Journal ArticleDOI
T-Cell–Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028
Patrick A. Ott,Yung-Jue Bang,Sarina Anne Piha-Paul,Albiruni Ryan Abdul Razak,Jaafar Bennouna,Jean-Charles Soria,Hope S. Rugo,Roger B. Cohen,Bert H. O'Neil,Janice M. Mehnert,Juanita Lopez,Toshihiko Doi,Emilie M.J. van Brummelen,Razvan Cristescu,Ping Yang,Kenneth Emancipator,Karen Stein,Mark Ayers,Andrew K. Joe,Jared Lunceford +19 more
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TLDR
Response patterns indicate that patients with tumors that had high levels of both TMB and inflammatory markers (GEP or PD-L1) represent a population with the highest likelihood of response to pembrolizumab in multiple tumor types.Abstract:
PURPOSEBiomarkers that can predict response to anti–programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell–inflamed gene-expression profile (GEP), programmed death liga...read more
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Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.
Aurélien Marabelle,Marwan Fakih,Juanita Lopez,Manisha H. Shah,Ronnie Shapira-Frommer,Kazuhiko Nakagawa,Hyun Cheol Chung,Hedy L. Kindler,Jose A. Lopez-Martin,Wilson H. Miller,Antoine Italiano,Steven Kao,Sarina Anne Piha-Paul,Jean Pierre Delord,Robert R. McWilliams,David Fabrizio,Deepti Aurora-Garg,Lei Xu,F. Jin,Kevin Norwood,Yung-Jue Bang +20 more
TL;DR: The association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1 monoclonal antibody pembrolizumab in patients with selected, previously treated, advanced solid tumours, was prospectively explored.
Journal ArticleDOI
Cholangiocarcinoma 2020: the next horizon in mechanisms and management
Jesus M. Banales,Jesus M. Banales,Jesus M. Banales,Jose J.G. Marin,Jose J.G. Marin,Angela Lamarca,Angela Lamarca,Pedro M. Rodrigues,Shahid A. Khan,Lewis R. Roberts,Vincenzo Cardinale,Guido Carpino,Jesper B. Andersen,Chiara Braconi,Diego F. Calvisi,Maria J. Perugorria,Maria J. Perugorria,Luca Fabris,Luca Fabris,Luke Boulter,Rocio I.R. Macias,Rocio I.R. Macias,Eugenio Gaudio,Domenico Alvaro,Sergio A. Gradilone,Mario Strazzabosco,Mario Strazzabosco,Marco Marzioni,Cédric Coulouarn,Laura Fouassier,Chiara Raggi,Pietro Invernizzi,Joachim C. Mertens,Anja Moncsek,Sumera Rizvi,Julie K. Heimbach,Bas Groot Koerkamp,Jordi Bruix,Jordi Bruix,Alejandro Forner,Alejandro Forner,John Bridgewater,Juan W. Valle,Juan W. Valle,Gregory J. Gores +44 more
TL;DR: This expert Consensus Statement, endorsed by the ENS-CCA, summarizes the latest advances in CCA, including classification, genetics and treatment, and provides recommendations for CCA management and priorities across basic, translational and clinical research.
Journal ArticleDOI
Pancreatic Cancer: A Review
TL;DR: In this article, a multidisciplinary management approach is recommended for PDAC patients, which includes a multi-agent chemotherapy regimens, including FOLFIRINOX, gemcitabine/nab-paclitaxel, and nanoliposomal irinotecan/fluorouracil.
Journal ArticleDOI
The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker.
TL;DR: Tumor mutational burden reflects cancer mutation quantity, and higher TMB results in more neo-antigens, increasing chances for T cell recognition, and clinically correlates with better ICI outcomes, Nevertheless, TMB is an imperfect response biomarker.
Journal ArticleDOI
Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study.
Charles M. Rudin,Mark M. Awad,Alejandro Navarro,Maya Gottfried,Solange Peters,Tibor Csőszi,Parneet Cheema,Delvys Rodriguez-Abreu,Mirjana Wollner,James Chih-Hsin Yang,Julien Mazieres,Francisco Orlandi,Alexander Luft,Mahmut Gumus,Terufumi Kato,Gregory P. Kalemkerian,Yiwen Luo,Victoria Ebiana,M. Catherine Pietanza,Hye Ryun Kim,Keynote Investigators +20 more
TL;DR: Pembrolizumab plus EP significantly improved progression-free survival (PFS) and overall survival (OS) compared with placebo plus EP as first-line therapy for patients with ES-SCLC, and these data support the benefit of pembrolIZumab in ES-sCLC.
References
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Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
Naiyer A. Rizvi,Naiyer A. Rizvi,Matthew D. Hellmann,Matthew D. Hellmann,Alexandra Snyder,Alexandra Snyder,Pia Kvistborg,Vladimir Makarov,Jonathan J. Havel,William Lee,Jianda Yuan,Phillip Wong,Teresa S. Ho,Martin L. Miller,Natasha Rekhtman,Andre L. Moreira,Fawzia Ibrahim,Cameron Bruggeman,Billel Gasmi,Roberta Zappasodi,Yuka Maeda,Chris Sander,Edward B. Garon,Taha Merghoub,Jedd D. Wolchok,Jedd D. Wolchok,Ton N. Schumacher,Timothy A. Chan,Timothy A. Chan +28 more
TL;DR: Treatment efficacy was associated with a higher number of mutations in the tumors, and a tumor-specific T cell response paralleled tumor regression in one patient, suggesting that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.
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The future of immune checkpoint therapy
Padmanee Sharma,James P. Allison +1 more
TL;DR: The way forward for this class of novel agents lies in the ability to understand human immune responses in the tumor microenvironment, which will provide valuable information regarding the dynamic nature of the immune response and regulation of additional pathways that will need to be targeted through combination therapies to provide survival benefit for greater numbers of patients.
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Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy
TL;DR: This work discusses biomarkers for anti-PD1 therapy based on immunological, genetic and virological criteria and suggests mechanism-based insights from such studies may guide the design of synergistic treatment combinations based on immune checkpoint blockade.
Journal ArticleDOI
Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy
Razvan Cristescu,Robin Mogg,Mark Ayers,Andrew Albright,Erin Murphy,Jennifer H. Yearley,Xinwei Sher,Xiaoqiao Liu,Hongchao Lu,Michael Nebozhyn,Chunsheng Zhang,Jared Lunceford,Andrew K. Joe,Jonathan D. Cheng,Andrea L. Webber,Nageatte Ibrahim,Elizabeth R. Plimack,Patrick A. Ott,Tanguy Y. Seiwert,Antoni Ribas,Terrill K. McClanahan,Joanne E. Tomassini,Andrey Loboda,David Ross Kaufman +23 more
TL;DR: The potential for TMB and a T cell–inflamed GEP to jointly predict clinical response to pembrolizumab was assessed in >300 patient samples with advanced solid tumors and melanoma across 22 tumor types from four KEYNOTE clinical trials.
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Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-γ-induced upregulation of B7-H1 (CD274)
Seung Jin Lee,Byeong Churl Jang,Soo Woong Lee,Young Il Yang,Seong Il Suh,Yeong Min Park,Sangtaek Oh,Jae-Gook Shin,Sheng Yao,Lieping Chen,In Hak Choi +10 more
TL;DR: A critical role of IRF‐1 is found in the regulation of constitutive and IFN‐γ‐induced expression of B7‐H1 in cancer cells, and AG490, a Janus activated kinase/signal transducer and activator of transcription inhibitor, greatly abolished the responsiveness of A549 cells to IFN-γ by reducing the IRF•1 transcription.
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