PCN68 An Incremental Effectiveness Analysis of Lorlatinib for the Treatment of ALK-Positive Advanced Non-Small Cell Lung Cancer that has Progressed after Another ALK...
PCN68 An Incremental Effectiveness Analysis of Lorlatinib for the Treatment of ALK-Positive Advanced Non-Small Cell Lung Cancer that has Progressed after Another ALK...

Objectives To evaluate the incremental effectiveness of anaplastic lymphoma kinase (ALK) inhibitor lorlatinib compared to platinum-based chemotherapy (PBC) for adult patients with ALK-positive advanced non-small cell lung cancer (NSCLC) whose disease progressed after alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy or after crizotinib and at least one other ALK TKI in the Portuguese setting. Conclusions Lorlatinib results in increased life expectancy and quality-adjusted life expectancy compared with PBC in previously treated adult patients with ALK-positive NSCLC in the Portuguese setting. READ ARTICLE

Value in Health DOI:10.1016/j.jval.2020.08.205

Authors: R. Guerreiro, A.T. Paquete, L. Iadeluca, C. Almond, F. Albuquerque de Almeida, M. Inês, J. Costa, M. Borges, L. Silva Miguel,

Read More
Review PaperKirk Smithlorlatinib, Portugal
PCN6 Matching-Adjusted Indirect Treatment Comparisons (MAIC) of the Effect of Lorlatinib Versus Chemotherapy on Overall Survival (OS) and Progression-Free Survival (PFS) for Patients with ...
PCN6 Matching-Adjusted Indirect Treatment Comparisons (MAIC) of the Effect of Lorlatinib Versus Chemotherapy on Overall Survival (OS) and Progression-Free Survival (PFS) for Patients with ...

Objectives: To compare the relative efficacy of the ALK-tyrosine kinase inhibitor (TKI) lorlatinib, investigated in the single-arm Phase I/II trial B7461001 as a second-line or later treatment for patients with advanced ALK-positive NSCLC, to chemotherapy, a key comparator within this indication. Conclusions Lorlatinib consistently demonstrated a significant improvement in the outcomes of both PFS and OS when compared with chemotherapy, although the evidence base is limited. READ ARTICLE

Value in Health DOI:10.1016/j.jval.2020.08.143

Authors: S. Smith, F. Albuquerque de Almeida, M. Inês, L. Iadeluca, M. Cooper

Read More
Review PaperKirk Smithlorlatinib
PCN107 Cost-Effectiveness Analysis of Lorlatinib in Patients Previously Treated with Anaplastic Lymphoma Kinase Inhibitors for NON-SMALL CELL LUNG Cancer in Greece
PCN107 Cost-Effectiveness Analysis of Lorlatinib in Patients Previously Treated with Anaplastic Lymphoma Kinase Inhibitors for NON-SMALL CELL LUNG Cancer in Greece

Objectives Lorlatinib is a potent 3rd generation anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of patients with ALK positive advanced non-small cell lung cancer (NSCLC) previously treated with one or more ALK tyrosine kinase inhibitors (TKIs). The present study assessed the cost-effectiveness of Lorlatinib versus pemetrexed with platinum combination of carboplatin or cisplatin (platinum based ChT) in Greece.Conclusions The present analysis suggests that Lorlatinib may be considered a cost-effective option over platinum based ChT in Greece, for the treatment of patients with ALK positive advanced NSCLC who have progressed after one or more ALK TKIs, while covering a significant unmet medical need. READ ARTICLE

Value in Health DOI:10.1016/j.jval.2020.08.244

Authors: G. Gourzoulidis, O. Zisimopoulou, N. Boubouchairopoulou, C. Michailidi, C. Almond, C. Tzanetakos, G. Kourlaba,

Read More
Real-World OutcomesKirk Smithlorlatinib, cost-effective, Greece
ALK rearrangement in TFE3-positive renal cell carcinoma: Alternative diagnostic option to exclude Xp112 translocation carcinoma
ALK rearrangement in TFE3-positive renal cell carcinoma: Alternative diagnostic option to exclude Xp112 translocation carcinoma

Anaplastic lymphoma kinase (ALK)-rearranged renal cell carcinoma (RCC) is a rare subtype of RCC with gene fusion involving ALK at 2p23. It was first included in the renal tumor classification system by WorldHealth organization (WHO) as a distinct emerging/provisional renal entity in 2016. To date, only a few cases of ALK-RCC have been reported. Here, we report an exceptional case of ALK-RCC in a 15-year-old girl and review the literature. The patient presented with gross hematuria and a tumor measured 7 cm × 6 cm was found in the left kidney by imaging examination. Then a laparoscopic radical nephrectomy combined with local lymph node dissection was performed. The pathologic stage of the tumor was pT1bN1Mx and postoperative pathology showed that the tumor corresponded to WHO/ISUP grade 3–4. Immunohistochemistry (IHC) demonstrated moderate nuclear expression of TFE3 protein. Interestingly, ALK gene rearrangement rather than TFE3 gene rearrangement was observed by fluorescence in situ hy..... READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2020.153286

Authors: Yiqi Zhu, Ning Liu, Wei Guo, Xiaohong Pu, Hongqian Guo, Weidong Gan, Dongmei Li

Read More
Case StudyKirk SmithRenal cell carcinoma, Translocation, FISH, ALK, HOOK1, TFE3
Successful treatment of de novo multiple primary malignancy with long term favorable outcome
Successful treatment of de novo multiple primary malignancy with long term favorable outcome

Multiple primary malignancies have been reported in anecdotal case reports and series in literature. The de novo occurrence poses diagnostic and therapeutic challenges. The co-occurrence of lung adenocarcinoma with acute myeloid leukemia synchronously has been reported in one small series in literature. There is limited data available regarding the treatment and response outcomes in such cases, where both malignancies are molecularly and therapeutically distinct. Hence, a comprehensive workup including a complete molecular profiling is necessary to render appropriate therapy to the patient. This report elucidates the same in a case of concurrent de novo lung adenocarcinoma and acute myeloid leukemia, where complete molecular workup culminated in a successful treatment outcome. READ ARTICLE

Current Problems in Cancer: Case Reports DOI:10.1016/j.cpccr.2020.100030

Authors: Ullas Batra, Shrinidhi Nathany, Anurag Mehta, Dinesh Bhurani, Mansi Sharma, Parveen Jain, NarenderTejwani

Read More
Case StudyKirk SmithNon small cell lung carcinoma, Acute Myeloid Leukemia, Synchronous malignancy, India
Risk of thromboembolism in patients with ALK‐ and EGFR‐mutant lung cancer: A cohort study
Risk of thromboembolism in patients with ALK‐ and EGFR‐mutant lung cancer: A cohort study

Patients with ALK‐mutant advanced lung adenocarcinoma have the highest rate of TE. TE is associated with worse survival across molecular subtypes. These findings should be taken into consideration in decision‐making regarding thromboprophylaxis. READ ARTICLE

Journal of Thrombosis Haemostasis DOI: 10.1111/jth.15215

Authors: Roopkumar J., Poudel S.K., Gervaso L., Reddy C.A., Velcheti V., Pennell N.A., McCrae K.R., Khorana A.A.

Read More
Case StudyKirk SmithALK, EGFR, molecular subtyping, NSCLC, thromboembolism
Understanding the Evolutionary Games in NSCLC Microenvironment
Understanding the Evolutionary Games in NSCLC Microenvironment

While initially highly successful, targeted therapies eventually fail as populations of tumor cells evolve mechanisms of resistance, leading to resumption of tumor growth. Historically, cell-intrinsic mutational changes have been the major focus of experimental and clinical studies to decipher origins of therapy resistance. While the importance of these mutational changes is undeniable, a growing body of evidence suggests that non-cell autonomous interactions between sub-populations of tumor cells, as well as with non-tumor cells within tumor microenvironment, might have a profound impact on both short term sensitivity of cancer cells to therapies, as well as on the evolutionary dynamics of emergent resistance. In contrast to well established tools to interrogate the functional impact of cell-intrinsic mutational changes, methodologies to understand non-cell autonomous interactions are largely lacking... This manuscript serves as a technical report and will be followed up with a research paper in a different journal. READ ARTICLE

BioRxiv DOI:10.1101/2020.11.30.404350

Authors: Ranjini Bhattacharya, Robert Vander Velde, Viktoriya Marusyk, Bina Desai, Artem Kaznatcheev, Andriy Marusyk, David Basanta

Read More
EditorialKirk SmithEvolutionary Games, NSCLC Microenvironment
Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC
Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

Introduction: Variable genomic breakpoints have been identified through the application of target-capture DNA next-generation sequencing (NGS) for ALK, ROS1, and RET fusion detection in NSCLC. We investigated whether ALK, ROS1, and RET genomic breakpoint location can predict matched targeted therapy efficacy. Conclusions: Uncommon ALK, ROS1, and RET genomic breakpoint is an unreliable predictor of matched targeted therapy efficacy. Functional validation by RNA or protein assay may add value for the accurate detection and interpretation of rare fusions. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.10.156

Authors: Weihua Li, Lei Guo, Yutao Liu, Lin Dong, Lin Yang, Li Chen, Kaihua Liu, Yang Shao, Jianming Ying

Read More
Pre-ClinicalKirk SmithDNA sequencing, Genomic breakpoint, Non–small cell lung cancer (NSCLC), Targeted therapy, Uncommon fusions
STRN-ALK, A Novel In-Frame Fusion With Response to Alectinib
STRN-ALK, A Novel In-Frame Fusion With Response to Alectinib

The ALK gene rearrangement is the second most common driver genomic alteration accounting for approximately 3% to 7% of patients with approved targeted therapies in NSCLC, after EGFR gene mutations. We here describe a rare case of a patient with STRN-ALK–rearranged NSCLC. READ ARTICLE

Journal of thoracic Oncology DOI: 10.1016/j.jtocrr.2020.100125

Authors: Misako Nagasaka, Nagaratna Sarvadevabatla, Shawn Iwata, Yubin Ge, Ammar Sukari, Christian Klosowski, Ronald Yanagihara

Read More
Case StudyKirk SmithALK Fusion
Spindle cell tumor with CD34 and S100 co-expression and distinctive stromal and perivascular hyalinization showing EML4-ALK fusion
Spindle cell tumor with CD34 and S100 co-expression and distinctive stromal and perivascular hyalinization showing EML4-ALK fusion

Recently, a novel group of CD34+ and S100+ spindle cell tumors with distinctive stromal and perivascular hyalinization showing recurrent gene fusions involving RAF1, BRAF, NTRK1/2/3, and RET has been identified. ALK rearrangements have been rarely reported in this group of tumors. We report a 24-year-old woman with a 1.5-cm pink mass of the scalp. The tumor was made of spindle cells organized in fascicles or haphazardly arranged in a patternless architecture, with areas of stromal and perivascular hyalinization. The tumor cells diffusely expressed CD34 and S100, without SOX-10 expression. The tumor showed diffuse immunopositivity for ALK. RNA sequencing using next-generation sequencing (NGS) detected an EML4-ALK fusion. This case extends the spectrum of this newly described group of CD34+/S100+ spindle cell tumors at the molecular-genetic level. Dermatopathologists should be aware of this recent entity, as it may fall in the differential diagnosis of many other spindle cell tumors with..... READ ARTICLE

Journal of Cutaneous Pathology DOI:10.1111/cup.13926

Authors: Diane Abs, Samuel Landman, Amélie Osio, Pauline Lepesant, Pierre Schneider, Déborah Obadia, Philippe Moguelet, Cécile Farges, Brigitte Poirot, Jacqueline Lehmann-Che, Céleste Lebbé, Maxime Battistella

Read More
Case StudyKirk SmithSpindle cell tumor, CD34 and S100 co-expression, stromal and perivascular hyalinization, EML4-ALK fusion
Effective RNA Knockdown Using CRISPR-Cas13a and Molecular Targeting of the EML4-ALK Transcript in H3122 Lung Cancer Cells
Effective RNA Knockdown Using CRISPR-Cas13a and Molecular Targeting of the EML4-ALK Transcript in H3122 Lung Cancer Cells

RNAi technology has significant potential as a future therapeutic and could theoretically be used to knock down disease-specific RNAs. However, due to frequent off-target effects, low efficiency, and limited accessibility of nuclear transcripts, the clinical application of the technology remains challenging. In this study, we first assessed the stability of Cas13a mRNA and guide RNA. Next, we titrated Cas13a and guide RNA vectors to achieve effective knockdown of firefly luciferase (FLuc) RNA, used as a target transcript. The interference specificity of Cas13a on guide RNA design was next explored. Subsequently, we targeted the EML4-ALK v1 transcript in H3122 lung cancer cells. As determined by FLuc assay, Cas13a exhibited activity only toward the orientation of the crRNA–guide RNA complex residing at the 5′ of the crRNA. The activity of Cas13a was maximal for guide RNAs 24–30 bp in length, with relatively low mismatch tolerance. After knockdown of the EML4-ALK transcript, cell viabili..... READ ARTICLE

International Journal of Molecular Sciences DOI:10.3390/ijms21238904

Authors: Saifullah, Sakari M, Suzuki T, Yano S, Tsukahara T.

Read More
Pre-ClinicalKirk Smith
Long-term response to Crizotinib in a 17-year-old boy with naive alk-positive Non-Small Cell Lung Cancer
Long-term response to Crizotinib in a 17-year-old boy with naive alk-positive Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related death. NSCLC accounts for 80-90% of cases. In younger patients, adenocarcinoma is the most frequent histotype and 3-7% expresses the rearrange-ment of ALK oncogene, sensitive to TKIs. Crizotinib is the first ALK inhibitor approved by FDA. We present the case of a 17-year-old male with metastatic naïve ALK-positive adenocarcinoma, treated with crizotinib. He received crizotinib and obtained a prolonged response with PFS of 33 months. Crizotinib can be extremely effective in adolescent with naïve ALK-positive NSCLC but it hardly penetrates blood-brain barrier. Resistance mechanisms will be investigated for a better man-agement. READ ARTICLE

Authorea DOI:10.22541/au.160620307.75734495/v1

Authors: megaro g, Miele E, Spinelli GP, et al.

Read More
Case StudyKirk SmithADENOCARCINOMA, ADOLESCENCE, ALK, CRIZOTINIB. LUNG
Comprehensive genomic profile of Chinese lung cancer patients and mutation characteristics of individuals resistant to icotinib/gefitinib
Comprehensive genomic profile of Chinese lung cancer patients and mutation characteristics of individuals resistant to icotinib/gefitinib

Lung cancer is the leading causes of cancer-related death worldwide. Precise treatment based on next-generation sequencing technology has shown advantages in the diagnosis and treatment of lung cancer. This cohort study included 371 lung cancer patients. The lung cancer subtype was related to the smoking status and sex of the patients. The most common mutated genes were TP53 (62%), EGFR (55%), and KRAS (11%). The mutation frequencies of EGFR, TP53, PIK3CA, NFE2L2, KMT2D, FGFR1, CCND1, and CDKN2A were significantly different between lung adenocarcinoma and lung squamous cell carcinoma. We identified the age-associated mutations in ALK, ERBB2, KMT2D, RBM10, NRAS, NF1, PIK3CA, MET, PBRM1, LRP2, and CDKN2B; smoking-associated mutations in CDKN2A, FAT1, FGFR1, NFE2L2, CCNE1, CCND1, SMARCA4, KEAP1, KMT2C, and STK11; tumor stage-associated mutations in ARFRP1, AURKA, and CBFB; and sex-associated mutations in EGFR. Tumor mutational burden (TMB) is associated with tumor subtype, age, sex, and s..... READ ARTICLE

Scientific Reports DOI:10.1038/s41598-020-76791-y

Authors: Yanhong Shang, Xiaofang Li, Weiwei Liu, Xiaoliang Shi, Shaohua Yuan, Ran Huo, Guotao Fang, Xiao Han, Jingnan Zhang, Kunjie Wang, Zhengyue Dou, Yan Zhang, Aimin Zang and Lin Zhang

Read More
Real-World OutcomesKirk SmithCancer, Biomarkers, Oncology
Humanistic burden of living with anaplastic lymphoma kinase-positive non-small-cell lung cancer: findings from the ALKConnect patient insight network and research platform
Humanistic burden of living with anaplastic lymphoma kinase-positive non-small-cell lung cancer: findings from the ALKConnect patient insight network and research platform

ALKConnect demonstrated that disease progression, HRQoL, fatigue/sleep, ALK TKIs and employment matter in ALK+ NSCLC. READ ARTICLE

Lung Cancer Management DOI: 10.2217/lmt-2020-0018

Authors: Lin HM, Pan X, Biller A, J Covey K, Huang H, Sugarman R, Scipione F, West H.

Read More
Case StudyKirk SmithctDNA, ALK, liquid biopsy, next-generation sequencing (NGS)
First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer
First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer

The efficacy of lorlatinib, as compared with that of crizotinib, as first-line treatment for advanced ALK-positive NSCLC is unclear.
We conducted a global, randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced ALK-positive NSCLC who had received no previous systemic treatment for metastatic disease.
In an interim analysis of results among patients with previously untreated advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels. READ ARTICLE

The New England Journal of Medicine
DOI:10.1056/NEJMoa2027187

Authors: Alice T. Shaw, Todd M. Bauer, Filippo de Marinis, Enriqueta Felip, Yasushi Goto, Geoffrey Liu, Julien Mazieres, Dong-Wan Kim, Tony Mok, Anna Polli, Holger Thurm, Anna M. Calella, Gerson Peltz, Benjamin J. Solomon

Read More
Clinical TrialsKirk SmithALK, Lorlatinib, Crizotinib, First-line, Phase 3
Spindle cell neoplasm with EML4-ALK gene fusion presenting as an intraosseous vertebral mass
Spindle cell neoplasm with EML4-ALK gene fusion presenting as an intraosseous vertebral mass

In this article, we describe a spindle cell neoplasm harboring an EML4-ALK gene fusion presenting as an intraosseous vertebral mass with extension into the adjacent soft tissue in a 65-year-old man. Histologically, the lesion was characterized by the presence of monotonous, cytologically bland spindle cells with loose myxoedematous stroma and interspersed areas of amianthoid-like collagen fiber deposition. Immunohistochemistry demonstrated strong diffuse staining for CD34 and S100, with absent immunoreactivity for SOX10. At 1 year of follow-up after resection, there is no evidence of local recurrence or metastatic disease. This case adds to the clinical and pathologic spectrum of the recently described group of kinase fusion-positive spindle cell neoplasms and represents the first reported intra-osseous example. The presence of ALK rearrangement in this lesion represents a potential therapeutic target, if clinically indicated. READ ARTICLE

Genes, Chromosomes & Cancer DOI:10.1002/gcc.22917

Authors: Jose G Mantilla, Hoiwan Cheung, Alice S Ha, Benjamin L Hoch, Yajuan J Liu, Robert W Ricciotti

Read More
Case StudyKirk SmithEML4-ALK, gene fusion, sarcoma, soft tissue pathology
Omental Metastasis from ALK-positive Lung Cancer — A Case Report
Omental Metastasis from ALK-positive Lung Cancer — A Case Report

In conclusion, ALK-positive NSCLC with metastasis to the omentum is very rare. However, in patients with atypical symptoms like ascites, the possibility of a metastasis must be considered and repeat biopsy is always recommended. Targeted therapy in selected patients has shown a more durable response than chemotherapy. READ ARTICLE

The Egyptian Journal of Internal Medicine DOI:10.1186/s43162-020-00010-3

Authors: Khalid, T., Phelan, B., Yousif, A

Read More
Case StudyKirk Smithomental metastasis, ALK, NSCLC
Outcome of Targeted Therapy Recommendations for Metastatic and Recurrent Head and Neck Cancers
Outcome of Targeted Therapy Recommendations for Metastatic and Recurrent Head and Neck Cancers

Recurrent/metastatic (R/M) head and neck cancers bear a poor prognosis. In this analysis, we examined the efficacy and the outcome of targeted therapy recommendations based on the patients’ molecular tumor portrait after failure of all standard therapy options. In this single-center, real-world retrospective analysis of our platform for precision medicine, we analyzed the molecular profile of 50 patients diagnosed with R/M head and neck cancer. Tumor samples of the patients were examined using next-generation sequencing panels of mutation hotspots, microsatellite instability (MSI) testing, and immunohistochemistry (IHC). In 31 cases (62.0% of all patients), a molecular-driven targeted therapy approach was recommended. Eventually, 14 patients (28%) received the suggested targeted therapy. Six of fourteen patients (43%) achieved stable disease conditions and four patients (29%) experienced a progressive disease. The median time to treatment failure was 2.8 months. Therapy recommendations were significantly more often issued for men (p = 0.037) than for women. This analysis demonstrated that precision medicine provided the basis for molecular-driven therapy recommendations in over half of the patients with advanced therapy refractory head and neck cancers, with significantly more therapy recommendations for men. Our analysis showed that although precision medicine approaches are implementable and feasible for the management of recurrent/metastatic head and neck cancers in daily clinical routine, there are major limitations and challenges that have to be overcome. READ ARTICLE

Cancers DOI: 10.3390/cancers12113381

Authors: Hossein Taghizadeh, Robert M. Mader, Leonhard Müllauer, Thorsten Fuereder, Alexandra Kautzky-Willer and Gerald W. Prager

Read More
Real-World OutcomesKirk Smithmetastatic and recurrent head and neck cancers, targeted therapy, molecular profiling, time to treatment failure, turnaround time, immunohistochemistry, gender-specific differences, precision medicine
Discovery of CJ-2360 as a Potent and Orally Active Inhibitor of Anaplastic Lymphoma Kinase Capable of Achieving Complete Tumor Regression
Discovery of CJ-2360 as a Potent and Orally Active Inhibitor of Anaplastic Lymphoma Kinase Capable of Achieving Complete Tumor Regression

We report herein the discovery of a class of potent small-molecule inhibitors of anaplastic lymphoma kinase (ALK) containing a fused indoloquinoline scaffold. The most promising compound CJ-2360 has an IC50 value of 2.2 nM against wild-type ALK and low-nanomolar potency against several clinically reported ALK mutants. This compound is capable of achieving complete tumor regression in the ALK-positive KARPAS-299 xenograft model with oral administration in mice. CJ-2360 represents a promising ALK inhibitor for advanced preclinical development. READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.0c01550

Authors: Jianyong Chen, Yunlong Zhou, Xuyuan Dong, Liu Liu, Longchuan Bai, Donna McEachern, Sally Przybranowski, Chao-Yie Yang, Jeanne Stuckey, Xiaoqin Li, Bo Wen, Ting Zhao, Siwei Sun, Duxin Sun, Lingling Jiao, Yu Jing, Ming Guo, Dajun Yang, and Shaomeng Wang

Read More
Pre-ClinicalKirk SmithRodent models, Inhibitors, Inhibition, Peptides and proteins, Tumors
STRN-ALK Fusion in Lung Adenocarcinoma with Excellent Response Upon Alectinib Treatment: A Case Report and Literature Review
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.

Read More
Case StudyKirk Smithlung adenocarcinoma, STRN-ALK fusion, ctDNA, alectinib, targeted NGS