Troubles du système nerveux central sous lorlatinib : comment les détecter et les gérer en pratique? Central nervous system disorders on lorlatinib: How to detect and manage in practice?

The therapeutic arsenal for advanced ALK positive non-small cell lung cancer has been enriched by specific treatments targeting this molecular abnormality, with five molecules available, including lorlatinib, approved since July 2020. This treatment can have side effects common to other tyrosine kinase inhibitors, as well as other less common disorders affecting the central nervous system such as impaired cognitive function, speech or mood. The prevalence of neuro-psychiatric effects under treatment with lorlatinib reported in studies is nearly 40 % with a mild to moderate intensity in most cases. Given the potential impact on patients’ quality of life and even on compliance with treatment, it is essential to include their detection during consultations. The main problem is still to have simple screening tools adapted to clinical practice. A multidisciplinary expert panel (pulmonologist, medical oncologist, psychiatrist, neurologist, pharmacist, nurse) therefore met to propose, based on data from the literature and their clinical experience, elements of management in order to detect these cognitive disorders at an early stage and optimize treatment tolerance. The subjects discussed concern screening and assessment tools, the management of side effects, and their prevention. The use of the practical elements proposed by the group could help optimize the identification and management of central nervous system disorders occurring on lorlatinib. READ ARTICLE

Bulletin du Cancer DOI:10.1016/j.bulcan.2022.01.011

Authors: Vincent Fallet, Pascal Rouby, Guido Ahle, Jennifer Arrondeau, Charles Naltet, Adeline Duflot-Boukobza, Françoise De Crozals, Hervé Lena, Alexis Cortot

Targeted RNA sequencing for upfront analysis of actionable driver alterations in non-small cell lung cancer

OBJECTIVES: Targeted RNA-based Next-Generation Sequencing (tRNA-seq) is increasingly being used in molecular diagnostics for gene fusion detection in non-small cell lung cancer (NSCLC). However, few data support its clinical application for the detection of single nucleotide variants (SNVs) and small insertions/deletions. In this study, we evaluated the performance of tRNA-seq using Archer FusionPlex for simultaneous detection of actionable gene fusions, splice variants, SNVs and indels in formalin-fixed, paraffin-embedded NSCLC tissue... Conclusion: Our results demonstrate that tRNA-seq can be implemented in a diagnostic setting as an efficient strategy for simultaneous detection of actionable gene fusions, splice variants, SNVs and indels in NSCLC provided that adequate RNA-seq analysis tools are available, especially for the detection of indels. This approach allows upfront identification of currently recommended targetable molecular alterations in NSCLC samples. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2022.02.013

Authors: Sofie, Claerhout, Stefan Lehnert, Sara Vander Borght, Lien Spans, Christophe Dooms, Els Wauters, Johan Vansteenkiste, Birgit Weynand, Karen Deraedt, Claire Bourgain, Isabelle Vanden Bempt

Malignant pleural mesothelioma with an EML4-ALK fusion: Expect the unexpected!

Case report of malignant pleural mesothelioma with an ALK gene rearrangement, detected by FISH and confirmed by RNA-based next-generation sequencing. The co-occurrence of ALK gene fusions with the more common genetic alterations in CDKN2A, NF2 and BAP1 has, to our best knowledge, not yet been described in malignant mesothelioma. Furthermore, this unexpected finding could suggest a potential target for therapy in this subset of malignant mesotheliomas. READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2022.153772

Authors: Fleur Cordier, Joni Van der Meulen, Nadinevan Roy, Jilke De Wilde, Herwigvan Dijck, Filip Vanhoenacker, Marc Lambrechts, Valentin Noyez, Koen Van de Vijver, Liesbeth Ferdinande, Amélie Dendooven, Jo Van Dorpe, David Creytens

A pilot of Blood-First diagnostic cell free DNA (cfDNA) next generation sequencing (NGS) in patients with suspected advanced lung cancer

Introduction: The diagnostic pathway for lung cancer can be long. Availability of front-line targeted therapies for NSCLC demands access to good quality tissue for genomic sequencing and rapid reporting of results. Diagnosis of lung cancer and availability of tissue was delayed during the COVID-19 pandemic... Conclusion: Blood-first cfDNA-NGS in NSCLC patients increased the breadth and rapidity of detection of actionable variants with high tissue concordance and led to timely treatment decisions. A blood-first approach should be considered to improve the speed and accuracy of therapeutic decision-making. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2022.01.009

Authors: Wanyuan Cui, Charlotte Milner-Watts, Terri P. McVeigh, Anna Minchom, Jaishree Bholse, Michael Davidson, Nadia Yousaf, Suzanne MacMahon, Hood Mugalaasi, Ranga Gunapala, Richard Lee, Angela George, Sanjay Popat, MaryO'Brien

Genetic alteration and PD-L1 expression profiles of Chinese patients with lung squamous cell carcinoma

Backgrounds: Despite the achievements made in treating lung cancer during the past decades, lung cancer still leads in cancer incidence and mortality worldwide. Compared to lung adenocarcinoma, the gene mutation profiles of Chinese lung squamous cell carcinoma (SQCC) have not been well established yet... Conclusion: Our study identified unique genomic profiles of Chinese SQCC patients and provided novel insights into the detection of additional actionable genes and ctDNA in further genotyping. Genetic testing on expanded panel merits further study to comprehensive understanding the therapeutic value of targetable alterations in Chinses SQCC patients. READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2022.153761

Authors: Ying Chen, Wencui Kong, Zongyang Yu, Zhongquan Zhao

Tumor Shrinkage With Combination of Alectinib and Trastuzumab in a Patient With ALK-Rearranged Non–small Cell Lung Cancer Harboring HER2-Amplification...

Clinical Practice Points:
• HER2 amplification is an acquired resistance mechanism in ALK-rearranged non–small cell lung cancer.
• FISH analysis revealed a minor subclone of HER2-amplified cells before becoming the dominant resistance mechanism.
• Combination of HER2 and ALK therapies may be an effective treatment approach for ALK-rearranged NSCLC with acquired HER2 amplification. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2021.06.012

Authors: David Chun Cheong Tsui, Dara Aisner, Hala Nijmeh, Liming Bao, Alexander Menter, D. Ross Camidge

Case StudyKirk SmithMarch 1, 2022ALK, HER2, Lung cancer, Acquired resistance, Trastuzumab

ALK fusion variant 3a/b, concomitant mutations, and high PD-L1 expression were associated with unfavorable clinical response to second-generation ALK TKIs...

Objectives: Second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have significantly improved clinical outcomes in patients with advanced ALK-positive non-small cell lung cancer (NSCLC), but clinical responses vary widely. In this study, the impacts of ALK fusion variants, concomitant mutations, and PD-L1 expression on the clinical response were evaluated in patients receiving second-generation ALK TKIs... Conclusion: ALK fusion variant 3a/b, concomitant mutations, and high PD-L1 expression were associated with unfavorable clinical response to second-generation TKIs in ALK-rearranged NSCLC. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2022.01.006

Authors: Meichen Li, Xue Hou, Jing Chen, Baishen Zhang, Na Wang, Hongyu Han, Likun Chen

The Pan-Immune-Inflammation Value predicts the survival of patients with anaplastic lymphoma kinase-positive non-small cell lung cancer treated with first-line ALK inhibitor

The Pan-Immune-Inflammation Value (PIV) has recently been demonstrated as a novel comprehensive biomarker to predict survival of patients with solid tumors. Our study aimed to evaluate the prognostic power of PIV in this group of patients. 94 patients with advanced ALK-positive NSCLC who received first-line ALK inhibitors were enrolled in this study. PIV was calculated as the product of peripheral blood neutrophil, monocyte, and platelet counts divided by lymphocyte count. The 1-year progression-free survival (PFS) was 63.5%, and the 5-year overall survival (OS) rate was 55.1%. Patients with higher PIV, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) had worse PFS in univariate analysis, but only the PIV (hazard ratio [HR] = 2.90, 95% confidence interval [CI]: 1.79–4.70, p < 0.001) was an independent prognostic factor in multivariate analysis. PIV is a comprehensive and convenient predictor of both PFS and OS in pat..... READ ARTICLE

Translational Oncology DOI:10.1016/j.tranon.2021.101338

Authors: Xinru Chen, Xiangchan Hong, Gang Chen, Jinhui Xue, Jie Huang, Fan Wang, Wael Ab dullah Sultan Ali, Jing Li, Li Zhang

The impact of driver mutation on the treatment outcome of early-stage lung cancer patients receiving neoadjuvant immunotherapy and chemotherapy

Neoadjuvant immunotherapy and chemotherapy have improved the major pathological response (MPR) in patients with early-stage operable non-small cell lung cancer (NSCLC). This study aimed to assess whether the presence of targetable driver mutations affects the efficacy of the combination of immunotherapy and chemotherapy. We enrolled patients with early-stage operable NSCLC who received preoperative neoadjuvant therapy between January 1, 2017, and December 30, 2020. Neoadjuvant therapy was delivered with platinum-doublet chemotherapy; moreover, pembrolizumab was added at the attending physician's discretion based on patient's request. Pathological responses were assessed; moreover, disease-free survival was estimated. Next-generation sequencing was performed in case sufficient preoperative biopsy specimens were obtained. We included 23 patients; among them, 11 received a combination of neoadjuvant immunotherapy and chemotherapy while 12 received neoadjuvant chemotherapy alone. The MPR and pathological complete response rates were 54.5% and 27.3%, respectively, in patients who received a combination of neoadjuvant immunotherapy and chemotherapy. These rates were significantly higher than those in patients who only received neoadjuvant chemotherapy. Three patients in the combination group experienced disease recurrence during the follow-up period even though two of them showed an MPR. These three patients had targetable driver mutations, including an EGFR exon 20 insertion, EGFR exon 21 L858R substitution, and MET exon 14 skipping. Only one patient who remained disease-free had a targetable driver mutation. Among patients with early-stage operable NSCLC requiring neoadjuvant therapy, comprehensive genomic profiling is crucial before the administration of the combination of neoadjuvant immunotherapy and chemotherapy. READ ARTICLE

Scientific Reports DOI:10.1038/s41598-022-07423-w

Authors: Su PL, Chen JY, Chu CY, Chen YL, Chen WL, Lin KY, Ho CL, Tsai JS, Yang SC, Chen CW, Wu YL, Tseng YL, Chang CC, Yen YT, Lin CY, Lin CC, Su WC.

Real-World OutcomesKirk SmithFebruary 28, 2022Non-small-cell lung cancer, Cancer immunotherapy

STAT3 inhibition suppresses adaptive survival of ALK-rearranged lung cancer cells through transcriptional modulation of apoptosis

Patients with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who are prescribed ALK-tyrosine kinase inhibitors (ALK-TKIs) rarely have complete responses, with residual tumors relapsing as heterogeneous resistant phenotypes. Herein, we investigated new therapeutic strategies to reduce and eliminate residual tumors in the early treatment phase. Functional genomic screening using small guide RNA libraries showed that treatment-induced adaptive survival of ALK-rearranged lung cancer cells was predominantly dependent on STAT3 activity upon ALK inhibition. STAT3 inhibition effectively suppressed the adaptive survival of ALK-rearranged lung cancer cells by enhancing ALK inhibition-induced apoptosis. The combined effects were characterized by treatment-induced STAT3 dependence and transcriptional regulation of anti-apoptotic factor BCL-XL. In xenograft study, the combination of YHO-1701 (STAT3 inhibitor) and alectinib significantly suppressed tumor regrowth after treatment cessation with near tumor remission compared with alectinib alone. Hence, this study provides new insights into combined therapeutic strategies for patients with ALK-rearranged lung cancer. READ ARTICLE

Precision Oncology DOI:10.1038/s41698-022-00254-y

Authors: Naohiro Yanagimura, Shinji Takeuchi, Koji Fukuda, Sachiko Arai, Azusa Tanimoto, Akihiro Nishiyama, Naohisa Ogo, Hiroyuki Takahashi, Akira Asai, Satoshi Watanabe, Toshiaki Kikuchi & Seiji Yano

Pre-ClinicalKirk SmithFebruary 28, 2022Non-small-cell lung cancer (NSCLC), Targeted therapies

Circulating Cell-free DNA as a Prognostic Biomarker in Patients with Advanced ALK+ Non-small Cell Lung Cancer in the Global Phase III ALEX Trial

Introduction: We retrospectively assessed prognostic value of circulating cell-free DNA (cfDNA) using data from the phase III ALEX study in treatment-naïve, advanced ALK+ NSCLC. Methods: Patients were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151). cfDNA was quantified from baseline plasma samples, with patients stratified into {less than or equal to}median and >median cfDNA biomarker-evaluable populations (BEP). Effect of cfDNA concentration on outcomes was analyzed using a Cox regression model with treatment group as covariate, and in multivariate analyses. Results: Median cfDNA concentration in the BEP was 11.53 ng/mL (n = 276). A positive correlation was found between cfDNA concentration and number of lesions, organ lesion sites, and tumor size (sum of longest diameter; all p<0.0001). In both treatment arms, patients in the >median BEP were more likely to experience disease progression than the {less than or equal to}median BEP (alectinib adjusted hazard ratio [HR] 2.04 [95% confidence interval (CI): 1.07-3.89], p=0.0305; crizotinib adjusted HR 1.83 [95% CI: 1.11-3.00], p=0.0169). Median progression-free survival was longer with alectinib than crizotinib in both {less than or equal to}median and >median BEPs (p<0.0001). Overall survival data remain immature; survival probability was lower in the >median versus {less than or equal to}median BEP in both treatment arms (alectinib HR 2.52 [95% CI: 1.08-5.88], p=0.0333; crizotinib HR 2.63 [95% CI: 1.27-5.47], p=0.0096). Conclusion: These data suggest that plasma cfDNA concentration may have prognostic value in advanced ALK+ NSCLC. Prospectively designed studies are warranted to investigate this finding. READ ARTICLE

Clinical Cancer Research DOI:10.1158/1078-0432.CCR-21-2840

Authors: Rafal Dziadziuszko, Solange Peters, Tony Mok, D. Ross. Camidge, Shirish M. Gadgeel, Sai-Hong Ignatius. Ou, Krzysztof Konopa, Johannes Noé, Malgorzata Nowicka, Walter Bordogna, Peter N. Morcos, Vlatka Smoljanovic, Alice T. Shaw

Clinical TrialsKirk SmithFebruary 23, 2022Chemotherapy, targeted therapy, imaging, chest, lung cancer

The role of next-generation sequencing in detecting gene FUSIONS with KNOWN and UNKNOWN partners: A single-center experience with methodologies’ integration

Aims: Next-generation sequencing (NGS) is becoming a new gold standard for determining molecular predictive biomarkers. This study aimed to evaluate the reliability of NGS in detecting gene fusions, focusing on comparing gene fusions with known and unknown partners... Conclusions: NGS is a reliable method for detecting gene fusions with known partners, but it is less accurate in identifying gene fusions with unknown partners, for which further analyses (such as FISH) are required. READ ARTICLE

Human Pathology DOI:10.1016/j.humpath.2022.02.005

Authors: Andrea Ambrosini-Spaltro, Anna Farnedi, Daniele Calistri, Claudia Rengucci, Giovanna Prisinzano, Elisa Chiadini, Laura Capelli, Davide Angeli, Chiara Bennati, Mirca Valli, Giovanni De Luca, Dora Caruso, Paola Ulivi, Giulio Rossi

Review PaperKirk SmithFebruary 15, 2022Next-generation sequencing, FISH, IHC, gene fusion, partner, NSCLC

Concomitant novel ALK-SSH2, EML4-ALK and ARID2-ALK, EML4-ALK double-fusion variants and confer sensitivity to crizotinib in two lung adenocarcinoma patients, respectively

Introduction: Anaplastic lymphoma kinase (ALK) gene rearrangements, have been identified in approximately 2-7% of patients with lung adenocarcinoma (LUAD). However, co-occurrence of double ALK fusions in one patient was rare. Herein, we reported two Chinese female LUAD patients with confirmed double ALK fusion variants by next generation sequencing.
Case presentation

Case 1, a 38-year-old female was diagnosed as peripheral LUAD in left upper lobe with synchronous multiple intrapulmonary metastases (pT2N0M1b, stage IVa). And case 2, a 58-year-old female had left lower lobe primary LUAD and synchronous multiple lung metastases (pT4N2M1b, stage IVa). In both patients, tumor cells displayed strong expression of ALK protein. Genetic profiling by next generation sequencing showed both patients concurrently harbored two types of ALK rearrangements. Case 1 had an unreported ALK-SSH2/EML4-ALK double fusions, and case 2 had an another novel ARID2-ALK/EML4‐ALK double fusions. Both of these patients responded to ALK inhibitor crizotinib.
Conclusions

Our study reported two novel ALK fusion partners never reported, which expands the knowledge of ALK fusion spectrum and provides insight into therapeutic options for patients with double ALK fusions. READ ARTICLE

Diagnostic Pathology DOI:10.1186/s13000-022-01212-9

Authors: Tao H, Liu Z, Mu J, Gai F, Huang Z, Shi L.

ALKtALK talk with Dr Alice Shaw

Meet the Queen of Alk, Dr. Alice Shaw. Join Dr. Shaw and Gina Hollenbeck for an informal chat as they discuss Dr. Shaw's take on how treatment for the ALK Positive mutation has evolved and where it is going. Bone metastasis, pregnancies and fertility while taking tki's, and treatment dosing are just a few of the topics covered. Dr. Alice Shaw worked for over 15 years at Massachusetts General Hospital as a clinical trial investigator. She helped lung cancer evolve from a disease with few options, to one of hope with clinically proven therapies. Dr. Shaw continues to push the envelope as the Global Head of Translational Clinical Oncology at the Novartis Institutes for BioMedical Research. WATCH VIDEO

ALK Positive Inc

Authors: Dr. Alice Shaw

VideoKirk SmithFebruary 6, 2022ALK

Oncogenic protein condensates modulate cell signal perception and drug tolerance

Drug resistance remains a central challenge towards durable cancer therapy, including for cancers driven by the EML4-ALK oncogene. EML4-ALK and related fusion oncogenes form cytoplasmic protein condensates that transmit oncogenic signals through the Ras/Erk pathway. However, whether such condensates play a role in drug response or resistance development is unclear. Here, we applied optogenetic functional profiling to examine how EML4-ALK condensates impact signal transmission through transmembrane receptor tyrosine kinases (RTKs), a common route of resistance signaling. We found that condensates dramatically suppress signaling through activated RTKs including EGFR. Conversely, ALK inhibition restored and hypersensitized RTK signals. Modulation of RTK sensitivity occurred because EML4-ALK condensates sequestered downstream adapters that are required to transduce signals from both EML4-ALK and ligand-stimulated RTKs. Strikingly, EGFR hypersensitization resulted in rapid and pulsatile Erk..... READ ARTICLE

bioRxiv DOI:10.1101/2022.02.02.478845

Authors: David Gonzalez-Martinez, Lee Roth, Thomas R. Mumford, Asmin Tulpule, Trever G. Bivona, Lukasz J. Bugaj

Alectinib Monotherapy in Isolated Central Nervous System Relapse of ALK-Positive Anaplastic Large Cell Lymphoma

Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK-positive ALCL) is an aggressive form of peripheral T cell lymphoma (PTCL), harbouring an underlying pathogenic ALK fusion gene that produces a constitutively activated tyrosine kinase. The ALK tyrosine kinase provides a targeted treatment option in the form of ALK inhibitors. ALK-positive ALCL may rarely involve the central nervous system (CNS), either at presentation or on relapse of disease. The outcomes of CNS relapse in PTCL are historically extremely poor. We present a case of a 20-year-old man diagnosed with stage IVB ALK-positive ALCL. He responded favourably to six cycles of cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP). He unfortunately relapsed with isolated CNS involvement only 3 weeks after completing his sixth cycle of CHOEP chemotherapy. The CNS-penetrating ALK inhibitor alectinib was identified as a targeted treatment option, as he was not a candidate for CNS-penetrating chemotherapy due to significant iatrogenic renal impairment. After commencing alectinib monotherapy, he rapidly achieved a clinical and radiological response. He has now remained in a durable remission for more than two years on alectinib monotherapy. READ ARTICLE

Case Reports in Hematology DOI:10.1155/2022/4749452

Authors: Julian Verran, Vidya Mathavan

Case StudyKirk SmithFebruary 3, 2022Alectinib, Central Nervous System, Anaplastic Large Cell Lymphoma

A Case of ALK‐Rearranged Combined Lung Adenocarcinoma and Neuroendocrine Carcinoma with Diffuse Bone Metastasis and Partial Response to Alectinib

We report a rare case of stage IV pulmonary combined large-cell neuroendocrine carcinoma
(LCNEC) and adenocarcinoma (ACA), both demonstrating anaplastic lymphoma kinase (ALK)
rearrangement by IHC and FISH. This 61-year-old lifelong nonsmoking Asian woman presented with
a cough, and after diagnosis and surgical treatment, completed four cycles of adjuvant cisplatin and
etoposide chemotherapy. She subsequently developed recurrence with bony metastases of exclusively
ALK-positive LCNEC. Alectinib was started, and the patient experienced a partial response READ ARTICLE

Current Oncology DOI:10.3390/curroncol29020072

Authors: Chloe A. Lim, Norbert Banyi, Tracy Tucker, Diana N. Ionescu, Barbara Melosky

Case StudyKirk SmithFebruary 3, 2022neuroendocrine, adenocarcinoma, driver mutation, ALK, LCNEC

Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK+ anaplastic large cell lymphoma

Anaplastic large cell lymphomas (ALCLs) frequently carry oncogenic fusions involving the anaplastic lymphoma kinase (ALK) gene. Targeting ALK using tyrosine kinase inhibitors (TKIs) is a therapeutic option in cases relapsed after chemotherapy, but TKI resistance may develop. By applying genomic loss-of-function screens, we identified PTPN1 and PTPN2 phosphatases as consistent top hits driving resistance to ALK TKIs in ALK+ ALCL. Loss of either PTPN1 or PTPN2 induced resistance to ALK TKIs in vitro and in vivo. Mechanistically, we demonstrated that PTPN1 and PTPN2 are phosphatases that bind to and regulate ALK phosphorylation and activity. In turn, oncogenic ALK and STAT3 repress PTPN1 transcription. We found that PTPN1 is also a phosphatase for SHP2, a key mediator of oncogenic ALK signaling. Downstream signaling analysis showed that deletion of PTPN1 or PTPN2 induces resistance to crizotinib by hyperactivating SHP2, the MAPK, and JAK/STAT pathways. RNA sequencing of patient samples that developed resistance to ALK TKIs showed downregulation of PTPN1 and PTPN2 associated with upregulation of SHP2 expression. Combination of crizotinib with a SHP2 inhibitor synergistically inhibited the growth of wild-type or PTPN1/PTPN2 knock-out ALCL, where it reverted TKI resistance. Thus, we identified PTPN1 and PTPN2 as ALK phosphatases that control sensitivity to ALK TKIs in ALCL and demonstrated that a combined blockade of SHP2 potentiates the efficacy of ALK inhibition in TKI-sensitive and -resistant ALK+ ALCL. READ ARTICLE

Blood DOI:10.1182/blood.2020008136

Authors: Karaca Atabay E, Mecca C, Wang Q, Ambrogio C, Mota I, Prokoph N, Mura G, Martinengo C, Patrucco E, Leonardi G, Hossa J, Pich A, Mologni L, Gambacorti-Passerini C, Brugières L, Geoerger B, Turner SD, Voena C, Cheong TC, Chiarle R.

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.

Targeting Alternative Splicing as Adjunctive Treatment in EML4-ALK v3a/b+ NSCLC: Knowing Our Socratic Paradox and Learning From Spinal Muscular Atrophy

After their seminal discovery of EML4-ALK variant 1 (v1) (E13:A20) and v2 (E20:A20) as a transforming driver mutation in NSCLC in 2007,1 Choi et al.2 went on to identify EML4-ALK v3 (E6:A20) in 2008 using reverse transcriptase-polymerase chain reaction. Two EML4-ALK v3 isoforms, v3a and v3b, which differs by an inclusion of a cryptic (exon EML4 6b) exon of 33 DNA base pairs into v3b, were identified together in two patients' samples... Currently, no combination therapy has been approved for the treatment of advanced ALK+ NSCLC despite our tremendous understanding of both on-target,17 and off-target resistances.18 The clinical approval of “double mutant active” ALK TKIs is at best years away with no guarantee that they will be developed to address the current unmet need of acquired double ALK mutations given that double mutations are only part of the spectrum of acquired resistances to ALK TKIs.19 The successful clinical development of six ALK TKIs globally leading to long-term surviva..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.11.010

Authors: Misako Nagasaka, Sai-Hong Ignatius Ou