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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 . This fusion oncogene rearrangement is transforming both in vitro and in vivo and defines a distinct clinicopathologic subset of NSCLC.
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) or KRAS mutations . 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 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'.)
MOLECULAR PATHOGENESIS — The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion oncogene arises from an inversion on the short arm of chromosome 2 (Inv(2)(p21p23)) that joins exons 1-13 of EML4 to exons 20-29 of ALK . The resulting chimeric protein, EML4-ALK, contains an N-terminus derived from EML4 and a C-terminus containing the entire intracellular tyrosine kinase domain of ALK.
Since the discovery of this fusion oncogene in 2007, multiple variants of EML4-ALK have been reported, all of which encode the same cytoplasmic portion of ALK but contain different truncations of EML4 (figure 1) [3-5]. In addition, fusions of ALK with other partners including TRK-fused gene TFG and KIF5B have also been described in lung cancer patients, but appear to be much less common than EML4-ALK [5,6].
For EML4-ALK, the EML4 fusion partner mediates ligand-independent dimerization and/or oligomerization of ALK, resulting in constitutive kinase activity. In cell culture systems, EML4-ALK possesses potent oncogenic activity . In transgenic mouse models, lung-specific expression of EML4-ALK leads to the development of numerous lung adenocarcinomas .
The oncogenic role of the ALK fusion oncogene provides a potential avenue for therapeutic intervention. Cancer cell lines harboring the EML4-ALK translocation are effectively inhibited by small molecule inhibitors that target the ALK tyrosine kinase (TK) . In vivo, treatment of EML4-ALK transgenic mice with ALK inhibitors results in tumor regression , supporting the notion that ALK-driven lung cancers are "addicted" to the fusion oncogene.
DIAGNOSIS — Anaplastic lymphoma kinase (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) .
●FISH – The gold standard assay for diagnosing ALK-positive non-small cell lung cancer (NSCLC) is FISH [10-13]. 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 . Thus, IHC can potentially be used to screen for and identify the presence of ALK positivity. In the United States, FISH and IHC are approved companion diagnostic tests to identify ALK-positive NSCLC. In Europe, IHC is widely used to detect ALK rearrangement.
●RT-PCR – RT-PCR of cDNA has been a commonly used screening strategy for detecting ALK gene rearrangements in NSCLC, but is no longer recommended . 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 [3,8,16]. 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 anaplastic lymphoma kinase (ALK) fusion oncogenes have been identified.
Epidemiology — In unselected non-small cell lung cancer (NSCLC) populations, the ALK rearrangement is a relatively rare event. In the initial report, 5 of 75 lung tumors (7 percent) demonstrated expression of the fusion transcript. The overall incidence of ALK gene rearrangements in subsequent series has been about 4 percent [3,8,11-13,16-18]. 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 .
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 . 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 [12,20]. 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) . The estimated median age for unselected patients with lung cancer is approximately 70 years .
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) [1,12,20]. In the crizotinib study database of 255 patients, never smokers and former smokers comprised 70 and 28 percent of cases, respectively [1,12,20].
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 . ALK rearrangement has been reported in squamous cell carcinoma, but this is rare [11,18].
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 . 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 lung cancer has biological 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.
CHEMOTHERAPY VERSUS TARGETED THERAPY — Advanced non-small cell lung cancer (NSCLC) associated with the anaplastic lymphoma kinase (ALK) fusion oncogene is highly sensitive to ALK tyrosine kinase (TK) inhibitors. Treatment with ALK TK inhibitors should be limited to patients whose tumors contain this abnormality as demonstrated by fluorescence in situ hybridization (FISH). (See 'Diagnosis' above and "Overview of the treatment of advanced non-small cell lung cancer", section on 'Initial systemic therapy'.)
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 and improved response rate and quality of life . No significant differences in overall survival were seen, potentially due to the confounding effects of crossover. (See 'Crizotinib' below.)
In other countries, its use may be restricted to those who have progressed following chemotherapy. Thus patients should have tumor tissue assessed for the presence of ALK rearrangement, as well as 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'.)
If systemic treatment is required before the results of genotype testing are available, systemic chemotherapy rather than targeted therapy is indicated . 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 (algorithm 1).
If an ALK fusion oncogene is identified after the initiation of treatment, we suggest continuing chemotherapy for four cycles if therapy is tolerated and there is no evidence of disease progression. There are no data directly comparing continuation using maintenance chemotherapy versus a switch to crizotinib after completion of this initial chemotherapy. The authors’ preference is to switch to crizotinib, rather than to use maintenance chemotherapy, because there are some patients who will deteriorate due to disease progression and thus miss the opportunity to be treated with an ALK inhibitor.
For patients who continue treatment with chemotherapy, crizotinib is indicated when there is evidence of disease progression. Factors that should be discussed with the patient in defining a treatment plan include the quality of the initial response to chemotherapy and the potential side effects of maintenance therapy.
ALK INHIBITORS: EFFICACY — Three tyrosine kinase inhibitors (TKI), crizotinib, ceritinib, and alectinib, have established roles in the treatment of anaplastic lymphoma kinase (ALK) fusion oncogene-positive non-small cell lung cancer (NSCLC), and additional agents are under development.
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 . This inhibition is associated with G1-S phase cell cycle arrest and induction of apoptosis in ALK-positive cells in vitro and in vivo . 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'.)
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 Ventana ALK (D5F3) CDx assay, in accordance with the FDA label. In Europe, immunohistochemistry is widely used to detect ALK rearrangement.
Randomized trials — 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 . 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, progression-free survival, the primary endpoint of the trial, was significantly increased with crizotinib compared with chemotherapy (median, 7.7 versus 3 months; hazard ratio [HR] for progression 0.49, 95% CI 0.37-0.64).
•The objective response rate based upon independent radiologic review was also significantly 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 significant 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.
●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 . Crossover to crizotinib was permitted for those treated with chemotherapy. Progression-free survival, the primary endpoint of the trial, was significantly 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 significantly 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 'Crizotinib against brain metastases' below.)
Duration of treatment — Treatment with crizotinib is generally continued until there is evidence of disease progression. The standard approach for patients with progressive disease is the use of the second-generation ALK inhibitor ceritinib. In carefully selected patients (eg, an isolated site of recurrence that can be treated with local therapy, those with extremely mild and asymptomatic progression), crizotinib may be continued after initial evidence of progressive disease . (See 'Ceritinib' below.)
Resistance to crizotinib — 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.
●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.
●Finally, a number of alternative or bypass signaling pathways have been shown to mediate crizotinib resistance. These include abnormalities in the epidermal growth factor receptor (EGFR), KIT, and insulin-like growth factor-1 receptor (IGF1R) pathways, and suggest the potential need for combination therapies to overcome resistance.
Ceritinib — Ceritinib is a second-generation TK inhibitor of ALK that is approximately 20 times more potent than crizotinib. Ceritinib is approved by the FDA for patients who have progressed on or are intolerant of crizotinib . 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 .
A randomized phase III study demonstrated that, among ALK-positive NSCLC patients who have progressed on crizotinib, ceritinib yields improved outcomes relative to single-agent chemotherapy. In preliminary results of 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 progression-free survival (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 . 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.
Ceritinib has also demonstrated improved efficacy over combination chemotherapy in the frontline setting. In preliminary results from ASCEND-4 including 376 treatment-naïve, ALK-positive NSCLC patients, those randomly assigned to ceritinib (750 mg/day) experienced improved progression-free survival (16.6 [12.6 to 17.2] versus 8.1 [5.8 to 11.1] months, HR 0.55), 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 . Results regarding intracranial efficacy of ceritinib from this study are discussed below. (See 'Next-generation inhibitors against brain metastases' below.)
In both of these studies, the most frequent toxicities associated with ceritinib were diarrhea, nausea, and vomiting, affecting the majority of patients, although adverse effects led to ceritinib discontinuation in only approximately 5 percent [30,31].
These results are consistent with previous early-phase trials [32,33], 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 .
Alectinib — Alectinib is another second-generation ALK inhibitor that has activity in crizotinib-resistant disease with reported activity in brain metastases [34-38]. It is FDA-approved for the treatment of patients with ALK-positive NSCLC who have progressed on or are intolerant of crizotinib. We also favor its use for the patient with newly diagnosed, ALK-positive NSCLC who presents with central nervous system (CNS) disease. Discussion of the systemic efficacy in advanced disease is found here, while results related to the subset of these patients with brain metastases are discussed below. (See 'Next-generation inhibitors against brain metastases' below.)
Data to support the FDA approval come from two phase II studies, both demonstrating response rates to alectinib of approximately 50 percent in patients with ALK-positive locally advanced or metastatic NSCLC who had progressed on crizotinib [38,39]. Details of each study are below.
●In the first study, 122 patients with evaluable, ALK-positive, crizotinib-resistant disease were included . 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 progression-free survival 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 .
Although alectinib in the first-line setting is also the subject of active study, there are insufficient data supporting the use of ceritinib or alectinib as the initial ALK inhibitor for patients who lack CNS disease. In J-ALEX, 207 Japanese ALK-positive, crizotinib-naïve NSCLC patients were randomly assigned to alectinib versus crizotinib . At a planned interim analysis, preliminary results demonstrate improved progression-free survival (PFS) with alectinib; median PFS was not reached in the alectinib arm and was 10.2 months in the crizotinib arm (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. Despite these results, it is unknown whether frontline alectinib improves survival outcomes compared with the strategy of frontline crizotinib followed by alectinib upon progression. A global study of first-line alectinib versus crizotinib (ALEX) has completed accrual and results are expected next year. The use of alectinib in patients with CNS disease is discussed below. (See 'Brain metastases' below and 'Next-generation inhibitors against brain metastases' below.)
Brigatinib — Brigatinib is an investigational ALK inhibitor that is not yet approved for clinical use. Preliminary results of a phase II study of 222 patients with crizotinib-refractory, ALK-positive NSCLC demonstrated PFS of 8.8 and 11.1 months among those receiving a lower and higher dose of the agent, respectively, with low incidence of grade ≥3 toxicities in both arms . However, brigatinib has been associated with early pulmonary toxicity in a small percentage of cases.
Lorlatinib — Lorlatinib is another investigational ALK inhibitor that has shown promising activity in a phase I study. Among 41 ALK-positive patients, the confirmed overall response rate was 46 percent and median PFS 11.4 months . Of note, 26 of the 41 patients had received two or more prior ALK inhibitors, 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.
Brain metastases — Surgery and/or radiation therapy have been the primary treatment modalities for most patients with brain metastases from NSCLC, including those with the EML4-ALK fusion oncogene [43,44]. However, advances in targeted therapy may eventually provide an important alternative. For the patient who presents with newly diagnosed, ALK-positive NSCLC with CNS metastases (including leptomeningeal disease), we favor alectinib over crizotinib given frequent CNS relapses on crizotinib and its poor penetration of the CNS, alectinib's excellent CNS penetration and high overall response rate and duration of response, and results from the J-ALEX study favoring alectinib over crizotinib in the subset of patients with brain metastases. (See 'Next-generation inhibitors against brain metastases' below.)
The presence of ALK rearrangements appears to be associated with a better prognosis than what is historically reported for NSCLC patients with brain metastases, likely due to the availability of brain-penetrable TKIs in addition to standard therapies. In a retrospective study of 90 patients with ALK-rearranged NSCLC, the median overall survival after development of brain metastases was 49.5 months . Nearly all of the patients received radiotherapy to the brain (whole brain RT and/or stereotactic radiosurgery) and a TKI.
Crizotinib against brain metastases — Crizotinib appears to have modest activity against brain metastases.
In a study of 343 patients with advanced ALK-positive lung cancer randomly assigned to crizotinib versus chemotherapy (pemetrexed and platinum chemotherapy), among 79 patients with treated brain metastases, crizotinib demonstrated an increased intracranial disease control rate (including stable disease, partial or complete response) both at 12 weeks (85 versus 45 percent with chemotherapy) and at 24 weeks (56 versus 25 percent with chemotherapy) . While there was only a trend towards improved intracranial time to tumor progression with crizotinib in the overall study population (which included patients with and without brain metastases), the sensitivity to detect differences between the two groups was low.
A retrospective analysis of patients from two randomized trials identified 275 patients with asymptomatic brain metastases who were treated with crizotinib; 166 had received prior RT while 109 had received no prior RT .
●Among patients who had received prior RT, the 12-week disease control rate was 65 percent for systemic disease and 62 percent for brain metastases. For patients with previously treated brain metastases, the median time to intracranial progression was 13 months.
●In asymptomatic patients who had not received prior RT, the 12-week disease control rates for systemic and intracranial disease were 63 and 56 percent, respectively. The median time to intracranial progression was seven months.
However, such responses are not durable, and central nervous system relapses can result in rapid neurologic deterioration and death. For patients with very small (<5 mm) brain metastases that are asymptomatic, crizotinib can be used initially and RT deferred. However, these patients should be monitored closely with magnetic resonance imaging (MRI) every two months.
Isolated brain metastases (a central nervous system [CNS] relapse without evidence of extracranial progression) may be a particular problem for patients treated with crizotinib. In this setting, continuation of treatment with crizotinib after treatment of the CNS relapse with surgery and/or RT may be associated with a significant period of control of extracranial disease .
Next-generation inhibitors against brain metastases — The ALK inhibitor alectinib appears to have important clinical activity in patients with brain metastases, including in patients with symptomatic brain metastases, patients with leptomeningeal disease, and patients who have CNS relapse on ceritinib [36,49], making it our preferred option for patients with brain metastases.
Evidence of the activity of alectinib among patients with brain metastases comes from phase II studies described below:
●In a study including 84 patients with evaluable, ALK-positive, crizotinib-resistant disease with brain metastases, the CNS disease control rate was 83 percent . The objective response rate among the 35 patients with measurable brain lesions was 57 percent; the median duration of CNS response was 10 months. The activity of alectinib against brain metastases was similar in those who had received prior radiation therapy (RT) and those who had not received RT.
●In a second study, among 16 patients with advanced ALK-positive, crizotinib-resistant NSCLC with CNS disease, 11 of whom had received previous RT, four patients (25 percent) had a complete CNS response, and eight (50 percent) had a partial CNS response. The disease control rate among those with CNS disease was 100 percent and the median duration of CNS response was 11 months .
Alectinib has also demonstrated improved outcomes relative to crizotinib among patients with brain metastases. In the phase III J-ALEX study, among 43 patients with ALK-positive NSCLC with brain metastases, alectinib demonstrated improved PFS relative to crizotinib (HR 0.08, CI 0.01-0.61). Further results of J-ALEX are discussed above. (See 'Alectinib' above.)
Further details of these studies among patients with advanced ALK-translocated lung cancer are discussed above. (See 'Alectinib' above.)
Other next-generation ALK inhibitors have also been reported to have activity against brain metastases; these include ceritinib [33,50,51], brigatinib , and lorlatinib (PF-06463922) . For example, in ASCEND-4 discussed above, among patients with at least one brain metastasis at baseline, intracranial objective response rate was higher with ceritinib (72.7 versus 27.3 percent) . (See 'Ceritinib' above.)
ALK INHIBITORS: TOXICITY — Treatment with the anaplastic lymphoma kinase (ALK) inhibitors crizotinib and ceritinib 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 both crizotinib and ceritinib, but are more severe with ceritinib. With crizotinib, 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'.)
Hepatotoxicity — Liver function test abnormalities are occasionally seen with crizotinib and are commonly seen with ceritinib. Hepatoxicity can 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'.)
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. 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 'Crizotinib, ceritinib, and alectinib'.)
Other toxicities that have been observed with crizotinib include the following:
●Sinus bradycardia is relatively frequent in patients treated with crizotinib and may be severe in some cases [54,55]. 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.
Our approach is to perform an electrocardiogram (EKG) at baseline in all patients treated with either crizotinib or ceritinib. 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'.)
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 the phase II studies . These were primarily associated with the transition from dark to light. Uncommon visual manifestations included photophobia, decreased visual acuity, and blurred vision. Similar symptoms have been reported with ceritinib, but their overall incidence is less that 10 percent.
Detailed ophthalmological assessment in over 200 patients from phase II experience with crizotinib did not demonstrate any objective abnormalities associated with visual symptoms . However, optic neuropathy and blindness has been reported in one case, although that may have been related to prior whole brain radiation therapy .
●With crizotinib, rapid depression of serum testosterone levels has been observed [58,59]. 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 . 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 . The cysts may be positive on positron emission tomography (PET) and can create confusion with renal metastases . 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 . (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 . 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.
Chemotherapy — Cytotoxic chemotherapy appears to have a similar level of activity in anaplastic lymphoma kinase (ALK)-positive patients with non-small cell lung cancer (NSCLC) compared with those with ALK-negative disease. 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 therapies for previously treated patients", section on 'Single-agent chemotherapy'.)
EGFR tyrosine kinase inhibitors — Patients with the ALK fusion oncogene do not appear to respond to epidermal growth factor receptor (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 .
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 'Molecular pathogenesis' above and 'Clinicopathologic features' above.)
●Whenever possible, therapy of patients with advanced NSCLC should be individualized based upon the molecular and histologic features of the tumor. If feasible prior to treatment, patients should have tumor tissue assessed for the presence of the ALK fusion oncogene, which is associated with sensitivity to ALK tyrosine kinase inhibitors, as well as other driver mutations such as those seen in the epidermal growth factor receptor (EGFR). (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer" and 'Chemotherapy versus targeted therapy' above.)
●For patients with advanced or metastatic NSCLC whose tumors contain a characteristic ALK fusion oncogene who lack central nervous system (CNS) disease, we recommend initial treatment with the ALK inhibitor crizotinib rather than chemotherapy (Grade 1B). Emerging data suggest that other ALK inhibitors may soon become standard initial treatments for ALK-positive NSCLC. (See 'ALK inhibitors: Efficacy' above.)
•Therapy with crizotinib should be continued until there is evidence of progressive disease. 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, crizotinib may be continued after initial evidence of progressive disease. (See 'Crizotinib' above.)
•Crizotinib should only be used in patients with ALK or ROS1 rearrangement. (See 'Crizotinib' above and "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'ROS1 translocation'.)
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 Ventana ALK (D5F3) CDx assay. In Europe, immunohistochemistry is widely used to detect ALK rearrangement. (See 'Crizotinib' above.)
•Crizotinib 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. (See 'Crizotinib' above.)
●For patients with advanced or metastatic, ALK-rearranged NSCLC with CNS disease at diagnosis, we offer initial systemic treatment with the second-generation, CNS-penetrable ALK inhibitor alectinib, rather than crizotinib or chemotherapy. Radiation (with stereotactic radiosurgery or gamma knife favored over whole-brain radiation therapy when appropriate) or surgery (particularly in the setting of an isolated symptomatic brain metastasis) may also be indicated. (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 ceritinib or alectinib (Grade 1B). (See 'Ceritinib' above and 'Alectinib' 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 therapies for previously treated patients".)
●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 and patients have an ongoing objective response or stable disease after completing their initial doublet chemotherapy, the authors prefer to switch to crizotinib, although both crizotinib and single-agent maintenance chemotherapy are options. Factors that should be discussed with the patient in defining a treatment plan include the quality of the initial response to chemotherapy and the potential side effects of maintenance therapy. (See "Systemic therapy for the initial management of advanced non-small cell lung cancer without a driver mutation", section on 'Molecular characterization of tumor'.)
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