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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 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. (See "Overview of the treatment of advanced non-small cell lung cancer".)
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 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 with crizotinib. ALK gene amplification alone is not predictive of crizotinib response and does not carry the same significance as rearrangement.
●IHC – Multiple monoclonal antibodies have been developed to use 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 is the only approved test to diagnose ALK-positive NSCLC, and thus FISH should be used to confirm the IHC results. In Europe, immunohistochemistry is widely used to detect ALK rearrangement.
●RT-PCR – RT-PCR of cDNA is another commonly used screening strategy for detecting ALK gene rearrangements in NSCLC. A number of multiplex assays have been developed to simultaneously capture all possible in-frame fusions between EML4 and ALK in which the kinase domain of ALK would be preserved [3,8,15]. 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 anaplastic lymphoma kinase (ALK) fusion oncogenes have been identified.
Epidemiology — In unselected 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 [3,8,11-13,15-17]. Except in rare cases, the presence of ALK gene rearrangements in NSCLC tumors tends to occur independent of 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 [12,19]. 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) . The estimated median age for other patients with lung cancer is approximately 66 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 packet years) [1,12,19]. In the crizotinib study database of 255 patients, never smokers and former smokers comprised 70 and 28 percent of cases, respectively [1,12,19].
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 . ALK rearrangement has been reported in squamous cell carcinoma but is rare [11,17].
Adenocarcinomas in ALK fusion oncogene positive cases from Caucasian patients are significantly more likely to have abundant signet ring cells than those with an epidermal growth factor receptor (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 the ALK TK inhibitor crizotinib. Treatment with crizotinib, an ALK TK inhibitor, should be limited to patients whose tumors contain this abnormality as demonstrated by FISH. (See 'Diagnosis' above and "Overview of the treatment of advanced non-small cell lung cancer", section on 'Initial systemic therapy'.)
Crizotinib is preferred as the initial therapy for patients whose tumor contains this genetic abnormality in countries where it is approved for this indication. 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".)
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 crizotinib 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 author’s 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 crizotinib.
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.
CRIZOTINIB — Crizotinib is a multitargeted small molecule tyrosine kinase inhibitor, which was originally developed as an inhibitor of mesenchymal epithelial transition growth factor (c-MET); it is also a potent inhibitor of anaplastic lymphoma kinase (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'.)
Efficacy — Crizotinib induces rapid tumor regression and objective responses in the majority of patients whose tumors contain the ALK gene rearrangement . These responses result in a significant prolongation in progression-free survival compared to single agent chemotherapy in previously treated patients.
The activity of crizotinib in ALK rearrangement positive NSCLC is illustrated by the results of an international phase III trial in which 347 patients with the ALK rearrangement were randomly assigned to crizotinib (250 mg twice daily) or single agent chemotherapy with either pemetrexed or docetaxel . All patients had received one prior chemotherapy regimen with a platinum regimen. Patients who were assigned to chemotherapy were allowed to cross over and receive treatment with crizotinib when they developed progressive disease.
Key efficacy results included the following:
●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 3.0 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.
Duration of therapy — Treatment with crizotinib is generally continued until there is evidence of disease progression. Therapy with crizotinib may be continued after the initial evidence of disease progression, if there is evidence of benefit and the extent of disease progression is limited, as is the case with other targeted therapies, such as use of an EGFR TKI in lung cancers with an EGFR mutation. An alternative approach is to switch to cytotoxic chemotherapy; as second generation ALK inhibitors become available, that may become the preferred approach. (See 'Second generation ALK inhibitors' below.)
A retrospective analysis compared 120 patients in whom crizotinib was continued after disease progression with 74 patients in whom crizotinib was discontinued . There was a significantly longer overall survival for those who continued on crizotinib, although the difference in survival may simply reflect the ability to continue crizotinib rather than a direct effect of treatment.
Brain metastases — Surgery and/or radiation therapy are the primary treatment modalities for patients with brain metastases from NSCLC, including those with the EML4-ALK fusion oncogene [25,26]. There are only limited data on the activity of crizotinib on brain metastases in this setting. (See "Overview of the clinical manifestations, diagnosis, and management of patients with brain metastases", section on 'Overview of management' and "Systemic therapy for brain metastases", section on 'Targeted agents'.)
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 radiation therapy may be associated with a significant period of control of extracranial disease .
Toxicity — Treatment with crizotinib is generally well tolerated. The key toxicities include:
●Visual disturbances were seen in 60 to 65 percent of cases in the phase II studies and are primarily associated with the transition from dark to light . Uncommon visual manifestations included photophobia, decreased visual acuity, and blurred vision. Detailed ophthalmological assessment in over 200 patients from the non-randomized phase II experience 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 .
●Less severe side effects included gastrointestinal symptoms, which were seen in 25 percent or more of patients and included nausea, vomiting, diarrhea, and constipation. Less than 1 percent of these were grade 3 or 4. Edema and fatigue each occurred in 20 to 40 percent of cases, but were severe in 2 percent or less of cases.
●Abnormal liver function tests were observed with elevations of ALT and AST in 71 percent and 61 percent of cases, respectively. These elevations of ALT and AST were grade 3 or 4 and required interruption of treatment and/or dose reduction in 7 and 3 percent of cases respectively. Additional evidence on the frequency of hepatotoxicity comes from the drug development database, in which five cases (<1 percent) of severe, potentially drug-related hepatotoxicity (two fatal) were reported with an estimated exposure of 1400 cases .
●Severe, life-threatening, or fatal treatment-related pneumonitis occurred in four cases (1.6 percent). The development of pneumonitis due to crizotinib should result in discontinuation of treatment with this agent.
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 [31,32]. 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'.)
●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 EKG at baseline in patients with known cardiac arrhythmia issues. For patients on treatment with crizotinib, we check an EKG if the patient develops bradycardia (whether symptomatic or not) or if the patient is started on a drug which is known to cause QTc prolongation. (See "Cardiotoxicity of nonanthracycline cancer chemotherapy agents", section on 'Crizotinib'.)
●Crizotinib is metabolized by cytochrome P450 CYP3A4. Thus caution should be used when it is given concomitantly with CYP3A4 inhibitors, and care is required when crizotinib is coadministered with other agents that are predominantly metabolized by this system (table 1).
●Rapid, significant depression of serum testosterone levels has been observed in men treated with crizotinib [33,34]. In a series of 32 patients treated with crizotinib, the mean serum testosterone levels 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".)
Ongoing trials — In two ongoing phase III trials, patients with ALK-positive lung cancer who have not received prior systemic therapy for advanced disease are being randomly assigned to either crizotinib or chemotherapy with pemetrexed plus a platinum compound (either cisplatin or carboplatin) (NCT01154140 and NCT01639001). Patients assigned to chemotherapy can crossover to crizotinib when progressive disease is documented. The primary endpoint in both trials is progression-free survival.
SECOND GENERATION ALK INHIBITORS — Several second generation anaplastic lymphoma kinase (ALK) inhibitors are under development for patients with ALK-rearranged cancers. Some of these agents are more potent and selective than crizotinib, and may offer advantages in terms of higher response rates or activity in patients who have acquired resistance to crizotinib.
LDK378 — LDK378 is being developed as an alternative to crizotinib, based upon increased potency and specificity.
In the phase I study, LDK378 was studied in 123 patients with ALK-positive non-small cell lung cancer (NSCLC), including 71 in the dose expansion cohort [35,36]. The results of this study were presented at the 2013 ASCO meeting. The objective response rate in the 114 evaluable patients treated at a dose of 400 mg/day or more was 58 percent, and the response rate was essentially the same in those who had progressed on prior crizotinib treatment and those who were crizotinib naïve (57 and 60 percent, respectively). The median progression-free survival and median duration of response were 8.6 and 8.2 months, respectively. Treatment with LDK378 was tolerated reasonably well up to the MTD of 750 mg PO qd with primarily GI side effects, including nausea, vomiting, and diarrhea.
Two phase III trials are planned in patients with ALK-positive NSCLC, one in which LDK378 will be compared with single-agent chemotherapy after progression on a platinum-based doublet and on crizotinib (NCT01828112), and the other as first line treatment compared with a platinum-based doublet (NCT01828099).
Alectinib — In a multicenter, phase I/II study, 46 patients with ALK-positive NSCLC were treated with alectinib (CH5424802) at the phase II dose level (300 mg twice daily); none had received prior treatment with an ALK inhibitor . An objective response was observed in 43 cases (93 percent), including 2 complete and 41 partial responses; 40 of the 43 responses were ongoing at data cutoff. Treatment was well tolerated.
Chemotherapy — Cytotoxic chemotherapy appears to have a similar level of activity in ALK-positive patients with NSCLC compared to 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 "Advanced non-small cell lung cancer: Subsequent therapies for previously treated patients", section on 'Single agent chemotherapy' and "Initial systemic chemotherapy for advanced non-small cell lung cancer without a driver mutation", section on 'Effect of histology'.)
Two small, retrospective studies suggested that pemetrexed was more effective in patients with the ALK fusion oncogene compared with those without this driver mutation [38,39]. However, a larger, multicenter retrospective series that compared 121 patients with an ALK-positive NSCLC with 266 patients with ALK-negative, EGFR-mutation negative disease found that a statistically significant improvement in progression-free survival was limited to the first-line setting when pemetrexed was combined with either cisplatin or carboplatin .
EGFR tyrosine kinase inhibitors — In one retrospective study, 141 patients with tumors harboring an ALK fusion oncogene, an EGFR mutation, or neither genetic alteration (wild type) were compared in terms of response rate, time to progression and overall survival . Among metastatic patients who received any platinum-based combination, the 19 patients who were positive for ALK had similar response rates and time to progression compared to the wild type patients.
In contrast to patients with EGFR mutations, patients with the ALK fusion oncogene do not appear to respond to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib or gefitinib. Within the ALK cohort in the retrospective study described above, there were no clinical responses to EGFR TKIs, and the median time to progression was only five months. These findings are consistent with preclinical studies showing that the EML4-ALK-containing NSCLC cell line H3122 is resistant to erlotinib. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor".)
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 crizotinib, 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 non-small cell lung cancer whose tumors contain a characteristic ALK fusion oncogene, we recommend initial treatment with crizotinib rather than chemotherapy (Grade 1B). For patients in areas where crizotinib is not available for first line therapy, enrollment in the phase III protocol may be an alternative. (See 'Efficacy' above.)
•Therapy with crizotinib should be continued until there is evidence of progressive disease. Therapy may be continued after initial evidence of progressive disease in patients who appear to be deriving benefit from treatment and who have only limited evidence of disease progression. (See 'Duration of therapy' above.)
•Crizotinib should not be used in patients without ALK rearrangement. In the United States, ALK-positivity must be demonstrated by FISH using the FDA-approved test (Vysis Probes) accordance with the FDA label. In Europe, immunohistochemistry is widely used to detect ALK rearrangement. (See 'Crizotinib' above.)
•Chemotherapy is an appropriate option as second-line therapy for patients who have progressed while on treatment with crizotinib. An alternative option is a trial with a second generation ALK inhibitor. Preliminary efficacy data with two second generation ALK inhibitors (LDK378 and AP26113) suggest that these drugs induce responses in the majority of patients who have previously relapsed on crizotinib. (See "Initial systemic chemotherapy for advanced non-small cell lung cancer without a driver mutation" and "Advanced non-small cell lung cancer: Subsequent therapies for previously treated patients".)
•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.)
●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 "Initial systemic chemotherapy for advanced non-small cell lung cancer without a driver mutation", section on 'Molecular characterization of tumor'.)
All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.