Drug resistance mechanisms in Japanese anaplastic lymphoma kinase-positive non–small cell lung cancer and the clinical responses based on the resistant mechanisms

The treatment for anaplastic lymphoma kinase (ALK)-positive lung cancer has been rapidly evolving since the introduction of several ALK tyrosine kinase inhibitors (ALK-TKI) in clinical practice. However, the acquired resistance to these drugs has become an important issue. In this study, we collected a total of 112 serial biopsy samples from 32 patients with ALK-positive lung cancer during multiple ALK-TKI treatments to reveal the resistance mechanisms to ALK-TKI. Among 32 patients, 24 patients received more than two ALK-TKI. Secondary mutations were observed in 8 of 12 specimens after crizotinib failure (G1202R, G1269A, I1171T, L1196M, C1156Y and F1245V). After alectinib failure, G1202R and I1171N mutations were detected in 7 of 15 specimens. G1202R, F1174V and G1202R, and P-gp overexpression were observed in 3 of 7 samples after ceritinib treatment. L1196M + G1202R, a compound mutation, was detected in 1 specimen after lorlatinib treatment. ALK-TKI treatment duration was longer in th..... READ ARTICLE

Cancer Science DOI:10.1111/cas.14314

Authors: Noriko Yanagitani, Ken Uchibori, Sumie Koike, Mika Tsukahara, Satoru Kitazono, Takahiro Yoshizawa, Atsushi Horiike, Fumiyoshi Ohyanagi, Yuichi Tambo, Shingo Nishikawa, Naoya Fujita, Ryohei Katayama, Makoto Nishio

Transformation of EML4-ALK fusion-positive adenocarcinoma into squamous cell carcinoma in association with acquired resistance to crizotinib

Background: Targeted therapies are a standard of care for first-line treatment of Anaplastic lymphoma kinase (ALK)-rearranged non small cell lung cancer (NSCLC). Giving the rapid pace of drug discovery and development in this area, reporting of adverse effects of ALK inhibitors is crucial. Here, we report a case of osteitis induced by an ALK inhibitor mimicking bone metastasis, a previously undescribed side effect of crizotinib. Conclusions: This is the first report of crizotinib-induced osteitis. Crizotinib differs from other ALK inhibitors as it targets other kinases as well, which may have been responsible for the osteitis. Crizotinib can induce rapidly extensive osteitis, which can mimic tumor progression. READ ARTICLE

BMC Cancer DOI:10.1186/s12885-019-6486-3

Authors: F. Guisier, N. Piton, M. Bellefleur, N. Delberghe, G. Avenel, E. Angot, O. Vittecoq, M. Ould-Slimane, H. Morisse-Pradier, M. Salaun, L. Thiberville

Case StudyKirk SmithJanuary 6, 2020ALK-rearranged NSCLC, ALK inhibitors, Crizotinib, Ceritinib, Drug toxicity, Osteitis

YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation

Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Limited information is currently available on the mechanisms underlying the initial survival of tumor cells against alectinib. Using patient-derived cell line models, we herein demonstrate that cancer cells survive a treatment with alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALK-rearranged xenografts when compared with alectinib monotherapy. These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer. READ ARTICLE

Nature Communications DOI:10.1038/s41467-019-13771-5

Authors: Takahiro Tsuji, Hiroaki Ozasa, Wataru Aoki, Shunsuke Aburaya, Tomoko Yamamoto Funazo, Koh Furugaki, Yasushi Yoshimura, Masatoshi Yamazoe, Hitomi Ajimizu, Yuto Yasuda, Takashi Nomizo, Hironori Yoshida, Yuichi Sakamori, Hiroaki Wake, Mitsuyoshi Ueda, Young Hak Kim & Toyohiro Hirai

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

Unique molecular features and clinical outcomes in young patients with non-small cell lung cancer harboring ALK fusion genes

Purpose: This study aimed to determine the molecular features and clinical outcomes of young patients with non-small cell lung cancer (NSCLC) harboring ALK fusion genes. Conclusion: Unique genetic characteristics were found in ALK-rearranged NSCLC patients with early disease onset, and these patients responded better to crizotinib and had longer PFS compared to patients with later disease onset. However, patients with concomitant TP53 mutations may not have a significant response to treatment. READ ARTICLE

Journal of Cancer Research and Clinical Oncology. DOI: 10.1007/s00432-019-03116-6

Authors: Panwen Tian, Yujie Liu, Hao Zeng, Yuan Tang, Analyn Lizaso, Junyi Ye, Lin Shao & Yalun Li

Association of ALK rearrangement and risk of venous thromboembolism in patients with non-small cell lung cancer: A prospective cohort study

Background: Isolated reports are inconsistent regarding the risk of venous thromboembolism (VTE) in patients with anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC). This study examined whether ALK rearrangement could have an influence on VTE in a prospective cohort. Conclusions: The presence of ALK rearrangement is associated with increased risk of VTE in patients with NSCLC. READ ARTICLE

Thrombosis Research DOI:10.1016/j.thromres.2019.12.009

Authors: Feifei Dou, Yuan Zhang, Jiawen Yi, Min Zhu, Shu Zhang, Di Zhang, Yuhui Zhang

Low ALK FISH positive metastatic non-small cell lung cancer (NSCLC) patients have shorter progression-free survival after treatment with ALK inhibitors

ALK FISH assay guides clinical decision to initiate therapy with ALK inhibitors in patients with stage IV non-small cells lung cancer (NSCLC). In this single institution retrospective study, we investigated the association between the strength of ALK positivity and progression-free survival (PFS) We screened 4,829 patients tested for ALK rearrangement by FISH from 01/06/2012 to 06/30/2018 and included 66 stage IV NSCLC ALK positive patients, who were ALK inhibitor naïve, received an ALK inhibitor, and been followed at least 10 months to the study. The median PFS for cases high positive cases [≥=50% positive nuclei; n = 49] and low positive cases [16–49% positive nuclei; n = 17] is 16 months and 4 months respectively, and the hazard ratio is 2.89 [95 CI 1.34–6.2] (p = 0.0068). When cases are stratified according to cut-off ≥=30% positive nuclei, the median PFS for cases above (n = 55) and below the cut-off (n = 11) is 12 and 3 months, respectively and the hazard ratio is 9.60 [95 CI 2.6..... READ ARTICLE

Cancer Genetics DOI:10.1016/j.cancergen.2019.12.003

Authors: Gokce A. Toruner, Zhenya Tang, Guilin Tang, L. Jeffrey Medeiros, Shimin Hu

Case StudyKirk SmithDecember 12, 2019ALK, FISH, PFS, Lung cancer

Coexistence of a Novel PRKCB-ALK, EML4-ALK Double-Fusion in a Lung Adenocarcinoma Patient and Response to Crizotinib

ALK receptor tyrosine kinase (ALK) rearrangement is a common driver mutation for patients with NSCLC. More than 20 other fusion partners for ALK in NSCLC have been reported.1 However, one patient with double ALK fusions simultaneously is still rare, and the double ALK fusions changing after treatment is also rarely reported. Here, a lung adenocarcinoma patient with EMAP like 4 (EML4)-ALK and protein kinase C beta (PRKCB)–ALK double fusion variant was presented who responded to crizotinib and showed the changes of two ALK fusions before and after treatment... In summary, this study is the first to describe a novel EML4-ALK, PRKCB-ALK double-ALK fusion lung adenocarcinoma patient who is sensitive to crizotinib. This is also the first study to describe a novel PRKCB-ALK fusion that may have promising efficacy by crizotinib treatment. In addition, the case also shows that liquid biopsy can provide more information of mutation to guide treatment and multiple liquid biopsy procedures can a..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.07.021

Authors: Jing Luo, Dejian Gu, Huasong Lu, Si Liu, Jinliang Kong

Case StudyKirk SmithDecember 1, 2019PRKCB-ALK, EML4-ALK Double-Fusion, Lung Adenocarcinoma, Crizotinib

Clinical observation of crizotinib in the treatment of ALK-positive advanced non-small cell lung cancer

Background: ALK is a prognostic and predictive tumor marker in non-small cell lung carcinoma (NSCLC), and is more often found in lung adenocarcinomas. Conclusions:The efficacy of crizotinib in patients with advanced NSCLC is related to the number of metastatic organs, age and timing of treatment. The use of crizotinib is prone to intracranial progression, and progression of simple brain metastases is not an indication that crizotinib is discontinued. Patients will continue to benefit from combination of local radiotherapy. READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2019.152695

Authors: Huiyan Deng, Bin Li, Lina Li, Jingcui Peng, Tongshuai Lv, Yueping Liu, CuiminDing

Driver genes as predictive indicators of brain metastasis in patients with advanced NSCLC: EGFR, ALK, and RET gene mutations

Background: A retrospective analysis verified the role of gene mutations in brain metastasis in patients with non-small cell lung cancer (NSCLC). Conclusions: An EGFR mutation, ALK gene fusion, and RET gene fusion in advanced NSCLC patients play roles in brain metastasis as positive driver genes. Impact: An EGFR mutation, and ALK and RET gene fusions are risk factors for brain metastasis in advanced NSCLC patients. READ ARTICLE

Cancer Medicine. DOI: 10.1002/cam4.2706

Authors: Huijuan Wang, Ziqi Wang, Guowei Zhang, Mina Zhang, Xiaojuan Zhang, Haixia Li, Xuanxuan Zheng, Zhiyong Ma

Sequential ALK inhibitor treatment benefits patient with leptomeningeal metastasis harboring non-EML4-ALK rearrangements detected from cerebrospinal fluid: A case report

A 47-year-old female with ALK-rearranged lung adenocarcinoma developed leptomeningeal metastasis (LM) after progression on first-line crizotinib. Alectinib 300 mg was commenced and the patient achieved clinical and radiographic improvements. After nine months of alectinib 300 mg, she started to experience symptomatic LM. Two concurrent non-EML4-ALK rearrangements, LOC388942-ALK and LINC00211-ALK, were identified from the CSF but not from the plasma samples. With the primary lung lesions remaining stable, the alectinib dose was increased to 600 mg twice daily which alleviated the clinical symptoms of symptomatic LM. After 7.6 months of alectinib 600 mg, the patient again experienced CNS progression. With both CSF and plasma samples revealing no druggable mutations, the alectinib dose was re-escalated to 900 mg twice daily, resulting in clinical benefits lasting for two months. Her therapy was then switched to lorlatinib which controlled the disease for 8.7 months until her demise. The L..... READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13259

Authors: Zhaona Li, Pupu Li, Bing Yan, Qiongqiong Gao, Xiangli Jiang, Zhongli Zhan, Qingna Yan, Analyn Lizaso, Chun Huang

PLEKHM2-ALK: A novel fusion in small-cell lung cancer and durable response to ALK inhibitors

Objectives: In non-small cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) rearrangement identifies a subgroup of patients who are sensitive to ALK tyrosine kinase inhibitors (TKIs). ALK fusion is extremely rare in small-cell lung cancer (SCLC). To the best of our knowledge, only two cases of SCLC harboring ALK fusion mutation has been reported previously, both of whom carrying EML4-ALK fusion. There are no standard treatment options for SCLC patients with ALK fusion mutations. Herein, we described a rare case of ALK-rearranged SCLC responding to ALK inhibitors. Conclusion: This case provides a meaningful reference for the treatment of SCLC patients with ALK fusion mutations. This case also provides valuable information on the response to ALK inhibitors of patients with PLEKHM2-ALK fusion and better understanding of ALK-TKI applications in the future. NGS may be used as a routine test to explore more treatment opportunities for tumor SCLC patients. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2019.11.002

Authors: Tao Li, Fan Zhang, Zhaozhen Wu, Longgang Cui, Xiaochen Zhao, Jinliang Wang, Yi Hu

Case StudyKirk SmithNovember 16, 2019Small-cell lung cancer, Novel ALK fusion, Durable clinical benefit, NGS

Intracranial remission with brigatinib rechallenge as fifth-line ALK inhibition therapy in a lung cancer patient

Several anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors have been developed for the treatment of EML4-ALK-rearranged non-small-cell lung cancer, with the newer generation agents brigatinib, alectinib and lorlatinib showing pronounced central nervous system activities. Intracranial efficacy is an important feature for these agents, as metastatic lesions frequently occur in the central nervous system in the ALK-positive setting. Here, we report on an updated case of a patient who received her diagnosis in 2005 and has had disease progression with new lesions on six occasions over the last 8 years. During the first two progressions, only local recurrence was observed. After that, the lungs stayed clear and the patient progressed exclusively in the brain and spinal cord. Initial treatments consisted of chemotherapy and radiotherapy. In 2012, ALK-directed targeted therapy became available, and crizotinib was administered. The treatment was switched to brigatinib 3 years later be..... READ ARTICLE

Anti-Cancer Drugs
DOI:10.1097/CAD.0000000000000800

Authors: Hochmair, Maximiliana; Weinlinger, Christopha; Prosch, Helmut

Acquired Resistance Mutations to ALK Inhibitors Identified by Single Circulating Tumor Cell Sequencing in ALK-Rearranged Non–Small-Cell Lung Cancer

Purpose: Patients with anaplastic lymphoma kinase (ALK)–rearranged non–small-cell lung cancer (NSCLC) inevitably develop resistance to ALK inhibitors. New diagnostic strategies are needed to assess resistance mechanisms and provide patients with the most effective therapy. We asked whether single circulating tumor cell (CTC) sequencing can inform on resistance mutations to ALK inhibitors and underlying tumor heterogeneity in ALK-rearranged NSCLC. Conclusions: Our results highlight the genetic heterogeneity and clinical utility of CTCs to identify therapeutic resistance mutations in ALK-rearranged patients. Single CTC sequencing may be a unique tool to assess heterogeneous resistance mechanisms and help clinicians for treatment personalization and resistance options to ALK-targeted therapies. READ ARTICLE

Clinical Cancer Research DOI:10.1158/1078-0432.CCR-19-1176

Authors: Emma Pailler, Vincent Faugeroux, Marianne Oulhen, Laura Mezquita, Mélanie Laporte, Aurélie Honoré, Yann Lecluse, Pauline Queffelec, Maud NgoCamus, Claudio Nicotra, Jordi Remon, Ludovic Lacroix, David Planchard, Luc Friboulet, Benjamin Besse and Françoise Farace

The clinical responses of TNIP2-ALK fusion variants to crizotinib in ALK-rearranged lung adenocarcinoma

Objectives: Anaplastic lymphoma kinase (ALK) has been proven to be another driver oncogene that accounts for 3%–7% of non-small-cell lung cancer, and it is more common in young patients and nonsmokers. ALK rearrangements have been previously identified in about 5.1% of lung adenocarcinoma, including EML4-ALK fusion variants, KIF5B-ALK and TFG-ALK. However, a TNIP2-ALK fusion has not been reported in lung adenocarcinoma. Herein, we described a rare case of ALK-rearranged lung adenocarcinoma responding to crizotinib. Conclusion: This case provides valuable information on the response to crizotinib of patients with TNIP2-ALK fusion and better understanding of ALK-TKI applications in the future. NGS is a new method that can offer effective detection of gene fusion and gene mutations. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2019.08.032

Authors: Tingting Feng, Zhongzhong Chen, Jianjun Gu, Yuxiu Wang, Jun Zhang, Lingfeng Min

Case StudyKirk SmithNovember 1, 2019NSCLC, ALK fusion, TNIP2-ALK, crizotinib, NGS

Anaplastic lymphoma kinase inhibitor related pneumonitis in patients with non-small cell lung cancer

Anaplastic lymphoma kinase (ALK) inhibitor-related pneumonitis (ALK-IIP) is relatively rare but sometimes fatal, so the timely diagnosis of ALK-IIP is important for enabling prompt management. However, the detailed radiologic characteristics and clinical course of ALK-IIP are still unclear. This study was performed to investigate the clinical and radiologic characteristics and risk factors of ALK-IIP in patients with non-small cell lung cancer (NSCLC).

A total of 250 NSCLC patients who had been treated with ALK inhibitors were retrospectively enrolled. Chest computed tomography (CT) was classified into 4 CT patterns using the 2013 guideline for idiopathic interstitial pneumonia: cryptogenic organizing pneumonia (COP), hypersensitivity pneumonitis (HP), acute interstitial pneumonia (AIP), and nonspecific interstitial pneumonia. Clinical characteristics including toxicity grading and treatment course were analyzed in regarding to CT patterns. Clinical characteristics were compared betwe..... READ ARTICLE

Medicine DOI:10.1097/MD.0000000000018131

Authors: Hwang Hye Jeon, Kim Mi Young, Choi Chang-Min, Lee Jae Cheol

Targeted next-generation sequencing revealed distinct clinicopathologic and molecular features of VCL-ALK RCC

Anaplastic lymphoma kinase (ALK)-rearranged renal cell carcinoma (RCC) is a novel entity of rare tumors with only 10 cases reported in the literature. Three RCC cases bearing VCL-ALK gene fusion were all young African American patients and associated with sickle cell trait notably. In contrast to the 3 reported cases, this neoplasm occurred in a middle-age woman (57 years old) without any evidence of sickle cell trait and demonstrated an infiltrating growth pattern with tubular, tubulopapillary, and tubulocystic structures, overlapping with collecting duct carcinoma and renal medullary carcinoma. Abundant intraluminal mucin was also noted significantly in the histologic sections. Immunostaining showed strong membranous labeling for ALK protein. We applied a large panel-targeted next-generation sequencing to explore the molecular alterations in the current case, revealing a driver oncogene VCL-ALK gene fusion co-occurring with pathogenic mutations in EP300 and TRRAP genes. Thereafter, f..... READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2019.152651

Authors: Xiao-tong Wang, Ru Fang, Sheng-bing Ye, Ru-song Zhang, Rui Li, Xuan Wang, Rong-hao Ji, Zhen-feng Lu, Heng-hui Ma, Xiao-jun Zhou, Qiu-yuan Xia, Qiu Rao

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

Complete Pathological Response to Crizotinib in a Patient with ALK-rearranged Lung Adenocarcinoma

Gene fusions of anaplastic lymphoma kinase (ALK) are common drivers in non–small-cell lung cancer that can be effectively treated with crizotinib. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2019.10.002

Authors: Marissa S. Mattar, Jason Chang, Ryma Benayed, Darragh Halpenny, Astin Powers, David E. Kleiner, Alexander Drilon, Mark G. Kris

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