Journal ArticleDOI
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
TLDR
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.Abstract:
Summary Background Tumour mutational burden (TMB) has been retrospectively correlated with response to immune checkpoint blockade. We prospectively explored 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. Methods In the multi-cohort, open-label, non-randomised, phase 2 KEYNOTE-158 study, patients were enrolled from 81 academic facilities and community-based institutions across 21 countries in Africa, the Americas, Asia, and Europe. Eligible patients were aged 18 years or older, had a histologically or cytologically confirmed advanced (ie, unresectable or metastatic, or both) incurable solid tumour (eligible tumour types were anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar), progression on or intolerance to one or more lines of standard therapy, had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) assessed by independent central radiological review, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, adequate organ function, and a tumour sample for biomarker analysis. Participants were given pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. Tissue TMB (tTMB) was assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay (Foundation Medicine, Cambridge, MA, USA). The prespecified definition of tTMB-high status was at least 10 mutations per megabase. The primary endpoint was the proportion of patients with an objective response (complete or partial response) as per Response Evaluation Criteria in Solid Tumours (version 1.1) by independent central review. This prespecified analysis assessed the association between antitumour activity and tTMB in treated patients with evaluable tTMB data. Efficacy was assessed in all participants who received at least one dose of pembrolizumab, had evaluable tTMB data, and were enrolled at least 26 weeks before data cutoff (June 27, 2019), and safety was assessed in all participants who received at least one dose of pembrolizumab and had tTMB-high status. KEYNOTE-158 is registered at ClinicalTrials.gov, NCT02628067, and is ongoing. Findings Between Jan 15, 2016, and June 25, 2019, 1073 patients were enrolled. 1066 participants were treated as of data cutoff (June 27, 2019), of whom 805 (76%) were evaluable for TMB, and 105 (13%) of 805 had tTMB-high status and were assessed for safety. 1050 (98%) of 1066 patients enrolled by at least 26 weeks before data cutoff, of whom 790 (75%) were evaluable for TMB and included in efficacy analyses. 102 (13%) of these 790 patients had tTMB-high status (≥10 mutations per megabase), and 688 (87%) patients had non-tTMB-high status ( Interpretation tTMB-high status identifies a subgroup of patients who could have a robust tumour response to pembrolizumab monotherapy. tTMB could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumours. Funding Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.read more
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Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.
Al B. Benson,Alan P. Venook,Mahmoud M. Al-Hawary,Mustafa A. Arain,Yi Jen Chen,Kristen K. Ciombor,Stacey Cohen,Harry S. Cooper,Dustin A. Deming,Linda Farkas,Ignacio Garrido-Laguna,Jean L. Grem,Andrew J. Gunn,J. Randolph Hecht,Sarah E. Hoffe,Joleen M. Hubbard,Steven C. Hunt,Kimberly L. Johung,Natalie Kirilcuk,Smitha S. Krishnamurthi,Wells A. Messersmith,Jeffrey A. Meyerhardt,Eric D. Miller,Mary F. Mulcahy,Steven J. Nurkin,Michael J. Overman,Aparna Raj Parikh,Hitendra Patel,Katrina S. Pedersen,Leonard B. Saltz,Charles Schneider,David Shibata,John M. Skibber,Constantinos T. Sofocleous,Elena M. Stoffel,Eden Stotsky-Himelfarb,Christopher G. Willett,Kristina M. Gregory,Lisa A. Gurski +38 more
TL;DR: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section as discussed by the authors.
Journal ArticleDOI
Current treatment and recent progress in gastric cancer.
TL;DR: Gastric cancer is not a top-10 malignancy in the United States but represents one of the most common causes of cancer death worldwide as mentioned in this paper, therefore, multidisciplinary treatment is paramount to treatment selection.
Journal ArticleDOI
NCCN Guidelines Insights: Non–Small Cell Lung Cancer, Version 2.2021
David S. Ettinger,David S. Ettinger,Douglas E. Wood,Douglas E. Wood,Dara L. Aisner,Wallace Akerley,Wallace Akerley,Jessica Bauman,Jessica Bauman,Ankit Bharat,Ankit Bharat,Debora S. Bruno,Debora S. Bruno,Joe Y. Chang,Joe Y. Chang,Lucian R. Chirieac,Thomas A. D'Amico,Thomas J. Dilling,Thomas J. Dilling,Jonathan E. Dowell,Scott N. Gettinger,Matthew A. Gubens,Aparna Hegde,Mark Hennon,Mark Hennon,Rudy P. Lackner,Michael Lanuti,Michael Lanuti,Ticiana A. Leal,Ticiana A. Leal,Jules Lin,Jules Lin,Billy W. Loo,Christine M. Lovly,Christine M. Lovly,Renato Martins,Renato Martins,Erminia Massarelli,Erminia Massarelli,Daniel Morgensztern,Daniel Morgensztern,Thomas Ng,Thomas Ng,Gregory A. Otterson,Gregory A. Otterson,Sandip P. Patel,Sandip P. Patel,Gregory J. Riely,Gregory J. Riely,Steven E. Schild,Steven E. Schild,Theresa A. Shapiro,Theresa A. Shapiro,Aditi P. Singh,Aditi P. Singh,James P. Stevenson,James P. Stevenson,Alda Tam,Alda Tam,Jane Yanagawa,Jane Yanagawa,Stephen C. Yang,Stephen C. Yang,Kristina M. Gregory,Miranda Hughes +64 more
TL;DR: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC as mentioned in this paper.
Journal ArticleDOI
High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types.
Daniel J. McGrail,Patrick G. Pilie,Naim U. Rashid,Leonie Voorwerk,Maarten Slagter,Marleen Kok,Eric Jonasch,Mustafa Khasraw,Amy B. Heimberger,Bora Lim,NT Ueno,Jennifer K. Litton,Renata Ferrarotto,Jeffrey T. Chang,S. L. Moulder,Sy Lin +15 more
TL;DR: In this article, the authors compared approaches to determine TMB and identify the correlation between predicted neoantigen load and CD8 T cells, and found that TMB-H tumors exhibited a 39.8% ORR to ICB [95% confidence interval (CI) 34.9-44.8], which was significantly higher than that observed in low TMB (TMB-L) tumors.
Journal ArticleDOI
Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.
Jaffer A. Ajani,Thomas A. D'Amico,David J. Bentrem,Joseph Chao,David Cooke,Carlos U. Corvera,Prajnan Das,Peter C. Enzinger,Thomas Enzler,Paul T. Fanta,Farhood Farjah,Hans Gerdes,C. Michael Gibson,Steven N. Hochwald,Wayne L. Hofstetter,David H. Ilson,Rajesh N. Keswani,Sunnie Kim,Lawrence Kleinberg,Samuel J. Klempner,Jill Lacy,Quan P. Ly,Kristina A. Matkowskyj,Michael McNamara,Mary F. Mulcahy,Darryl Alan Outlaw,Haeseong Park,Kyle A. Perry,Jose M. Pimiento,George A. Poultsides,Scott I. Reznik,Robert Ross,Vivian E. Strong,Stacey Su,Hanlin L. Wang,Georgia L. Wiesner,Christopher G. Willett,Danny Yakoub,Harry H. Yoon,Nicole R. McMillian,Lenora A. Pluchino +40 more
TL;DR: Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer.
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New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)
Elizabeth Eisenhauer,P. Therasse,Jan Bogaerts,Lawrence H. Schwartz,Daniel J. Sargent,Robert Ford,Janet Dancey,S. Arbuck,S. Gwyther,Margaret M. Mooney,Larry Rubinstein,Lalitha K. Shankar,Lori E. Dodd,Robert M. Kaplan,Denis Lacombe,Jaap Verweij +15 more
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Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
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Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden
Matthew D. Hellmann,Tudor-Eliade Ciuleanu,Adam Pluzanski,Jong-Seok Lee,Gregory A. Otterson,Clarisse Audigier-Valette,Elisa Minenza,Helena Linardou,Sjaak Burgers,Pamela Salman,Hossein Borghaei,Suresh S. Ramalingam,Julie R. Brahmer,Martin Reck,Kenneth J. O'Byrne,William J. Geese,George Green,Han Chang,Joseph D. Szustakowski,Prabhu Bhagavatheeswaran,Diane Healey,Yali Fu,F. E. Nathan,Luis Paz-Ares +23 more
TL;DR: The benefit of nivolumab plus ipilimumab over chemotherapy was broadly consistent within subgroups, including patients with a PD‐L1 expression level of at least 1% and those with a level of less than 1%.
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Tumor Mutational Burden and Response Rate to PD-1 Inhibition
TL;DR: In a survey of the spectrum of mutational burdens in 27 types of cancers, there was a correlation between an increased mutational burden and the response to checkpoint inhibition of PD-1 and PD-L1.
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Genomic correlates of response to CTLA-4 blockade in metastatic melanoma
Eliezer M. Van Allen,Eliezer M. Van Allen,Diana Miao,Diana Miao,Bastian Schilling,Sachet A. Shukla,Sachet A. Shukla,Christian U. Blank,Lisa Zimmer,Antje Sucker,Uwe Hillen,Marnix H Geukes Foppen,Simone M. Goldinger,Jochen Utikal,Jochen Utikal,Jessica C. Hassel,Benjamin Weide,Katharina C. Kaehler,Carmen Loquai,Peter Mohr,Ralf Gutzmer,Reinhard Dummer,Stacey Gabriel,Catherine J. Wu,Catherine J. Wu,Dirk Schadendorf,Levi A. Garraway,Levi A. Garraway +27 more
TL;DR: Investigating the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab found no recurrent neoantigen peptide sequences predicted responder patient populations, suggesting detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.
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