Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials.
Sandra P. D'Angelo,Sandra P. D'Angelo,Michelle R. Mahoney,Brian A. Van Tine,James N. Atkins,Mohammed M. Milhem,Balkrishna N. Jahagirdar,Balkrishna N. Jahagirdar,Cristina R. Antonescu,Elise Horvath,Elise Horvath,William D. Tap,William D. Tap,Gary K. Schwartz,Howard Streicher +14 more
TLDR
Nivolumab alone does not warrant further study in an unselected sarcoma population given the limited efficacy, and combined with ipilimumab demonstrated promising efficacy in certain Sarcoma subtypes with a manageable safety profile comparable to current available treatment options.Abstract:
Summary Background Patients with metastatic sarcoma have limited treatment options. Nivolumab and ipilimumab are monoclonal antibodies targeting PD-1 and CTLA-4, respectively. We investigated the activity and safety of nivolumab alone or in combination with ipilimumab in patients with locally advanced, unresectable, or metastatic sarcoma. Methods We did a multicentre, open-label, non-comparative, randomised, phase 2 study that enrolled patients aged 18 years or older and had central pathology confirmation of sarcoma with at least one measurable lesion by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, evidence of metastatic, locally advanced or unresectable disease, an ECOG performance status of 0–1, and received at least one previous line of systemic therapy. Patients were assigned to treatment in an unblinded manner, as this trial was conducted as two independent, non-comparative phase 2 trials. Enrolled patients were assigned (1:1) via a dynamic allocation algorithm to intravenous nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses. Thereafter, all patients received nivolumab monotherapy (3 mg/kg) every 2 weeks for up to 2 years. The primary endpoint was the proportion of patients with locally advanced, unresectable or metastatic soft tissue sarcoma achieving a confirmed objective response. Analysis was per protocol. This study is ongoing although enrolment is closed. It is registered with ClinicalTrials.gov, number NCT02500797. Findings Between Aug 13, 2015, and March 17, 2016, 96 patients from 15 sites in the USA underwent central pathology review for eligibility and 85 eligible patients, including planned over-enrolment, were allocated to receive either nivolumab monotherapy (43 patients) or nivolumab plus ipilimumab (42 patients). The primary endpoint analysis was done according to protocol specifications in the first 76 eligible patients (38 patients per group). The number of confirmed responses was two (5% [92% CI 1–16] of 38 patients) in the nivolumab group and six (16% [7–30] of 38 patients) in the nivolumab plus ipilimumab group. The most common grade 3 or worse adverse events were anaemia (four [10%] patients), decreased lymphocyte count (three [7%]), and dehydration, increased lipase, pain, pleural effusion, respiratory failure, secondary benign neoplasm, and urinary tract obstruction (two [5%] patients each) among the 42 patients in the nivolumab group and anaemia (eight [19%] patients), hypotension (four [10%] patients), and pain and urinary tract infection (three [7%] patients each) among the 42 patients in the nivolumab plus ipilimumab group. Serious treatment-related adverse events occurred in eight (19%) of 42 patients receiving monotherapy and 11 (26%) of 42 patients receiving combination therapy, and included anaemia, anorexia, dehydration, decreased platelet count, diarrhoea, fatigue, fever, increased creatinine, increased alanine aminotransferase, increased aspartate aminotransferase, hyponatraemia, pain, pleural effusion, and pruritus. There were no treatment-related deaths. Interpretation Nivolumab alone does not warrant further study in an unselected sarcoma population given the limited efficacy. Nivolumab combined with ipilimumab demonstrated promising efficacy in certain sarcoma subtypes, with a manageable safety profile comparable to current available treatment options. The combination therapy met its predefined primary study endpoint; further evaluation of nivolumab plus ipilimumab in a randomised study is warranted. Funding Alliance Clinical Trials in Oncology, National Cancer Institute Cancer Therapy Evaluation Program, Bristol-Myers Squibb, Cycle for Survival.read more
Citations
More filters
Journal ArticleDOI
B cells are associated with survival and immunotherapy response in sarcoma.
Florent Petitprez,Aurélien de Reyniès,Emily Z. Keung,Tom Wei-Wu Chen,Cheng-Ming Sun,Cheng-Ming Sun,Julien Calderaro,Yung-Ming Jeng,Li Ping Hsiao,Laetitia Lacroix,Laetitia Lacroix,Antoine Bougoüin,Antoine Bougoüin,Marco Moreira,Marco Moreira,Guillaume Lacroix,Guillaume Lacroix,Ivo Natario,Ivo Natario,Julien Adam,Carlo Lucchesi,Yec′han Laizet,Maud Toulmonde,Melissa Amber Burgess,Vanessa Bolejack,Denise K. Reinke,Khalid M. Wani,Wei Lien Wang,Alexander J. Lazar,Christina L. Roland,Jennifer A. Wargo,Antoine Italiano,Catherine Sautès-Fridman,Catherine Sautès-Fridman,Hussein Abdul-Hassan Tawbi,Wolf H. Fridman,Wolf H. Fridman +36 more
TL;DR: Immune profiling of the tumour microenvironment of soft-tissue sarcoma identifies a group of patients with high levels of B-cell infiltration and tertiary lymphoid structures that have improved survival and a high response rate to immune checkpoint blockade therapy.
Journal ArticleDOI
Combination of CTLA-4 and PD-1 blockers for treatment of cancer
TL;DR: This review aims to support future research in combination immunotherapy by discussing the basic details of CTLA-4 and PD-1 pathways and the results from clinical studies that evaluated combination of CT LA4 andPD-1/PD-L1 blockers.
Journal ArticleDOI
Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis.
Yucai Wang,Shouhao Zhou,Shouhao Zhou,Fang Yang,Xinyue Qi,Xin Wang,Xiaoxiang Guan,Xiaoxiang Guan,Chan Shen,Narjust Duma,Jesus Vera Aguilera,Ashish V. Chintakuntlawar,Katharine A. Price,Julian R. Molina,Lance C. Pagliaro,Thorvardur R. Halfdanarson,Axel Grothey,Axel Grothey,Svetomir N. Markovic,Grzegorz S. Nowakowski,Stephen M. Ansell,Michael L. Wang +21 more
TL;DR: Different PD-1 and PD-L1 inhibitors appear to have varying treatment-related adverse events; a comprehensive summary of the incidences of treatment- related adverse events in clinical trials provides an important guide for clinicians.
Journal ArticleDOI
Soft-tissue sarcoma in adults: An update on the current state of histiotype-specific management in an era of personalized medicine.
TL;DR: The latest evidence guiding the histiotype‐specific management of extremity/truncal and retroperitoneal STS with regard to surgery, radiation, and chemotherapy is summarized.
Journal ArticleDOI
Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial.
Breelyn A. Wilky,Matteo Trucco,Ty K. Subhawong,Vaia Florou,Wungki Park,Deukwoo Kwon,Eric D. Wieder,Despina Kolonias,Andrew E. Rosenberg,Darcy A. Kerr,Efrosyni Sfakianaki,Mark Foley,Jaime R. Merchan,Krishna V. Komanduri,Jonathan C. Trent +14 more
TL;DR: Axitinib plus pembrolizumab has manageable toxicity and preliminary activity in patients with advanced sarcomas, particularly patients with ASPS, warranting further investigation in randomised controlled trials.
References
More filters
Book ChapterDOI
Nonparametric Estimation from Incomplete Observations
Edward L. Kaplan,Paul Meier +1 more
TL;DR: In this article, the product-limit (PL) estimator was proposed to estimate the proportion of items in the population whose lifetimes would exceed t (in the absence of such losses), without making any assumption about the form of the function P(t).
Journal ArticleDOI
Cancer statistics, 2016
TL;DR: Overall cancer incidence trends are stable in women, but declining by 3.1% per year in men, much of which is because of recent rapid declines in prostate cancer diagnoses, and brain cancer has surpassed leukemia as the leading cause of cancer death among children and adolescents.
Journal ArticleDOI
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.
F. Stephen Hodi,Steven J. O'Day,David F. McDermott,R. W. Weber,Jeffrey A. Sosman,John B. A. G. Haanen,Rene Gonzalez,Caroline Robert,Dirk Schadendorf,Jessica C. Hassel,Wallace Akerley,Alfons J.M. van den Eertwegh,Jose Lutzky,Paul Lorigan,Julia Vaubel,Gerald P. Linette,David W. Hogg,Christian H. Ottensmeier,Céleste Lebbé,Christian Peschel,Ian Quirt,Joseph I. Clark,Jedd D. Wolchok,Jeffrey S. Weber,Jason Tian,Michael Yellin,Geoffrey M. Nichol,Axel Hoos,Walter J. Urba +28 more
TL;DR: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.
Journal ArticleDOI
The blockade of immune checkpoints in cancer immunotherapy
TL;DR: Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
Journal ArticleDOI
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.
Related Papers (5)
Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial
Hussein Abdul-Hassan Tawbi,Melissa Amber Burgess,Vanessa Bolejack,Brian A. Van Tine,Scott M. Schuetze,James C. Hu,Sandra P. D'Angelo,Steven Attia,Richard F. Riedel,Dennis A. Priebat,Sujana Movva,Lara E. Davis,Scott H. Okuno,Damon R. Reed,John Crowley,Lisa H. Butterfield,Ruth Salazar,Jaime Rodriguez-Canales,Alexander J. Lazar,Ignacio I. Wistuba,Laurence H. Baker,Robert G. Maki,Denise K. Reinke,Shreyaskumar Patel +23 more
Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial
Winette T. A. van der Graaf,Jean-Yves Blay,Sant P. Chawla,Dong Wan Kim,B. Bui-Nguyen,Paolo G. Casali,Patrick Schöffski,Massimo Aglietta,Arthur P. Staddon,Yasuo Beppu,Axel Le Cesne,Hans Gelderblom,Ian Judson,Nobuhito Araki,M. Ouali,Sandrine Marreaud,Rachel Hodge,Mohammed R. Dewji,Corneel Coens,George D. Demetri,Christopher D.M. Fletcher,Angelo Paolo Dei Tos,Peter Hohenberger +22 more
Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas
Adam Abeshouse,Clement Adebamowo,Sally N. Adebamowo,Rehan Akbani,Teniola Akeredolu,Adrian Ally,Matthew L. Anderson,Pavana Anur,Elizabeth L. Appelbaum,Joshua Armenia,J. Todd Auman,Matthew A. Bailey,Laurence H. Baker,Miruna Balasundaram,Saianand Balu,Floris P. Barthel,John Bartlett,Stephen B. Baylin,Madhusmita Behera,Dmitry Belyaev,Joesph Bennett,Christopher C. Benz,Rameen Beroukhim,Michael J. Birrer,Therese Bocklage,Tom Bodenheimer,Lori Boice,Moiz S. Bootwalla,Jay Bowen,Reanne Bowlby,Jeff Boyd,Andrew S. Brohl,Denise Brooks,Lauren Averett Byers,Rebecca Carlsen,Patricia Castro,Hsiao-Wei Chen,Andrew D. Cherniack,Frédéric Chibon,Lynda Chin,Juok Cho,Eric Chuah,Sudha Chudamani,Carrie Cibulskis,Lee Cooper,Leslie Cope,Matthew G. Cordes,Daniel Crain,Erin Curley,Ludmila Danilova,Fanny Dao,Ian J. Davis,Lara E. Davis,Timothy Defreitas,Keith A. Delman,John A. Demchok,George D. Demetri,Elizabeth G. Demicco,Noreen Dhalla,Lixia Diao,Li Ding,Phil DiSaia,Peter Dottino,Leona A. Doyle,Esther Drill,Michael Dubina,Jennifer M. Eschbacher,Konstantin V. Fedosenko,Ina Felau,Martin L. Ferguson,Scott Frazer,Catrina Fronick,Victoria Fulidou,Lucinda Fulton,Robert S. Fulton,Stacey Gabriel,Jianjiong Gao,Qingsong Gao,Johanna Gardner,Julie M. Gastier-Foster,Nils Gehlenborg,Mark Gerken,Gad Getz,Andrew K. Godwin,Eryn M. Godwin,Elena Gordienko,Juneko E. Grilley-Olson,David A. Gutman,David H. Gutmann,D. Neil Hayes,Apurva M. Hegde,David I. Heiman,Zachary J. Heins,Carmen Helsel,Austin J. Hepperla,Kelly Higgins,Katherine A. Hoadley,Shital Hobensack,Robert A. Holt,Dave B. Hoon,Jason L. Hornick,Alan P. Hoyle,Xin Hu,Mei Huang,Carolyn M. Hutter,Mary Iacocca,Davis R. Ingram,Michael Ittmann,Lisa Iype,Stuart R. Jefferys,Kevin B. Jones,Corbin D. Jones,Steven J.M. Jones,Tamara Kalir,Beth Y. Karlan,Apollon Karseladze,Katayoon Kasaian,Jaegil Kim,Ritika Kundra,Hanluen Kuo,Marc Ladanyi,Phillip H. Lai,Peter W. Laird,Erik G. Larsson,Michael S. Lawrence,Alexander J. Lazar,Sanghoon Lee,Darlene Lee,Kjong-Van Lehmann,Kristen M. Leraas,Jenny Lester,Douglas A. Levine,Irene Li,Tara M. Lichtenberg,Pei Lin,Jia Liu,Wen-Bin Liu,Eric Minwei Liu,Laxmi Lolla,Yiling Lu,Yussanne Ma,Rashna Madan,Dennis T. Maglinte,Anthony M. Magliocco,Robert G. Maki,David Mallery,Georgy Manikhas,Elaine R. Mardis,Armaz Mariamidze,Marco A. Marra,John A. Martignetti,Cathleen Martinez,Michael Mayo,Michael D. McLellan,Sam Meier,Shaowu Meng,Matthew Meyerson,Piotr A. Mieczkowski,Christopher A. Miller,Gordon B. Mills,Richard A. Moore,Scott Morris,Lisle E. Mose,Evgeny Mozgovoy,Andrew J. Mungall,Karen Mungall,Michael Nalisnik,Rashi Naresh,Yulia Newton,Michael S. Noble,Janet E. Novak,Angelica Ochoa,Narciso Olvera,Taofeek K. Owonikoko,Oxana Paklina,Jeremy Parfitt,Joel S. Parker,Alessandro Pastore,Joseph Paulauskis,Robert Penny,Elena Pereira,Charles M. Perou,Amy H. Perou,Todd Pihl,Raphael E. Pollock,Olga Potapova,Amie Radenbaugh,Suresh S. Ramalingam,Nilsa C. Ramirez,W. Kimryn Rathmell,Chandrajit P. Raut,Richard F. Riedel,Colleen Reilly,Sheila Reynolds,Jeffrey Roach,A. Gordon Robertson,Jason Roszik,Brian P. Rubin,Sara Sadeghi,Gordon Saksena,Andrew Salner,Francisco Sanchez-Vega,Chris Sander,Jacqueline E. Schein,Heather Schmidt,Nikolaus Schultz,Steven E. Schumacher,Harman Sekhon,Yasin Senbabaoglu,Galiya Setdikova,Candace Shelton,Troy Shelton,Ronglai Shen,Yan Shi,Juliann Shih,Ilya Shmulevich,Gabriel Sica,Janae V. Simons,Samuel Singer,Payal Sipahimalani,Tara Skelly,Nicholas D. Socci,Heidi J. Sofia,Matthew G. Soloway,Paul T. Spellman,Qiang Sun,Patricia Swanson,Angela Tam,Donghui Tan,Roy Tarnuzzer,Nina Thiessen,Eric M. Thompson,Leigh B. Thorne,Pan Tong,Keila E. Torres,Matt van de Rijn,David Van Den Berg,Brian A. Van Tine,Umadevi Veluvolu,Roel G.W. Verhaak,Doug Voet,Olga Voronina,Yunhu Wan,Zhining Wang,Jing Wang,John N. Weinstein,Daniel J. Weisenberger,Matthew D. Wilkerson,Richard K. Wilson,Lisa Wise,Tina Wong,Wing Hing Wong,John Wrangle,Ye Wu,Matthew A. Wyczalkowski,Liming Yang,Christina Yau,Venkata Yellapantula,Jean C. Zenklusen,Jiashan Zhang,Hailei Zhang,Hongxin Zhang,Erik Zmuda +262 more
B cells are associated with survival and immunotherapy response in sarcoma.
Florent Petitprez,Aurélien de Reyniès,Emily Z. Keung,Tom Wei-Wu Chen,Cheng-Ming Sun,Cheng-Ming Sun,Julien Calderaro,Yung-Ming Jeng,Li Ping Hsiao,Laetitia Lacroix,Laetitia Lacroix,Antoine Bougoüin,Antoine Bougoüin,Marco Moreira,Marco Moreira,Guillaume Lacroix,Guillaume Lacroix,Ivo Natario,Ivo Natario,Julien Adam,Carlo Lucchesi,Yec′han Laizet,Maud Toulmonde,Melissa Amber Burgess,Vanessa Bolejack,Denise K. Reinke,Khalid M. Wani,Wei Lien Wang,Alexander J. Lazar,Christina L. Roland,Jennifer A. Wargo,Antoine Italiano,Catherine Sautès-Fridman,Catherine Sautès-Fridman,Hussein Abdul-Hassan Tawbi,Wolf H. Fridman,Wolf H. Fridman +36 more
Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial
Ian Judson,Jaap Verweij,Hans Gelderblom,Jörg T. Hartmann,Jörg T. Hartmann,Patrick Schöffski,Jean-Yves Blay,J. Martijn Kerst,Josef Sufliarsky,Jeremy Whelan,Peter Hohenberger,Anders Krarup-Hansen,Thierry Alcindor,Thierry Alcindor,Sandrine Marreaud,Saskia Litière,Catherine Hermans,Cyril Fisher,Pancras C.W. Hogendoorn,A Paolo dei Tos,Winette T. A. van der Graaf +20 more