Dramatic response to brigatinib in a lung adenocarcinoma patient harboring EML4-ALK fusion and a G1202R de novo gene mutation

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors are the preferred initial treatment for ALK rearranged non-small cell lung cancer (NSCLC). While initial responses to next-generation inhibitors are robust, acquired resistance is expected for nearly all patients. The emergence of the G1202R mutation represents a significant concern for oncologists, as it predicts resistance to almost all ALK inhibitors (ALKi) other than lorlatinib. However, we report the first case of ALK de novo mutation in a patient with advanced NSCLC that responded to brigatinib. READ ARTICLE

European Journal of Cancer DOI:10.1016/j.ejca.2022.02.001

Authors: Yue Pan, Yue Zeng, Yurong Peng, Xiaohan Liu, Yizheng Li, Fang Wu

Case StudyKirk SmithApril 1, 2022Brigatinib, lung adenocarcinoma, EML4-ALK, G1202R, gene mutation

Real-world circulating tumor DNA analysis depicts resistance mechanism and clonal evolution in ALK inhibitor-treated lung adenocarcinoma patients

Sequential postprogression plasma profiling revealed that increased lines of ALK inhibitors can accelerate the accumulation of ALK resistance mutations and may lead to treatment-refractory compound ALK mutations. The selection for optimal first-line TKI is very important to achieve a more efficacious long-term strategy and prevent the emergence of on-target resistance, which may provide guidance for clinical decision making. READ ARTICLE

ESMO Open DOI:100337. doi: 10.1016/j.esmoop.2021.100337

Authors: Hua G, Zhang X, Zhang M, Wang Q, Chen X, Yu R, Bao H, Liu J, Wu X, Shao Y, Liang B, Lu K.

Is Elevation of Alkaline Phosphatase a Predictive Factor of Response to Alectinib in NSCLC?

In the following report, we describe a case of alkaline phosphatase (ALP) elevation occurring during treatment with alectinib (Alecensa™), which was administered for anaplastic lymphoma kinase (ALK) mutated metastatic non-small cell lung cancer (mNSCLC). A 51 year-old female with widespread metastatic disease exhibited a rapid and significant response within a very short period to alectinib therapy, accompanied by a rapid increase of ALP to more than six times the upper limit of normal (grade 3) ALP, decreasing to within normal limits within 3 weeks after initiation of therapy without any dose modification. READ ARTICLE

Current Oncology DOI:10.3390/curroncol29010016

Authors: Walid Shalata, Alexander Yakobson, Rachel Steckbeck, Ashraf Abu Jama, Omar Abu Saleh and Abed Agbarya

Case Study, group1Kirk SmithDecember 31, 2021lung adenocarcinoma, ALK mutation, Alectinib, alkaline phosphatase, toxicity

Identification of triple gene fusion ALK-LRRN2, LTBP1-ALK, and HIP1-ALK in advanced lung adenocarcinoma and response to alectinib: A case report

Together, we identified a rare triple ALK fusion variant, ALK-LRRN2, LTBP1-ALK and HIP1-ALK, in a patient with lung adenocarcinoma. The patient benefited from alectinib treatment, which could provide a certain reference for the patients with such gene alteration. READ ARTICLE

Medicine DOI:10.1097/MD.0000000000027999

Authors: Ning S, Shi C, Zhang H and Li J.

Case Study, group1Kirk SmithDecember 23, 2021alectinib, ALK-LRRN2, HIP1-ALK, LTBP1-ALK, lung adenocarcinoma, triple fusions

Identification of a Novel SLC8A1-ALK Fusion and Non-Canonical Expression Significantly Responding to ALK-TKIs in Lung Adenocarcinoma: A Case Report

Approximately 2–7% of patients with non-small cell lung cancer harbor anaplastic lymphoma kinase (ALK) rearrangement events. Of note, typical ALK actionable rearrangements are sensitive to treatment with tyrosine kinase inhibitors (TKIs). However, different types of ALK fusion influence the clinical outcomes of this therapeutic approach. Approximately 10–40% of patients with ALK-fusion positive non-small cell lung cancer do not response to ALK-TKI therapy. Therefore, it is important to accurately identify the types of ALK rearrangement for appropriate selection of clinical treatment. We find a strategy combining DNA-targeted next-generation sequencing with RNA reverse transcriptase-polymerase chain reaction and sequencing, besides fluorescence in situ hybridization and immunohistochemistry, may provide an effective and practical solution for correct identification of partner genes and fusion structures in the diagnosis of ALK rearrangements, particularly for non-canonical expression patterns of ALK fusion events. The combined approach may lead to more benefits for patients. READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S319845

Authors: Xingyu Zhu, Yuqi He, Yin Wang,Yan Lei, Xiaoxing Su, Yifan Liu, Shuangxiu Wu, Zhengfu He

Case Report: Identification of Two Rare Fusions, PDK1-ALK and STRN-ALK, That Coexist in a Lung Adenocarcinoma Patient and the Response to Alectinib

Several double ALK fusions coexisting in one patient have been reported. However, few studies have reported the clinical efficacy of ALK inhibitors in rare double ALK fusions. Here, we described a rare PDK1-ALK, STRN-ALK double-fusion variant in a patient with metastatic lung adenocarcinoma. The patient responded well to alectinib (600 mg) twice daily. This case shows a promising treatment option for patients with rare ALK double-fusion variants. READ ARTICLE

Frontiers in oncology DOI:10.3389/fonc.2021.722843

Authors: Zeng H, Li Y, Wang Y, Huang M, Zhang Y, Tian P, Li W.

Treatment Strategy of Lung Adenocarcinoma with Concomitant EGFR Mutation and ALK Rearrangement

The incidence of synchronous mutations of Epidermal growth factor receptor (EGFR) and anaplastic large-cell lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC) was low. Now clinical experience is still insufficient. Simultaneously the treatment of brain metastasis hemorrhage in the acute phase with lung cancer is still controversial. We described the clinical treatment strategy of a patient with synchronous mutations of EGFR and ALK.We found that the tumor was well controlled. Progression-free survival (PFS)1 was 4 months, PFS2 was 3 months, PFS3 was 5 months, PFS4 was 5 months, and PFS5 was 9 months. At present, the patient still maintains partial response (PR) status. READ ARTICLE

Research Square DOI:10.21203/rs.3.rs-718876/v1

Authors: Li Li , Wei Liu , Chunhua Xu, Jue Zou

Catenin Alpha-2 Mutation Changes the Immune Microenvironment in Lung Adenocarcinoma Patients Receiving Immune Checkpoint Inhibitors

Our findings provide novel insights into the underlying pathogenesis of LUAD. CTNNA2 mutation can change the immune microenvironment, thereby improving patient prognosis. The results also suggest that CTNNA2 may become a new biomarker and therapeutic target for LUAD in the future. READ ARTICLE

Frontiers in Pharmacology DOI: 10.3389/fphar.2021.645862

Authors: Wen Y., Lin A., Zhu W., Wei T., Luo P., Guo L. and Zhang J.

Circulating tumor DNA to investigate resistance mechanism and clone evolution of ALK TKI treated lung adenocarcinoma

Conference PaperKirk SmithMay 28, 2021ctDNA, resistance mechanism, ALK, TKI sequence, lung adenocarcinoma

RNA sequencing effectively identifies gene fusions undetected by DNA sequencing in lung adenocarcinomas

Background: Next-generation sequencing of DNA, which can provide valid information for clinical therapeutic decision-making, has been widely used in the management of lung cancer especially adenocarcinoma. However, due to its technical limitations for detecting certain alterations such as gene rearrangement, the DNA-based sequencing (DNA-seq) may miss the actionable alteration in some cases, who would have benefited from targeted therapy. The study aimed to evaluate the capability of RNA sequencing (RNA-seq) in identifying DNA-seq undetectable gene alterations in lung adenocarcinomas. Conclusions: Targeted RNA-seq can effectively identify genomic rearrangements that are undetectable by DNA-seq and provide lung adenocarcinoma patients with more opportunities for targeted therapy. Therefore, it should be recommended for all patients, in whom DNA-seq fails to detect driver alteration. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.3052

Authors: Ruiying Zhao, Yuchen Han, Chan Xiang, Shengnan Chen, Jikai Zhao, Lianying Guo, Anbo Yu, Jinchen Shao, Lei Zhu, Yue Tian, Fan Yang, Lin Shao, Xuejing Li, Lu Zhang

Conference PaperKirk SmithMay 28, 2021RNA sequencing, DNA sequencing, lung adenocarcinoma

STRN-ALK Fusion in Lung Adenocarcinoma with Excellent Response Upon Alectinib Treatment: A Case Report and Literature Review

More than 90 fusion partners of ALK have been reported in NSCLC patients.
Striatin gene (STRN)-ALK fusion has rarely been reported. Case study of NSCLC patient harboring an STRN-ALK fusion and exhibiting an excellent response to alectinib treatment. READ ARTICLE

OncoTargets and Therapy DOI: 10.2147/OTT.S282933

Authors: Su C, Jiang Y, Jiang W, Wang H, Liu S, Shao Y, Zhao W, Ning R, Yu Q.

Case StudyKirk SmithNovember 6, 2020lung adenocarcinoma, STRN-ALK fusion, ctDNA, alectinib, targeted NGS

A novel EML4-ALK BIRC6-ALK double fusion variant in lung adenocarcinoma confers sensitivity to alectinib

ALK receptor tyrosine kinase gene (ALK) rearrangement is a common driver mutation for patients with NSCLC. At present, more than 20 fusion partners for ALK in NSCLC have been reported. The most common partner of ALK rearrangement is echinoderm microtubule-associated protein-like 4 gene (EML4). But ALK double fusion is rare. ALK inhibitors are widely used in cancer-targeted therapy now. The progression-free survival of patients with ALK-positive NSCLC treated with alectinib as a first-line treatment is varied due to different fusion forms of ALK [ [1] ]. Therefore, it is of great clinical significance to continuously explore new forms of ALK fusion and study its correlation with drug sensitivity. With the development of next-generation sequencing (NGS) technology, ALK detection is becoming more and more precise, Herein we described a patient with advanced lung adenocarcinoma who presented simultaneously with two novel fusions, EML4-ALK and BIRC6-ALK, and with sensitivity to alectinib. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.04.030

Authors: Jiang-Ming Zhong, Gui-Feng Zhang, Li Lin, De-Yu Li, Zhen-Hua Liu

Tree-in-bud Pattern in ALK-positive Lung Adenocarcinoma

A 62-year-old woman presented with a 3-month history of cough and hemoptysis. CT revealed nodular shadows with centrilobular distribution in the left lung. Three sputum smears for acid-fast bacillus were negative. Based on the results of a transbronchial biopsy, she was diagnosed with stage IVA lung lepidic adenocarcinoma harboring ALK translocation. At this point, CT showed progressive shadows, and alectinib was immediately initiated. Acid-fast bacillus culture of bronchoscopic biopsy tissue was negative. One month later, marked remission was observed, providing definitive evidence to exclude mycobacterial infection. The tree-in-bud pattern occurs commonly in patients with mycobacterial infection. Central lung cancer is reportedly another common cause of the treein-bud pattern. Nevertheless, when encountering a treein-bud pattern, physicians tend to be anxious about the possibility of tuberculosis; even when mycobacterial tests are negative, the absence of evidence is not evidence of ..... READ ARTICLE

Internal Medicine (The Japanese Society of Internal Medicine) DOI:10.2169/internalmedicine.4076-19

Authors: Takayuki Shiroyama, Shingo Nasu, Ayako Tanaka and Tomonori Hirashima

Case StudyKirk SmithMarch 12, 2020tree-in-bud, lung adenocarcinoma, ALK, alectinib

ALK Rearrangement Adenocarcinoma with Histological Transformation to Squamous Cell Carcinoma Resistant to Alectinib and Ceritinib

Specific tyrosine-kinase inhibitors (TKIs) are widely used for the treatment of non-small-cell lung cancers with anaplastic lymphoma kinase (ALK) translocations. However, most treated patients eventually develop resistance to the TKIs. The histological transformation into small cell carcinoma is well known to be the underlying mechanism for acquired resistance; however, transformation to squamous cell carcinoma is extremely rare. We, herein, report a case of ALK rearrangement-positive adenocarcinoma that transformed to squamous cell carcinoma after administration of alectinib, and was found to be resistant to ceritinib. READ ARTICLE

OncoTargets and therapy DOI:10.2147/OTT.S236706

Authors: Kaiho T, Nakajima T, Iwasawa S, Yonemori Y, Yoshino I.

Adverse Events of Concurrent Radiotherapy and ALK Inhibitors for Brain Metastases of ALK-Rearranged Lung Adenocarcinoma

Background: We investigated acute adverse events in patients with brain metastases (BMs) of anaplastic lymphoma kinase-rearranged (ALKr) non-small cell lung cancer (NSCLC) treated with both cranial radiotherapy and tyrosine kinase inhibitors (TKIs) of ALK. Patients and Methods: Acute AEs were retrospectively investigated in patients with BMs of ALKr-NSCLC who received both whole-brain radiotherapy (WBRT) and ALK-TKI. For comparison, they were also assessed in patients with epidermal growth factor receptor (EGFR)-mutated NSCLC and wild-type with neither ALK rearrangement nor EGFR mutation treated with WBRT. Results: Two ALKr cases were consequently eligible. Grade 3 otitis media unexpectedly occurred in both cases, while there was one case out of 11 and one case out of 18 of grade 2 otitis media among the EGFR-mutated cases and wild-type cases (p=0.013), respectively. Conclusion: Concurrent treatment with WBRT and ALK-TKI may be associated with acute severe ear toxicity in patients with BMs of ALKr-NSCLC. READ ARTICLE

In Vivo DOI:10.21873/invivo.11767

Authors: TAKAAKI NAKASHIMA, TAKESHI NONOSHITA, HIDENARI HIRATA, KOUJI INOUE, AKIRA NAGASHIMA, TADAMASA YOSHITAKE, KAORI ASAI and YOSHIYUKI SHIOYAMA

Case StudyKirk SmithJanuary 1, 2020ALK-TKI, radio therapy, adverse events, lung adenocarcinoma, brain metastases

Sequential EGFR mutation and ALK rearrangement in adenocarcinoma lung, with rare metastasis to bilateral breast, ovary and endometrium

With the advent of targeted therapies there was a paradigm shift in the treatment of metastatic adenocarcinoma of lung. Immuno-histopathology and molecular subtyping in metastatic adenocarcinoma lung have enabled personalized treatment for each patient. Oncogenic driver mutations in non-small cell lung cancer are commonly EGFR (Epidermal Growth Factor Receptor) gene mutation and ALK (Anaplastic Lymphoma Kinase) gene rearrangement, which are mutually exclusive. Almost 60–64% patients have oncogenic mutation, which are mutually exclusive. Here, we present a case with EGFR mutation and ALK gene rearrangement which was expressed sequentially and with metastasis to rarest sites bilateral breast, ovaries and endometrium. Even though presented with upfront metastatic disease, patient was treated with multiple lines of targeted agents, by which patient survived for 5 years with good quality of life. READ ARTICLE

Respiratory Medicine Case Reports DOI:10.1016/j.rmcr.2019.100954

Authors: V. R. Anjali, Rambha Pandey, Astha Srivastava, Madhu Rajeshwari, Durgatosh Pandey, M. C. Sharma

EP114-47 Lung Adenocarcinoma with Concurrent KRAS Mutation and ALK Rearrangement Responding to Crizotinib

We reported a rare case of 47-year-old female was diagnosed with lung adenocarcinoma and treated with three cycles of chemotherapy. A biopsy acquired after disease progression revealed concurrent KRAS mutation and ALK translocation by a NGS assay. Based on molecular findings, treatment was initiated with crizotinib in September, 2016. After 2 months of therapy, the patient achieved a partial response. Afterwards, the patient was further administrated with crizotinib for 9 months with a stable disease before tumor progression.A further understanding of the molecular biology with multiple oncogenic drivers will promote the optimal treatment for NSCLC. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.2332

Authors: Y. Zhu, W. Wang, C. Xu, X. Li, W. Zhuang, K. Du, G. Chen, M. Fang, T. Lv, Y. Song

Case StudyKirk SmithOctober 1, 2019lung adenocarcinoma, ALK rearrangement, KRAS mutation

P2.01-31 Preliminary Results of Second Generation ALK Inhibitor PLB1003: A Phase La Study

Crizotinib is initially effective in the treatment of ALK-rearranged NSCLC, but the disease eventually progresses. PLB1003, a high-efficiency second generation ALK inhibitor, was developed due to the increased resistance of EML4-ALK fusion genes. Preclinical data show that PLB1003 is safe and effective in cell-based assays and Crizotinib-resistant animal models. This is the ongoing phase Ia study of PLB1003. An open-label, multicenter phase I clinical trial was conducted in patients with locally advanced or metastatic NSCLC who had previously failed or were intolerable to Crizotinib or chemotherapy. The study result shows PLB1003 is safe, tolerable and has potential clinical benefit to locally advanced or metastatic NSCLC patients with ALK rearrangement mutation and had disease progression or were intolerable to previously treatment of Crizotinib or chemtherapy. (ClinicalTrials.gov number, NCT03130881) READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1375

Authors: B. Han, T. Chu, J. Qian, B. Yan, Y. Zhang, Q. Chang

P114-39 Acquired ALK Rearrangement in EGFR-Mutant Lung Adenocarcinoma Treated with EGFR TKIs

Few studies have been reported on acquired anaplastic lymphoma kinase (ALK) rearrangement in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma patients with EGFR tyrosine kinase inhibitors (TKIs).EGFR-mutant lung adenocarcinoma patients were screened after resistance to EGFR TKIs from September 2017 to December 2018 at the Guangdong Lung Cancer Institute. Both EGFR mutation and ALK rearrangement were tested by next-generation sequencing (NGS). Acquired ALK rearrangement was defined as positive ALK rearrangement after resistance to EGFR TKIs, but negative result detected by NGS at the baseline of EGFR TKI treatments.The frequency of acquired ALK rearrangement is similar in EGFR-mutant lung adenocarcinomas after resistance to the first-, second-, or third-generation EGFR TKIs. The majority of acquired ALK-fusion partners are non-EML4. Combination of EGFR TKIs and ALK inhibitors might be a strategy to overcome such resistance. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1190

Authors: Q. Wang, R. Chen, J. Kang, H. Chen, B. Wang, Z. Wang, Q. Zhou, Y. Wu, J. Yang

Conference PaperKirk SmithOctober 1, 2019lung adenocarcinoma, ALK rearrangement, EGFR

P214-38 ATAD2B-ALK, a Novel Fusion in Lung Adenocarcinoma Identified Using Next-Generation Sequencing (NGS)

Background: Anaplastic lymphoma kinase (ALK) rearrangements is an important molecular subtype of non-small cell lung cancer (NSCLC), and patients with this variant are sensitive to ALK inhibitors. Since the discovery of the EML4-ALK fusion ten years ago, several fusion partners of ALK in NSCLC have been reported, including KIF5B, KLC1, HIP1, TPR and so on. According to previous reports, different fusion partner lead to various function and activity of the fusion product. Here, we identified a novel fusion partner for ALK in a lung adenocarcinoma patient. Conclusion: The novel ALK fusion gene probably served as oncogenic driver of the patient’s tumor. This case is the first report of ATAD2B-ALK fusion in clinical tumor samples and could provide a new diagnostic and therapeutic candidate target for patients with lung cancer. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1823

Authors: H. Bai, W. Jia, X. Jin, H. Mao, D. Wu, R. Chen, X. Xia, H. Wu

Conference PaperKirk SmithOctober 1, 2019ALK, ATAD2B, ALK rearrangement, NGS, lung adenocarcinoma