Mapping the Phospho-dependent ALK Interactome to Identify Novel Components in ALK Signaling

Protein-protein interactions (PPIs) play essential roles in Anaplastic Lymphoma Kinase (ALK) signaling. Systematic characterization of ALK interactors helps elucidate novel ALK signaling mechanisms and may aid in the identification of novel therapeutics targeting related diseases. In this study, we used the Mammalian Membrane Two-Hybrid (MaMTH) system to map the phospho-dependent ALK interactome. By screening a library of 86 SH2 domain-containing full length proteins, 30 novel ALK interactors were identified. Many of their interactions are correlated to ALK phosphorylation activity: oncogenic ALK mutations potentiate the interactions and ALK inhibitors attenuate the interactions. Among the novel interactors, NCK2 was further verified in neuroblastoma cells using co-immunoprecipitation. Modulation of ALK activity by addition of inhibitors lead to concomitant changes in the tyrosine phosphorylation status of NCK2 in neuroblastoma cells, strongly supporting the functionality of the ALK/NCK2 interaction. Our study provides a resource list of potential novel ALK signaling components for further study. READ ARTICLE

Journal of Molecular Biology DOI:10.1016/j.jmb.2021.167283

Authors: Farzaneh Aboualizadeh, ZhongYao, Jikui Guan, Luka Drecun, Shivanthy Pathmanathan, Jamie Snider, Ganesh Umapathy, Max Kotlyar, Igor Jurisica, Ruth Palmer and Igor Stagljar

The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

Anaplastic lymphoma kinase (ALK) is a validated molecular target for non-small-cell lung cancer (NSCLC). The use of tyrosine kinase inhibitors (TKIs) has led to significantly improved survival benefits. However, the clinical benefits of targeting ALK using TKIs are limited due to the emergence of drug resistance. The landscape of resistance mechanisms and treatment decisions has become increasingly complex. Therefore, continued research into new drugs and combinatorial therapies is required to improve outcomes in NSCLC. In this review, we explore the resistance mechanisms of ALK TKIs in advanced NSCLC in order to provide a theoretical basis and research ideas for solving the problem of ALK drug resistance. READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.713530

Authors: Yue Pan, Chao Deng, Zhenhua Qiu, Chenghui Cao and Fang Wu

Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms

Cancer-associated fibroblasts (CAFs) are highly heterogeneous. With the lack of a comprehensive understanding of CAFs' functional distinctions, it remains unclear how cancer treatments could be personalized based on CAFs in a patient's tumor. We have established a living biobank of CAFs derived from biopsies of patients' non-small lung cancer (NSCLC) that encompasses a broad molecular spectrum of CAFs in clinical NSCLC. By functionally interrogating CAF heterogeneity using the same therapeutics received by patients, we identify three functional subtypes: (1) robustly protective of cancers and highly expressing HGF and FGF7; (2) moderately protective of cancers and highly expressing FGF7; and (3) those providing minimal protection. These functional differences among CAFs are governed by their intrinsic TGF-β signaling, which suppresses HGF and FGF7 expression. This CAF functional classification correlates with patients' clinical response to targeted therapies and also associates with th..... READ ARTICLE

Cancer Cell DOI:10.1016/j.ccell.2021.09.003

Authors: Hu H, Piotrowska Z, Hare PJ, Chen H, Mulvey HE, Mayfield A, Noeen S, Kattermann K, Greenberg M, Williams A, Riley AK, Wilson JJ, Mao YQ, Huang RP, Banwait MK, Ho J, Crowther GS, Hariri LP, Heist RS, Kodack DP, Pinello L, Shaw AT, Mino-Kenudson M, Hata AN, Sequist LV, Benes CH, Niederst MJ, Engelman JA.

Anti-epidermal growth factor vaccine antibodies increase the antitumor activity of kinase inhibitors in ALK and RET rearranged lung cancer cells

Advanced NSCLC patients harboring EML4-ALK and CCDC6-RET rearrangements derive benefit from treatment with ALK and RET TKIs but not immune checkpoint inhibitors. New immunotherapeutic approaches, such as immunization against growth factors, can be of particular interest for combination treatment in these patients. Here, we investigated the effects of anti-EGF antibodies generated by vaccination (anti-EGF VacAbs), TKIs and combinations in EML4-ALK and CCDC6-RET NSCLC cell lines. We found that EGF and tumor growth factor alpha (TGFα) significantly decreased the antiproliferative activity of the RET inhibitor BLU-667 in CCDC6-RET cells and brigatinib, alectinib and crizotinib in EML4-ALK translocated cells. The addition of anti-EGF VacAbs reversed the effects of EGF and TGFα, potentiated the antitumor effects of the kinase inhibitors and delayed the appearance in vitro of resistant clones. Western blotting demonstrated that the combination of anti-EGF VacAbs with ALK or RET TKIs effective..... READ ARTICLE

Translational Oncology DOI:10.1016/j.tranon.2020.100887

Authors: Jordi Codony-Servat, Silvia García-Roman, Miguel Ángel Molina-Vila, Jordi Bertran-Alamillo, Santiago Viteri, Erik d'Hondt, Rafael Rosell,

Pre-Clinical, group3Kirk SmithSeptember 21, 2021ALK, RET, anti-EGF VacAbs

Pharmacometric analyses of alectinib to facilitate approval of the optimal dose for the first-line treatment of anaplastic lymphoma kinase–positive non-small cell lung cancer

Alectinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK-positive non-small cell lung cancer. Population pharmacokinetic (PK) models were developed for alectinib and its major active metabolite M4 using phase I/II PK data in crizotinib-failed patients (N = 138). The PK profiles were best described by two separate models with similar structure for both entities: open one-compartment models with sequential zero/first-order input and first-order elimination rate. Body weight with fixed allometric scaling factor on clearance and volume of both entities was the only significant covariate. Bayesian feedback analyses of the PK data collected from Japanese and global treatment-naïve patients in phase III studies (N = 334) confirmed the body weight effect. Landmark Cox proportional hazards analyses of progression-free survival in treatment-naïve patients identified the average molar concentrations of both entities alectinib and M4 during the first 6 weeks of trea..... READ ARTICLE

CPT: Pharmacometrics & Systems Pharmacology DOI:10.1002/psp4.12702

Authors: Joy C. Hsu, Felix Jaminion, Elena Guerini, Bogdana Balas, Walter Bordogna, Peter N. Morcos, Nicolas Frey

Pre-Clinical, group3Kirk SmithSeptember 21, 2021Non-small cell lung cancer, ALK, Alectinib, Pharmacometric analyses, Optimal dose

BioID-Screening Identifies PEAK1 and SHP2 as Components of the ALK Proximitome in Neuroblastoma Cells

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is mutated in approximately 10% of pediatric neuroblastoma (NB). To shed light on ALK-driven signaling processes, we employed BioID-based in vivo proximity labeling to identify molecules that interact intracellularly with ALK. NB-derived SK-N-AS and SK-N-BE(2) cells expressing inducible ALK-BirA* fusion proteins were generated and stimulated with ALKAL ligands in the presence and absence of the ALK tyrosine kinase inhibitor (TKI) lorlatinib. LC/MS-MS analysis identified multiple proteins, including PEAK1 and SHP2, which were validated as ALK interactors in NB cells. Further analysis of the ALK-SHP2 interaction confirmed that the ALK-SHP2 interaction as well as SHP2-Y542 phosphorylation was dependent on ALK activation. Use of the SHP2 inhibitors, SHP099 and RMC-4550, resulted in inhibition of cell growth in ALK-driven NB cells. In addition, we noted a strong synergistic effect of combined ALK and SHP2 inhibition that was specific to ALK-driven NB cells, suggesting a potential therapeutic option for ALK-driven NB. READ ARTICLE

Journal of Molecular Biology

Authors: Ezgi Uçkun, Joachim T. Siaw, Jikui Guan, Vimala Anthonydhason, Johannes Fuchs, Georg Wolfstetter, Bengt Hallberg and Ruth H.Palmer

Pre-Clinical, group3Kirk SmithSeptember 17, 2021BirA*, signaling, SHP099, RMC-4550, lorlatinib

MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients. READ ARTICLE

Nature DOI:10.1038/s41467-021-25728-8

Authors: Johannes Brägelmann, Carina Lorenz, Sven Borchmann, Kazuya Nishii, Julia Wegner, Lydia Meder, Jenny Ostendorp, David F. Ast, Alena Heimsoeth, Takamasa Nakasuka, Atsuko Hirabae, Sachi Okawa, Marcel A. Dammert, Dennis Plenker, Sebastian Klein, Philipp Lohneis, Jianing Gu, Laura K. Godfrey, Jan Forster, Marija Trajkovic-Arsic, Thomas Zillinger, Mareike Haarmann, Alexander Quaas, Stefanie Lennartz, Marcel Schmiel, Joshua D’Rozario, Emily S. Thomas, Henry Li, Clemens A. Schmitt, Julie George, Roman K. Thomas, Silvia von Karstedt, Gunther Hartmann, Reinhard Büttner, Roland T. Ullrich, Jens T. Siveke, Kadoaki Ohashi, Martin Schlee & Martin L. Sos

STRN-ALK Fusion in a Case of Malignant Peritoneal Mesothelioma: Mixed Response to Crizotinib, Mode of Resistance, and Brigatinib Sequential Therapy

To our knowledge, this is the first description of an STRN-ALK fusion(+) MPM sequentially treated with two different ALK inhibitors. This case underlines the benefit of molecular testing in MPM. Furthermore, it suggests the generalizability of the lessons learned from lung cancer to another entity, which can offer some guidance in the treatment of this rare disease. READ ARTICLE

Journal of Clinical Oncology: Precision Oncology DOI:10.1200/PO.21.00184

Authors: Valeria Gerthofer, Alexander Scheiter, Florian Lüke, Felix Keil, Kirsten Utpatel, Laura-Maria-Giovanna
Pöhmerer, Johannes Seitz, Christoph Niessen, Atanas Ignatov, Wolfgang Dietmaier, Diego F. Calvisi, Matthias Evert, Olaf Ortmann, and Stephan Seitz

Pathological cytomorphologic features and the percentage of ALK FISH-positive cells predict pulmonary adenocarcinoma prognosis: a prospective cohort study

We conducted a study to explore the relationship between pathological cytomorphologic features and the percentage of anaplastic lymphoma kinase (ALK)-positive cells to better predict pulmonary adenocarcinoma prognosis with crizotinib treatment.
We investigated 60 cases of patients with ALK-positive advanced or metastatic non-small cell lung cancer (NSCLC). Immunohistochemistry was performed to screen for ALK rearrangement. Fluorescence in situ hybridization (FISH) was used to detect the percentage of ALK-positive cells. The primary objectives of the study were the progression-free survival (PFS), the 3-year overall survival, and the 3-year overall survival (OS) rates. The secondary objectives of the study were the disease control rate (DCR) and the overall response rate (ORR).
We concluded that signet ring cell cytomorphologic characteristics of pulmonary adenocarcinoma are associated with the percentage of ALK-positive cells. Signet ring cell cytomorphologic characteristics and the percentage of ALK-positive cells might predict the prognosis of pulmonary adenocarcinoma with crizotinib treatment. READ ARTICLE

World Journal of Surgical Oncology DOI:10.1186/s12957-021-02386-0

Authors: Fenge Jiang, Congcong Wang, Ping Yang, Ping Sun, Jiannan Liu

Sensitivity of eight types of ALK fusion variant to alectinib in ALK-transformed cells

Tyrosine kinase inhibitors of anaplastic lymphoma kinase (ALK-TKIs) including alectinib have been the standard therapy against ALK fusion gene-positive non-small cell lung cancers (NSCLCs). Many ALK fusion variants have been identified in NSCLCs, and the predominant variants are echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) variant 1 (V1), V2 and V3a/b. However, there have been conflicting reports on the clinical responses of these variants to ALK-TKIs, and there are few reports on other less common ALK variants. To examine the influence of ALK variants on the efficacy of ALK-TKIs, we analyzed the sensitivity to alectinib of eight types of ALK variant: three major variants (V1, V2 and V3a) and five less common variants (V4; kinesin family member 5-ALK; kinesin light chain 1-ALK; striatin, calmodulin-binding protein-ALK; and tropomyosin-receptor kinase fused gene-ALK). Analysis was done by cell-free kinase assays using the recombinant proteins and by cell, growth assay..... READ ARTICLE

Anticancer Drugs DOI:10.1097/CAD.0000000000001249

Authors: Furugaki K, Harada N, Yoshimura Y.

Pre-Clinical, group3Kirk SmithSeptember 13, 2021alectinib, ALK, EML4, fusion, KIF5B, KLC1, lung cancer, STRN, TFG, variant

ALKtALK Laura Petrillo

Dr. Laura Petrillo speaks to the ALK Positive community about Palliative Care. Some website of interest: getpalliativecare.org, https://www.mghpact.org/
Here is the ASCO guideline recommending the early integration of palliative care, cites a lot of evidence and includes information about the domains of palliative care:https://ascopubs.org/doi/full/10.1200/JCO.2016.70.1474
Cancer.net also has a nice section on what palliative care is: https://www.cancer.net/coping-with-cancer/physical-emotional-and-social-effects-cancer/what-palliative-care WATCH VIDEO

ALK Positive Inc.

Authors: Laura Petrillo

Video, group3Kirk SmithSeptember 13, 2021pallative care

Use of tyrosine kinase inhibitors during pregnancy for oncogenic-driven advanced non-small cell lung carcinoma

Lung cancer associated with pregnancy is rare but on the increase. The use of tyrosine kinase inhibitor (TKI) therapy for advanced oncogenic-driven non-small cell lung carcinoma (NSCLC) has improved overall survival. Oncological and obstetric outcomes of patients diagnosed with NSCLC and treated by TKIs during pregnancy have been poorly evaluated. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.09.001

Authors: Anne-Sophie Boudy, Noémie Grausz, Lise Selleret, Cyril Touboul, Emile Daraï, Jacques Cadranel

Therapeutic Targeting of the Anaplastic Lymphoma Kinase (ALK) in Neuroblastoma—A Comprehensive Update

Neuroblastoma (NBL) is an embryonic malignancy of the sympathetic nervous system and mostly affects children under the age of five. NBL is highly heterogeneous and ranges from spontaneously regressing to highly aggressive disease. One of the risk factors for poor prognosis are aberrations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK), which is involved in the normal development and function of the nervous system. ALK mutations lead to constitutive activation of ALK and its downstream signalling pathways, thus driving tumorigenesis. A wide range of steric ALK inhibitors has been synthesized, and several of these inhibitors are already in clinical use. Major challenges are acquired drug resistance to steric inhibitors and pathway evasion strategies of cancer cells upon targeted therapy. This review will give a comprehensive overview on ALK inhibitors in clinical use in high-risk NBL and on the potential and limitations of novel inhibitors. Because combinatory treatment..... READ ARTICLE

Pharmaceutics DOI:10.3390/pharmaceutics13091427

Authors: Annette K. Brenner and Maria W. Gunnes

ALK Rearrangement–Positive Pancreatic Cancer with Brain Metastasis Has Remarkable Response to ALK Inhibitors: A Case Report

Patients with metastatic pancreatic cancer typically have poor prognosis due to the limited effectiveness of existing treatment options. ALK rearrangement–positive is rare in pancreatic cancer, but may occur in those with KRAS-wild type. We present a 34-year-old young man with ALK rearrangement–positive and KRAS-wild pancreatic cancer who had a remarkable response to crizotinib after resistance to prior chemotherapy and re-response to alectinib after brain metastases developed. This clinical observation suggests that comprehensive molecular profiling to guide targeted therapies is not only feasible, but also significantly improves survival outcomes for a subgroup of patients with pancreatic cancer. READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.724815

Authors: Kai Ou, Xiu Liu, Weihua Li, Yi Yang, Jianming Ying and Lin Yang

Case Study, group3Kirk SmithSeptember 6, 2021ALK, KRAS, pancreatic cancer

Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase−Positive Non–Small Cell Lung Cancer, A Randomized Clinical Trial

Question Is ensartinib superior to crizotinib for patients with advanced anaplastic lymphoma kinase (ALK)–positive non–small cell lung cancer (NSCLC) who have not been treated previously with an ALK inhibitor?
Findings This randomized clinical phase 3 trial including 290 patients met the primary end point; the median progression-free survival was statistically significantly longer with ensartinib than with crizotinib (25.8 vs 12.7 months), and the confirmed intracranial response rate was 64% with ensartinib vs 21% with crizotinib for patients with brain metastases at baseline. Ensartinib had a favorable safety profile.
Meaning Ensartinib represents a new first-line treatment option for patients with ALK-positive NSCLC. READ ARTICLE

JAMA Oncology DOI:10.1001/jamaoncol.2021.3523

Authors: Leora Horn, Ziping Wang, Gang Wu, Elena Poddubskaya, Tony Mok, Martin Reck, Heather Wakelee, Alberto A. Chiappori, Dae Ho Lee, Valeriy Breder, Sergey Orlov, Irfan Cicin, Ying Cheng, Yunpeng Liu, Yun Fan, Jennifer G. Whisenant, Yi Zhou, Vance Oertel, Kim Harrow, Chris Liang, Li Mao, Giovanni Selvaggi and Yi-Long Wu,

Clinical Trials, group3Kirk SmithSeptember 2, 2021ALK, Ensartinib, eXalt3 trial, non-small cell lung cancer (NSCLC)

TPX-0131, a Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and ALK-resistant Mutation

Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, anaplastic lymphoma kinase (ALK) inhibitors have become important treatments for a subset of patients with lung cancer. Each generation of ALK inhibitor showed improvements in terms of central nervous system (CNS) penetration and potency against wild-type (WT) ALK, yet a key continued limitation is their susceptibility to resistance from ALK active-site mutations. The solvent front mutation (G1202R) and gatekeeper mutation (L1196M) are major resistance mechanisms to the first two generations of inhibitors while patients treated with the third-generation ALK inhibitor lorlatinib often experience progressive disease with multiple mutations on the same allele (mutations in cis, compound mutations). TPX-0131 is a compact macrocyclic molecule designed to fit within the ATP-binding boundary to inhibit ALK fusion proteins. In cellular assays, TPX-0131 was more potent than all five approv..... READ ARTICLE

Molecular Cancer Therapeutics DOI:1535-7163.MCT-21-0221

Authors: Brion W. Murray, Dayong Zhai, Wei Deng, Xin Zhang, Jane Ung, Vivian Nguyen, Han Zhang, Maria Barrera, Ana Parra, Jessica Cowell, Dong J. Lee, Herve Aloysius and Evan Rogers

Testing for EGFR Mutations and ALK Rearrangements in Advanced Non-Small-Cell Lung Cancer: Considerations for Countries in Emerging Markets

The treatment of patients with advanced non-small-cell lung cancer (NSCLC) in recent years has been increasingly guided by biomarker testing. Testing has centered on driver genetic alterations involving the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) rearrangements. The presence of these mutations is predictive of response to targeted therapies such as EGFR tyrosine kinase inhibitors (TKIs) and ALK TKIs. However, there are substantial challenges for the implementation of biomarker testing, particularly in emerging countries. Understanding the barriers to testing in NSCLC will be key to improving molecular testing rates worldwide and patient outcomes as a result. In this article, we review EGFR mutations and ALK rearrangements as predictive biomarkers for NSCLC, discuss a selection of appropriate tests and review the literature with respect to the global uptake of EGFR and ALK testing. To help improve testing rates and unify procedures, we review our exp..... READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S313669

Authors: Mercedes L Dalurzo, Alejandro Avilés-Salas, Fernando Augusto Soares, Yingyong Hou, Yuan Li, Anna Stroganova, Büge Öz, Arif Abdillah, Hui Wan and Yoon-La Choi

Detection of Multiple Types of Cancer Driver Mutations Using Targeted RNA Sequencing in NSCLC

Currently, DNA and RNA are used separately to capture different types of gene mutations. DNA is commonly used for the detection of SNVs, indels and CNVs; RNA is used for analysis of gene fusion and gene expression. To perform both DNA sequencing (DNA-seq) and RNA-seq, material is divided into two copies, and two different procedures are required for sequencing. Due to overconsumption of samples and experimental process complexity, it is necessary to create an experimental method capable of analyzing SNVs, indels, fusions and expression.We developed an RNA-based hybridization capture panel targeting actionable driver oncogenes in solid tumors and corresponding sample preparation and bioinformatics workflows. Analytical validation with an RNA standard reference containing 16 known fusion mutations and 6 SNV mutations demonstrated a detection specificity of 100.0% [95% CI 88.7%~100.0%] for SNVs and 100.0% [95% CI 95.4%~100.0%] for fusions. The targeted RNA panel achieved a 0.73-2.63 cop..... READ ARTICLEBioRxiv DOI:10.1101/2021.08.25.457723Authors: Sheng Ju, Zihan Cui, Yuayuan Hong, Xiaoqing Wang, Weina Mu, Zhuolin Xie, Xuexia Zeng, Lin Su, Qi Zhang, Xiaofeng Song, Songxia You, Ruixin Chen, Weizhi Chen, Xuchun, Jun Zhao

Review Paper, group3Kirk SmithAugust 26, 2021Cancer Driver Mutations, Targeted RNA Sequencing, NSCLC

Brain Metastases in EGFR- and ALK-Positive NSCLC: Outcomes of Central Nervous System-Penetrant Tyrosine Kinase Inhibitors Alone Versus in Combination With Radiation

Management of central nervous system (CNS) metastases in patients with driver-mutated NSCLC has traditionally incorporated both tyrosine kinase inhibitors (TKIs) and intracranial radiation. Whether next generation, CNS-penetrant TKIs can be used alone without upfront radiation, however, remains unknown. This multi-institutional retrospective analysis aimed to compare outcomes in patients with EGFR- or ALK-positive NSCLC who received CNS-penetrant TKI therapy alone versus in combination with radiation for new or progressing intracranial metastases. A total of 147 patients were included (EGFR n = 94, ALK n = 52, both n = 1). In patients receiving radiation, larger metastases, neurologic symptoms, and receipt of steroids were more common. There were no significant differences between TKI and CNS radiation therapy plus TKI groups for any of the study outcomes, including time to progression (8.5 versus 6.9 mo, p = 0.13 [EFGR] and 11.4 versus 13.4 mo, p = 0.98 [ALK]), time to intracranial pr..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.08.009

Authors: Nicholas J.Thomas, Nathaniel J. Myall, Fangdi Sun, Tejas Patil, Rao Mushtaq, Chandler Yu, Sumi Sinha, Erqi L. Pollom, Seema Nagpal. Ross Camidge, Chad G. Rusthoven, Steve E. Braunstein, Heather A. Wakelee and Caroline E. McCoach

Lorlatinib in a Child with ALK-Fusion–Positive High-Grade Glioma

A child near death with an ALK-fusion–positive high-grade glioma refractory to standard treatment had a dramatic response when treatment with lorlatinib was begun. The drug was stopped once the child had an apparent complete remission, but treatment with lorlatinib resumed when relapse occurred 6 months later. At this time, the child is attending preschool and has normal neurologic function. READ ARTICLE

New England Journal of Medicine DOI:10.1056/NEJMc2101264

Authors: Aditi Bagchi, Brent A Orr, Olivia Campagne, Sandeep Dhanda, Sreenath Nair, Quynh Tran, Anthony M Christensen, Amar Gajjar, Larissa V Furtado, Aksana Vasilyeva, Frederick Boop, Clinton Stewart and Giles W Robinson

Case Study, group3Kirk SmithAugust 19, 2021ALK, glioma, loraltinib, pediatric