Differential protein stability and clinical responses of EML4-ALK fusion variants to various ALK inhibitors in advanced ALK-rearranged non-small cell lung cancer.

Background: Anaplastic lymphoma kinase (ALK) inhibition using crizotinib has become the standard of care in advanced ALK-rearranged non-small cell lung cancer (NSCLC), but the treatment outcomes and duration of response vary widely. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK is the most common translocation, and the fusion variants show different sensitivity to crizotinib in vitro. However, there are only limited data on the specific EML4-ALK variants and clinical responses of patients to various ALK inhibitors. Patients and methods: By multiplex reverse-transcriptase PCR, which detects 12 variants of known EML4-ALK rearrangements, we retrospectively determined ALK fusion variants in 54 advanced ALK rearrangement-positive NSCLCs. We subdivided the patients into two groups (variants 1/2/others and variants 3a/b) by protein stability and evaluated correlations of the variant status with clinical responses to crizotinib, alectinib, or ceritinib. Moreover, we established the EML4-ALK variant-expressing system and analyzed patterns of sensitivity of the variants to ALK inhibitors. Results: Of the 54 tumors analyzed, EML4-ALK variants 3a/b (44.4%) was the most common type, followed by variants 1 (33.3%) and 2 (11.1%). The 2-year progression-free survival (PFS) rate was 76.0% [95% confidence interval (CI) 56.8-100] in group EML4-ALK variants 1/2/others versus 26.4% (95% CI 10.5-66.6) in group variants 3a/b (P = 0.034) among crizotinib-treated patients. Meanwhile, the 2-year PFS rate was 69.0% (95% CI 49.9-95.4) in group variants 1/2/others versus 32.7% (95% CI 15.6-68.4) in group variants 3a/b (P = 0.108) among all crizotinib-, alectinib-, and ceritinib-treated patients. Variant 3a- or 5a-harboring cells were resistant to ALK inhibitors with >10-fold higher half maximal inhibitory concentration in vitro. Conclusion: Our findings show that group EML4-ALK variants 3a/b may be a major source of ALK inhibitor resistance in the clinic. The variant-specific genotype of the EML4-ALK fusion allows for more precise stratification of patients with advanced NSCLC.

Tracking a CAD-ALK gene rearrangement in urine and blood of a colorectal cancer patient treated with an ALK inhibitor.

BACKGROUND: Monitoring response and resistance to kinase inhibitors is essential to precision cancer medicine, and is usually investigated by molecular profiling of a tissue biopsy obtained at progression. However, tumor heterogeneity and tissue sampling bias limit the effectiveness of this strategy. In addition, tissue biopsies are not always feasible and are associated with risks due to the invasiveness of the procedure. To overcome these limitations, blood-based liquid biopsy analysis has proven effective to non-invasively follow tumor clonal evolution. PATIENTS AND METHODS: We exploited urine cell-free, trans-renal DNA (tr-DNA) and matched plasma circulating tumor DNA (ctDNA) to monitor a metastatic colorectal cancer patient carrying a CAD-ALK translocation during treatment with an ALK inhibitor. RESULTS: Using a custom next generation sequencing panel we identified the genomic CAD-ALK rearrangement and a TP53 mutation in plasma ctDNA. Sensitive assays were developed to detect both alterations in urine tr-DNA. The dynamics of the CAD-ALK rearrangement in plasma and urine were concordant and paralleled the patient's clinical course. Detection of the CAD-ALK gene fusion in urine tr-DNA anticipated radiological confirmation of disease progression. Analysis of plasma ctDNA identified ALK kinase mutations that emerged during treatment with the ALK inhibitor entrectinib. CONCLUSION: We find that urine-based genetic testing allows tracing of tumor-specific oncogenic rearrangements. This strategy could be effectively applied to non-invasively monitor tumor evolution during therapy. The same approach could be exploited to monitor minimal residual disease after surgery with curative intent in patients whose tumors carry gene fusions. The latter could be implemented without the need of patient hospitalization since urine tr-DNA can be self-collected, is stable over time and can be shipped at specified time-points to central labs for testing.

ALK translocation detection in non-small cell lung cancer cytological samples obtained by TBNA or EBUS-TBNA.

OBJECTIVE: As the diagnosis of non-small cell lung cancer (NSCLC) is based on cytology in around 70% of cases, it is important to use the same material for molecular analyses. Fluorescence in situ hybridization (FISH) is the only approved test for the detection of the translocation and inversion of anaplastic lymphoma kinase (ALK), but the optimal procedures for the fixation or staining of the sample before FISH evaluation have not been established. We investigated whether ALK gene status determined by FISH in a prospectively enrolled case series of patients was affected by fixation and staining. METHODS: One hundred and fifteen cytological samples were obtained by transbronchial needle aspiration (TBNA) or endobronchial ultrasound (EBUS)-TBNA from 109 patients with NSCLC. All samples were evaluated for epidermal growth factor receptor (EGFR) mutation by pyrosequencing and for ALK rearrangement by FISH. Specimens for ALK determination had been fixed with Cytofix(®) and/or Carnoy's solution or 10% formalin (cell blocks) and variously stained. RESULTS: Sixteen (14%) of the 115 samples were mutated for EGFR and 99 (86%) showed wild-type EGFR status. Of these 115 samples, 79 (69%) were negative for echinoderm microtubule-associated protein like 4 (EML4)-ALK translocation, nine (8%) were positive and 27 (23%) were unevaluable. In particular, 19 (26%) of the 72 Papanicolaou-stained smears fixed with Cytofix were unevaluable because of inadequate samples or cell overlapping; neither of the two May-Grünwald-Giemsa-stained samples were evaluable. Ten of 17 smears used for rapid on-site evaluation (ROSE) and immediately post-fixed in Carnoy's solution or 80% alcohol were evaluable. CONCLUSIONS: In this series, smears were unevaluable as a result of inadequate samples, cell overlapping or lack of fixation performed immediately after FNA.

The future of targeted therapies for brain metastases.

Brain metastases (BM) are an increasing challenge in the management of patients with advanced cancer. Treatment options for BM are limited and mainly focus on the application of local therapies. Systemic therapies including targeted therapies are only poorly investigated, as patients with BM were frequently excluded from clinical trials. Several targeted therapies have shown promising activity in patients with BM. In the present review we discuss existing and emerging targeted therapies for the most frequent BM primary tumor types. We focus on challenges in the conduction of clinical trials on targeted therapies in BM patients such as patient selection, combination with radiotherapy, the obstacles of the blood-brain barrier and the definition of study end points.

TFG::ALK fusion in ALK positive large B-cell lymphoma: a case report and review of literature.

Anaplastic lymphoma kinase (ALK) positive large B-cell lymphoma (ALK+ LBCL) is an aggressive and rare subtype of B-cell lymphoma. Patients typically present with advanced clinical stage disease and do not respond to conventional chemotherapy; the median overall survival is 1.8 years. The genetic landscape of this entity remains poorly understood. Here we report a unique case of ALK+ LBCL harbouring a rare TFG::ALK fusion. Targeted next-generation sequencing showed no significant single nucleotide variants, insertions/deletions, or other structural variants beyond the TFG::ALK fusion; deep deletions of FOXO1, PRKCA, and the MYB locus were also detected. Our case report draws attention to this rare disease, highlights a need for larger genetic profiling studies, and focuses on the pathogenesis and potential therapeutic targets of this aggressive disease. To our knowledge, this is the first report of a TFG::ALK fusion in ALK+ LBCL.

An advanced NSCLC patient with ALK-RNF144A and HIP1-ALK fusions treated with ALK-TKI combination therapy: a case report.

Background: Anaplastic lymphoma kinase (ALK) rearrangement is one of the most important drivers in non-small cell lung cancer (NSCLC). Despite the effectiveness to canonical 3'-ALK fusions, the clinical efficacy of ALK inhibitors in patients with complex ALK fusions, such as nonreciprocal/reciprocal translocation remains uncertain. Exploring the optimal therapeutic regimens for this subset of patients is of crucial clinical significance. Case Description: We reported a female patient diagnosed with stage IVB lung adenocarcinoma (LUAD) harboring a novel ALK-RNF144A fusion, concurrent with a Huntingtin-interacting protein 1 (HIP1)-ALK fusion and a RB1 loss-of-function variant. The patient sequentially received multiple lines of treatment with ALK-tyrosine kinase inhibitor (TKI), chemotherapy, radiotherapy and ALK-TKI combined with anti-angiogenesis. Disease progression accompanied by a squamous cell carcinoma transformation was indicated after ALK-TKI combined with anti-angiogenesis and both ALK-RNF144A and HIP1-ALK fusions were retained in the tumor. The patient was subsequently treated with a third generation ALK-TKI, lorlatinib, in combination with albumin-bound paclitaxel and anlotinib, and then achieved stable disease. The patient remained on the treatment as of the last follow-up resulting in an overall survival (OS) of more than 18 months. Conclusions: We have reported an advanced NSCLC patient with a complex nonreciprocal/reciprocal ALK translocation containing a novel ALK-RNF144A fusion, concurrent with a RB1 loss-of-function mutation, who subsequently experienced pathological squamous cell carcinoma transformation. The combined treatment with ALK-TKI, chemotherapy, and anti-angiogenesis demonstrates clinical efficacy and may provide optional therapeutic strategies for this phenotype.

Beyond Crizotinib: A Systematic Review and Meta-Analysis of the Next-Generation ALK Inhibitors as First-Line Treatment for ALK-Translocated Lung Cancer.

Background: Second and third-generation ALK inhibitors (ALKIs) have been recently approved for ALK-translocated lung cancer treatment, improving - and expanding - the first-line scenario. Methods: In this systematic review and metanalysis, we investigated the efficacy and safety of next-generation ALKIs in untreated advanced ALK-translocated lung cancer patients, searching for randomized phase III controlled trials through databases (PubMed, EMBASE, and the Cochrane Library). Inclusion and exclusion of studies, quality assessment, data extraction, and synthesis were independently accomplished by two reviewers, with discrepancies adjudicated by a third reviewer. Stata (StataCorp., v.16) software was used for the metanalysis. Results: In total, seven randomized controlled trials met our inclusion criteria. Comparing the results of next-generation ALKIs and control therapy (crizotinib or chemotherapy), next-generation ALKIs significantly improved progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), any lesion (aCNSRR) and measurable lesions of central nervous system response rate (mCNSRR). Safety results were similar between the experimental and control groups. Conclusion: Our analysis confirmed that next-generation ALKIs are the preferred first-line treatment option for ALK-translocated lung cancer. They are superior to crizotinib or chemotherapy in several clinical endpoints, including OS, PFS, ORR and CNS disease control, without increased toxicity. In the absence of head-to-head data, the choice between these molecules should be guided by physician experience and preference, drug-specific safety profile and schedule.

Effective Systemic Treatment of Choroidal Metastases NSCLC With Surgery After Crizotinib: A Case Report.

Choroidal metastasis as an initial presenting feature of lung cancer with EML4-ALK translocation is exceedingly rare and greatly impacts patient quality of life (QOL). There are no recommended treatments for such patients, and palliative care remains limited. It is unclear whether surgical resection of primary pulmonary lesions, systemic antitumor therapy, targeted therapy, or localized ocular therapy are effective in treating choroidal metastases in EML4-ALK rearranged oligometastatic non-small cell lung cancer (NSCLC). Here, we present the case of choroidal metastases secondary to lung cancer and EML4-ALK translocation in a 57-year-old woman who firstly underwent resection of lung lesions followed by oral administration of crizotinib without local treatment or systemic chemotherapy. Since then she had a rapid and complete response to crizotinib with 27 months of progression-free survival.

Treatment of brain metastases in ALK-positive non-small cell lung cancer.

Brain metastases are quite frequent in patients with ALK-translocated non-small cell lung cancer (NSCLC): they are often not amenable to surgical resection and are generally treated with radiotherapy (RT). This however causes severe late toxic side effects that may become invalidating considering the relatively long survival provided by recent medical treatment with target therapies. Several clinical trials have demonstrated that ALK-inhibitors (crizotinib, alectinib, brigatinib) show excellent activity also against brain metastases. It is therefore reasonable, in asymptomatic patients, to start treatment with specific inhibitors: RT will be used at the time of tumor progression or when symptoms appear. This sequence provides the best quality of life for patients.

Clinical and therapeutic management of a pleural fibrous tumor with ALK translocation.

We present a clinical case of a solitary fibrous pleural tumor (TFSP) with abnormal behavior due to its high aggressiveness and poor short-term prognosis, where an ALK translocation was identified. TFSP is an infrequent tumor, with an estimated incidence of around 8 per 100,000 inhabitants and with few cases reported in the literature. The most common is that it is a neoplasm of benign behavior, with debut as a localized mass and whose The treatment of choice is surgical resection. All the data in the literature contrast with our experience, which we report below.

Presentamos un caso clínico de un tumor fibroso solitario pleural (TFSP) de comportamiento anómalo por su alta agresividad y mal pronóstico a corto plazo, en el que se identificó una translocación de ALK. El TFSP es un tumor infrecuente, con una incidencia estimada en torno a 8 casos por 100,000 habitantes y con pocos reportes en la literatura. Lo más habitual es que se trate de una neoplasia de comportamiento benigno, con debut como una masa localizada y cuyo tratamiento de elección es la resección quirúrgica. Todos los datos de la literatura contrastan con nuestra experiencia, que presentamos a continuación.

Aberrant Expression of and Cell Death Induction by Engagement of the MHC-II Chaperone CD74 in Anaplastic Large Cell Lymphoma (ALCL).

In 50-60% of cases, systemic anaplastic large cell lymphoma (ALCL) is characterized by the t(2;5)(p23;q35) or one of its variants, considered to be causative for anaplastic lymphoma kinase (ALK)-positive (ALK+) ALCL. Key pathogenic events in ALK-negative (ALK-) ALCL are less well defined. We have previously shown that deregulation of oncogenic genes surrounding the chromosomal breakpoints on 2p and 5q is a unifying feature of both ALK+ and ALK- ALCL and predisposes for occurrence of t(2;5). Here, we report that the invariant chain of the MHC-II complex CD74 or li, which is encoded on 5q32, can act as signaling molecule, and whose expression in lymphoid cells is usually restricted to B cells, is aberrantly expressed in T cell-derived ALCL. Accordingly, ALCL shows an altered DNA methylation pattern of the CD74 locus compared to benign T cells. Functionally, CD74 ligation induces cell death of ALCL cells. Furthermore, CD74 engagement enhances the cytotoxic effects of conventional chemotherapeutics in ALCL cell lines, as well as the action of the ALK-inhibitor crizotinib in ALK+ ALCL or of CD95 death-receptor signaling in ALK- ALCL. Additionally, a subset of ALCL cases expresses the proto-oncogene MET, which can form signaling complexes together with CD74. Finally, we demonstrate that the CD74-targeting antibody-drug conjugate STRO-001 efficiently and specifically kills CD74-positive ALCL cell lines in vitro. Taken together, these findings enabled us to demonstrate aberrant CD74-expression in ALCL cells, which might serve as tool for the development of new treatment strategies for this lymphoma entity.

High risk of thrombosis in patients with advanced lung cancer harboring rearrangements in ROS1.

INTRODUCTION: Based on the high incidence of thromboembolic events (TEs) observed in lung adenocarcinomas with ALK translocations and taking into account the biological proximity of ROS1 and ALK, we conducted a retrospective analysis of patients with advanced lung carcinoma carrying rearrangements in ROS1 from 23 centres in Spain and one centre in Portugal. METHODS: The main objective of the study was to analyse the incidence of TE in this population, looking for predictive risk factors, and its impact on overall survival. RESULTS: A total of 58 patients were included. The incidence of TEs throughout the disease was 46.6% (n = 27) with a median follow-up of 19 months (range: 1-78 months) and a median overall survival of 52 months in the total population and 50 months for the patients presenting TEs, with a hazards ratio of 1.12 (95% confidence interval: 0.47-2.65) p = 0.78. The majority of the events were venous (n = 24; 89%) and occurred in the ambulatory setting (n = 18; 67%). Almost half of the patients (n = 13; 48%) presented the TE in the peri-diagnostic period. CONCLUSIONS: The high incidence of thrombosis, especially during the cancer diagnosis process, requires special attention from a clinician. Despite the limitations of such a small descriptive study, its results are in accordance with previously reported data. It would be important to design prospective studies of antithrombotic prophylaxis in this population because of their possible impact in reducing the risk of TEs.

ALK-Brain Prognostic Index-Preliminary Study of a Prognostic Tool for Patients with ALK-Rearranged, Non-small Cell Lung Cancer and Brain Metastases.

BACKGROUND: Disease-specific Graded Prognostic Assessment (DS-GPA) is the most validated prognostic tool for patients with brain metastasized lung cancer. The Lung-molGPA scoring system was recently introduced for oncogenic-driven brain metastasized lung cancer, but has not yet been validated in cohorts including only ALK-translocated tumors. METHODS: We designed a retrospective cohort study consisting of 44 patients with brain metastasized ALK-positive, non-small cell lung cancer (NSCLC) who were treated between January 2009 and November 2019 at Karolinska University Hospital in Stockholm, Sweden. Information about demographics and clinicopathological parameters were collected. Predictors of overall survival (OS) were identified by Cox regression analyses. A bootstrap validation with 1000 samples was performed in order to compare the different prognostic scores. RESULTS: The variables found to independently influence OS in the multivariate analysis, i.e., PS, sex and brain metastases at diagnosis, were used as prognostic variables in our new prognostic index (ALK-BPI). Patients were divided into two prognostic groups. The median OS was 65.7 months for the good prognostic group and 22.7 months for the poor prognostic group (p = 0.0068). In the univariate analysis of the different prognostic scores, ALK-BPI performed better than the others (HR = 3.6; 95% CI: 1.3-9.9). The mean C-statistics of the different prognostic scores were compared to each other, and no significant difference was observed. CONCLUSION: We propose the ALK-BPI score as a new prognostic tool that can easily be applied for ALK-positive lung cancer patients with brain metastases in daily clinical practice, as it has at least the same prognostic value as Lung-molGPA.

Detection of Nonreciprocal/Reciprocal ALK Translocation as Poor Predictive Marker in Patients With First-Line Crizotinib-Treated ALK-Rearranged NSCLC.

INTRODUCTION: During nonreciprocal/reciprocal translocation process, 5'-anaplastic lymphoma kinase (ALK) sometimes gets retained in the genome and is detectable by next-generation sequencing; however, no study has investigated its clinical significance. Our study aimed to assess the impact of harboring 5'-ALK on the efficacy of crizotinib. METHODS: A total of 150 patients with next-generation sequencing-identified ALK-rearranged NSCLC from March 2014 to July 2018 at the Hunan Cancer Hospital were enrolled in this study. The efficacy of crizotinib as first-line therapy was evaluated in 112 patients according to the retention of 5'-ALK. RESULTS: Among the 150 patients with NSCLC, nonreciprocal/reciprocal translocation was detected in 18.7% (28 of 150), and 3'-ALK fusion alone was detected in 81.3% (122 of 150). Among the 112 patients who received first-line crizotinib, 89 had 3'-ALK fusion alone (79 echinoderm microtubule associated protein-like 4 [EML4]-ALK and 10 non-EML4-ALK), and 23 had nonreciprocal/reciprocal ALK translocation. Among the patients with nonreciprocal/reciprocal ALK translocation, three patients harbored dual concurrent 3'-ALK fusions. Patients with nonreciprocal/reciprocal ALK translocation had higher incidence of brain metastasis at baseline than those with 3'-ALK fusion alone (39.1% versus 13.4%, p = 0.028). Crizotinib-treated patients with nonreciprocal/reciprocal ALK translocation had significantly shorter median progression-free survival (PFS) compared with patients carrying 3'-ALK fusion alone (6.1 m versus 12.0 m, p = 0.001) or with EML4-ALK fusion alone (6.1 m versus 12.6 m, p = 0.001). Multivariate analysis revealed that harboring nonreciprocal/reciprocal ALK translocation was an independent predictor of worse PFS for crizotinib-treated ALK-rearranged NSCLC (p = 0.0046). CONCLUSIONS: Presence of nonreciprocal/reciprocal ALK translocation was predictive for worse PFS and greater likelihood of baseline brain metastases in patients with ALK-rearranged NSCLC who received first-line crizotinib.

EML4-ALK translocation identification in RNA exosomal cargo (ExoALK) in NSCLC patients: a novel role for liquid biopsy.

The introduction of druggable targets has significantly improved the outcomes of non-small cell lung cancer patients (NSCLC). EML4-ALK translocation represents 4-6% of the druggable alterations in NSCLC. With the approval of Crizotinib, first discovered drug for the EML4-ALK translocation, on first line treatment for patients with detected mutation meant a complete change on the treatment landscape. The current standard method for EML4-ALK identification is immunohistochemistry or FISH in a tumor biopsy. However, a big number of NSCLC patients have not tissue available for analysis and others are not suitable for biopsy due to their physical condition or the location of the tumor. Liquid biopsy seems the best alternative for identification in these patients that have no tissue available. Circulating free RNA has not been validated for the identification of this mutation. As a complementary tool, exosomes might represent a good tool for predictive biomarkers study, and due to their stability, they preserve the genetic material contained in them. Our group has described for the first time the translocation EML4-ALK in RNA isolated from exosomes derived from NSCLC patients using next generation sequencing.

The Transcriptional Roles of ALK Fusion Proteins in Tumorigenesis.

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase involved in neuronal and gut development. Initially discovered in T cell lymphoma, ALK is frequently affected in diverse cancers by oncogenic translocations. These translocations involve different fusion partners that facilitate multimerisation and autophosphorylation of ALK, resulting in a constitutively active tyrosine kinase with oncogenic potential. ALK fusion proteins are involved in diverse cellular signalling pathways, such as Ras/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt and Janus protein tyrosine kinase (JAK)/STAT. Furthermore, ALK is implicated in epigenetic regulation, including DNA methylation and miRNA expression, and an interaction with nuclear proteins has been described. Through these mechanisms, ALK fusion proteins enable a transcriptional programme that drives the pathogenesis of a range of ALK-related malignancies.

Circulating free tumor DNA in non-small cell lung cancer (NSCLC): clinical application and future perspectives.

Major advances in the treatment of non-small cell lung cancer (NSCLC) patients have been obtained during the last decade. Molecular testing of tumor samples is therefore mandatory in routine clinical practice. Tumor DNA is also present as cell-free molecules in blood, which is therefore a very useful and convenient source of tumor DNA. In this review, we discuss pre-analytical and analytical aspects of circulating tumor DNA (ctDNA) analysis. We also describe the use of ctDNA analysis in routine clinical practice, and discuss the potential use of ctDNA monitoring both to identify minimal residual disease and as a potential tool to early identify patients' response to treatment.

Response to crizotinib in advanced ALK-rearranged non-small cell lung cancers with different ALK-fusion variants.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). NSCLCs with ALK-rearrangement can be effectively treated with crizotinib. However, magnitude and duration of responses are found to be heterogeneous. This study explored the clinical efficacy of crizotinib in different ALK variants. METHODS: Among 96 ALK-rearrangement patients treated with crizotinib, 60 patients were identified with tumor specimens that could be evaluated by next-generation sequencing (NGS). We retrospectively evaluated the efficacy of crizotinib in different ALK variants. RESULTS: The median Progression-free survival (PFS) of the 96 ALK-rearrangement patients was 14.17 months. Among the 60 patients with NGS results, the most frequent variants were variant 3a/b (33.33%), variant 1 (23.33%) and variant 2 (15.00%). The percentage of rare EML4-ALK variants and non EML4-ALK variants were 10.00% and 18.33%. Survival analysis showed that patients with variant 2 appeared to have longer PFS than others (P = .021); also, patients with TP53 mutation seemed to have an unfavorable PFS than those with TP53 wild-type with a borderline p value (P = .068). After adjusting for other baseline characteristics, EML4-ALK variant 2 was identified as an important factor for a better PFS of crizotinib. We also found that patients with variant 3a/b had shorter duration of response to crizotinib; however, no significant difference of PFS was observed between the PFS of variant3a/b and non-v3 EML4-ALK variants. CONCLUSIONS: Our results indicate prolonged PFS in patients with EML4-ALK variant 2.

EML4-ALK rearrangement in squamous cell carcinoma shows significant response to anti-ALK inhibitor drugs crizotinib and alectinib.

EML4-ALK alterations are more common in adenocarcinomas and are rarely found in squamous cell histology. In documented cases, the majority of EML4-ALK translocations are identified in squamous cell histology and occur in patients with no or light smoking history. We report an EML4-ALK4 translocation in a 50-year-old patient with squamous cell carcinoma and an 18 pack-year smoking history. The patient had a near complete response in the CNS to alectinib treatment. Our observation suggests that EML4-ALK genomic testing may be clinically useful in patients with heavy smoking history.