Use Of Anaplastic Lymphoma Kinase Inhibitors Research Articles

Concomitant double-fusion of PLEKHA7-ALK and INPP5D-ALK reveals favorable alectinib sensitivity in lung adenocarcinoma: a case report and literature review

Anaplastic lymphoma kinase (ALK) gene fusion is a classic driver mutation in non-small cell lung cancer (NSCLC); however, ALK double-fusion variants in NSCLC have rarely been reported. In this study, we reported a case with extremely uncommon ALK double-fusion variants. A 32-year-old female diagnosed with lung adenocarcinoma, who had developed multiple intrapulmonary and brain metastases, experienced worsening of her condition despite undergoing prior chemotherapy. Subsequent testing using next-generation sequencing (NGS) detected the presence of PLEKHA7-ALK and INPP5D-ALK double-fusion. The prescription of alectinib revealed potent efficacy and resulted in an increase in the survival rate. This case presented two uncommon and concomitant ALK fusion partners in NSCLC; more importantly, the INPP5D-ALK subtype has not been reported, therefore this study broadens the spectrum of ALK double-fusion variants and provides insight into the use of ALK inhibitors for the treatment of NSCLC in patients with double ALK fusions.

Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma.

Bile duct cancer (cholangiocarcinoma, CCA) has a poor prognosis for patients, and despite recent advances in targeted therapies for other cancer types, it is still treated with standard chemotherapy. Anaplastic lymphoma kinase (ALK) has been shown to be a primary driver of disease progression in lung cancer, and ALK inhibitors are effective therapeutics in aberrant ALK-expressing tumors. Aberrant ALK expression has been documented in CCA, but the use of ALK inhibitors has not been investigated. Using CCA cell lines and close-to-patient primary cholangiocarcinoma cells, we investigated the potential for ALK inhibitors in CCA. ALK, cMET, and ROS1 expression was determined in CCA patient tissue by immunohistochemistry and digital droplet polymerase chain reaction, and that in cell lines was determined by immunoblot and immunofluorescence. The effect on cell viability and mechanism of action of ALK, cMet, and ROS1 inhibitors was determined in CCA cell lines. To determine whether ceritinib could affect primary CCA cells, tissue was taken from four patients with biliary tract cancer, without ALK rearrangement, mutation, or overexpression, and grown in three-dimensional tumor growth assays in the presence or absence of humanized mesenchymal cells. ALK and cMet but not ROS were both upregulated in CCA tissues and cell lines. Cell survival was inhibited by crizotinib, a c-met/ALK/ROS inhibitor. To determine the mechanism of this effect, we tested c-Met-specific and ALK/ROS-specific inhibitors, capmatinib and ceritinib, respectively. Whereas capmatinib did not affect cell survival, ceritinib dose-dependently inhibited survival in all cell lines, with IC50 ranging from 1 to 9 µM and co-treatments with gemcitabine and cisplatin further sensitized cells, with IC50 ranging from IC50 0.60 to 2.32 µM. Ceritinib did not inhibit cMet phosphorylation but did inhibit ALK phosphorylation. ALK was not mutated in any of these cell lines. Only ceritinib inhibited 3D growth of all four patient samples below mean peak serum concentration, in the presence and absence of mesenchymal cells, whereas crizotinib and capmatinib failed to do this. Ceritinib appeared to exert its effect more through autophagy than apoptosis. These results indicate that ceritinib or other ALK/ROS inhibitors could be therapeutically useful in cholangiocarcinoma even in the absence of aberrant ALK/ROS1 expression.

Real-World Data on Treatment Outcome of ALK-Positive Non-Small Cell Lung Cancer from an Indian Multicentric Cancer Registry

The Anaplastic lymphoma kinase inhibitors (ALKi) represent the standard of care for metastatic non-small cell lung cancer (NSCLC) patients with EML4-ALK rearrangements. Various ALKi agents are available; however, not all eligible patients receive treatment with them due to various reasons. Given the limited real-world data available in our country, we aimed to assess treatment outcomes through a multicenter collaboration. This retrospective, multi-institutional study was conducted under the Network of Oncology Clinical Trials India and included a total of 67 ALK-positive metastatic lung cancer patients from 10 institutes across India, with a median follow-up of 23 months. In the first line setting, the objective response rate (ORR) with ALKi was 63.6% (crizotinib: 60.7%, ceritinib: 70%, alectinib: 66.6%, p = 0.508), while with chemotherapy, it was 26.1%. The median progression-free survival (mPFS) for the first line ALKi group was significantly higher than that for chemotherapy (19 vs. 9 months, p = 0.00, hazard ratio [HR] = 0.30, 95% confidence interval [CI]: 0.17–0.54). The mPFS for crizotinib, alectinib, and ceritinib was 17, 22, and 19 months, respectively (p = 0.48). Patients who received ALKi upfront or after 1 to 3 cycles of chemotherapy or after 4 or more cycles of chemotherapy had mPFS of 16, 22, and 23 months, respectively (p = 0.47). ALKi showed superior mPFS compared to chemotherapy in the second line (14 vs. 5 months; p = 0.002) and the third line (20 vs. 4 months; p = 0.009). The median overall survival (OS) was significantly better in patients who received ALKi in any line of therapy (44 vs. 14 months, p < 0.001, HR = 0.10, 95% CI: 0.04–0.23). Brain progression was higher among those who did not receive ALKi (69.2 vs. 31.5%). In conclusion, the use of ALKi as first line treatment for ALK-positive metastatic NSCLC patients resulted in improved PFS. PFS and ORR did not significantly differ between patients who received ALKi upfront or after initiating chemotherapy. Notably, patients who received ALKi in second or later lines demonstrated significantly better outcomes compared to those receiving chemotherapy. The use of ALKi in any line of therapy was associated with significantly prolonged OS.

The treatment of relapsed/refractory anaplastic large cell lymphoma expressing the anaplastic lymphoma kinase: a single-center experience

The treatment of relapsed/refractory anaplastic large cell lymphoma expressing the anaplastic lymphoma kinase: a single-center experience

Real-world adherence and persistence with anaplastic lymphoma kinase inhibitors in non-small cell lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths in the United States. Several anaplastic lymphoma kinase (ALK) rearrangement inhibitors have been approved for the treatment of metastatic ALK-positive non-small cell lung cancer (NSCLC). Effective disease management requires an understanding of how these treatments are used in clinical practice, since low treatment adherence and/or early discontinuation have been associated with poor patient outcomes. Owing to the recency of approvals, real-world data on the use of ALK inhibitors in patients with ALKpositive NSCLC are currently limited; this represents a notable gap in our understanding of ALK treatment use. OBJECTIVE: To assess real-world adherence and persistence with ALK inhibitors in patients with ALK-positive NSCLC. METHODS: This retrospective observational study used US commercial claims for patients aged at least 18 years with lung cancer receiving ALK inhibitors (alectinib, brigatinib, ceritinib, crizotinib) between July 1, 2015, and December 31, 2018. Patients' first and any subsequent ALK inhibitor uses were categorized into ALK inhibitor-naive and ALK inhibitor-pretreated cohorts, respectively. Adherence was measured by medication possession ratio and persistence by time from treatment initiation to discontinuation (earliest of a treatment switch or greater than a 60-day gap). Descriptive statistics were used to summarize patient characteristics. Cohort comparisons were made using chi-square tests and t-tests. Persistence and time to next ALK inhibitor were analyzed using Kaplan-Meier methods and the log-rank test. Poisson and Cox regression models of adherence and persistence, respectively, were applied to compare ALK inhibitors. RESULTS: We identified 1,482 patients treated with alectinib (n = 445) or crizotinib (n = 1,037) in the ALK inhibitor-naive cohort; 604, 142, and 134 patients received alectinib, brigatinib, or ceritinib in the ALK inhibitor-pretreated cohort. Adherence during the treatment period (95%-97%) and the proportion of patients with a medication possession ratio of at least 0.8 (92%-95%) were similar for all ALK inhibitors. In the ALK inhibitor-naive cohort, median time to treatment discontinuation with alectinib and crizotinib was 27.1 and 8.8 months, respectively; patients receiving alectinib were 46% less likely to discontinue than patients receiving crizotinib (adjusted hazard ratio [aHR] [95% CI]: 0.54 [0.44-0.65]; P < 0.0001). In the ALK inhibitor-pretreated cohort, the discontinuation risk for alectinib was 64% lower than for ceritinib (aHR [95% CI]: 0.36 [0.27-0.49]; P < 0.0001) and 34% lower than for brigatinib (aHR [95% CI]: 0.66 [0.42-1.02]; P = 0.062). CONCLUSIONS: To our knowledge, this study is the first to address a current research gap by assessing real-world adherence and persistence with ALK inhibitors among patients with ALK-positive NSCLC in real-world clinical practice. Alectinib was associated with longer real-world persistence than other ALK inhibitors, despite similar adherence. Further research with more patients and longer follow-up is needed to link persistence to real-world clinical outcomes. DISCLOSURES: This study was funded by Genentech Inc. Ganti has received research support from Takeda and has provided consulting services to Genentech Inc., AstraZeneca, Flagship Biosciences, Cardinal Health, BioGene, Mirati Therapeutics, Blueprint Medicines, and G1 Therapeutics. Lin, Wong, and Ogale are employees of Genentech Inc. and may own stock in F. Hoffmann-La Roche. Yang was employed by Genentech Inc. at the time of this study. Part of the study findings were presented as a poster at the NCCN 2020 Virtual Annual Conference, April 9, 2020.

The potential diagnostic and predictive role of anaplastic lymphoma kinase (ALK) gene alterations in melanocytic tumors.

Anaplastic lymphoma kinase (ALK) gene has been demonstrated to be rearranged, mutated or amplified in several haematological and solid tumors. Moreover, the use of ALK inhibitors has recently revolutionized the treatment of ALK-rearranged patients affected by non-small cell lung carcinoma. Herein we review the genetic alterations of ALK in melanocytic neoplasms described in literature, focusing on their potential diagnostic and predictive role. The Authors reviewed the pertinent literature through research on PubMed server was performed typing the terms "ALK", "Anaplastic lymphoma kinase", "ALKATI", "Melanoma", "Spitz", "Spitzoid". ALK translocations were demonstrated in melanocytic neoplasms, particularly in acral melanoma and spitzoid tumors. ALKATI was described in primary and metastatic melanoma, indicating its early occurrence in oncogenesis, with varying immunohistochemical expression of the protein. The identification of the specific type of ALK mutations could be interesting for planning biologic therapy of melanoma patients. Further studies are needed to evaluate the possibility to introduce an ALK-targeted therapy in patients affected by malignant melanoma.

Brefeldin Α Reduces STAT3 Dependent Survival of Acute Leukemia and Neuroblastoma Cells

Leukemic stem cells have several dysregulated pathways and the Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) pathway are prominent among them. High STAT3 expression in leukemia has been associated with an increased risk for relapse and decreased overall survival. In addition, phosphorylated STAT3 can be found following prolonged activation of the anaplastic lymphoma kinase (ALK) ligand binding site, but the level of phospho-STAT3 engendered by ligand-independent activation of ALK was exponentially higher. In ALK positive tumors, ALK-STAT3 activation promotes tumor cell outgrowth and directly prevents apoptosis. The role of ALK in several types of ALK-expressing solid tumors as well as the therapeutic use of ALK inhibitors in treating these cancers also have been reviewed in a number of recent papers.However, clinical resistance to ALK inhibitors invariably occurs. Amplified ALK or mutated ALK was identified in ~14% of neuroblastomas (NB), the most common and aggressive childhood malignancy, and phase I trial of ALK inhibitor such as crizotinib showed a lack of response in patients harboring certain ALK mutations. In this study, we implemented a high throughput chemical screen in 4 NB-derived cell lines to identify compounds with the potential of inhibiting oncogenic activity of ALK in NB, using a curated library of ~450 compounds. Brefeldin A (BFA),an inhibitor of the transport of proteins from the endoplasmic reticulum (ER) to the Golgi, was identified as a suitable candidate. It was previously reported that BFA inhibited phosphorylation of ALK and its downstream molecule, STAT3. Since an increasing number of studies have found that STAT3 abnormal expression and activation are accompanied by leukemia development, which indicates the potential role of STAT3 in the pathogenesis of leukemia, we analyzed the cytotoxicity of BFA against 12 T-ALL and 6 AML cell lines. Assessment of BFA antitumor effect using an MTT assay revealed BFA to possess potent cytotoxic activity across a broad spectrum of hematopoietic malignancies, with 10 T-ALL and 5 AML being especially responsive. For example, T-ALL cell lines, as well as AML lines, were potently inhibited by BFA ( IC50 values: ICH-TALL-UK, 168.1 nM; MOLT-4, 23.2nM; Jurkat, 66.6 nM; MOLT14, 97.3 nM; ICH-TALL-SM, 54.9 nM). In an expanded panel of 20 NB cell lines, those with or without MYCN-amplification or 11q loss of heterozygousity which have been identified as two major oncogenic events in NB pathogenesis, especially in the high-risk group were the most sensitive to low nanomolar concentrations of BFA. In NB cell lines harboring F1174L or R1275Q-mutated ALK,BFAshowed cytotoxicity.BFA reduced the phosphorylation of ALK in NIH3T3 cells stably expressed F1174L ALK or TGW, cell line harboring R1275Q-mutated ALK. Of the molecules that are phosphorylated downstream of ALK that have been reported to be important for ALCL cells, the phosphorylation of STAT3, AKT and ERK was inhibited by BFA. These results suggested that BFA can be used to target STAT3 signaling pathways for leukemia treatment. Furthermore these results indicated that the effect of BFA on ALK mutated NB cell lines is accompanied by inhibition of the phosphorylation of ALK and its downstream key effector molecule STAT3.These findings provide the significance of ALK and STAT3 as they relate to NB or leukemia, explores the significance of STAT3, AKT and ERK downstream of ALK, and touches on the potential for new chemotherapeutics targeting ALK and STAT3 to improve high risk NB and leukemia patient prognosis. Disclosures No relevant conflicts of interest to declare.

Role of the Anaplastic Lymphoma Kinase Inhibitor Crizotinib in the Management of Neuroblastoma

Abstract Neuroblastoma (NB) is a common extra-cranial solid malignancy of childhood. NB displays several clinical and biological features as well as many indeterminate aspects. Studies attempting to determine a prognostic factor in NB have been performed for a long time. Recent studies have focused on the anaplastic lymphoma kinase (ALK) gene. ALK mutations are one of the most prevalent and important biological disorders in NB. The presence of ALK mutations contributes to a more malignant character in NB. However, there is a limited number of studies on the clinical relevance of the expression of ALK or of its mutations. Th e elucidation of gene expression analyses in ALK can guide in the identification of risk groups and selection of treatment protocols. There is a need for further studies, as it is important to define patients eligible for use of ALK inhibitors.

Real-world anaplastic lymphoma kinase (ALK) rearrangement testing patterns, treatment sequences, and survival of ALK inhibitor-treated patients

Background: The anaplastic lymphoma kinase (ALK) treatment landscape is crowded following recent ALK inhibitor approvals, and updated information on real-world treatment patterns in advanced non-small-cell lung cancer (aNSCLC) with ALK rearrangement (ALK+) is needed.Methods: This retrospective US cohort study used Flatiron Health’s longitudinal electronic health record (EHR)-derived database. Patients (≥ 18 years old) diagnosed with stage IIIB/IV aNSCLC, with documented ALK rearrangement and ≥2 visits after January 1, 2011 were followed until February 28, 2016. Patients enrolled on a clinical trial or exposed to ALK inhibitors other than crizotinib or ceritinib were excluded. Treatment patterns, time and type of biomarker testing, and overall survival (OS) were analyzed.Results: Median age (n = 300) was 62.5 years; 55% female; 48% non-smokers; 8.7% central nervous system (CNS) metastases at diagnosis. Overall, 73% and 86% received their first ALK biomarker test before/at diagnosis, or before/during first-line treatment, respectively. In total, 90.0%, 78.1%, and 74.7% received first-, second-, and third-line therapy, respectively. Most patients received ALK-targeted treatment; 62% received crizotinib, of which 21% reported a dose reduction. Progression was the most common reason for crizotinib (78%) and ceritinib (41%) discontinuation. Median OS was 29.4 months (95% CI =24.7–39.6) overall; 27.1 months (95% CI =22.0–35.0) in patients with CNS metastases, and 36.9 months (95% CI =25.1–not reached) without.Conclusions: Despite widespread crizotinib use in patients with ALK+ aNSCLC, a high proportion of patients progressed. Ongoing analyses of EHR-derived cohorts are valuable in assessing real-world testing rates and therapeutic use of ALK inhibitors.

Sequential Use of Anaplastic Lymphoma Kinase Inhibitors in Japanese Patients With ALK-Rearranged Non–Small-Cell Lung Cancer: A Retrospective Analysis

BackgroundSecond-generation anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib and ceritinib, have recently been approved for treatment of ALK-rearranged non–small-cell lung cancer (NSCLC). An optimal strategy for using 2 or more ALK inhibitors has not been established. We sought to investigate the clinical impact of sequential use of ALK inhibitors on these tumors in clinical practice. Patients and MethodsPatients with ALK-rearranged NSCLC treated from May 2010 to January 2016 at the National Cancer Center Hospital were identified, and their outcomes were evaluated retrospectively. ResultsFifty-nine patients with ALK-rearranged NSCLC had been treated and 37 cases were assessable. Twenty-six received crizotinib, 21 received alectinib, and 13 (35.1%) received crizotinib followed by alectinib. Response rates and median progression-free survival (PFS) on crizotinib and alectinib (after crizotinib failure) were 53.8% (95% confidence interval [CI], 26.7%-80.9%) and 38.4% (95% CI, 12.0%-64.9%), and 10.7 (95% CI, 5.3-14.7) months and 16.6 (95% CI, 2.9-not calculable), respectively. The median PFS of patients on sequential therapy was 35.2 months (95% CI, 12.7 months-not calculable). The 5-year survival rate of ALK-rearranged patients who received 2 sequential ALK inhibitors from diagnosis was 77.8% (95% CI, 36.5%-94.0%). ConclusionThe combined PFS and 5-year survival rates in patients who received sequential ALK inhibitors were encouraging. Making full use of multiple ALK inhibitors might be important to prolonging survival in patients with ALK-rearranged NSCLC.

Assessment of ALK gene fusions in lung cancer using the differential expression and exon integrity methods.

Anaplastic lymphoma kinase (ALK) gene fusion is a driving mutation underlying the development of non-small cell lung cancer (NSCLC). Accurate detection of ALK fusion is critical for the use of ALK inhibitors in the treatment of NSCLC. Commonly utilized methods for ALK detection include fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). However, these methods are time-consuming and costly. In the present study, a method for assessing ALK gene fusion based on the differential expression levels of the ALK kinase and non-kinase domains was developed and evaluated, with the aim of providing a convenient and reliable method for the detection of ALK fusion. In addition, another method was established to determine the integrity of exons 19-20 and 20-21 of ALK, two genomic loci that are typically broken in ALK fusions. These novel methods were applied to detect ALK fusion in 100 NSCLC patients, and were compared with IHC and FISH methods. The novel methods developed in the present study successfully detected ALK fusions in 10 samples. The concordances between the novel methods and IHC and FISH were 100%. Furthermore, the differential expression method was able to detect ALK fusions in cell-free urine samples, which was advantageous over FISH and IHC. The novel methods developed in the present study are cost-effective and easy to perform, and may provide simple and convenient techniques for the clinical assessment of ALK fusions, facilitating the use of targeted therapy for NSCLC.

ALK inhibitors for clinical use in cancer therapy.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase protein implicated in a variety of tumors, both solid and hematological. Few years ago crizotinib, an inhibitor of the receptor tyrosine kinases c-Met and ALK, demonstrated its activity in ALK positive non-small-cell lung cancer and other tumors with excellent toxicity profile. Subsequently several ALK inhibitors have been developed, offering new personalized treatment options. This review addresses some clinical considerations on the use of ALK inhibitors in ALK positive tumors and on the development of resistance to them.

A Pan-Cancer Review of ALK Mutations: Implications for Carcinogenesis and Therapy.

The anaplastic lymphoma kinase (ALK) is a druggable target for cancer therapy. By and large, the oncogenic activation of ALK in human tumors is known to occur by gene rearrangement (e.g. EML4-ALK, NMP-ALK, etc.). Clinical use of ALK inhibitors for "ALK-rearranged" lung cancers has remarkably improved patient survival. To date, much has been known about ALK gene rearrangement in human carcinogenesis and its drug sensitivity relationship. However, emerging genomic data from the Cancer Genome Atlas (TCGA, USA) are now revealing common ALK point mutations (~3.06%) in various cancer types other than lung cancer. Importantly, several recent studies have demonstrated that ALK point mutations, independent of ALK-gene rearrangement, can be oncogenic. Thus, ALK mutations can be pathogenically and perhaps therapeutically important for various cancer types. Here, we summarized the latest ALK mutation frequencies and mutation patterns across 17 human cancer types stemming from TCGA. Unlike many other oncogenes with high frequency of hotspot mutations, ALK point mutations tend to span along the entire gene. Up till now, several recurrent mutations (G263, R401, R551, P968 and E1242) and mutation-rich cluster regions have been identified, but their functional effects remain unknown. We also conducted a comprehensive review of all ALK-mutated human cancer cell lines (from the Cell Line Encyclopedia (CCLE) and the NCI-60 panel), which can be used as model systems for ALK mutation biology and drug screening studies. Lastly, we summarized both the preclinical and clinical findings of ALK mutations on carcinogenesis and drug sensitivity, which may provide important insight into new treatment strategies and prompt future ALK mutation studies in various cancer types.

Development of anaplastic lymphoma kinase (ALK) inhibitors and molecular diagnosis in ALK rearrangement-positive lung cancer

The fusion of echinoderm microtubule-associated protein-like 4 with anaplastic lymphoma kinase (ALK) was identified as a transforming gene for lung cancer in 2007. This genetic rearrangement accounts for 2%–5% of non-small-cell lung cancer (NSCLC) cases, occurring predominantly in younger individuals with adenocarcinoma who are never- or light smokers. A small-molecule tyrosine-kinase inhibitor of ALK, crizotinib, was rapidly approved by the US Food and Drug Administration on the basis of its pronounced clinical activity in patients with ALK rearrangement-positive NSCLC. Next-generation ALK inhibitors, such as alectinib, LDK378, and AP26113, are also being developed in ongoing clinical trials. In addition, the improvement and validation of methods for the detection of ALK rearrangement in NSCLC patients will be key to the optimal clinical use of ALK inhibitors. We here summarize recent progress in the development of new ALK inhibitors and in the molecular diagnosis of ALK rearrangement-positive NSCLC.

Anaplastic lymphoma kinase: a glimmer of hope in lung cancer treatment?

Anaplastic lymphoma kinase (ALK) rearrangements (ALK-Rs) have been identified in 3–7% of all non-small-cell lung cancers (NSCLCs) and represent an important molecular target for NSCLC treatment. The authors discuss the role of ALK-Rs in the prediction of clinical–pathological features of NSCLCs and the technical problems related to their determination in specimens. The authors also describe the preclinical and clinical results derived from the use of ALK inhibitors. ALK-R is generally detected in patients with specific clinical–pathological features: never-smokers, young males, adenocarcinoma histotype and EGF receptor/KRAS wild-type. The diagnosis of ALK-R remains a challenge, implicating the need of a careful filtering of patients. NSCLC patients harboring ALK-R have shown sensitivity to ALK inhibitors even if their activity is limited at the time by the occurrence of mechanisms of resistance. The authors summarize the strategies that in the future could overcome these mechanisms of escape.

The role of anaplastic lymphoma kinase inhibitors in the treatment of advanced nonsmall cell lung cancer

Treatment of advanced nonsmall cell lung cancer (NSCLC) has rapidly changed over the last decade. On the basis of the progress made in cancer biology, the old-fashioned 'one size fits all' chemotherapeutic approach is shifting to a novel approach in which treatment choice is mainly based on the tumor's biological genotype. The aim of the present review is to describe the anaplastic lymphoma kinase (ALK) translocation as a prominent molecular driver aberration in NSCLC, its prognostic and predictive role, and the new available treatment options. Crizotinib is a tyrosine kinase inhibitor of MET, ALK and ROS1. Its impressive clinical activity shown in a phase IB trial led to accelerated approval for patients with ALK-positive advanced NSCLC. More recently, a phase III trial confirmed the high activity of crizotinib in this subset of lung tumors. Many new-generation ALK inhibitors are currently also in clinical development. ALK-positive NSCLC has emerged as a distinct, well defined subset of lung malignancies. The use of ALK inhibitors deeply impacts the therapy of patients harboring such translocation. Nevertheless, to date, several issues remain open, such as the most suitable screening and diagnostic method for the detection of ALK gene rearrangement and expression and particularly the mechanisms of acquired resistance for further clinical development of these agents.