The eXalt3 trial included 290 ALK-positive, TKI-naïve patients with stage IIIB/IV NSCLC treated with up to one line of prior chemotherapy. Ensartinib demonstrated a significantly improved blinded independent review committee-assessed PFS of 25.8 months compared to crizotinib of 12.7 months, HR 0.51 (95% CI 0.35-0.72, p=0.0001). READ ARTICLE
Oncology Times DOI:10.1097/01.COT.0000721308.30680.3f
Authors: Selina Wong, Amanda Cass and Leora Horn
We report a case wherein a combination of crizotinib and hematopoietic stem cell transplantation (HSCT) cured a 20-year-old woman with relapsed and refractory anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK-positive ALCL). Although she received cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) as the first-line chemotherapy from the beginning, the disease progressed rapidly with the emergence of bone marrow invasion and hemophagocytic syndrome. Vincristine, idarubicin, l-asparaginase, and prednisone (VILP) chemotherapy was not effective. Therefore, the patient received off-label use of crizotinib (an ALK inhibitor) and her condition improved rapidly. Subsequently, she received allogeneic hematopoietic stem cell transplantation (allo-HSCT) and achieved complete remission (CR) a month later. Later, crizotinib was used as a maintenance treatment for 3 months and discontinued because of adverse reactions. Our patient has been in CR for 3 years.
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Indian Journal of Cancer DOI:10.4103/ijc.IJC_961_19
Authors: Xue Sun, Xiaosheng Fang, Yujie Jiang
In order to explore novel ALK and ROS1 dual inhibitors capable of overcoming crizotinib-resistant mutants, two series of 2,4-diarylaminopyrimidine derivatives were designed, synthesized and evaluated for their in vitro cytotoxic activity. In this work, we retained the 2,4-diarylaminopyrimidine scaffold and derivatize the DAAP scaffold with sulfonyl and acrylamide moieties to extend the structure–activity relationship (SAR) study. To our delight, some compounds exhibited excellent inhibitory activity with a double-digit nanomolar level in MTT assay. Four compounds were selected for enzymic assays further, the results led to the identification of a potent ALK and ROS1 dual inhibitor X-17, with IC50 values of 3.7 nM, 2.3 nM, 8.9 nM and 1.9 nM against ALK, ALKL1196M, ALKG1202R and ROS1, respectively. Ultimately, the molecular docking studies on X-17 clearly disclosed reasonable and optimal binding interactions with ALK. READ ARTICLE
Bioorganic & Medicinal Chemistry DOI:10.1016/j.bmc.2020.115719
Authors: Minglin Zhu, Wei Li, Tianming Zhao, Yuxiang Chen, Tong Li, Shangfei Wei, Ming Guo, Xin Zhai
We report two inflammatory myofibroblastic tumor (IMT) patients with ALK fusions (RRBP-ALK and TNS1-ALK, respectively). They both received tumor resection surgery and treatment with ALK inhibitors crizotinib followed by alectinib, and upon receiving each of the drugs, showed a brief response, then experienced recurrence or progression of the disease. During the treatment, whole exome sequencing (WES) and RNA sequencing (RNA-Seq) were applied to monitor potential drug-induced gene mutation and expression changes. A novel, secondary mutation in ALK exon 23 (L1196Q) was identified in patient 1 after alectinib resistance developed. Guided by this result, a newer ALK inhibitor, ceritinib was prescribed. The patient was able to achieve a partial response (PR) and is in good condition as of the manuscript date. On the contrary, there was no secondary mutation identified in ALK in patient 2 after drug resistance. While the expression of PTCH1, a negative regulator of the sonic hedgehog (SHH) signaling pathway, was significantly reduced at the time after the treatment with crizotinib before that of alectinib. The expression of PTCH1 was also reduced after the treatment with alectinib. It was reported that ALK can exert its biological functions partially by activating SHH signaling pathway. The down-regulation of PTCH1 suggests the compensatory activation of SHH pathway may cause resistance to ALK inhibitors in IMT. Going forward, monitoring gene mutation and expression changes through DNA and RNA sequencing will be able to offer opportunities to investigate potential mechanisms of drug resistance and will help to achieve precise prescription for better treatment outcomes. READ ARTICLE
OncoTargets and Therapy DOI: 10.2147/OTT.S270481
Authors: Chenlu Zhang, Zhiming Wang, Rongyuan Zhuang, Xi Guo, Yi Feng, Feng Shen, Wenshuai Liu, Yong Zhang, Hanxing Tong, Wending Sun, Jun Liu, Guan Wang, Chun Dai, Weiqi Lu and Yuhong Zhou
Read MoreThe expression of anaplastic lymphoma kinase (ALK), a target of tyrosine kinase is altered in several kinds of cancer, including in non-small cell lung cancer (NSCLC). For this reason, the use of crizotinib to treat locally advanced or metastatic ALK-positive NSCLC was approved by the US Food and Drug Administration in 2011. The reported adverse events during clinical trials with crizotinib included esophageal disorders in 11% of the patients, although none of them experienced severe events. Drug-induced esophagitis or more severe ulcerations are considerably rare according to the available case reports. We report a patient who presented with severe esophageal ulcers after 2-year treatment with crizotinib for metastatic, ALK-positive NSCLC. These clinical conditions improved after education on proper eating habits and an additional prescription of a proton pump inhibitor. Several months later, the patient developed colitis with severe diarrhea, which was successfully controlled with me..... READ ARTICLE
Advances in Digestive Medicine DOI:10.1177/1078155220961549
Authors: Wei-Wen Su,Hui-Ting Hsu,Po-Ke Hsu
Background: The aim of this study was to determine the demographic prole ofdriver gene alterations, especially low-frequency gene alterations in Chinesepatients with non-small cell lung cancer (NSCLC).Methods: A total of 7395 Chinese patients with NSCLC were enrolled in thestudy. Next-generation sequencing (NGS) was performed on formalin-xedparafn-embedded specimens collected via either surgical resection or biopsy.Results: The frequent genomic alteration s found in the study were EGFR muta-tions (51.7%), KRAS mutations (13.1%), MET alterations (5.6%; 3.2% copy num-ber gains and 0.5% exon 14 skipping mutation), HER2 alterations (7.0%; 2.0%copy number gains and 5.4% mutations), ALK alterations (7.2%; 3.9%rearrangements), RET rearrangements (1.4%), ROS1 rearrangements (0.9%), andNTRK rearrangements (0.6%). The EGFR mutation rate was found to be signi-cantly higher in women than in men (69.1% vs. 38.5%, P < 0.001), while theKRAS mutation (17.5% vs. 7.3%, P < 0.001) and MET alteration ..... READ ARTICLE
Thoracic Cancer DOI:10.1111/1759-7714.13757
Authors: Xiaoyan Si, Ruili Pan, Shaohua Ma, Lin Li, Li Liang, Ping Zhang, Yuping Chu, Hanping Wang, Mengzhao Wang, Xiaotong Zhang, Li Zhang
In the last years, several efforts have been made to classify colorectal cancer (CRC) into well-defined molecular subgroups, representing the intrinsic inter-patient heterogeneity, known as Consensus Molecular Subtypes (CMSs). In this work, we performed a meta-analysis of 1700 CRC patients stratified into four CMSs. We identified a negative correlation between a high level of anaplastic lymphoma kinase (ALK) expression and relapse-free survival, exclusively in CMS1 subtype. Stemming from this observation, we tested several CMSs in vitro models with crizotinib (CZB) or alectinib (ALC), potent ALK inhibitors, already approved for clinical use. ALK interception strongly inhibits cell proliferation already at nanomolar doses, specifically in CMS1 cell lines, while no effect was found in CMS2/3/4 groups. Furthermore, in vivo imaging identified a role for ALK in the dynamic formation of 3D spheroids, which was impaired by the pharmacological inhibition of ALK. Consistently, CZB was responsib..... READ ARTICLE
BioRxiv DOI:10.1101/2020.10.07.307991
Authors: Martina Mazzeschi, Michela Sgarzi, Donatella Romaniello, Valerio Gelfo, Carola Cavallo, Spartaco Santi, Michelangelo Fiorentino, Gabriele D’Uva, Balázs Győrffy, Ruth Palmer, Mattia Lauriola
Lung cancer is the leading cause of cancer death worldwide. In the past decade EGFR, ALK and ROS1 TKIs lead to an unprecedented survival improvement of oncogene-addicted NSCLC patients, with better toxicity profile compared to chemotherapy. In recent years the implementation of high-throughput sequencing platforms led to the identification of uncommon molecular alterations in oncogenic drivers, such as BRAF, MET, RET, HER2 and NTRK. Moreover, newly developed drugs have been found to be active against hard to target drivers, such as KRAS. Specific TKIs targeting these genomic alterations are currently in clinical development and showed impressive activity and survival improvement, leading to FDA-accelerated approval for some of them. However, virtually all patients develop resistance to TKIs by on-target or off-target mechanisms. Here we review the clinicopathological features, the emerging targeted therapies and mechanisms of resistance and strategies to overcome them of KRAS, BRAF, MET, RET, HER2 and NTRK-addicted advanced NSCLCs. READ ARTICLE
Critical Reviews in Oncology/Hematology DOI: 10.1016/j.critrevonc.2020.103119
Authors: Giuseppe Lamberti, Elisa Andrini, Monia Sisi, Alessandro RizzoaClaudia Parisi, Alessandro Di Federico, Francesco Gelsomino and Andrea Ardizzoni
Read MoreLorlatinib is a third-generation tyrosine-kinases inhibitor (TKI) targeting ALK/ROS1 fusions. The FDA has approved lorlatinib for TKI-pretreated ALK(+) NSCLC, while its approval for ROS1(+) is still pending. Here we present the largest real-world data of NSCLC patients harboring ALK/ROS1 rearrangements treated with lorlatinib... Conclusion: Lorlatinib shows outstanding EC/IC efficacy in ALK/ROS1(+) NSCLC. The observed mOS of 89 ± 19 months in ALK(+) NSCLC supports previous reports, while mOS from of 90 ± 24 months is unprecedented for ROS1(+) NSCLC. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2020.07.022
Authors: Nir Peled, Roni Gillis, Saadettin Kilickap, Patrizia Froesch, Sergei Orlov, Elena Filippova, Umut Demirci, Petros Christopoulos, Irfan Cicin, Fatma Bugdayci Basal, Cengiz Yilmaz, Moiseenko Fedor, Taner Korkmaz, Semra Paydas, Oliver Gautschi, Alisan Zirtiloglu, Yesim Eralp, Havva Yesil Cinkir,… Laila C. Roisman
Background: Cancer-associated fibroblasts (CAFs) are predominant stromal cells associated with cancer development and drug resistance. Due to the complexity of the crosstalk between CAFs and cancer cells, the underlying mechanism often remains elusive. Here, we aim to elucidate the complex, bidirectional signaling network that governs CAF-mediated resistance to targeted drugs in EML4-ALK-rearranged non-small-cell lung cancer (NSCLC) cells. READ ARTICLE
European Journal of Cancer DOI:10.1016/S0959-8049(20)31205-3
Authors: Q. Hu, L. L. Remsing Rix, X. Li, E. A. Welsh, B. Fang, S. Yun, J. Kroeger, H. R. Lawrence, A. Marusyk, J. M. Koomen, E. B. Haura, U. Rix
However, the concurrent two ALK rearrangements within the same patient have rarely previously been reported. Here, we describe a novel CCNY-ALK (C1:A20) and ATIC-ALK (A7:A20), coexisting in the same case with poorly differentiated NSCLC and providing evidence of its sensitivity to ALK inhibitors. The newly identified rearrangement partners can be added to the list of ALK rearrangements that occurred in ALK-positive NSCLC, as it could lead to prolonged disease control. Also, while different ALK rearrangement variants might bring differing clinical outcomes, we discuss the impact of the co-mutations of these two ALK rearrangements on the sensitivity to ALK inhibitors. However, the impact of co-mutations on the pathogenesis of NSCLC should be further studied to supply more theoretical insight that co-mutations present for personalized anti-cancer therapy. READ ARTICLE
Translational Lung Cancer Research DOI: 10.21037/tlcr-20-1049
Authors: Xuan Wu, Hanqiong Zhou, Zhen He, Zhe Zhang, Wen Feng, Jiuzhou Zhao3, Haiyang Chen, Shuai Wang, Wei Wang, Qiming Wang
Read MoreAiming to identify new optimization strategy effective for ALK-mutations, two series of pyrroformyl-containing 2,4-diaminopyrimidine compounds (11a-o, 12a-o) were designed, synthesized and evaluated for their anti-proliferative activities against three cancer cell lines in vitro by MTT assay. The biological evaluations on cellular assay resulted in discovery of compound 11k, which performed considerable activity with IC50 value of 0.034 μM against H2228 cell. Meanwhile, 11k exhibited outstanding enzymatic inhibitory potency with IC50 values of 1.9 nM and 3.1 nM against ALKWT and ALKL1196M, respectively, surpassing the reference ceritinib (IC50 = 2.4 nM and 7.6 nM). Ultimately, the binding mode of 11k with ALK was established to explore the SARs. Overall, 11k was considered as a promising ALK inhibitor for mutation treatment. READ ARTICLE
Bioorganic & Medicinal Chemistry DOI:10.1016/j.bmc.2020.115715
Authors: Meng Cao, Yuxiang Chen, Tianming Zhao, Shangfei Wei, Ming Guo, Xin Zhai
Median rwPFS in patients with advanced ALK+ NSCLC was < 8 months for first‐ and second‐line ALK TKI therapy and was even shorter in patients with brain metastasis, highlighting the need for more effective treatments in this patient population. Results presented herein describe real‐world treatment of advanced ALK+ NSCLC with ALK TKI therapies from January 2011 through June 2018. Crizotinib was the most commonly prescribed first‐line ALK TKI therapy in this patient population, but the majority of data analyzed were obtained prior to Food and Drug Administration approval of alectinib and ceritinib in the first‐line ALK TKI setting. Physicians should monitor patients closely to help identify when a change in treatment should occur. READ ARTICLE
The Oncologist DOI:10.1634/theoncologist.2020-0011
Authors: Mohammad Jahanzeb, Huamao M. Lin, Xiaoyun Pan, Yu Yin, Yanyu Wu, Beth Nordstrom, and Mark A. Socinski
Lorlatinib exhibited meaningful activity in TKI-refractory ALK+ or ROS1+ patients with NSCLC enrolled in early or expanded access programs. READ ARTICLE
Journal of Thoracic Oncology DOI: 10.1016/j.jtho.2020.04.019
Authors: Viola W. Zhu, Yen-Ting Lin, Dong-Wan Kim, Herbert H. Loong, Misako Nagasaka, Hao To, Yvonne Li-En Ang, Chan-Young Ock, Nishan Tchekmedyian, Sai-Hong Ignatius Ou, Nicholas L. Syn, Thanyanan Reungwetwattana, Chia-Chi Lin, Ross A. Soo
Read MoreObjectives: The molecular profiles and prognosis of anaplastic lymphoma kinase (ALK) fusion and resectable non-small cell lung cancer (NSCLC) remain unclear. This study aimed to explore the distribution of ALK fusion variants and prognostic factors in patients with surgically resected NSCLC. Conclusions: This study illustrated the patterns of EML4-ALK fusion variants and gene profiles in patients with resected NSCLC. Advanced T stage and EML4-ALK variant 3 were associated with worse prognosis. The role of TP53 mutations in prognosis is worthy of further study. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2020.09.012
Authors: Hong Tao, Liang Shi, Aoxue Zhou, Hongxia Li, Fei Gai, Zhan Huang, Nanying Che, Zhe Liu
Discussion: Our case demonstrates objective evidence for proteinuria induced by lorlatinib, which may also be dose dependent. READ ARTICLE
Journal of Oncology Pharmacy Practice DOI:10.1177/1078155220961549
Authors: Lee CS, Wanchoo R, Seetharamu N.
The advent of specific ALK-targeting drugshas radically changed the outcome of patients withALKtranslocated non-small-cell lung cancer(NSCLC). However, emerging resistance to treatmentwithALKinhibitors in these patients remains amajor concern. In previous studies, we analysed twoALK+patient cohorts (TP53wild-type/TP53mutated) in terms of copy number alterations. Allpatients belonging to theTP53wild-type group hadmainly genetically stable genomes, with one excep-tion showing chromosomal instability and amplifica-tions of several gene loci, includingTERT. Here, weaimed to determine the prevalence ofTERTamplifi-cations in theseALK+lung cancer patients by ana-lysing an independent cohort of 109ALKtranslocated cases. We further analysed the copy numbers of numerous cancer-relevant genes andother genetic aberrations. The prevalence ofTERTamplifi-cations was determined by means of FISH analyses.Copy numbers of 87 cancer-relevant genes were deter-mined by NanoString nCounterâtechnolo..... READ ARTICLE
Histopathology DOI:10.1111/his.14256
Authors: Alidousty C, Duerbaum N, Wagener-Ryczek S, Baar T, Martelotto L G, Heydt C, Siemanowski J, Holz B, Binot E,Fassunke J, Merkelbach-Bruse S, Wolf J, Kron A, Buettner R, Schultheis A M
Background: Brain metastasis is common in non-small-cell lung cancer (NSCLC) with driver gene mutations. Anaplastic lymphoma kinase (ALK) gene rearrangement is one of the common driver mutations in NSCLC. Tyrosine kinase inhibitor (TKI) has been the research hotspot at present. However, there are relatively few studies specified on the treatment of brain metastasis from ALK gene rearrangement NSCLC. The prognosis of these patients, the role of ALK-TKI, and the proper combination model of ALK-TKI with radiotherapy are worth further exploring. This review focuses on new data on the prognosis of ALK-TKI and the proper combination model of ALK-TKI with radiotherapy. Key Messages: Next-generation ALK-TKIs are now replacing crizotinib as first-line treatment in ALKi-naïve ALK rearrangement NSCLC patients with brain metastasis, and they alone might have a strong efficacy against intracranial tumors in crizotinib-refractory situations in which occasion radiotherapy might be omitted. SRS and W..... READ ARTICLE
Oncology Research and Treatment DOI:10.1159/000502755
Authors: Wang W., Sun X., Hui Z.
Dr. Ross Camidge explains how a lung cancer patient knows if they have ALK-positive lung cancer. ALK is an important biomarker that can impact lung cancer treatment options. Talk to your doctor about comprehensive biomarker testing.
Visit Lung.org/alk for more information. Support for this educational program provided by Amgen, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Genentech, Lilly Oncology, Merck, Novartis and Pfizer.
WATCH VIDEO
American Lung Association
Authors: Dr. Ross Camidge
Dr. Ross Camidge explains the treatment options for ALK-positive lung cancer. ALK is an important biomarker that can impact lung cancer treatment options. Talk to your doctor about comprehensive biomarker testing. Visit Lung.org/alk for more information. Support for this educational program provided by Amgen, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Genentech, Lilly Oncology, Merck, Novartis and Pfizer.
WATCH VIDEO
American Lung Association
Authors: Dr. Ross Camidge
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