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

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.

Short communication: The activity of brigatinib in patients with disease progression after next generation anaplastic lymphoma tyrosine kinase inhibitors...

Highlights:
- Brigatinib demonstrated activity in patients with disease progression after next-generation anaplastic lymphoma (ALK) tyrosine kinase inhibitors (TKI’s).
- The objective response was similar in patients who received next generation ALK inhibitors as first-line or second line therapy, and patients with and without brain metastases at baseline.
- Circulating tumor DNA testing (ctDNA) for ALK resistance mutations is feasible; however, a number of patients did not have detectable ctDNA or an ALK resistance mutations. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.12.019

Authors: Thomas E. Stinchcombe, Xiaofei Wang, Robert C. Doebele, Leylah M. Drusbosky, David E. Gerber, Leora Horn, Erin M. Bertino, Geoff Liu, Liza C. Villaruz, D. Ross Camidge

Clinical TrialsKirk SmithJanuary 3, 2022Targeted therapy, biomarker, ctDNA, liquid biopsy

Clinical Outcomes for Plasma-Based Comprehensive Genomic Profiling Versus Standard-of-Care Tissue Testing in Advanced Non–Small Cell Lung Cancer

Background: Somatic genomic testing is recommended by numerous expert guidelines to inform targeted therapy treatment for patients with advanced nonsquamous non–small cell lung cancer (aNSCLC). The NILE study was a prospective observational study that demonstrated noninferiority of cell-free circulating tumor DNA (cfDNA)-based tumor genotyping compared to tissue-based genotyping to find targetable genomic alterations in patients with newly diagnosed nonsquamous aNSCLC. As the cohort has matured, clinical outcomes data can now be analyzed... Conclusions: cfDNA detects guideline-recommended biomarkers at a rate similar to tissue genotyping, and therapeutic outcomes based on plasma-based comprehensive genomic profiling are comparable to published targeted therapy outcomes with tissue profiling, even in community-based centers. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2021.10.001

Authors: Ray D. Page, Leylah M. Drusbosky, Hiba Dada, Victoria M. Raymond, Davey B. Daniel, Stephen G. Divers, Karen L. Reckamp, Miguel A. Villalona-Calero, Daniel Dix, Justin I. Odegaard, Richard B. Lanman, Vassiliki, A. Papadimitrakopoulou, Natasha B. Leighl

Efficacy of Targeted Inhibitors in Metastatic Lung Squamous Cell Carcinoma With EGFR or ALK Alterations

The efficacy of targeted therapies in oncogene-driven lung adenocarcinomas (LUADs) has been well established; however, the benefit for EGFR-mutant or ALK-rearranged lung squamous cell carcinomas (LUSCs) is less known, partially owing to the rarity of the incidence. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtocrr.2021.100237

Authors: Whitney E. Lewis, Lingzhi Hong, Frank E. Mott, George Simon, Carol C. Wu, Waree Rinsurongkawong, J. Jack Lee, Vincent K. Lam, John V. Heymach, Jianjun Zhang, Xiuning Le

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

Targeted therapy in advanced non-small cell lung cancer: current advances and future trends

Lung cancer remains the leading cause of cancer-related mortality in both men and women in the US and worldwide. Non-small cell lung cancer is the most common variety accounting for 84% of the cases. For a subset of patients with actionable mutations, targeted therapy continues to provide durable responses. Advances in molecular and immunohistochemical techniques have made it possible to usher lung cancer into the era of personalized medicine, with the patient getting individualized treatment based on these markers. This review summarizes the recent advances in advanced NSCLC targeted therapy, focusing on first-in-human and early phase I/II clinical trials in patients with advanced disease. We have divided our discussion into different topics based on these agents' mechanisms of action. This article is aimed to be the most current review of available and upcoming targeted NSCLC treatment options. We will also summarize the currently available phase I/II clinical trial for NSCLC patient..... READ ARTICLE

Journal of Hematology & Oncology DOI:10.1186/s13045-021-01121-2

Authors: Umair Majeed, Rami Manochakian, Yujie Zhao & Yanyan Lou

Retrospective Real-World Outcomes for Patients With ALK-Rearranged Lung Cancer Receiving ALK Receptor Tyrosine Kinase Inhibitors

Clinical trials have firmly established that ALK TKIs are safe, well tolerated, and effective; these findings reveal that their impact in a real-world setting is just as profound. The availability and use of ALK TKI therapies contribute to the impressive gains in survival experienced by contemporary patients with ALK-rearranged disease, rendering patients with this oncodriven form of NSCLC among the longest surviving patients with lung cancer. READ ARTICLE

Journal of Thoracic Oncology, Clinical and Research Reports DOI:10.1016/j.jtocrr.2021.100157

Authors: Amanda J. W. Gibson, Adrian Box, Michelle L. Dean, Anifat A. Elegbede, Desiree Hao, Randeep Sangha, D. Gwyn Bebb

Real-World OutcomesKirk SmithApril 1, 2021ALK, NSCLC, Targeted therapy, adverse events

Immunotherapy Treatment Patterns and Outcomes Among ALK-Positive Patients With Non–Small-Cell Lung Cancer

Real-world effectiveness (rwPFS) of ICIs in ALK-positive NSCLC patients, whether provided before or after TKIs, was limited, underscoring the relative lack of efficacy of ICI in this patient population, particularly compared to approved ALK TKIs. READ ARTICLE

Clinical Lung Cancer DOI: 10.1016/j.cllc.2020.08.003

Authors: Mohammad Jahanzeb, Huamao M.Lin, Xiaoyun Pan, Yu Yin, Pia Baumann, Corey J. Langer

Immunotherapy in EGFR-Mutant and ALK-Positive Lung Cancer: Implications for Oncogene-Driven Lung Cancer

Non-small cell lung cancer (NSCLC) is a heterogeneous disease, commonly defined by genetic alterations in oncogenic drivers. Targeted therapies have transformed the management of oncogene-driven lung cancers, with targeted agents now approved in the United States for 7 distinct molecular alterations. Nonetheless, acquired resistance remains an ongoing challenge, underscoring the need for alternative therapeutic approaches. Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) axis have emerged as important therapies in the management of advanced NSCLC, but the role of these agents in patients with oncogenic driver mutations remains unclear. Here, we focus on epidermal growth factor receptor-mutant and anaplastic lymphoma kinase-rearranged NSCLC as paradigms to explore the role of immune checkpoint inhibitors in oncogene-driven NSCLC. We provide an overview of the clinical data examining programmed death ligand 1 (PD-L1) inhibitor monotherapy, PD-(L)1 inhibitors, and tyrosine kinase inhibitor combinations, as well as combinations of PD-(L)1 inhibitors and chemotherapy. READ ARTICLE

The Cancer Journal DOI: 10.1097/PPO.0000000000000491

Authors: Gavralidis A, Gainor JF.

Review PaperKirk SmithDecember 26, 2020EGFR, ALK, combinations, Targeted therapy

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

Introduction: Variable genomic breakpoints have been identified through the application of target-capture DNA next-generation sequencing (NGS) for ALK, ROS1, and RET fusion detection in NSCLC. We investigated whether ALK, ROS1, and RET genomic breakpoint location can predict matched targeted therapy efficacy. Conclusions: Uncommon ALK, ROS1, and RET genomic breakpoint is an unreliable predictor of matched targeted therapy efficacy. Functional validation by RNA or protein assay may add value for the accurate detection and interpretation of rare fusions. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.10.156

Authors: Weihua Li, Lei Guo, Yutao Liu, Lin Dong, Lin Yang, Li Chen, Kaihua Liu, Yang Shao, Jianming Ying

Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing

Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell-state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes. READ ARTICLE

Cell DOI:10.1016/j.cell.2020.07.017

Authors: Ashley Maynard, Caroline E. McCoach, Julia K. Rotow, Lincoln Harris, Franziska Haderk, D. Lucas Kerr, Elizabeth A. Yu, Erin L. Schenk, Weilun Tan, Alexander Zee, Michelle Tan, Philippe Gui, Tasha Lea, Wei Wu, Anatoly Urisman, Kirk Jones, Rene Sit, Pallav K. Kolli, Eric Seeley, Yaron Gesthalter, Daniel D. Le, Kevin A. Yamauchi, David M. Naeger, Sourav Bandyopadhyay, Khyati Shah, Lauren Cech, Nicholas J. Thomas, Anshal Gupta, Mayra Gonzalez, Hien Do, Lisa Tan, Bianca Bacaltos, Rafael Gomez-Sjoberg, Matthew Gubens, Thierry Jahan, Johannes R. Kratz, David Jablons, Norma Neff, Robert C. Doebele, Jonathan Weissman, Collin M. Blakely, Spyros Darmanis, Trever G. Bivona

Pre-ClinicalKirk SmithAugust 20, 2020single-cell RNA, lung cancer, ALK, EGFR, Targeted therapy

Lung Adenocarcinoma during Pregnancy: 11-Year Follow-Up

The incidence of lung cancer during pregnancy is rising due to the high rate of smokers in young women and the late mean age of pregnancy; in addition, considering that the patients are young women with a higher incidence of molecular alterations, molecular testing in lung adenocarcinoma should always be performed, even in pregnancy. Here, we report the case of a lung adenocarcinoma diagnosed during pregnancy with a long survival who benefitted from brain radiotherapy, conventional chemotherapy, and ALK TKI-targeted treatment. It reveals the safety of whole brain radiotherapy during pregnancy and consideration of other brain radiation techniques even in palliative cases, which should be personalized and managed by a multidisciplinary team. However, upfront management of brain metastasis in ALK-positive patients remains unresolved. READ ARTICLE

Case Reports in Oncology DOI:10.1159/000508360

Authors: Acosta Rojas A., Collazo-Lorduy A., Remon J., Hernando Requejo O., Jiménez-Munarriz B., Rubio Rodríguez M.C., De Castro J.

Intergenic Breakpoints Identified by DNA Sequencing Confound Targetable Kinase Fusion Detection in NSCLC

Introduction: Next-generation sequencing (NGS) based on genomic DNA has been widely applied for gene rearrangement detection in patients with NSCLC. However, intergenic-breakpoint fusions, in which one or both genomic breakpoints localize to intergenic regions, confound kinase fusion detection. We evaluated the function of intergenic-breakpoint fusions with multiplex molecular testing approaches... Conclusions: Intergenic-breakpoint fusions detected by DNA sequencing confound kinase fusion detection in NSCLC, as functional fusion transcripts may be generated or not. Additional validation testing using RNA/protein assay should be performed in intergenic-breakpoint fusion cases to guide optimal treatment. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.02.023

Authors: Weihua Li, Yutao Liu, Wenbin Li, Li Chen, Jianming Ying

HDAC inhibition synergizes with ALK inhibitors to overcome resistance in a novel ALK mutated lung adenocarcinoma model

Objectives: Somatic chromosomal rearrangements resulting in ALK fusion oncogenes are observed in 3–7 % of lung adenocarcinomas. ALK tyrosine kinase inhibitors (ALKi) induce initially response, however, various resistance mechanisms limit their efficacy. Novel therapeutic approaches are of utmost importance to tailor these targeted therapies... Conclusion: Using a patient-derived ALKi resistant lung cancer model we demonstrated the synergism of HDAC and ALK inhibition. Furthermore, our findings provide strong evidence for intratumoral heterogeneity under targeted therapy and highlight the importance of site-specific mutational analysis. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.04.002

Authors: Paul Stockhammer, Cassandra Su Lyn Ho, Luca Hegedus, Gabor Lotz, Eszter Molnár, Agnes Bankfalvi, Thomas Herold, Stavros Kalbourtzis, Till Ploenes, Wilfried E. E. Eberhardt, Martin Schuler, Clemens Aigner, Alexander Schramm, Balazs Hegedus

Advances in Treatment of Locally Advanced or Metastatic Non–Small Cell Lung Cancer: Targeted Therapy

KEY POINTS:
Most epidermal growth factor receptor (EGFR)-mutated NSCLC (exon 19 del and L858R) should be
initially treated with osimertinib.
Anaplastic lymphoma kinase (ALK) fusion-positive NSCLC should be initially treated with alectinib,
brigatinib, or ceritinib; however, tolerability issues limit the use of ceritinib.
ROS1 fusion-positive NSCLC should be initially treated with entrectinib over crizotinib given central
nervous system activity.
BRAF V600E-mutated NSCLC should be initially treated with dabrafenib plus trametinib.
Neurotrophic tropomyosin receptor kinase fusion-positive NSCLC should be initially treated with
entrectinib or larotrectinib.
Patients with HER2 or EGFR exon 20 insertions, RET fusions, NRG1 fusions, MET amplification and
exon 14 skipping mutations, and KRAS G12C mutations should be initially treated with standard-ofcare chemoimmunotherapy; however, there are targeted therapies under investigation showing
promise. READ ARTICLE

Clinics in Chest Medicine DOI:10.1016/j.ccm.2020.02.003

Authors: Nicholas P. Giustini, Ah-Reum Jeong, James Buturla, Lyudmila Bazhenova

Targeted Therapy and Checkpoint Immunotherapy in Lung Cancer

Lung cancer is the leading cause of cancer
mortality. It is classified into different histologic subtypes, including adenocarcinoma, squamous carcinoma, and large cell carcinoma (commonly referred as non–small cell lung cancer) and small cell lung cancer. Comprehensive molecular characterization of lung cancer has expanded our understanding of the cellular origins and molecular pathways affected in each of these subtypes. Many of these genetic alterations represent potential therapeutic targets for which drugs are constantly under development. This article discusses the molecular characteristics of the main lung cancer subtypes and discusses the current guidelines and novel targeted therapies, including checkpoint immunotherapy. READ ARTICLE

Surgical Pathology Clinics DOI:10.1016/j.path.2019.11.002

Authors: Roberto Ruiz-Cordero, Walter Patrick Devine

EP114-07 Efficacy and Safety of ALK Inhibitors in ALK-Rearranged Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

We conducted a systematic review and meta-analysis to assess the efficacy and safety of ALK inhibitors compared to chemotherapy (ALK vs. chemo) and 2nd generation ALK inhibitors compared to 1st generation ALK inhibitors (ALK 2G vs. ALK 1G).The electronic databases PubMed and EMBASE, were searched for relevant randomized trials. Pooled hazard ratios (HR) for overall survival (OS) and progression free survival (PFS), and pooled risk ratios for objective response rates (ORR) and grade 3 or higher toxicity were meta-analyzed using the generic inverse variance and the Mantel-Haenszel methods. To account for between-studies heterogeneity, random-effect models were used. Subgroup analyses compared PFS by gender, smoking status, brain metastases, race and age.This meta-analysis is the first, to our knowledge, to report an OS improvement with the use of ALK vs. chemo. A trend toward a better OS was also seen with ALK 2G vs. ALK 1G and this is likely because of crossover effects and limited OS f..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.2292

Authors: D. Breadner, S. Shanmuganatjan, G. Boldt, P. Blanchette, J. Raphael

Conference PaperKirk SmithOctober 1, 2019ALK, Targeted therapy, advanced NSCLC

EP109-17 Spanish Lung Cancer Biomarker Testing Registry (Lungpath): Descriptive Analysis Focus in ALK Traslocation Results

Biomarker testing on pathology specimens is an essential requirement to properly treat lung cancer (LC) patients. LungPath is an on-line tool developed by the Spanish Society of Pathology (SEAP) with free and voluntary participation of differents Departments of Pathology to registry, monitor and trace biomarker results in clinical practice. After initial data reclutation step, first objective is to realize a descriptive analysis of LungPath focusing on ALK traslocation testing. Descriptive analysis of the LungPath registry. Biomarkers determinations of LC patients were collected from March 2018 to January 2019, from 38 Spanish Departments of Pathology. Development of central biomarker databases, such as Lungpath, provide an opportunity to registry clinical practice data and in the future could be an useful tool to monitor, correlate results between different centers and improve the available knowledge regarding biomarkers in LC. According the international guidelines, EGFR mutation and..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.2213

Authors: J. Martin Lopez, L. Aduz Alexandre, S. Gatius Caldero, A. Navarro Gonzales, P. Saiz Lopez, C. Gomez Bellvert,, C. Camacho García, L. Melgar, E. Costa Navarro, I. Abdulkader Nallib, C.A. Vasquez Dongo, M. Saiz Camin, A. Yagüe Hernando, L. Atienza Cuevas, L. Pijuan, T. Hernández Iglesias, A. Martinez Pozo, C. Salas Anton

Conference PaperKirk SmithOctober 1, 2019ALK, Targeted therapy, Biomarker

$Treatment of Refractory ALK Rearranged Anaplastic Large Cell Lymphoma With Alectinib$

Treatment of Refractory ALK Rearranged Anaplastic Large Cell Lymphoma With Alectinib

Discussion: ALK translocations, most commonly involving chromosome 2 translocations resulting in EML4-ALK fusion, occur in approximately 3% to 5% of lung adenocarcinomas. Therapies targeting the ALK tyrosine kinase have been well studied in patients with ALK-rearranged NSCLC. The first generation ALK-tyrosine kinase inhibitor, crizotinib, was approved for use in ALK-rearranged NSCLC in 2011 based on the PROFILE 1001 study and received full United States Food and Drug Administration approval after... Conclusion: In summary, to the authors' knowledge, this is the first published case of a patient with ALK-rearranged ALCL successfully treated with alectinib. Given the rapid progression and the significant neurologic toxicities related to the primary treatment with CHOEP, our patient had limited second-line treatment options. Within 2 months of therapy with alectinib, he experienced resolution of fever and had an impressive and sustained radiographic response on PET/CT imaging, which allowed him to... READ ARTICLE

Clinical Lymphoma Myeloma and Leukemia DOI:10.1016/j.clml.2019.03.001

Authors: Daniel R. Reed, Richard D. Hall, Ryan D. Gentzler, Leonid Volodin, Michael G. Douvas, Craig A. Portell