Lung cancer remains the leading cause of cancer death world-wide. This is in part due patients presenting late with disseminated disease and despite recent advances, a limited therapeutic landscape... Despite these advances there remains a significant unmet clinical need with much research needed to elucidate the optimal treatment paradigm to improve response rates, mortality and quality of life for patients with advanced NSCLC. READ ARTICLE

Encyclopedia of Respiratory Medicine (Second Edition) DOI:10.1016/B978-0-08-102723-3.00265-1

Authors: Alice Davies, Martin Forster

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

Blood-based liquid biopsy: Insights into early detection and clinical management of lung cancer

Currently, early detection of lung cancer relies on the characterisation of images generated from computed tomography (CT). However, lung tissue biopsy, a highly invasive surgical procedure, is required to confirm CT-derived diagnostic results with very high false-positive rates. Hence, a non-invasive or minimally invasive biomarkers is essential to complement the existing low-dose CT (LDCT) for early detection, improve responses to a certain treatment, predict cancer recurrence, and to evaluate prognosis. In the past decade, liquid biopsies (e.g., blood) have been demonstrated to be highly effective for lung cancer biomarker discovery. In this review, the roles of emerging liquid biopsy-derived biomarkers such as circulating nucleic acids, circulating tumour cells (CTCs), long non-coding RNA (lncRNA), and microRNA (miRNA), as well as exosomes, have been highlighted. The advantages and limitations of these blood-based minimally invasive biomarkers have been discussed. Furthermore, the current progress of the identified biomarkers for clinical management of lung cancer has been summarised. Finally, a potential strategy for the early detection of lung cancer, using a combination of LDCT scans and well-validated biomarkers, has been discussed. READ ARTICLE

Cancer Letters DOI:10.1016/j.canlet.2021.10.013

Authors: Cuiliu Liu, Xiaoqiang Xiang, Shuangqing Han, Hannah Ying Lim, Lingrui Li, Xing Zhang, Zhaowu Ma, Li Yang, Shuliang Guo, Ross Soo, Boxu Ren, Lingzhi Wang, Boon Cher Goh

EditorialKirk SmithJanuary 1, 2022Liquid biopsy, Biomarkers, Lung cancer, Early detection, Clinical management

Post-chemotherapy and targeted therapy imaging of the chest in lung cancer

Non-small-cell lung cancer (NSCLC) is frequently diagnosed when it is not amenable to local therapies; therefore, systemic agents are the mainstay of therapy for many patients. In recent years, treatment of advanced NSCLC has evolved from a general approach primarily involving chemotherapy to a more personalised strategy in which biomarkers such as the presence of genomic tumour aberrations and the expression of immune proteins such as programmed death-ligand 1 (PD-L1), in combination with other elements of clinical information such as histology and clinical stage, guide management. For instance, pathways resulting in uncontrolled growth and proliferation of tumour cells due to epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements may be targeted by tyrosine kinase inhibitors (TKIs). In this article, we review the current state of medical oncology, imaging characteristics of mutations, pitfalls in response assessments and the imaging of complications. READ ARTICLE

Clinical Radiology DOI:10.1016/j.crad.2021.08.001

Authors: B. W. Carter, M. Altan, G. S. Shroff, M. T. Truong, I. Vlahos

EditorialKirk SmithJanuary 1, 2022Chemotherapy, targeted therapy, imaging, chest, lung cancer

Diagnosis of cholangiocarcinoma from microscopic hyperspectral pathological dataset by deep convolution neural networks

This paper focuses on automatic Cholangiocarcinoma (CC) diagnosis from microscopic hyperspectral (HSI) pathological dataset with deep learning method. The first benchmark based on the microscopic hyperspectral pathological images is set up. Particularly, 880 scenes of multidimensional hyperspectral Cholangiocarcinoma images are collected and manually labeled each pixel as either tumor or non-tumor for supervised learning. Moreover, each scene from the slide is given a binary label indicating whether it is from a patient or a normal person. Different from traditional RGB images, the HSI acquires pixels in multiple spectral intervals, which is added as an extension on the channel dimension of 3-channel RGB image. This work aims at fully exploiting the spatial-spectral HSI data through a deep Convolution Neural Network (CNN). The whole scene is first divided into several patches. Then they are fed into CNN for the tumor/non-tumor binary prediction and the tumor area regression. The furthe..... READ ARTICLE

Methods DOI:10.1016/j.ymeth.2021.04.005

Authors: Li Sun, Mei Zhou, Qingli Li, Menghan Hu, Ying Wen, Jian Zhang, Yue Lu, Junhao Chu

Lorlatinib Should Not be Considered as the Preferred First-Line Option in Patients With Advanced ALK Rearranged NSCLC

In theory, you might think there should be no debate over whether lorlatinib should be the preferred first-line ALK inhibitor. If the CROWN study data are viewed in isolation, lorlatinib seems to have the best-in-class differential progression-free survival (PFS) benefit over crizotinib (hazard ratio [HR] = 0.28, 95% confidence interval [CI]: 0.19–0.41). 1 In contrast, other next-generation ALK inhibitors alectinib, brigatinib, and ensartinib with comparable head-to-head trials versus crizotinib generated PFS HRs ranging from 0.51 to 0.37. 2 , 3 , 4 , 5 , 6 , 7 Whereas, admittedly, for the lowest of these estimates (from the J-ALEX study [alectinib versus crizotinib in a Japanese population]), the CIs of the PFS HR (0.37, 95% CI: 0.26–0.52) overlap with those of the CROWN study, there is a clear delineation between the upper limit of CROWNs HR CIs and the lower limit of the HR CIs for the other studies. Yet, here we are in a pro and con debate, because, frankly, there is something abou..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.12.022

Authors: David Ross Camidge

EditorialKirk SmithMarch 27, 2021Lorlatinib, First-Line, ALK-Rearranged NSCLC

Lorlatinib Should Be Considered as the Preferred First-Line Option in Patients With Advanced ALK-Rearranged NSCLC

Since the discovery of ALK-positive (ALK+) fusion in NSCLC in 2007, 1 ,2 we now know patients with ALK+ NSCLC can live up to 9 years after stage 4 diagnosis 3 , 4 , 5 but are constantly overshadowed by an unrelenting cumulative incidence of brain metastasis with time (>60% by year 6). 6 At the molecular level, the two most common EML4-ALK fusion variants, variant 1 (v1) and variant 3 (v3), have differential responses to ALK tyrosine kinase inhibitors (TKIs) 7 ,8 with the recalcitrant solvent-front ALK G1202R mutation arising more often from the background of EML4-ALK variant 3. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.12.021

Authors: Misako Nagasaka, Sai-Hong Ignatius Ou

EditorialKirk SmithMarch 27, 2021lorlatinib, First-Line, ALK-Rearranged, NSCLC

Brigatinib After Progression From Alectinib or Crizotinib: Paving the Way for Treatment Sequencing of ALK Inhibitors in ALK-Positive NSCLC

Among the 47 Japanese patients who received brigatinib at the standard dose after progression from alectinib with or without history of crizotinib use, objective response rate (ORR) and disease control rate (DCR) were 34% (16 of 47) and 79% (37 of 47), respectively, with a median progression-free survival (PFS) of 7.3 months. READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1016/J.JTHO.2020.11.023

Authors: Lianxi Song, Qinqin Xu, Analyn Lizaso, Yongchang Zhang,

EditorialKirk SmithMarch 1, 2021Alectinib progression, Crizotinib progression, Brigatinib

An Expert Perspective on Antibody–Drug Conjugates in Non-Small-Cell Lung Cancer

Until recently, the focus for the treatment of lung cancer has been on immunotherapy and targeted therapy, but I think that antibody–drug conjugates (ADCs) are going to have a massive role in the management of this disease in the future. READ ARTICLE

Clinical Care Options

Author: Dr. Ross Camidge

An Expert Perspective on Antibody–Drug Conjugates in Non-Small-Cell Lung Cancer

Until recently, the focus for the treatment of lung cancer has been on immunotherapy and targeted therapy, but I think that antibody–drug conjugates (ADCs) are going to have a massive role in the management of this disease in the future. READ ARTICLE

Clinical Care Options: Oncology

Authors: Ross Camidge

EditorialKirk SmithJanuary 26, 2021Antibody-Drug Conjugates, NSCLC

Understanding the Evolutionary Games in NSCLC Microenvironment

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

BioRxiv DOI:10.1101/2020.11.30.404350

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

EditorialKirk SmithNovember 30, 2020Evolutionary Games, NSCLC Microenvironment

CircRNAs and Fusion-circRNAs in cancer: New players in an old game

Circular RNAs (circRNAs) are generated from 'back-splicing' events. Their circular structure makes them stable in cells and body fluids. These entities are involved in several human diseases including cancer, as they affect the expression of genes promoting proliferation, invasion, apoptosis, and angiogenesis. Moreover, they are secreted in extracellular vesicles, such as exosomes, having a potential role as messengers in cell-to-cell communications. CircRNAs are also generated by the back-splicing of linear fusion transcripts derived from genomic rearrangements, giving rise to fusion circRNAs (f-circRNAs).
Here we discuss the most relevant results achieved by studying the role of circRNAs in cancer onset and progression, particularly focusing on f-circRNAs in hematological and solid tumors. Moreover, we report recent advances in the application of circRNAs as novel “liquid biopsy” biomarkers for early and non-invasive diagnosis of tumors, and as therapeutic targets in human cancer. Th..... READ ARTICLE

Cellular Signalling DOI:10.1111/1759-7714.13376

Authors: Grazia Visci, DoronTolomeo, Antonio Agostini, Debora Traversa, Gemma Macchia, Clelia Tiziana Storlazzi

EditorialKirk SmithNovember 1, 2020CircRNA, Fusion-circRNA, Cancer, Chimera, Biomarker

174 Poster - Dissecting the landscape of CAF-mediated drug resistance mechanisms in ALK-rearranged NSCLC

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

Pyrroformyl-containing 2,4-diaminopyrimidine derivatives as a new optimization strategy of ALK inhibitors combating mutations

Aiming 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

Treatment Algorithm for Advanced ALK-Rearranged NSCLC: Reply

... We agree that crizotinib will still have a role in the treatment of patients with advanced ALK-rearranged NSCLC, however, probably only as a supplementary drug. In cell lines, crizotinib has been reported to be active in Ba/F3 cells harboring EML4-ALK resistance 1198F mutations or E1210K mutations... Finally, we agree with Urbanska et al. that comprehensive molecular profiling is also very important for treatment-naive patients, which may help identify potentially “detrimental” factors, such as TP53 mutations or BIM deletion polymorphisms.11,12 Nevertheless, a deeper understanding of the underlying biology mechanisms of acquired resistance to ALK inhibitors will help us further complement the therapeutic algorithm for patients with advanced ALK-rearranged NSCLC. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.06.005

Authors: Fei Zhou, Caicun Zhou

EditorialKirk SmithSeptember 1, 2020ALK, NSCLC

ALK Inhibitors in ALK-positive NSCLC with Central Nervous System Metastases

In anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer, brain metastases occur in 22–33% of cases at diagnosis and could reach up to 70% after crizotinib failure. Next-generation ALK inhibitors (ngALKi) have superior intracranial activity and prolonged responses compared with crizotinib and chemotherapy, as was shown in treatment-naïve or crizotinib pre-treated patients, irrespective of prior brain irradiation. Nevertheless, central nervous system relapse is also seen with ngALKi. Tailored treatment is necessary to obtain long-term survival without detrimental effects on cognition. Possible options include profiling secondary mutations to select sequential ngALKi, stereotactic radiotherapy and/or surgery, with the aim to avoid/deter whole brain irradiation. READ ARTICLE

touchONCOLOGY DOI:10.17925/EOH.2020.16.1.18

Authors: Mihaela Aldea, Benjamin Besse, Lizza EL Hendriks

N-[18F]-Fluoroacetylcrizotinib: A potentially potent and selective PET tracer for molecular imaging of non-small cell lung cancer

N-[18F]fluoroacetylcrizotinib, a fluorine-18 labeled derivative of the first FDA approved tyrosine kinase inhibitor (TKI) for the treatment of Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC), crizotinib, was successfully synthesized for use in positron emission tomography (PET). Sequential in vitro biological evaluation of fluoracetylcrizotinib and in vivo biodistribution studies of [18F]fluoroacetylcrizotinib demonstrated that the biological activity of the parent compound remained unchanged, with potent ALK kinase inhibition and effective tumor growth inhibition. These results show that [18F]fluoroacetylcrizotinib has the potential to be a promising PET ligand for use in NSCLC imaging. The utility of PET in this context provides a non-invasive, quantifiable method to inform on the pharmacokinetics of an ALK-inhibitor such as crizotinib prior to a clinical trial, as well as during a trial in the event of acquired drug resistance. READ ARTICLE

Bioorganic & Medicinal Chemistry Letters DOI:10.1016/j.bmcl.2020.127257

Authors: Jason R. Buck, Samir Saleh, Trey Claus, Christine Lovly, Matthew R. Hight, Michael L. Nickels, M. Noor Tantawy, H.Charles Manning

EditorialKirk SmithAugust 15, 2020Crizotinib, NSCLC, PET, Cancer, Therapy

Is Retention of the 5′ Nononcogenic ALK Fusion Variant a Novel Poor Prognostic Factor in ALK-Positive NSCLC?

... A simple question that has remained unanswered since the discovery of the EML4-ALK fusion in 2007 is “what happens to the 5′ ALK DNA chromosomal fragment that contains ALK exons 1-19?” Routine clinical use of NGS in NSCLC allows the detection of the presence of reciprocal or nonreciprocal translocations in a subset of cases, which could not be identified using FISH or IHC platforms... Patients with ALK+ NSCLC with brain metastases but did not retain the 5′ ALK fragment had similar poor outcomes when treated with crizotinib.21 Last, whether the shorter PFS from crizotinib treatment can be translated to next-generation ALK tyrosine kinase inhibitors is also unknown. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.04.031

Authors: Susan J. Hsiao, Sai-Hong Ignatius Ou

A User’s Guide to Lorlatinib

Rearrangements of the ALK gene are found in approximately 5% of non-small-cell lung cancer. It is of particular importance to test for this rearrangement in patients with metastatic lung adenocarcinoma because these tumors are highly sensitive to therapy with ALK-targeted inhibitors.

Lorlatinib is a reversible potent third generation tyrosine kinase inhibitor that is highly selective and targets ALK and ROS1. It was developed to target resistant ALK mutants including the most common G1202R. Lorlatinib has excellent central nervous system (CNS) penetration and its efficacy has also been demonstrated even in patients with intracranial metastases after progression on second generation ALK inhibitors. Potential toxicities include neurocognitive effects and hyperlipidemia.

“A User’s Guide to Lorlatinib” reviews the mechanism of action, pharmacology and clinical trial data. Also covering the management of adverse events, this “guide” has been prepared to be a practical reference tool to both clinicians and basic researchers. READ ARTICLE

Critical Reviews in Oncology/Hematology DOI:10.1016/j.critrevonc.2020.102969

Authors: Misako Nagasaka, Yubin Ge, Ammar Sukari, Geetika Kukreja, Sai-Hong IgnatiusOu

Chapter 13 - Gastrointestinal Toxicities of Targeted Therapy

Although targeted therapies are generally better tolerated than standard chemotherapy, there are some gastrointestinal side effects that should be kept in consideration. Most side effects are mild to moderate in severity, but some can be life threatening. Diarrhea is the most common side effects of tyrosine kinase inhibitors (TKIs). The majority of the cases can be managed with prophylactic and rescue use of anti-diarrhea medications. Aplastic lymphoma kinase (ALK) inhibitors, mesenchymal epithelial transition factor(c-MET) and poly ADP-ribose polymerase (PARP) inhibitors are known to cause nausea and vomiting. Most cases of nausea and vomiting can be managed by medications such as serotonin antagonists, NK-1 antagonists, dopamine antagonists or anti-anxiety medications. Prior to prescribing c-KIT TKIs (sunitinib, regorafenib), multi-TKIs (pazopanib), MEK inhibitors (trametinib), anti-HER-2 therapy (lapatinib) and anti-EGFR targeting agents (gefitinib, erlotinib), baseline liver function tests should be performed and then monitored periodically to prevent liver damage. READ ARTICLE

Handbook of Cancer Treatment-Related Symptoms and Toxicities DOI:10.1016/B978-0-323-67241-2.00013-6

Authors: Tahmida Chowdhury, Ammar Sukari, Misako Nagasaka