Association of anticoagulant use with clinical outcomes from crizotinib in ALK- and ROS1-rearranged advanced non-small cell lung cancers: A retrospective analysis of PROFILE 1001

Background: ROS1- and ALK-rearranged advanced NSCLCs are associated with increased thromboembolic risk. We hypothesized that a prothrombotic phenotype offers an evolutionary advantage to subsets of these cancers. The impact of this phenotype could alter outcomes from targeted therapy.

Methods: In a retrospective analysis of ROS1- and ALK-rearranged NSCLCs treated with crizotinib in a phase 1 trial, we compared progression-free survival (PFS) and objective response rate (ORR) based on the history of anticoagulation use (a possible surrogate of thromboembolism) at baseline (within 90 days before study enrollment) or within 90 days of study treatment.

Results: Twelve out of 53 (22.6%) ROS1- and 39 out of 153 (25.5%) ALK-rearranged NSCLCs received anticoagulation before or during the trial. Most ROS1 and ALK patients on anticoagulation received low-molecular-weight heparin (75% and 64.1%, respectively). In the ROS1-rearranged group, the median PFS (95% CI) values were 5.1 (4.4-14.4) and 29.0 (16.5-48.8) months, and the ORR values were 41.7% (95% CI: 15.2 to 72.3) and 80.5% (95% CI: 65.1 to 91.2) among those with and without anticoagulation treatment, respectively. In the ALK-rearranged group, the median PFS (95% CI) was 7.1 (5.4-7.7) and 12.0 (9.4-18.3) months, and the ORR was 41% (95% CI: 25.6 to 57.9) and 74.3% (95% CI: 65.3 to 82.1) among those with and without anticoagulation, respectively.

Conclusions: Anticoagulation (as a potential surrogate of a prothrombotic subset) in ROS1- and ALK-rearranged NSCLCs may be associated with a lower PFS and ORR to crizotinib. READ ARTICLE

Cancer Medicine DOI:10.1002/cam4.4789.

Authors: Ng TL, Tsui DCC, Wang S, Usari T, Patil T, Wilner K, Camidge DR.

Clinical TrialsKirk SmithMay 5, 2022ALK, ROS1, crizotinib, lung cancer, thromboembolism

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

Targeted Therapy for Older Patients with Non-Small Cell Lung Cancer: Systematic Review and Guidelines from the French Society of Geriatric Oncology...

Targeted therapy has become essential in the treatment of non-small cell lung cancer (NSCLC). There are currently no guidelines for older patients who are frailer with regard to this type of treatment. Two learned societies, the French Society of Geriatric Oncology (SoFOG) and the French-language Society of Pulmonology (SPLF)/French-language Oncology Group (GOLF), joined forces to conduct a systematic review of the literature from May 2010 to May 2021 regarding the efficacy, toxicity, and feasibility of targeted therapy in older patients with NSCLC. Guidelines were then drawn up to enable clinicians to adapt the type of targeted therapy proposed according to the oncological and geriatric profile of the older patient with NSCLC. READ ARTICLE

Cancers DOI:10.3390/cancers14030769

Authors: Greillier, L.; Gauvrit, M.; Paillaud, E.; Girard, N.; Montégut, C.;
Boulahssass, R.; Wislez, M.; Pamoukdjian, F.; Corre, R.;
Cabart, M.; et al.

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

A focal adhesion kinase-YAP signaling axis drives drug tolerant persister cells and residual disease in lung cancer

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant tumor cells which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residu..... READ ARTICLE

BioRxiv DOI:10.1101/2021.10.23.465573

Authors: Franziska Haderk, Celia Fernández-Méndez, Lauren Čech, Johnny Yu, Ismail M. Meraz, Victor Olivas, Dora Barbosa Rabago, D. Lucas Kerr, Carlos Gomez, David V. Allegakoen, Juan Guan, Khyati N. Shah, Kari A. Herrington, Oghenekevwe M. Gbenedio, Shigeki Nanjo, Mourad Majidi, Whitney Tamaki, Julia K. Rotow, Caroline E. McCoach, Jonathan W. Riess, J. Silvio Gutkind, Tracy T. Tang, Leonard Post, Bo Huang, Pilar Santisteban, Hani Goodarzi, Sourav Bandyopadhyay, Calvin J. Kuo, Jeroen P. Roose, Wei Wu, Collin M. Blakely, Jack A. Roth, Trever G. Bivona

New Advances in Liquid Biopsy Technologies for Anaplastic Lymphoma Kinase (ALK)—Positive Cancer

A new methodology of cancer testing, called “liquid biopsy”, has been under investigation in the past few years. It is based on blood tests that can be analyzed by novel genetics and bioinformatics tools, in order to detect cancer, predict or follow the response to therapies and understand the mechanisms of relapse. This technology is still experimental, yet it has sparked much interest within the scientific community because it promises a new era of cancer management. We here review its application in a subset of tumors characterized by the presence of the ALK oncogene: patients affected by these tumors can benefit from targeted therapy, but show frequent relapses, which call for improved methods of disease detection.
READ ARTICLE

Cancers DOI:10.3390/cancers13205149

Authors: Villa, Matteo, Geeta G. Sharma, Chiara Manfroni, Diego Cortinovis, and Luca Mologni

Review Paper, group2Kirk SmithOctober 14, 2021ALK, lung cancer, liquid biopsy

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.

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

SPP1 overexpression is associated with poor outcomes in ALK fusion lung cancer patients without receiving targeted therapy

The screening of non-small cell lung cancer (NSCLC) tumors for anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements is important because of the dramatically favorable therapy response to ALK inhibitor. However, the exact mechanism of poor survival in ALK fusion lung cancer patients without receiving targeted therapy is unclear. In this study, total of 521 tumor specimens from Chinese patients with lung cancer were screened for ALK fusion by immunohistochemistry (IHC) and confirmed by fluorescence in situ hybridization (FISH). As results, there were no cases of coexisting EGFR and ALK mutations identified. Fourteen cases (2.7%) harbored ALK fusion, including eight solid adenocarcinomas with signet ring cell features, four acinar adenocarcinomas with cribriform pattern containing mucin, one adenosquamous carcinoma and one micropapillary adenocarcinoma with mucin. Six (42.9%) of fourteen patients with ALK-positive lung cancer had stage IV disease, and five ALK-positive p..... READ ARTICLE

Scientific Reports DOI:10.1038/s41598-021-93484-2

Authors: Xiaolin Ji, Yan Liu, Fang Mei, Xinyang Li, Mengxue Zhang, Buwen Yao, Rui Wu, Jiangfeng You & Fei Pei

Pre-Clinical, group4Kirk SmithJuly 7, 2021SPP1, ALK, lung cancer, TKI, chemotherapy

Tumor shrinkage with Combination of Alectinib and Trastuzumab in a Patient with ALK-Rearranged NSCLC Harboring HER2-amplification as an Acquired Resistance Mechanism to ALK Inhibitor Therapy

HER2 amplification is an acquired resistance mechanism in ALK-rearranged non-small cell lung cancer. 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 and Ross Camidge

Case Study, group4Kirk SmithJuly 3, 2021ALK, HER2, lung cancer, acquired resistance, trastuzumab

New Insights into the Clinical Implications of Yes-Associated Protein in Lung Cancer: Roles in Drug Resistance, Tumor Immunity, Autophagy, and Organoid Development

Innovative advancements in lung cancer treatment have developed over the past decade with the advent of targeted and immune therapies. Yes-associated protein (YAP), an effector of the Hippo pathway, promotes the resistance of these targeted drugs and modulates tumor immunity in lung cancer. YAP is involved in autophagy in lung cancer and plays a prominent role in forming the tubular structure in lung organoids and alveolar differentiation. In this review, we discuss the central roles of YAP in lung cancer and present YAP as a novel target for treating resistance to targeted therapies and immunotherapies in lung cancer. READ ARTICLE

Cancers DOI: 10.3390/cancers13123069

Authors: Yoo G, Park D, Kim Y and Chung C.

Review Paper, group5Kirk SmithJune 17, 2021YAP, TAZ, Hippo pathway, lung cancer, drug resistance, EGFR-TKI, PD-L1, autophagy, organoid

Proximity Proteomics Has Potential for Extracellular Vesicle Identification

Extracellular vesicles (EVs) are biomarkers and mediators of intercellular communication. In biological samples, EVs are secreted by various types of cells. The proteomic identification of proteins expressed in EVs has potential to contribute to research and clinical applications, particularly for cancer. In this study, the proximity-labeling method-based proteomic approach was used for EV identification, labeling membrane components proximal to a given molecule on the EV membrane surface. Due to the small labeling range, proteins on the surface of the same EVs are likely to be labeled by selecting a given EV surface antigen. The protein group of cancer cell-secreted EV (cEV), which abundantly expresses a close homologue of L1 (CHL1), was examined using a model mouse for lung cancer (LC). cEV-expressed proteins were identified by proteomic analysis of enzyme-mediated activation of radical sources by comparing serum EVs from wild-type and LC mice. SLC4A1 was found to be co-expressed in CHL1-expressing EVs, highlighting EVs expressing both CHL1 and SLC4A1 as candidates for cEVs. Serum EVs expressing both CHL1 and caspase 14 were significantly elevated in LC patients compared with healthy individuals. Thus, the combination of proximity labeling and proteomic analysis allows for effective EV identification. READ ARTICLE

Journal of Proteome Research DOI: 10.1021/acs.jproteome.1c00149

Authors: Hisako Kaneda, Yui Ida, Ryusuke Kuwahara, Izumi Sato, Takanari Nakano, Haruhiko Tokuda, Tsuyoshi Sato, Takayuki Murakoshi, Koichi Honke and Norihiro Kotani

TPX-0131, a Potent CNS-Penetrant, Next-Generation Inhibitor of Wild-Type ALK and ALK-Resistant Mutations

Since 2011, with the approval of crizotinib and subsequent approval of four additional targeted therapies, ALK inhibitors have become important treatments for a subset of patients with lung cancer. Each generation of ALK inhibitor showed improvements in terms of CNS penetration and potency against wild-type 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 approved ALK inhibitors against wild-type ALK and many types of ALK resistance mutations, e.g. G1202R, L1196M, and compound mutations. In biochemical assays, TPX-0131 potently inhibited (IC50 <10 nmol/L) wild-type ALK and 26 ALK mutants (single and compound mutations). TPX-0131, but not lorlatinib, caused complete tumor regression in ALK (G1202R) and ALK compound mutation-dependent xenograft models. Following repeat oral administration of TPX-0131 to rats, brain levels of TPX-0131 were ~66% of those observed in plasma. Taken together, preclinical studies show that TPX-0131 is a CNS-penetrant, next-generation ALK inhibitor that has potency against wild-type ALK and a spectrum of acquired resistance mutations, especially the G1202R solvent front mutation and compound mutations, for which there are currently no effective therapies. READ ARTICLE

Molecular Caner Therapeutics DOI: 10.1158/1535-7163.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

EML4-ALK induces cellular senescence in mortal normal human cells and promotes anchorage-independent growth in hTERT-transduced normal human cells.

Background: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes.EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells. Methods:Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes. Results: The lentiviral expression of EML4-ALK in mortal, normal human fibroblasts caused, through its constitutive ALK kinase activity, an early induction of cellular senescence with accumulated DNA damage, upregulation of p16INK4A and p21WAF1, and senescence-associated β-galactosidase (SA-β-gal)..... READ ARTICLE

BMC Cancer DOI:10.1186/s12885-021-07905-6

Authors: Miyanaga A, Matsumoto M, Beck JA, Horikawa I, Oike T, Okayama H, Tanaka H, Burkett SS, Robles AI, Khan M, Lissa D, Seike M, Gemma A, Mano H, Harris CC

Detecting Resistance to Therapeutic ALK Inhibitors in Tumor Tissue and Liquid Biopsy Markers: An Update to a Clinical Routine Practice

The survival of most patients with advanced stage non-small cell lung cancer is prolonged by several months when they are treated with first- and next-generation inhibitors targeting ALK rearrangements, but resistance inevitably emerges. Some of the mechanisms of resistance are sensitive to novel ALK inhibitors but after an initial tumor response, more or less long-term resistance sets in. Therefore, to adapt treatment it is necessary to repeat biological sampling over time to look for different mechanisms of resistance. To this aim it is essential to obtain liquid and/or tissue biopsies to detect therapeutic targets, in particular for the analysis of different genomic alterations. This review discusses the mechanisms of resistance to therapeutics targeting genomic alterations in ALK as well as the advantages and the limitations of liquid biopsies for their identification. READ ARTICLE

Cells DOI:10.3390/cells10010168

Authors: Paul Hofman

Review PaperKirk SmithJanuary 15, 2021liquid biopsy, lung cancer, ALK, resistance, targeted therapy

The Clinical Characteristics and Prognosis of Different Age Patients with Lung Cancer

Cancer is closely related to age, and the incidence of cancer increases with age. However, there are few studies on the relationship between age and clinical characteristics of lung cancer. We collected all the consecutive lung cancer cases from 2012 to 2017 in our hospital and divided them into 6 groups according to their ages: ≤ 40 y/o, 41∼ 50 y/o, 51∼ 60 y/o, 61∼ 70 y/o, 71∼ 80 y/o and > 80 y/o. There were more non-smokers (p< 0.01), stage IV (p< 0.01) and anaplastic lymphoma kinase (ALK) fusion (p< 0.01) patients but less stage I patients in ≤ 40 y/o group compared with other age groups. It seemed that older patients were more likely had co-exist driver gene mutations (p=0.04). There are some differences in clinical characteristics and prognosis among different age groups. The reasons behind the phenomenon are largely unclear. The age should be taken into account when we develop clinical trials...... READ ARTICLE

Cancer Management and Research DOI:10.2147/CMAR.S240318

Authors: Chen X, Han X, Zhou H, Liang Y, Huang Z, Li S, Lin Y, Huang X, Wu J, Su W, Lai Z and Yang Z

Real-World OutcomesKirk SmithSeptember 14, 2020age, lung cancer, clinical characteristics, clinical trials

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

A multicenter real-world study of tumor-derived DNA from pleural effusion supernatant in genomic profiling of advanced lung cancer

Background: Pleural effusion (PE) is commonly observed in advanced lung cancer. Researches have suggested molecular profiling of PE represents a minimally invasive approach of detecting tumor driver mutations for clinical decision making. The objective of this study is to investigate the efficacy and precision of detecting gene alterations in PE samples in the real world setting... Conclusions: This real world large cohort study verified that genomic profiling of PE-supernatant has higher actionable mutation detection sensitivity than plasma. It offers an alternative approach in assessing tumor genomics in advanced lung cancer when tumor tissue is not available. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.e21584

Authors: Renhua Guo, Likun Chen, Chengzhi Zhou, Xinghao Ai, Jun Zhao, Rongrong Chen, Xuefeng Xia

A phase II study of lorlatinib in patients (pts) with ALK-positive (ALK+) lung cancer with brain-only progression

Background: Lorlatinib is a 3rd-generation ALK tyrosine kinase inhibitor (TKI) developed to penetrate the central nervous system (CNS) and overcome resistance to 2nd-generation (2nd-gen) ALK TKIs. In a phase II study, lorlatinib demonstrated significant intracranial (IC) activity after failure of 2nd-gen TKIs. As treatment discontinuation for extracranial (EC) progression can confound assessment of durability of IC response, we performed a phase II study (NCT02927340) to selectively evaluate lorlatinib activity in ALK+ pts with CNS-only disease... Conclusions: Lorlatinib induces durable intracranial responses in pts with CNS-only progression on 2nd-gen ALK TKIs, suggesting that CNS-specific relapses are primarily driven by ALK-dependent mechanisms. Further studies are needed to characterize the molecular basis of sensitivity to lorlatinib in this unique subgroup of pts with ALK+ lung cancer. Clinical trial information: NCT02927340 READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.9595

Authors: Ibiayi Dagogo-Jack, Geoffrey R. Oxnard, Jessica Fink, Gianluca Diubaldi, Caitlyn Helms, Justin F. Gainor, Michael S. Rabin, Rebecca Suk Heist, Jessica Jiyeong Lin, Jennifer Ackil, Alona Muzikansky, Alice Tsang Shaw

Clinical TrialsKirk SmithMay 25, 2020Lorlatinib, ALK-positive (ALK+), lung cancer, brain, progression

Impact of ALK Rearrangement on Venous and Arterial Thrombotic Risk in NSCLC

In time-to-event analyses controlling for thrombosis risk factors, the ALK rearrangement conferred a fourfold increase in VTE risk and a threefold increase in arterial thrombosis risk in NSCLC. These patients may benefit from pharmacologic thromboprophylaxis. READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1016/j.jtho.2020.04.033

Authors: Hanny Al-Samkari, Orly Leiva, Ibiayi Dagogo-Jack, Alice Shaw, Jochen Lennerz, Anthony J Iafrate, Pavan K Bendapudi, Jean M Connors