Journal ArticleDOI
Randomized Phase III Placebo-Controlled Trial of Carboplatin and Paclitaxel With or Without the Vascular Disrupting Agent Vadimezan (ASA404) in Advanced Non–Small-Cell Lung Cancer
Primo N. Lara,Jean-Yves Douillard,Kazuhiko Nakagawa,Joachim von Pawel,Mark J. McKeage,I. Albert,György Losonczy,Martin Reck,Dae Seog Heo,Xiaolin Fan,Abderrahim Fandi,Giorgio V. Scagliotti +11 more
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TLDR
The addition of ASA404 to carboplatin and paclitaxel, although generally well tolerated, failed to improve frontline efficacy in advanced NSCLC.Abstract:
Purpose This phase III trial was conducted to test whether the novel vascular disrupting agent ASA404 (vadimezan), when combined with first-line platinum-based chemotherapy, improves survival in patients with advanced non–small-cell lung cancer (NSCLC) versus chemotherapy alone. Patients and Methods Patients with advanced stage IIIB or IV NSCLC, stratified by sex and tumor histology, were randomly assigned 1:1 to paclitaxel (200 mg/m 2 ) and carboplatin (area under the curve, 6.0) with or without ASA404 (1,800 mg m 2 ), given intravenously once every 3 weeks for six cycles followed by maintenance ASA404 or placebo. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR) and progression-free survival (PFS). Results One thousand two hundred ninety-nine patients were randomly assigned. The trial was stopped for futility at interim analysis. At final analysis, there was no difference in OS seen between ASA404 (n 649) and placebo (n 650) arms: median OS was 13.4 and 12.7 months respectively (hazard ratio [HR], 1.01; 95% CI, 0.85 to 1.19; P .535). Similarly, no OS difference was seen in the histologic (squamous or nonsquamous) and sex (male or female) strata. Median PFS was 5.5 months in both arms (HR, 1.04; P .727), while ORR was 25% in both arms (P 1.0). Overall rate of adverse events (AEs) was comparable between the ASA404 and placebo arms. Grade 4 neutropenia (27% v 19%) and infusion site pain (10% v 0.5%) were reported more frequently in the ASA404 arm.read more
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Journal ArticleDOI
Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity
Leticia Corrales,Laura Hix Glickman,Sarah M. McWhirter,David B. Kanne,Kelsey E. Sivick,George E. Katibah,Seng-Ryong Woo,Edward E. Lemmens,Tamara Banda,Justin Leong,Ken Metchette,Thomas W. Dubensky,Thomas F. Gajewski +12 more
TL;DR: It injection of STING agonists induced profound regression of established tumors in mice and generated substantial systemic immune responses capable of rejecting distant metastases and providing long-lived immunologic memory.
Journal ArticleDOI
Targeted therapy for non-small cell lung cancer: current standards and the promise of the future
Bryan A. Chan,Brett G.M. Hughes +1 more
TL;DR: The major subtypes of oncogenic drivers behind NSCLC are examined as well as the development of targeted agents available to treat them both now and in the foreseeable future.
Journal ArticleDOI
Cyclic GMP-AMP as an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA.
TL;DR: Recent progress made in the structural dissection of this cGAS/STING signaling pathway is summarized and possible directions of forthcoming research are indicated.
Journal ArticleDOI
Structure-function analysis of STING activation by c[G(2',5')pA(3',5')p] and targeting by antiviral DMXAA.
Pu Gao,Manuel Ascano,Thomas Zillinger,Weiyi Wang,Peihong Dai,Artem A. Serganov,Barbara L. Gaffney,Stewart Shuman,Roger A. Jones,Liang Deng,Gunther Hartmann,Winfried Barchet,Thomas Tuschl,Dinshaw J. Patel +13 more
TL;DR: A unique point mutation (S162A) was identified within the cyclic-dinucleotide-binding site of hSTING that rendered it sensitive to the otherwise mouse-specific drug DMXAA, a conclusion validated by binding studies.
Journal ArticleDOI
The Next Hurdle in Cancer Immunotherapy: Overcoming the Non-T-Cell-Inflamed Tumor Microenvironment.
TL;DR: A growing body of evidence suggests that a major subset of patients with advanced solid tumors shows evidence for a T-cell-inflamed tumor microenvironment, suggesting that the attempt by the host to generate an anti-tumor immune response reflects a biologic process associated with improved patient outcomes.
References
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Journal ArticleDOI
Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer
Alan B. Sandler,Robert Gray,Michael C. Perry,Julie R. Brahmer,Joan H. Schiller,Afshin Dowlati,Rogerio Lilenbaum,David H. Johnson +7 more
TL;DR: The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non-small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths.
Journal ArticleDOI
Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.
Joan H. Schiller,David P. Harrington,Chandra P. Belani,Corey J. Langer,Alan B. Sandler,James E. Krook,Junming Zhu,David H. Johnson +7 more
TL;DR: None of four chemotherapy regimens offered a significant advantage over the others in the treatment of advanced non-small-cell lung cancer.
Journal ArticleDOI
Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial.
Robert Pirker,José Rodrigues Pereira,Aleksandra Szczesna,Joachim von Pawel,Maciej Krzakowski,Rodryg Ramlau,Ihor Vynnychenko,Keunchil Park,Chih Teng Yu,Valentyn Ganul,Jae Kyung Roh,Emilio Bajetta,Kenneth J. O'Byrne,Filippo de Marinis,Wilfried Eberhardt,Thomas Goddemeier,M. Emig,Ulrich Gatzemeier +17 more
TL;DR: Addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced non-small-cell lung cancer.
Journal ArticleDOI
Randomized Phase III Trial of Paclitaxel Plus Carboplatin Versus Vinorelbine Plus Cisplatin in the Treatment of Patients With Advanced Non–Small-Cell Lung Cancer: A Southwest Oncology Group Trial
Karen Kelly,John Crowley,Paul A. Bunn,Cary A. Presant,Patra K. Grevstad,Carol M. Moinpour,Scott D. Ramsey,Antoinette J. Wozniak,Geoffrey R. Weiss,Dennis F. Moore,Valerie Israel,Robert B. Livingston,David R. Gandara +12 more
TL;DR: PC is equally efficacious as VC for the treatment of advanced non--small-cell lung cancer, and overall costs on the PC arm were higher than on the VC arm because of drug costs.
Journal ArticleDOI
Vascular Targeting Agents as Cancer Therapeutics
TL;DR: VTAs can kill indirectly the tumor cells that are resistant to conventional antiproliferative cancer therapies, i.e., cells in areas distant from blood vessels where drug penetration is poor, and hypoxia can lead to radiation and drug resistance.
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