ALK fusion oncogene, and IHC using these antibodies is highly sensitive and specific [10]. Thus, IHC is an appropriate method to screen for and identify the presence of ALK positivity, and the Ventana ALK (D5F3) CDx assay has been approved for use in the United States by the FDA [11].

RT-PCR of cDNA has been a commonly used screening strategy for detecting ALK gene rearrangements in NSCLC, but is no longer recommended [12]. A number of multiplex assays were developed to simultaneously capture all possible in-frame fusions between EML4 and ALK in which the kinase domain of ALK would be preserved [13-15]. While different breakpoints in EML4 or ALK may be detected, novel ALK fusion partners will not. Furthermore, this method is frequently limited by the quality of the RNA that can be isolated from archival tissue.

CLINICOPATHOLOGIC FEATURES — With increasing identification of this molecular abnormality, the key epidemiologic, demographic, and pathologic features associated with ALK fusion oncogenes have been identified.

Epidemiology – In unselected NSCLC populations, the ALK rearrangement is a relatively rare event, on the order of about 4 percent [7-9,13-17]. Except in rare cases, the presence of ALK gene rearrangements in NSCLC tumors tends to occur independent of epidermal growth factor receptor (EGFR) or KRAS mutations. Similar frequencies of ALK gene rearrangements have been reported in Asian and Western populations [18].

While the overall frequency of ALK fusion oncogene in the general NSCLC population is low, knowledge of the clinicopathologic features enables enrichment for this genetically defined subset. In one study in which patients were selected for genetic screening based on clinical features commonly associated with EGFR mutation, including never/light smoking status and adenocarcinoma histology, 13 percent harbored the ALK fusion oncogene. Within the group of never or light smokers in this study, the frequency of ALK positivity was 22 percent, and among never or light smokers who did not have an EGFR mutation, the frequency was 33 percent [8]. These findings suggest that in NSCLC patients with clinical characteristics associated with EGFR mutation but with negative EGFR testing, as many as one in three may harbor the ALK fusion oncogene. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'Rationale'.)

Age of onset – Patients with ALK fusion oncogene-positive lung cancer are relatively younger at onset than those without this abnormality [8,19]. The two studies that were used to support the approval of crizotinib included 255 patients whose tumors contained an ALK fusion oncogene; in this database, the median age was 52 years (range, 21 to 82 years) [19]. The estimated median age for unselected patients with lung cancer is approximately 70 years [20].

Interestingly, other cancers known to harbor ALK rearrangements such as NPM-ALK-positive anaplastic large cell lymphoma are also associated with younger age and are, in fact, most common in children and young adults.

Smoking history – The ALK fusion oncogene in patients with NSCLC is strongly associated with a history of never or light smoking (<10 pack-years) [1,8,19]. In the crizotinib study database of 255 patients, never smokers and former smokers comprised 70 and 28 percent of cases, respectively [1,8,19].

Histology – The vast majority of lung tumors that harbor the ALK fusion oncogene are adenocarcinomas. In the 255 patients with the ALK fusion oncogene included in the crizotinib database, 97 percent were adenocarcinoma [19]. ALK rearrangement has been reported in squamous cell carcinoma, but this is rare [7,17].

Adenocarcinomas in ALK fusion oncogene-positive cases from Caucasian patients are significantly more likely to have abundant signet ring cells than those with an EGFR mutation or wild type tumors [21]. Signet ring cells are frequently found in gastric cancers and rarely in cancers of other organs such as the lung. Several small case series suggest that signet ring cells may be associated with an aggressive clinical course and a poor prognosis. Whether the presence of signet ring cells in ALK fusion oncogene-positive lung cancer has biologic or clinical significance remains to be determined.

Other studies of ALK in NSCLC have not reported an association with signet ring cells, but have noted a possible association with the acinar subtype of adenocarcinoma, at least in Asian patients. This discrepancy may reflect differences in pathologic interpretation rather than ethnic differences in patients with ALK fusion oncogene-positive lung cancer.

TREATMENT APPROACH

Rationale for ALK inhibitors over chemotherapy — Advanced NSCLC associated with the ALK fusion oncogene is highly sensitive to ALK tyrosine kinase inhibitors (TKIs). Treatment with ALK TKIs should be limited to patients whose tumors contain this abnormality as demonstrated by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC). Patients should have tumor tissue assessed not only for the presence of ALK rearrangement, but also for other driver mutations (especially in the epidermal growth factor receptor [EGFR]). (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'Molecular testing'.)

An ALK inhibitor is preferred as the initial therapy for patients whose tumor contains this genetic abnormality in countries where it is approved for this indication. Results of a phase III trial comparing ALK inhibition using crizotinib with chemotherapy in treatment-naïve patients have demonstrated a prolongation in progression-free survival (PFS) and improved response rate and quality of life [22]. No significant differences in overall survival were seen, potentially due to the confounding effects of crossover. (See 'Crizotinib' below.)

If urgent systemic treatment is required before the results of genotype testing are available, systemic chemotherapy rather than targeted therapy is indicated [23]. When the results of genotype testing become available, the treatment plan should be reassessed. There are no clinical trials that directly address the optimal timing of ALK inhibitors in patients who have already started on chemotherapy. For such patients, we prefer to switch to an ALK inhibitor when genotyping results identify ALK-positive disease.

Preferred first-line targeted therapy — Based on the available clinical data, including the global ALEX study, we suggest alectinib for front-line therapy for those with newly diagnosed, ALK-positive NSCLC. For those without access to alectinib, appropriate alternatives include crizotinib or ceritinib.

An ALK inhibitor is indicated as second-line therapy when progressive disease occurs for patients whose tumor contains the ALK fusion oncogene and initially were treated with chemotherapy.

Alectinib — Alectinib is a second-generation ALK inhibitor that has breakthrough therapy designation by the US Food and Drug Administration (FDA) for the front-line treatment of patients with ALK-positive NSCLC. It is already approved for those who have progressed on crizotinib. Discussion of results in the front-line setting is found here, while data related to its use in the second-line setting and among patients with brain metastases are discussed below. (See 'Alectinib' below and 'Brain metastases' below.)

In J-ALEX, 207 Japanese ALK-positive, crizotinib-naïve NSCLC patients were randomly assigned to alectinib versus crizotinib [24]. At a planned interim analysis, results demonstrate improved PFS with alectinib; median PFS was not reached in the alectinib arm and was 10.2 months in the crizotinib arm (hazard ratio [HR] 0.34, 99.7% CI 0.17-0.70). Alectinib was also better tolerated, with the most frequent adverse event being constipation (36 percent). Patients receiving crizotinib experienced nausea (74 percent), diarrhea (73 percent), visual disturbances (55 percent), and ALT/AST elevations (>30 percent), among other toxicities.

One limitation of this study was that it was performed in an entirely Asian population, and it was not known whether the results would be more broadly applicable [25]. However, in a global study of 303 patients randomly assigned to first-line alectinib versus crizotinib (ALEX), those receiving alectinib had a reduction in risk of progression or death of 53 percent (HR 0.47, 95% CI 0.34-0.65), with median PFS not reached versus 11.1 months for those receiving crizotinib at a median follow-up of approximately 18 months [26]. Based on independent review, median PFS was 25.7 months with alectinib and 10.4 months with crizotinib (HR 0.50). Overall survival results are not yet mature. The time to central nervous system (CNS) progression in the overall population was improved with alectinib (HR 0.16, 95% CI 0.10-0.28). Grade 3 to 5 toxicities were less frequent with alectinib (41 versus 50 percent). (See 'Toxicity' below.)

Alternatives — Although we prefer alectinib in the front-line setting for those who are found to have ALK-positive advanced NSCLC, many patients will have been treated with crizotinib, which was the first available ALK inhibitor. The next-generation inhibitor ceritinib is also available and demonstrates increased potency over crizotinib. Both agents demonstrate improved outcomes over chemotherapy for advanced ALK-positive NSCLC.

Crizotinib — Crizotinib is a multitargeted small molecule TKI, which was originally developed as an inhibitor of mesenchymal epithelial transition growth factor (c-MET); it is also a potent inhibitor of ALK phosphorylation and signal transduction [27]. This inhibition is associated with G1-S phase cell cycle arrest and induction of apoptosis in ALK-positive cells in vitro and in vivo [27]. Crizotinib also inhibits the related ROS1 receptor tyrosine kinase. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'ROS1 translocation'.)

Crizotinib was the first ALK inhibitor used clinically and has demonstrated markedly improved outcomes in patients with ALK-positive advanced NSCLC relative to chemotherapy, both in the front-line and subsequent-line setting [22,28]. However, newer, more potent ALK inhibitors with greater systemic and CNS efficacy have since been developed and are preferred over crizotinib. (See 'Alectinib' above and 'Ceritinib' below.)

As newer ALK inhibitors are being used in the front-line setting only more recently, many patients will have been treated initially with and have developed resistance to crizotinib, making second-line ALK inhibitor treatment an important consideration. (See 'Resistance to crizotinib' below.)

The efficacy of crizotinib has been demonstrated in randomized trials limited to patients whose tumors had the ALK rearrangement:

Previously treated patients − A phase III trial randomly assigned 347 patients who had previously been treated with one prior platinum-based chemotherapy regimen to either crizotinib or single-agent pemetrexed or docetaxel [28]. Patients who were assigned to chemotherapy were allowed to be treated with crizotinib when they developed progressive disease.

At a median follow-up of 12 months, PFS, the primary endpoint of the trial, was increased with crizotinib compared with chemotherapy (median, 7.7 versus 3 months; HR for progression 0.49, 95% CI 0.37-0.64).

The objective response rate based upon independent radiologic review was also increased (65 versus 20 percent). Responses were achieved more rapidly than with chemotherapy (median time to response, 6.3 versus 12.6 weeks) and were of longer duration (32 versus 24 weeks).

There was no difference in overall survival (median, 20.3 versus 22.8 months; HR for death 1.02). The absence of an overall survival benefit presumably reflects subsequent treatment since 64 percent of chemotherapy-treated patients had crossed over to crizotinib after progressing on chemotherapy. (See 'Preferred first-line targeted therapy' above.)

Chemotherapy-naïve patients − In a second trial, 343 chemotherapy-naïve patients were randomly assigned to crizotinib or chemotherapy with pemetrexed plus either cisplatin or carboplatin [22]. Crossover to crizotinib was permitted for those treated with chemotherapy. PFS, the primary endpoint of the trial, was prolonged with crizotinib compared with chemotherapy (median, 10.9 versus 7 months; HR 0.45, 95% CI 0.35-0.60). The objective response rate was also increased (74 versus 45 percent). The difference in overall survival was not significant (HR 0.82, 95% CI 0.54-1.26). However, the majority of patients assigned to initial chemotherapy subsequently were treated with crizotinib. Outcomes related to intracranial disease control are discussed below. (See 'Brain metastases' below.)

Ceritinib — Ceritinib is a second-generation TKI of ALK that is approximately 20 times more potent than crizotinib. Ceritinib is approved by the FDA for patients with metastatic NSCLC whose tumors are ALK-positive as detected by an FDA-approved test [29]. While initial trials have been conducted using a fasting dose of 750 mg daily, a randomized open-label trial demonstrated equivalence between this dose and 450 mg daily with food, which may be used as an alternative dosing strategy [30].

Ceritinib has demonstrated improved efficacy over combination chemotherapy in the front-line setting. In the ASCEND-4 trial, which included 376 treatment-naïve, ALK-positive NSCLC patients, those randomly assigned to ceritinib (750 mg/day) experienced improved PFS (16.6 versus 8.1 months; HR 0.55, 95% CI 0.42-0.73), objective response rate (72.5 versus 26.7 percent), and duration of response (23.9 versus 11.1 months) compared with those assigned to pemetrexed and a platinum agent [31]. Results regarding intracranial efficacy of ceritinib from this study are discussed below. (See 'Brain metastases' below.)

In studies, the most frequent toxicities associated with ceritinib have been diarrhea, nausea, and vomiting, affecting the majority of patients, although adverse effects lead to ceritinib discontinuation in only approximately 5 percent [32,33]. (See 'Toxicity' below.)

Duration of treatment — Treatment with ALK inhibitors is generally continued until there is evidence of disease progression. In carefully selected patients (eg, an isolated site of recurrence that can be treated with local therapy, those with extremely mild and asymptomatic progression), an ALK inhibitor may be continued after initial evidence of progressive disease [34]. Upon progression, treatment with a next-generation ALK inhibitor or with standard therapy may be indicated. (See 'Treatment after progression on an ALK inhibitor' below.)

Treatment after progression on an ALK inhibitor

Resistance to crizotinib — For ALK-positive patients who develop resistance to crizotinib or who are unable to tolerate crizotinib, we recommend treatment with one of the second-generation ALK inhibitors brigatinib, alectinib, or ceritinib. Our preference in this setting is alectinib, given the CNS and systemic efficacy as well as tolerability, though we recognize that in the absence of head-to-head comparisons, any of these agents is an appropriate option.

While crizotinib is highly active in patients with ALK-positive NSCLC, almost all patients develop resistance to the drug, typically within the first few years of treatment. Several distinct mechanisms of resistance have been reported in the literature including:

In approximately one-third of resistant cases, tumors have acquired a secondary mutation within the ALK tyrosine kinase domain. The most common resistance mutation is the gatekeeper L1196M mutation, followed closely by the G1269A mutation. Other mutations occur at residues 1151, 1152, 1156, 1174, 1202, 1203, and 1206. The G1202R mutation is notable, as it confers high-level resistance to crizotinib as well as to next-generation ALK inhibitors (see below).

A second mechanism of crizotinib resistance is amplification of the ALK fusion gene. This can occur alone or in combination with a secondary resistance mutation.

Activation of alternative or bypass signaling pathways has also been shown to mediate crizotinib resistance. These include abnormalities in EGFR, KIT, and insulin-like growth factor-1 receptor (IGF1R) pathways, and suggest the potential need for combination therapies to overcome resistance.

Alectinib — Alectinib is an ALK inhibitor that is approved for clinical use in patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib [35]. Phase II studies have demonstrated response rates to alectinib of approximately 50 percent in patients with ALK-positive locally advanced or metastatic NSCLC who had progressed on crizotinib [36,37]. Details are below.

In the first study, 122 patients with evaluable, ALK-positive, crizotinib-resistant disease were included [36]. Eighty percent had progressed after prior platinum-based chemotherapy. With a median follow-up of 47 weeks, alectinib was associated with an overall objective response rate of 50 percent, a disease control rate (objective response plus stable disease) of 79 percent, and median duration of response was 11 months. The median PFS was 8.9 months.

A second phase II study including 69 patients with measurable advanced ALK-positive NSCLC who had progressed on crizotinib found that alectinib was associated with an objective response rate of 48 percent at a follow-up of 4.8 months [37].

Ceritinib — Ceritinib is approved by the FDA for patients with metastatic NSCLC whose tumors are ALK-positive as detected by an FDA-approved test [29]. A randomized phase III study also demonstrated that, among ALK-positive NSCLC patients who have progressed on crizotinib, ceritinib yields improved outcomes relative to single-agent chemotherapy. In the open-label ASCEND-5 study, in which 231 patients who had received crizotinib were randomly assigned to ceritinib 750 mg/day or chemotherapy, those receiving ceritinib experienced improved PFS (5.4 versus 1.6 months; HR 0.49) and objective response rate (39.1 versus 6.9 percent), differences that were both statistically significant [38]. Although no improvement in overall survival was noted among those assigned to ceritinib, the overall survival analysis is immature. Furthermore, 75 patients assigned to chemotherapy crossed over to ceritinib upon progression, potentially diluting an overall survival benefit.

These results are consistent with previous early-phase trials [39,40], and with preclinical studies demonstrating activity of ceritinib against cells that were either sensitive or resistant to crizotinib, including those with the most common L1196M and G1269A resistance mutations [39].

Brigatinib — Brigatinib is an ALK inhibitor that is approved for clinical use in patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib [41]. A phase II study of 222 patients with crizotinib-refractory, ALK-positive NSCLC demonstrated PFS of 9.2 and 12.9 months among those receiving a lower and higher dose of the agent, respectively, with low incidence of grade ≥3 toxicities in both arms [42]. However, brigatinib has been associated with early pulmonary toxicity in approximately 9 percent of cases [41]. (See 'Toxicity' below.)

Resistance to other ALK inhibitors — Preclinical and early clinical studies suggest that patients who have acquired ALK resistance mutations upon progression on next-generation ALK inhibitors may still be ALK-dependent. The most common ALK resistance mutation seen after alectinib is ALK G1202R, which is susceptible to the third-generation inhibitor lorlatinib. The second most common ALK resistance mutation is I1171 mutations, which are susceptible to either ceritinib or lorlatinib [43]. (See 'Ceritinib' above.)

Given these observations, we typically obtain tumor rebiopsy after failure on a next-generation ALK inhibitor, because the identification of an ALK resistance mutation may help guide selection of a next line of ALK inhibitor or participation on a clinical trial. In the absence of ALK resistance mutations after failure of alectinib, preclinical data suggest that these tumors may no longer be sensitive to ALK inhibitor monotherapy [43]. In this setting, we favor trials of ALK-based combinations or standard approaches, such as chemotherapy. The data are still emerging for management of patients post-alectinib, and we await evidence-based guidelines.

Lorlatinib is an investigational ALK inhibitor that has shown promising activity in a phase I/II study [44], and has been granted FDA breakthrough therapy designation. In preliminary data of a phase I/II study including 82 ALK-positive patients who had been treated with at least one prior ALK inhibitor, the overall response rate to lorlatinib was 26 percent [45]. Of note, among 44 patients who had received two or more prior ALK inhibitors, the objective response rate was 25 percent, highlighting the potent activity of this agent in refractory disease. Importantly, lorlatinib has demonstrated activity in patients whose tumors harbor the highly resistant mutation ALK G1202R. This mutation confers resistance to other next-generation ALK inhibitors, including ceritinib, alectinib, and brigatinib. Among patients with brain metastases, the intracranial objective response rate was 48 percent. Hypercholesterolemia is the most frequent adverse event with lorlatinib.

Brain metastases — For asymptomatic and symptomatic patients, alectinib (and other brain-penetrable ALK TKIs) may be used. (Brigatinib also has CNS activity [31], but may be less tolerable than alectinib owing to pulmonary toxicity.) While crizotinib does have some CNS activity and has demonstrated improved outcomes over chemotherapy for those with newly diagnosed ALK-positive NSCLC and brain metastases [46,47], we prefer alectinib. Except in situations where there is impending herniation, most patients with brain metastases (either TKI-naϊve or on crizotinib) will respond to alectinib, and surgery and or/radiation may be deferred. However, in the case of severe mass effect or impending herniation, we proceed with surgery [48,49].

Patients with brain metastases receiving systemic therapy should be monitored closely with magnetic resonance imaging (MRI), although the optimal frequency is unknown. Our approach is to monitor every three to six months, although for those on alectinib and other brain-penetrable TKIs, it may be possible to monitor less frequently.

For patients who proceed with surgery, ALK inhibitors may be initiated soon after surgery (assuming the patient is tolerating an oral diet). For patients who receive whole-brain radiation, we hold ALK inhibitors during treatment given potential for toxicity. For those treated with stereotactic radiation surgery, we either hold ALK inhibitors for one to three days, or continue through treatment, with close monitoring for toxicity.

Support for alectinib over crizotinib as front-line treatment among those with brain metastases comes from phase III trials. In the J-ALEX study, among 43 crizotinib-naïve patients with ALK-positive NSCLC with brain metastases, alectinib demonstrated improved PFS relative to crizotinib (HR 0.08, CI 0.01-0.61). Similarly, in ALEX, among those with CNS metastases, alectinib improved PFS relative to crizotinib (HR 0.40, 95% CI 0.25-0.64) and intracranial response rate (81 versus 50 percent). Further results of J-ALEX and ALEX are discussed above [26]. (See 'Alectinib' above.)

Evidence of the activity of alectinib among patients with brain metastases among those who have crizotinib-resistant disease comes from phase II studies. In a pooled analysis of two phase II studies, among 136 patients with baseline CNS metastases, 70 percent of whom had prior CNS radiotherapy, the CNS objective response rate, disease control rate, and duration of response for alectinib were 43 percent, 85 percent, and 11.1 months, respectively [48].

Other next-generation ALK inhibitors have also been reported to have activity against brain metastases; these include ceritinib [31,40,49,50], brigatinib [41,51,52], and lorlatinib (PF-06463922) [53]. For example, in the phase II study discussed above, among patients who were refractory to crizotinib, the intracranial response rate of brigatinib was 67 percent, with a median duration of intracranial response of 5.6 months [41,51]. In ASCEND-4 discussed above, among patients with at least one brain metastasis at baseline, intracranial objective response rate was higher with first-line ceritinib than for platinum-based chemotherapy (72.7 versus 27.3 percent) [31]. (See 'Brigatinib' above and 'Ceritinib' above.)

TOXICITY — Treatment with the ALK inhibitors is generally well tolerated. However, there are a number of significant toxicities that may require dose modification or treatment discontinuation.

Gastrointestinal side effects – Nausea, vomiting, and diarrhea are common with crizotinib and ceritinib, but are more severe with ceritinib. With crizotinib and alectinib, less than 1 percent of these side effects were severe. However, more than one-half of patients treated with ceritinib required dose modification, and 9 percent required treatment discontinuation. (See "Enterotoxicity of chemotherapeutic agents", section on 'ALK inhibitors'.)

Liver function test abnormalities can be seen with all of the ALK inhibitors. Transaminase elevation is commonly seen with crizotinib and ceritinib. Elevated blood bilirubin can been seen with alectinib. Liver function tests should be checked every two weeks for the first eight weeks of treatment. Hepatoxicity can develop and progress, and may require dose modification or discontinuation. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease", section on 'Crizotinib, ceritinib, and alectinib'.)

Constipation has been observed in over a third of patients receiving alectinib. (See 'Alectinib' above.)

Pneumonitis – Severe, life-threatening, or fatal treatment-related pneumonitis has been reported in 1 to 4 percent of patients treated with either crizotinib or ceritinib. Alectinib is associated with an 0.4 percent incidence of interstitial lung disease (ILD)/pneumonitis, whereas brigatinib has a higher incidence (9.1 percent) [41]. Of note, brigatinib has an unusual early pulmonary toxicity reaction (respiratory symptoms after one to two doses) [54]. The development of pneumonitis should result in discontinuation of treatment with these agents. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'ALK inhibitors'.)

Cardiac toxicity – Cardiac toxicity is observed with crizotinib, brigatinib, and ceritinib. Our approach is to perform an electrocardiogram (EKG) at baseline in all patients treated with these agents. Subsequently, we check an EKG if the patient develops bradycardia (whether symptomatic or not) or if the patient is started on a drug that is known to cause QTc prolongation. (See "Cardiotoxicity of nonanthracycline cancer chemotherapy agents", section on 'Crizotinib and ceritinib' and "Cardiotoxicity of nonanthracycline cancer chemotherapy agents", section on 'Brigatinib'.)

Sinus bradycardia is relatively frequent in patients treated with crizotinib and may be severe in some cases [55,56]. However, patients with sinus bradycardia were asymptomatic, and the bradycardia was not explained by other comorbidity or medications. Caution should be used in the concomitant administration of beta blockers in patients treated with crizotinib. (See "Cardiotoxicity of nonanthracycline cancer chemotherapy agents", section on 'Crizotinib and ceritinib'.)

QTc interval prolongation has been observed with crizotinib, and crizotinib should be avoided in patients with congenital long QT syndrome. Treatment should be temporarily discontinued if severe QTc prolongation develops and permanently discontinued if it recurs or is accompanied by an arrhythmia, heart failure, hypotension, shock, syncope, or torsade de pointes.

Cytochrome p450 interactions – Both crizotinib and ceritinib are metabolized by cytochrome P450 CYP3A4. Thus, caution should be used when it is given concomitantly with CYP3A4 inhibitors, and care is required when these agents are coadministered with other agents that are predominantly metabolized by this system (table 1).

Visual disturbances – Visual disturbances were seen in 60 to 65 percent of patients treated with crizotinib in phase II studies [19]. The main complaints are trailing lights, flashes, and brief image persistence, primarily associated with the transition from dark to light. Uncommon visual manifestations included photophobia, decreased visual acuity, and blurred vision. Visual symptoms have been reported with ceritinib, but their overall incidence is less than 10 percent.

Symptoms often improve over time, and treatment cessation is usually not needed. However, the United States prescribing information recommends discontinuation of crizotinib in patients with new onset of severe visual loss [19]. (See "Ocular side effects of systemically administered chemotherapy" and "Ocular side effects of systemically administered chemotherapy", section on 'ALK inhibitors'.)

Endocrine – Endocrine complications have been reported with crizotinib.

With crizotinib, rapid depression of serum testosterone levels has been observed [57,58]. In a series of 32 patients treated with crizotinib, the mean serum testosterone level was below the lower limit of normal in 27 of 32 men (84 percent) compared with 6 of 19 (32 percent) among those not receiving crizotinib [58]. Levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were also low, suggesting a centrally mediated mechanism. A large component of the lowered total testosterone may be due to significant depression of sex hormone binding globulin. Male patients who report symptoms of hypogonadism can be referred to endocrinology to discuss potential testosterone replacement. These findings require validation in larger cohorts. (See "Clinical features and diagnosis of male hypogonadism".)

Renal cysts – Renal cysts have been reported in 4 percent of patients treated with crizotinib [19]. The cysts may be positive on positron emission tomography (PET) and can create confusion with renal metastases [59]. These cysts may be complex. Although the natural history of crizotinib-associated renal cysts is not fully known, one report found that complex renal cysts regress when treatment with crizotinib is discontinued [60]. (See "Simple and complex renal cysts in adults".)

Hypersensitivity reactions – Hypersensitivity reactions have been described in two patients treated with crizotinib, manifested by a generalized rash developing hours after the administration of oral dosing [61]. Desensitization was carried out using escalating doses of crizotinib administered every 15 minutes over a three-hour period, preceded by one hour with single doses of loratadine (10 mg), cetirizine (10 mg), and fexofenadine (180 mg). Following desensitization there were no further symptoms suggesting a hypersensitivity reaction.

OTHER APPROACHES

Chemotherapy – Cytotoxic chemotherapy appears to have slightly increased activity in ALK-positive patients with NSCLC compared with the general population of adenocarcinoma patients. The choice of a specific chemotherapy agent or regimen is based upon the same criteria applied in other cases of advanced NSCLC. When patients with ALK-positive advanced NSCLC require chemotherapy, pemetrexed or a pemetrexed-based regimen is generally preferred, since almost all of these patients have adenocarcinoma histology. (See "Systemic therapy for the initial management of advanced non-small cell lung cancer without a driver mutation", section on 'Effect of histology' and "Advanced non-small cell lung cancer: Subsequent systemic therapy for previously treated patients", section on 'Single-agent chemotherapy'.)

Immunotherapy – Early- and later-phase immunotherapy trials suggest lower response rates among never-smoking patients, including those with ALK and epidermal growth factor receptor (EGFR) genetic aberrations, and subsequent trials have frequently excluded this subset of patients. Nevertheless, we consider immunotherapy to be an appropriate option for patients with ALK-positive NSCLC who have progressed on available ALK inhibitors, at least one line of systemic chemotherapy, and who are candidates for subsequent treatment. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition".)

Patients with the ALK fusion oncogene do not appear to respond to EGFR tyrosine kinase inhibitors (TKIs). In a retrospective cohort of 19 patients with the ALK fusion oncogene, there were no clinical responses to EGFR TKIs, and the median time to progression was only five months [8].

SUMMARY AND RECOMMENDATIONS

The presence of an anaplastic lymphoma kinase (ALK) fusion oncogene defines a molecular subset of non-small cell lung cancer (NSCLC) with distinct clinical and pathologic features. The patients most likely to harbor ALK rearrangement are relatively young, never or light smokers with adenocarcinoma. (See 'Clinicopathologic features' above.)

In the United States, ALK positivity must be demonstrated by either fluorescence in situ hybridization (FISH) using the US Food and Drug Administration (FDA)-approved test (Vysis Probes), or by immunohistochemistry using the FDA-approved Ventana ALK (D5F3) CDx assay. In Europe, immunohistochemistry is widely used to detect ALK rearrangement. (See 'Diagnosis' above.)

For patients with advanced or metastatic NSCLC whose tumors contain a characteristic ALK fusion oncogene, we recommend initial treatment with an ALK inhibitor rather than chemotherapy (Grade 1B). (See 'Rationale for ALK inhibitors over chemotherapy' above.)

In some cases, chemotherapy is required before the results of molecular testing are available. If the tumor is found to contain the ALK fusion oncogene, the authors prefer to switch to an ALK inhibitor. (See 'Preferred first-line targeted therapy' above and 'Rationale for ALK inhibitors over chemotherapy' above.)

For those with newly diagnosed ALK-positive NSCLC, we recommend alectinib as first-line treatment (Grade 1B), based on two randomized trials showing improved efficacy (both systemic and intracranial) as well as a more favorable side effect profile compared with crizotinib. For those without access to alectinib, appropriate alternatives include crizotinib or ceritinib. (See 'Preferred first-line targeted therapy' above.)

Therapy should be continued until there is evidence of progressive disease or prohibitive toxicity. In carefully selected patients with an isolated site of recurrence that can be treated with local therapy or those with extremely mild and asymptomatic progression, the chosen ALK inhibitor may be continued after initial evidence of progressive disease. (See 'Duration of treatment' above.)

For most patients with brain metastases from ALK-positive NSCLC, we treat with alectinib. Surgery and/or radiation therapy may be pursued if urgent decompression is needed. (See 'Brain metastases' above and "Overview of the treatment of brain metastases".)

For ALK-positive patients who develop resistance to crizotinib or who are unable to tolerate crizotinib, we recommend treatment with one of the second-generation ALK inhibitors brigatinib, alectinib, or ceritinib (Grade 1B). Our preference in this setting is alectinib, given the central nervous system (CNS) and systemic efficacy as well as tolerability, though we recognize that in the absence of head-to-head comparisons, any of these agents is an appropriate option. (See 'Ceritinib' above and 'Alectinib' above and 'Brigatinib' above.)

Chemotherapy is an appropriate option for patients who no longer respond to ALK inhibition. (See "Systemic therapy for the initial management of advanced non-small cell lung cancer without a driver mutation" and "Advanced non-small cell lung cancer: Subsequent systemic therapy for previously treated patients".)

Treatment with the ALK inhibitors is generally well tolerated, though associations with pneumonitis, liver function test abnormalities, bradycardia, and visual disturbances have been noted. (See 'Toxicity' above.)

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