PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Dung T. Le,Jennifer N. Uram,Hao Wang,Bjarne Bartlett,Holly Kemberling,Aleksandra Eyring,Andrew D. Skora,Brandon Luber,Nilofer S. Azad,Daniel A. Laheru,Barbara A. Biedrzycki,Ross C. Donehower,Atif Zaheer,George A. Fisher,Todd S. Crocenzi,James J. Lee,Steven M. Duffy,Richard M. Goldberg,Richard M. Goldberg,Albert de la Chapelle,Albert de la Chapelle,Minori Koshiji,Feriyl Bhaijee,Thomas Huebner,Ralph H. Hruban,Laura D. Wood,Nathan Cuka,Drew M. Pardoll,Nickolas Papadopoulos,Kenneth W. Kinzler,Shibin Zhou,Toby C. Cornish,Janis M. Taube,Robert A. Anders,James R. Eshleman,Bert Vogelstein,Luis A. Diaz +36 more
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TLDR
This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab, and high somatic mutation loads were associated with prolonged progression-free survival.Abstract:
BackgroundSomatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. MethodsWe conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. ResultsThe immune-related objective response rate and immune-related progression-free survival ...read more
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Pembrolizumab for the treatment of non-small cell lung cancer
Edward B. Garon,Naiyer A. Rizvi,Rina Hui,Natasha B. Leighl,Ani Sarkis Balmanoukian,Joseph Paul Eder,Amita Patnaik,Charu Aggarwal,Matthew A. Gubens,Leora Horn,Enric Carcereny,Myung-Ju Ahn,Enriqueta Felip,Jong-Seok Lee,Matthew D. Hellmann,Omid Hamid,Jonathan W. Goldman,Jean-Charles Soria,Marisa Dolled-Filhart,Ruth Z. Rutledge,Jin Zhang,Jared Lunceford,Reshma A. Rangwala,Gregory M. Lubiniecki,Charlotte Roach,Kenneth Emancipator,Leena Gandhi +26 more
TL;DR: Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer and PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolIZumab.
Journal ArticleDOI
Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade
Dung T. Le,Dung T. Le,Jennifer N. Durham,Jennifer N. Durham,Kellie N. Smith,Hao Wang,Bjarne Bartlett,Bjarne Bartlett,Laveet K. Aulakh,Laveet K. Aulakh,Steve Lu,Steve Lu,Holly Kemberling,Cara Wilt,Brandon Luber,Fay Wong,Fay Wong,Nilofer S. Azad,Agnieszka A. Rucki,Daniel A. Laheru,Ross C. Donehower,Atif Zaheer,George A. Fisher,Todd S. Crocenzi,James J. Lee,Tim F. Greten,Austin G. Duffy,Kristen K. Ciombor,Aleksandra Eyring,Bao H. Lam,Andrew K. Joe,S. Peter Kang,Matthias Holdhoff,Ludmila Danilova,Leslie Cope,Christian F. Meyer,Shibin Zhou,Shibin Zhou,Richard M. Goldberg,Deborah K. Armstrong,Katherine M. Bever,Amanda N. Fader,Janis M. Taube,Franck Housseau,David Spetzler,Nianqing Xiao,Drew M. Pardoll,Nickolas Papadopoulos,Nickolas Papadopoulos,Kenneth W. Kinzler,Kenneth W. Kinzler,James R. Eshleman,Bert Vogelstein,Bert Vogelstein,Robert A. Anders,Robert A. Anders,Luis A. Diaz,Luis A. Diaz +57 more
TL;DR: Evaluating the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1).
Journal ArticleDOI
The consensus molecular subtypes of colorectal cancer
Justin Guinney,Rodrigo Dienstmann,Rodrigo Dienstmann,Xingwu Wang,Xingwu Wang,Aurélien de Reyniès,Andreas Schlicker,Charlotte Soneson,Laetitia Marisa,Paul Roepman,Gift Nyamundanda,Paolo Angelino,Brian M. Bot,Jeffrey S. Morris,Iris Simon,Sarah Gerster,Evelyn Fessler,Felipe De Sousa E Melo,Edoardo Missiaglia,Hena R. Ramay,David Barras,Krisztian Homicsko,Dipen M. Maru,Ganiraju C. Manyam,Bradley M. Broom,Valérie Boige,Beatriz Perez-Villamil,Ted Laderas,Ramon Salazar,Joe W. Gray,Douglas Hanahan,Josep Tabernero,René Bernards,Stephen H. Friend,Pierre Laurent-Puig,Jan Paul Medema,Anguraj Sadanandam,Lodewyk F. A. Wessels,Mauro Delorenzi,Mauro Delorenzi,Scott Kopetz,Louis Vermeulen,Sabine Tejpar +42 more
TL;DR: An international consortium dedicated to large-scale data sharing and analytics across expert groups is formed, showing marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMSs) with distinguishing features.
Journal ArticleDOI
Elements of cancer immunity and the cancer–immune set point
Daniel S. Chen,Ira Mellman +1 more
TL;DR: Clinical studies are beginning to define these factors as immune profiles that can predict responses to immunotherapy, suggesting that a broader view of cancer immunity is required.
Journal ArticleDOI
Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial
Jonathan E. Rosenberg,Jean H. Hoffman-Censits,Thomas Powles,Michiel S. van der Heijden,Arjun Vasant Balar,Andrea Necchi,Nancy A. Dawson,Peter H. O'Donnell,Ani Balmanoukian,Yohann Loriot,Sandy Srinivas,Margitta Retz,Petros Grivas,Richard W. Joseph,Matthew D. Galsky,Mark D. Fleming,Daniel P. Petrylak,Jose Luis Perez-Gracia,Howard A. Burris,Daniel Castellano,Christina Canil,Joaquim Bellmunt,Dean F. Bajorin,Dorothee Nickles,Richard Bourgon,Garrett M. Frampton,Na Cui,Sanjeev Mariathasan,Oyewale O. Abidoye,Gregg Fine,Robert Dreicer +30 more
TL;DR: Treatment with atezolizumab resulted in a significantly improved RECIST v1.1 response rate, compared with a historical control overall response rate of 10%, and Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolediazepine.
References
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The analysis of microsatellite instability in extracolonic gastrointestinal malignancy
TL;DR: This review aims to summarise the recent literature on MSI in extracolonic LS-related GI tract malignancies with special attention to the assessment of the MMR system by evaluation of specific microsatellite markers and/or immunohistochemical evaluation of MMR protein expression.
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